Key clinical point: High dietary intake of sodium, estimated according to 24-hour urinary sodium excretion, was associated with a greater likelihood of atopic dermatitis (AD) diagnosis, having active AD, and increasing severity of AD.

Major finding: A 1-g increase in estimated 24-hour urine sodium excretion was associated with an increased likelihood of AD (adjusted odds ratio [aOR] 1.11; 95% CI 1.07-1.14), active AD (aOR 1.16; 95% CI 1.05-1.28), and increasing AD severity (aOR 1.11; 95% CI 1.07-1.15).

Study details: This cross-sectional study evaluated the association between high levels of dietary sodium intake and AD prevalence, activity, and severity in 215,832 adults from the UK Biobank cohort, of whom 10,839 had AD.

Disclosures: This study was supported by grants from the Medical Student in Aging Research Program and US National Institute on Aging and by the National Eczema Association. One author declared receiving research funding to her institution and consulting fees from various sources.

Source: Chiang BM, Ye M, Chattopadhyay A, et al. Sodium intake and atopic dermatitis. JAMA Dermatol. 2024 (Jun 5). doi: 10.1001/jamadermatol.2024.1544 Source

Key clinical point: High dietary intake of sodium, estimated according to 24-hour urinary sodium excretion, was associated with a greater likelihood of atopic dermatitis (AD) diagnosis, having active AD, and increasing severity of AD.

Major finding: A 1-g increase in estimated 24-hour urine sodium excretion was associated with an increased likelihood of AD (adjusted odds ratio [aOR] 1.11; 95% CI 1.07-1.14), active AD (aOR 1.16; 95% CI 1.05-1.28), and increasing AD severity (aOR 1.11; 95% CI 1.07-1.15).

Study details: This cross-sectional study evaluated the association between high levels of dietary sodium intake and AD prevalence, activity, and severity in 215,832 adults from the UK Biobank cohort, of whom 10,839 had AD.

Disclosures: This study was supported by grants from the Medical Student in Aging Research Program and US National Institute on Aging and by the National Eczema Association. One author declared receiving research funding to her institution and consulting fees from various sources.

Source: Chiang BM, Ye M, Chattopadhyay A, et al. Sodium intake and atopic dermatitis. JAMA Dermatol. 2024 (Jun 5). doi: 10.1001/jamadermatol.2024.1544 Source

Key clinical point: High dietary intake of sodium, estimated according to 24-hour urinary sodium excretion, was associated with a greater likelihood of atopic dermatitis (AD) diagnosis, having active AD, and increasing severity of AD.

Major finding: A 1-g increase in estimated 24-hour urine sodium excretion was associated with an increased likelihood of AD (adjusted odds ratio [aOR] 1.11; 95% CI 1.07-1.14), active AD (aOR 1.16; 95% CI 1.05-1.28), and increasing AD severity (aOR 1.11; 95% CI 1.07-1.15).

Study details: This cross-sectional study evaluated the association between high levels of dietary sodium intake and AD prevalence, activity, and severity in 215,832 adults from the UK Biobank cohort, of whom 10,839 had AD.

Disclosures: This study was supported by grants from the Medical Student in Aging Research Program and US National Institute on Aging and by the National Eczema Association. One author declared receiving research funding to her institution and consulting fees from various sources.

Source: Chiang BM, Ye M, Chattopadhyay A, et al. Sodium intake and atopic dermatitis. JAMA Dermatol. 2024 (Jun 5). doi: 10.1001/jamadermatol.2024.1544 Source

Marstacimab, a novel, investigational monoclonal antibody, shows long-term safety and efficacy in the prevention of bleeding events in patients with hemophilia A as well as B without inhibitors, potentially adding to the toolbox for hemophilia A and representing a first of its kind therapy for hemophilia B.

“In the long-term extension study treatment with marstacimab demonstrates sustained or improved efficacy for treated and total annualized bleeding rates (ABR) in adults and adolescents with hemophilia A or hemophilia B in this data set of patients without inhibitors,” first author Shamsah Kazani, MD, of Pfizer, Cambridge, Massachusetts, said in presenting the findings at the 2024 annual meeting of the European Hematology Association (EHA) in Madrid.

“The majority of the patients from the pivotal study chose to transition into the long-term extension, and we are finding that these patients are highly compliant with their weekly marstacimab dose, with more than 98% compliance,” Dr. Kazani said.

Marstacimab targets the tissue factor pathway inhibitor, a natural anticoagulation protein that prevents the formation of blood clots, and is administered as a once-weekly subcutaneous injection.

The therapy has been granted fast-track and orphan drug status in the United States, in addition to orphan drug status in the European Union for the prevention of hemophilia bleeding episodes.

If approved, the therapy would become the first once-weekly subcutaneous therapy for either hemophilia A or B. Emicizumab, which also is administered subcutaneously, is only approved to prevent or reduce bleeding in hemophilia A.

The latest findings are from an interim analysis of a long-term extension study involving 107 of 116 patients who were in the non-inhibitor cohort in the pivotal BASIS trial. Data from that trial, involving patients aged 12-75 previously showed favorable outcomes in the non-inhibitor cohort receiving marstacimab, and a cohort of patients with inhibitors is ongoing.

Participants entering the extension study were continuing on 150-mg subcutaneous doses of marstacimab, which had been administered in the BASIS study for 12 months after a loading dose of 300 mg.

Of the patients, 89 (83%) were adult and 18 (17%) were adolescents. Overall, they had a mean age of 29 years; 83 (76%) patients had hemophilia A, while 24 (22.4%) had hemophilia B.

Prior to switching to marstacimab treatment, 32 patients had been treated with factor replacement therapy on demand, while 75 received the therapy as routine prophylaxis.

With a mean additional duration of follow-up of 12.5 months in the extension study (range, 1-23.1 months), the overall rate of compliance was very high, at 98.9%.

In the pivotal and extension studies combined, 21% of patients had their marstacimab dose increased from 150 mg to 300 mg weekly, which was an option if patients had 2 or more spontaneous bleeds in a major joint while on the 150-mg dose.

In the hemophilia A and B groups combined, those previously treated with on-demand factor replacement therapy (n = 33) had substantial reductions in estimated ABR for treated bleeds from the baseline of 38.0 prior to initiating marstacimab, to 3.2 after 12 months of the treatment in the trial (P < .001).That reduction was sustained at an ABR of 3.7 after the mean additional 12.5 months in the extension study.

The corresponding estimated ABR rates in the routine prophylaxis group (n = 83) were 7.9 at baseline, 5.1 at the end of the trial, and 2.8 in the extension study analysis interim cutoff.

The authors then further stratified the results based on hemophilia A or B groups: Among patients with hemophilia A (n = 26), the on-demand subgroup had a baseline ABR of 40.6, which dropped substantially to just 3.6 after 12 months on marstacimab in the pivotal trial and was sustained at 5.3 in the extension study.

Similar trends were observed in the hemophilia A group who received routine prophylaxis (n = 65), with an ABR of 9.2 at baseline; 5.3 after the trial, and 3.1 at the extension study interim.

The trends were similar among those with hemophilia B, albeit with lower numbers of patients, consistent with hemophilia B being more rare.

The mean ABR at baseline in the on-demand group of those patients (n = 7) was 28.7, which was reduced to just 1.7 after the 12-months of active marstacimab treatment and sustained at 1.8 by the interim analysis of the extension study.

Of hemophilia B patients previously on routine prophylaxis (n = 18), the mean ABR at baseline was 3.3 and was at 4.7 at the end of the trial. The rate declined to 2.3 in the extension phase.

“We see that these trends of improvement with marstacimab are sustained into the long-term extension study, both in the on-demand group and in the routine prophylaxis groups,” Dr. Kazani said.

Importantly, she noted that marstacimab continued to be well tolerated and safe in the long-term extension study, with no reports of thromboembolic events, which had been a concern with the drug.

Commenting on the study, Margaret Ragni, MD, MPH, a professor of medicine and clinical and translational research in the Division of Hematology/Oncology at the University of Pittsburgh, Pittsburgh, Pennsylvania, noted that marstacimab could represent an important addition in the prevention of bleeds in hemophilia. “[If marstacimab is approved], hemophilia B patients [will] have a drug that can be given subcutaneously weekly to rebalance hemostasis, reducing bleeds, just as hemophilia A patients have with emicizumab.”

Dr. Ragni underscored, however, that caveats include the important point that “neither [marstacimab nor emicizumab] treats bleeds. For that, standard factor replacement therapy or bypass for inhibitors, would be required.”

Also, “a limitation with marstacimab is the lack of weight-dependent dosing. All use one dose [however, in the studies they did use 150 mg or 300 mg]. ... Furthermore, emicizumab can be given weekly, biweekly, or monthly, while that [variation in dosing] is not yet studied with marstacimab.”

And while no thromboembolic events occurred during the trial, Dr. Ragni underscored that “longer-term follow-up is needed.”

The marstacimab long-term extension study is designed to extend to 7 years of follow-up.

The study was sponsored by Pfizer, and Dr. Kazani is an employee of Pfizer. Dr. Ragni reported no disclosures.

Marstacimab, a novel, investigational monoclonal antibody, shows long-term safety and efficacy in the prevention of bleeding events in patients with hemophilia A as well as B without inhibitors, potentially adding to the toolbox for hemophilia A and representing a first of its kind therapy for hemophilia B.

“In the long-term extension study treatment with marstacimab demonstrates sustained or improved efficacy for treated and total annualized bleeding rates (ABR) in adults and adolescents with hemophilia A or hemophilia B in this data set of patients without inhibitors,” first author Shamsah Kazani, MD, of Pfizer, Cambridge, Massachusetts, said in presenting the findings at the 2024 annual meeting of the European Hematology Association (EHA) in Madrid.

“The majority of the patients from the pivotal study chose to transition into the long-term extension, and we are finding that these patients are highly compliant with their weekly marstacimab dose, with more than 98% compliance,” Dr. Kazani said.

Marstacimab targets the tissue factor pathway inhibitor, a natural anticoagulation protein that prevents the formation of blood clots, and is administered as a once-weekly subcutaneous injection.

The therapy has been granted fast-track and orphan drug status in the United States, in addition to orphan drug status in the European Union for the prevention of hemophilia bleeding episodes.

If approved, the therapy would become the first once-weekly subcutaneous therapy for either hemophilia A or B. Emicizumab, which also is administered subcutaneously, is only approved to prevent or reduce bleeding in hemophilia A.

The latest findings are from an interim analysis of a long-term extension study involving 107 of 116 patients who were in the non-inhibitor cohort in the pivotal BASIS trial. Data from that trial, involving patients aged 12-75 previously showed favorable outcomes in the non-inhibitor cohort receiving marstacimab, and a cohort of patients with inhibitors is ongoing.

Participants entering the extension study were continuing on 150-mg subcutaneous doses of marstacimab, which had been administered in the BASIS study for 12 months after a loading dose of 300 mg.

Of the patients, 89 (83%) were adult and 18 (17%) were adolescents. Overall, they had a mean age of 29 years; 83 (76%) patients had hemophilia A, while 24 (22.4%) had hemophilia B.

Prior to switching to marstacimab treatment, 32 patients had been treated with factor replacement therapy on demand, while 75 received the therapy as routine prophylaxis.

With a mean additional duration of follow-up of 12.5 months in the extension study (range, 1-23.1 months), the overall rate of compliance was very high, at 98.9%.

In the pivotal and extension studies combined, 21% of patients had their marstacimab dose increased from 150 mg to 300 mg weekly, which was an option if patients had 2 or more spontaneous bleeds in a major joint while on the 150-mg dose.

In the hemophilia A and B groups combined, those previously treated with on-demand factor replacement therapy (n = 33) had substantial reductions in estimated ABR for treated bleeds from the baseline of 38.0 prior to initiating marstacimab, to 3.2 after 12 months of the treatment in the trial (P < .001).That reduction was sustained at an ABR of 3.7 after the mean additional 12.5 months in the extension study.

The corresponding estimated ABR rates in the routine prophylaxis group (n = 83) were 7.9 at baseline, 5.1 at the end of the trial, and 2.8 in the extension study analysis interim cutoff.

The authors then further stratified the results based on hemophilia A or B groups: Among patients with hemophilia A (n = 26), the on-demand subgroup had a baseline ABR of 40.6, which dropped substantially to just 3.6 after 12 months on marstacimab in the pivotal trial and was sustained at 5.3 in the extension study.

Similar trends were observed in the hemophilia A group who received routine prophylaxis (n = 65), with an ABR of 9.2 at baseline; 5.3 after the trial, and 3.1 at the extension study interim.

The trends were similar among those with hemophilia B, albeit with lower numbers of patients, consistent with hemophilia B being more rare.

The mean ABR at baseline in the on-demand group of those patients (n = 7) was 28.7, which was reduced to just 1.7 after the 12-months of active marstacimab treatment and sustained at 1.8 by the interim analysis of the extension study.

Of hemophilia B patients previously on routine prophylaxis (n = 18), the mean ABR at baseline was 3.3 and was at 4.7 at the end of the trial. The rate declined to 2.3 in the extension phase.

“We see that these trends of improvement with marstacimab are sustained into the long-term extension study, both in the on-demand group and in the routine prophylaxis groups,” Dr. Kazani said.

Importantly, she noted that marstacimab continued to be well tolerated and safe in the long-term extension study, with no reports of thromboembolic events, which had been a concern with the drug.

Commenting on the study, Margaret Ragni, MD, MPH, a professor of medicine and clinical and translational research in the Division of Hematology/Oncology at the University of Pittsburgh, Pittsburgh, Pennsylvania, noted that marstacimab could represent an important addition in the prevention of bleeds in hemophilia. “[If marstacimab is approved], hemophilia B patients [will] have a drug that can be given subcutaneously weekly to rebalance hemostasis, reducing bleeds, just as hemophilia A patients have with emicizumab.”

Dr. Ragni underscored, however, that caveats include the important point that “neither [marstacimab nor emicizumab] treats bleeds. For that, standard factor replacement therapy or bypass for inhibitors, would be required.”

Also, “a limitation with marstacimab is the lack of weight-dependent dosing. All use one dose [however, in the studies they did use 150 mg or 300 mg]. ... Furthermore, emicizumab can be given weekly, biweekly, or monthly, while that [variation in dosing] is not yet studied with marstacimab.”

And while no thromboembolic events occurred during the trial, Dr. Ragni underscored that “longer-term follow-up is needed.”

The marstacimab long-term extension study is designed to extend to 7 years of follow-up.

The study was sponsored by Pfizer, and Dr. Kazani is an employee of Pfizer. Dr. Ragni reported no disclosures.

Marstacimab, a novel, investigational monoclonal antibody, shows long-term safety and efficacy in the prevention of bleeding events in patients with hemophilia A as well as B without inhibitors, potentially adding to the toolbox for hemophilia A and representing a first of its kind therapy for hemophilia B.

“In the long-term extension study treatment with marstacimab demonstrates sustained or improved efficacy for treated and total annualized bleeding rates (ABR) in adults and adolescents with hemophilia A or hemophilia B in this data set of patients without inhibitors,” first author Shamsah Kazani, MD, of Pfizer, Cambridge, Massachusetts, said in presenting the findings at the 2024 annual meeting of the European Hematology Association (EHA) in Madrid.

“The majority of the patients from the pivotal study chose to transition into the long-term extension, and we are finding that these patients are highly compliant with their weekly marstacimab dose, with more than 98% compliance,” Dr. Kazani said.

Marstacimab targets the tissue factor pathway inhibitor, a natural anticoagulation protein that prevents the formation of blood clots, and is administered as a once-weekly subcutaneous injection.

The therapy has been granted fast-track and orphan drug status in the United States, in addition to orphan drug status in the European Union for the prevention of hemophilia bleeding episodes.

If approved, the therapy would become the first once-weekly subcutaneous therapy for either hemophilia A or B. Emicizumab, which also is administered subcutaneously, is only approved to prevent or reduce bleeding in hemophilia A.

The latest findings are from an interim analysis of a long-term extension study involving 107 of 116 patients who were in the non-inhibitor cohort in the pivotal BASIS trial. Data from that trial, involving patients aged 12-75 previously showed favorable outcomes in the non-inhibitor cohort receiving marstacimab, and a cohort of patients with inhibitors is ongoing.

Participants entering the extension study were continuing on 150-mg subcutaneous doses of marstacimab, which had been administered in the BASIS study for 12 months after a loading dose of 300 mg.

Of the patients, 89 (83%) were adult and 18 (17%) were adolescents. Overall, they had a mean age of 29 years; 83 (76%) patients had hemophilia A, while 24 (22.4%) had hemophilia B.

Prior to switching to marstacimab treatment, 32 patients had been treated with factor replacement therapy on demand, while 75 received the therapy as routine prophylaxis.

With a mean additional duration of follow-up of 12.5 months in the extension study (range, 1-23.1 months), the overall rate of compliance was very high, at 98.9%.

In the pivotal and extension studies combined, 21% of patients had their marstacimab dose increased from 150 mg to 300 mg weekly, which was an option if patients had 2 or more spontaneous bleeds in a major joint while on the 150-mg dose.

In the hemophilia A and B groups combined, those previously treated with on-demand factor replacement therapy (n = 33) had substantial reductions in estimated ABR for treated bleeds from the baseline of 38.0 prior to initiating marstacimab, to 3.2 after 12 months of the treatment in the trial (P < .001).That reduction was sustained at an ABR of 3.7 after the mean additional 12.5 months in the extension study.

The corresponding estimated ABR rates in the routine prophylaxis group (n = 83) were 7.9 at baseline, 5.1 at the end of the trial, and 2.8 in the extension study analysis interim cutoff.

The authors then further stratified the results based on hemophilia A or B groups: Among patients with hemophilia A (n = 26), the on-demand subgroup had a baseline ABR of 40.6, which dropped substantially to just 3.6 after 12 months on marstacimab in the pivotal trial and was sustained at 5.3 in the extension study.

Similar trends were observed in the hemophilia A group who received routine prophylaxis (n = 65), with an ABR of 9.2 at baseline; 5.3 after the trial, and 3.1 at the extension study interim.

The trends were similar among those with hemophilia B, albeit with lower numbers of patients, consistent with hemophilia B being more rare.

The mean ABR at baseline in the on-demand group of those patients (n = 7) was 28.7, which was reduced to just 1.7 after the 12-months of active marstacimab treatment and sustained at 1.8 by the interim analysis of the extension study.

Of hemophilia B patients previously on routine prophylaxis (n = 18), the mean ABR at baseline was 3.3 and was at 4.7 at the end of the trial. The rate declined to 2.3 in the extension phase.

“We see that these trends of improvement with marstacimab are sustained into the long-term extension study, both in the on-demand group and in the routine prophylaxis groups,” Dr. Kazani said.

Importantly, she noted that marstacimab continued to be well tolerated and safe in the long-term extension study, with no reports of thromboembolic events, which had been a concern with the drug.

Commenting on the study, Margaret Ragni, MD, MPH, a professor of medicine and clinical and translational research in the Division of Hematology/Oncology at the University of Pittsburgh, Pittsburgh, Pennsylvania, noted that marstacimab could represent an important addition in the prevention of bleeds in hemophilia. “[If marstacimab is approved], hemophilia B patients [will] have a drug that can be given subcutaneously weekly to rebalance hemostasis, reducing bleeds, just as hemophilia A patients have with emicizumab.”

Dr. Ragni underscored, however, that caveats include the important point that “neither [marstacimab nor emicizumab] treats bleeds. For that, standard factor replacement therapy or bypass for inhibitors, would be required.”

Also, “a limitation with marstacimab is the lack of weight-dependent dosing. All use one dose [however, in the studies they did use 150 mg or 300 mg]. ... Furthermore, emicizumab can be given weekly, biweekly, or monthly, while that [variation in dosing] is not yet studied with marstacimab.”

And while no thromboembolic events occurred during the trial, Dr. Ragni underscored that “longer-term follow-up is needed.”

The marstacimab long-term extension study is designed to extend to 7 years of follow-up.

The study was sponsored by Pfizer, and Dr. Kazani is an employee of Pfizer. Dr. Ragni reported no disclosures.

LYON, France – Lerodalcibep, a novel, third-generation anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, helps high-risk patients already receiving maximally tolerated statins to achieve guideline lipid targets, reported investigators.

In the randomized, placebo-controlled LIBerate-CVD trial of more than 900 patients, lerodalcibep led to reductions from baseline in low-density lipoprotein (LDL) cholesterol levels of more than 60%.

“We believe that lerodalcibep offers a novel, effective alternative to current PCSK9 inhibitors for patients with cardiovascular disease or at very high risk for cardiovascular disease,” said Evan Stein, MD, PhD, chief scientific officer and cofounder of LIB Therapeutics in Chicago, who presented the findings at the European Atherosclerosis Society (EAS) 2024.

Moreover, it leads to “substantial additional LDL cholesterol reductions on top of existing oral agents” and allows more than 90% of patients to achieve the latest European Society of Cardiology (ESC) guideline targets, he said.

Lerodalcibep has “tolerability and safety similar to placebo,” Dr. Stein said, and requires only “a small monthly injection, which takes about 12 seconds.”

“The drug doesn’t require refrigeration” and is “stable, so far, over 9 months,” he reported.

The latest data “confirm the efficacy of lerodalcibep,” said Giuseppe Danilo Norata, PhD, from the Department of Pharmacological and Biomolecular Sciences at the University of Milan, Milan, Italy, who was not involved in the study.

The LDL cholesterol reduction in this phase 3 trial is “in line with what was observed in LIBerate-FH,” and the high proportion of patients achieving their LDL cholesterol target is “impressive,” he added.
 

Effective and Well Tolerated

The safety results are “suggestive of a drug that is well tolerated, with injection-site reactions being the only remarkable adverse event increased in the treatment group,” Dr. Norata reported.

Only a “limited number” of patients developed neutralizing antidrug antibodies, which did not affect the efficacy of lerodalcibep. However, “given that the therapy is expected to be administered for years,” a longer analysis is needed to exclude the concern that a small percentage of neutralizing antidrug antibodies could reduce the efficacy, he said.

If approved, lerodalcibep could end up as a first-line option in the treatment pathway for high-risk cardiovascular disease because the efficacy “is similar to that of other injectable PCSK9 inhibitors,” he said, adding that its position in the market will “largely depend on the price.”

As the mechanism of action is similar to that of other monoclonal antibodies, “there is no pharmacological rationale to use it after another PSCK9 inhibitor,” he explained.

Lerodalcibep is a small recombinant fusion protein that combines a PCSK9-binding domain with human serum albumin.

The binding domain blocks the interaction between PCSK9 and the LDL cholesterol receptor, and the albumin linkage increases the half-life to 12-15 days, allowing low-volume injections to be given every 4 weeks.

A prior phase 2 study suggested that lerodalcibep substantially decreases LDL cholesterol levels in patients already taking maximally tolerated statins. The 300-mg dose was associated with an average reduction from baseline in LDL cholesterol levels of 77% over 12 weeks, whereas free PCSK9 levels decreased by 88%.

The current phase 3 study enrolled individuals at 65 centers in 100 countries who had or were at a very high risk for cardiovascular disease and who had an LDL cholesterol level of ≥ 1.8 mmol/L despite being on maximally tolerated statins.

Study participants were randomized in a 2:1 ratio to receive monthly subcutaneous lerodalcibep (n = 614) or placebo (n = 308) for 52 weeks and were assessed for the co-primary endpoints of the percentage change in LDL cholesterol levels from baseline to week 52 and the mean of levels at weeks 50 and 52.

The mean age was similar in the lerodalcibep and placebo groups (63.3 vs 64.5 years), as were the proportion of female (30% vs 30%) and White (80% vs 79%) participants.

The vast majority of participants in the lerodalcibep and placebo groups had a documented cardiovascular event (85.3% vs 86.4%) and were receiving secondary prevention, and 87% and 82%, respectively, were receiving a statin (any dose).

In a modified intention-to-treat analysis, the mean placebo-adjusted reduction in LDL cholesterol levels from baseline with lerodalcibep was 62% at week 52 (P < .0001), and the mean of levels at weeks 50 and 52 was 69.4% (P < .0001).

Similar results were seen in a per protocol analysis and an intention-to-treat analysis with imputation, which is a US Food and Drug Administration measure introduced in 2021 that assumes patients who discontinue the study treatment have an outcome similar to that in the placebo patients.

Moreover, 98.2% of patients in the lerodalcibep group achieved the ESC and European Atherosclerosis Society recommended reduction in LDL cholesterol levels of ≥ 50%, whereas only 8.8% in the placebo group did.
 

Hitting the LDL Cholesterol Target

More patients in the lerodalcibep group than in the placebo group achieved the LDL cholesterol target of < 1.4 mmol/L (95.3% vs 18.5%), and more patients in the lerodalcibep group achieved both that target and the ≥ 50% target (94.5% and 6.8%).

Lerodalcibep was also associated with significant reductions from baseline in levels of non–high-density lipoprotein (HDL) cholesterol, apolipoprotein B, very LDL cholesterol, and triglycerides, as well as an increase in HDL cholesterol levels (P < .0001 for all).

In terms of safety, lerodalcibep was associated with an adverse event rate leading to withdrawal similar to that seen with placebo (4.2% vs 3.6%), and 15.9% and 14.8% of patients, respectively, experienced at least one serious adverse event.

In-stent restenosis occurred more often in the lerodalcibep group than in the placebo group (5.4% vs 2.0%).

The study drug was associated with low levels of transient and sporadic antidrug antibodies and a low rate of neutralizing antidrug antibodies (0.9%), which were not associated with restenosis, a reduction in free PCSK9 levels, or the ability of lerodalcibep to lower LDL cholesterol levels.

A version of this article first appeared on Medscape.com.

LYON, France – Lerodalcibep, a novel, third-generation anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, helps high-risk patients already receiving maximally tolerated statins to achieve guideline lipid targets, reported investigators.

In the randomized, placebo-controlled LIBerate-CVD trial of more than 900 patients, lerodalcibep led to reductions from baseline in low-density lipoprotein (LDL) cholesterol levels of more than 60%.

“We believe that lerodalcibep offers a novel, effective alternative to current PCSK9 inhibitors for patients with cardiovascular disease or at very high risk for cardiovascular disease,” said Evan Stein, MD, PhD, chief scientific officer and cofounder of LIB Therapeutics in Chicago, who presented the findings at the European Atherosclerosis Society (EAS) 2024.

Moreover, it leads to “substantial additional LDL cholesterol reductions on top of existing oral agents” and allows more than 90% of patients to achieve the latest European Society of Cardiology (ESC) guideline targets, he said.

Lerodalcibep has “tolerability and safety similar to placebo,” Dr. Stein said, and requires only “a small monthly injection, which takes about 12 seconds.”

“The drug doesn’t require refrigeration” and is “stable, so far, over 9 months,” he reported.

The latest data “confirm the efficacy of lerodalcibep,” said Giuseppe Danilo Norata, PhD, from the Department of Pharmacological and Biomolecular Sciences at the University of Milan, Milan, Italy, who was not involved in the study.

The LDL cholesterol reduction in this phase 3 trial is “in line with what was observed in LIBerate-FH,” and the high proportion of patients achieving their LDL cholesterol target is “impressive,” he added.
 

Effective and Well Tolerated

The safety results are “suggestive of a drug that is well tolerated, with injection-site reactions being the only remarkable adverse event increased in the treatment group,” Dr. Norata reported.

Only a “limited number” of patients developed neutralizing antidrug antibodies, which did not affect the efficacy of lerodalcibep. However, “given that the therapy is expected to be administered for years,” a longer analysis is needed to exclude the concern that a small percentage of neutralizing antidrug antibodies could reduce the efficacy, he said.

If approved, lerodalcibep could end up as a first-line option in the treatment pathway for high-risk cardiovascular disease because the efficacy “is similar to that of other injectable PCSK9 inhibitors,” he said, adding that its position in the market will “largely depend on the price.”

As the mechanism of action is similar to that of other monoclonal antibodies, “there is no pharmacological rationale to use it after another PSCK9 inhibitor,” he explained.

Lerodalcibep is a small recombinant fusion protein that combines a PCSK9-binding domain with human serum albumin.

The binding domain blocks the interaction between PCSK9 and the LDL cholesterol receptor, and the albumin linkage increases the half-life to 12-15 days, allowing low-volume injections to be given every 4 weeks.

A prior phase 2 study suggested that lerodalcibep substantially decreases LDL cholesterol levels in patients already taking maximally tolerated statins. The 300-mg dose was associated with an average reduction from baseline in LDL cholesterol levels of 77% over 12 weeks, whereas free PCSK9 levels decreased by 88%.

The current phase 3 study enrolled individuals at 65 centers in 100 countries who had or were at a very high risk for cardiovascular disease and who had an LDL cholesterol level of ≥ 1.8 mmol/L despite being on maximally tolerated statins.

Study participants were randomized in a 2:1 ratio to receive monthly subcutaneous lerodalcibep (n = 614) or placebo (n = 308) for 52 weeks and were assessed for the co-primary endpoints of the percentage change in LDL cholesterol levels from baseline to week 52 and the mean of levels at weeks 50 and 52.

The mean age was similar in the lerodalcibep and placebo groups (63.3 vs 64.5 years), as were the proportion of female (30% vs 30%) and White (80% vs 79%) participants.

The vast majority of participants in the lerodalcibep and placebo groups had a documented cardiovascular event (85.3% vs 86.4%) and were receiving secondary prevention, and 87% and 82%, respectively, were receiving a statin (any dose).

In a modified intention-to-treat analysis, the mean placebo-adjusted reduction in LDL cholesterol levels from baseline with lerodalcibep was 62% at week 52 (P < .0001), and the mean of levels at weeks 50 and 52 was 69.4% (P < .0001).

Similar results were seen in a per protocol analysis and an intention-to-treat analysis with imputation, which is a US Food and Drug Administration measure introduced in 2021 that assumes patients who discontinue the study treatment have an outcome similar to that in the placebo patients.

Moreover, 98.2% of patients in the lerodalcibep group achieved the ESC and European Atherosclerosis Society recommended reduction in LDL cholesterol levels of ≥ 50%, whereas only 8.8% in the placebo group did.
 

Hitting the LDL Cholesterol Target

More patients in the lerodalcibep group than in the placebo group achieved the LDL cholesterol target of < 1.4 mmol/L (95.3% vs 18.5%), and more patients in the lerodalcibep group achieved both that target and the ≥ 50% target (94.5% and 6.8%).

Lerodalcibep was also associated with significant reductions from baseline in levels of non–high-density lipoprotein (HDL) cholesterol, apolipoprotein B, very LDL cholesterol, and triglycerides, as well as an increase in HDL cholesterol levels (P < .0001 for all).

In terms of safety, lerodalcibep was associated with an adverse event rate leading to withdrawal similar to that seen with placebo (4.2% vs 3.6%), and 15.9% and 14.8% of patients, respectively, experienced at least one serious adverse event.

In-stent restenosis occurred more often in the lerodalcibep group than in the placebo group (5.4% vs 2.0%).

The study drug was associated with low levels of transient and sporadic antidrug antibodies and a low rate of neutralizing antidrug antibodies (0.9%), which were not associated with restenosis, a reduction in free PCSK9 levels, or the ability of lerodalcibep to lower LDL cholesterol levels.

A version of this article first appeared on Medscape.com.

LYON, France – Lerodalcibep, a novel, third-generation anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, helps high-risk patients already receiving maximally tolerated statins to achieve guideline lipid targets, reported investigators.

In the randomized, placebo-controlled LIBerate-CVD trial of more than 900 patients, lerodalcibep led to reductions from baseline in low-density lipoprotein (LDL) cholesterol levels of more than 60%.

“We believe that lerodalcibep offers a novel, effective alternative to current PCSK9 inhibitors for patients with cardiovascular disease or at very high risk for cardiovascular disease,” said Evan Stein, MD, PhD, chief scientific officer and cofounder of LIB Therapeutics in Chicago, who presented the findings at the European Atherosclerosis Society (EAS) 2024.

Moreover, it leads to “substantial additional LDL cholesterol reductions on top of existing oral agents” and allows more than 90% of patients to achieve the latest European Society of Cardiology (ESC) guideline targets, he said.

Lerodalcibep has “tolerability and safety similar to placebo,” Dr. Stein said, and requires only “a small monthly injection, which takes about 12 seconds.”

“The drug doesn’t require refrigeration” and is “stable, so far, over 9 months,” he reported.

The latest data “confirm the efficacy of lerodalcibep,” said Giuseppe Danilo Norata, PhD, from the Department of Pharmacological and Biomolecular Sciences at the University of Milan, Milan, Italy, who was not involved in the study.

The LDL cholesterol reduction in this phase 3 trial is “in line with what was observed in LIBerate-FH,” and the high proportion of patients achieving their LDL cholesterol target is “impressive,” he added.
 

Effective and Well Tolerated

The safety results are “suggestive of a drug that is well tolerated, with injection-site reactions being the only remarkable adverse event increased in the treatment group,” Dr. Norata reported.

Only a “limited number” of patients developed neutralizing antidrug antibodies, which did not affect the efficacy of lerodalcibep. However, “given that the therapy is expected to be administered for years,” a longer analysis is needed to exclude the concern that a small percentage of neutralizing antidrug antibodies could reduce the efficacy, he said.

If approved, lerodalcibep could end up as a first-line option in the treatment pathway for high-risk cardiovascular disease because the efficacy “is similar to that of other injectable PCSK9 inhibitors,” he said, adding that its position in the market will “largely depend on the price.”

As the mechanism of action is similar to that of other monoclonal antibodies, “there is no pharmacological rationale to use it after another PSCK9 inhibitor,” he explained.

Lerodalcibep is a small recombinant fusion protein that combines a PCSK9-binding domain with human serum albumin.

The binding domain blocks the interaction between PCSK9 and the LDL cholesterol receptor, and the albumin linkage increases the half-life to 12-15 days, allowing low-volume injections to be given every 4 weeks.

A prior phase 2 study suggested that lerodalcibep substantially decreases LDL cholesterol levels in patients already taking maximally tolerated statins. The 300-mg dose was associated with an average reduction from baseline in LDL cholesterol levels of 77% over 12 weeks, whereas free PCSK9 levels decreased by 88%.

The current phase 3 study enrolled individuals at 65 centers in 100 countries who had or were at a very high risk for cardiovascular disease and who had an LDL cholesterol level of ≥ 1.8 mmol/L despite being on maximally tolerated statins.

Study participants were randomized in a 2:1 ratio to receive monthly subcutaneous lerodalcibep (n = 614) or placebo (n = 308) for 52 weeks and were assessed for the co-primary endpoints of the percentage change in LDL cholesterol levels from baseline to week 52 and the mean of levels at weeks 50 and 52.

The mean age was similar in the lerodalcibep and placebo groups (63.3 vs 64.5 years), as were the proportion of female (30% vs 30%) and White (80% vs 79%) participants.

The vast majority of participants in the lerodalcibep and placebo groups had a documented cardiovascular event (85.3% vs 86.4%) and were receiving secondary prevention, and 87% and 82%, respectively, were receiving a statin (any dose).

In a modified intention-to-treat analysis, the mean placebo-adjusted reduction in LDL cholesterol levels from baseline with lerodalcibep was 62% at week 52 (P < .0001), and the mean of levels at weeks 50 and 52 was 69.4% (P < .0001).

Similar results were seen in a per protocol analysis and an intention-to-treat analysis with imputation, which is a US Food and Drug Administration measure introduced in 2021 that assumes patients who discontinue the study treatment have an outcome similar to that in the placebo patients.

Moreover, 98.2% of patients in the lerodalcibep group achieved the ESC and European Atherosclerosis Society recommended reduction in LDL cholesterol levels of ≥ 50%, whereas only 8.8% in the placebo group did.
 

Hitting the LDL Cholesterol Target

More patients in the lerodalcibep group than in the placebo group achieved the LDL cholesterol target of < 1.4 mmol/L (95.3% vs 18.5%), and more patients in the lerodalcibep group achieved both that target and the ≥ 50% target (94.5% and 6.8%).

Lerodalcibep was also associated with significant reductions from baseline in levels of non–high-density lipoprotein (HDL) cholesterol, apolipoprotein B, very LDL cholesterol, and triglycerides, as well as an increase in HDL cholesterol levels (P < .0001 for all).

In terms of safety, lerodalcibep was associated with an adverse event rate leading to withdrawal similar to that seen with placebo (4.2% vs 3.6%), and 15.9% and 14.8% of patients, respectively, experienced at least one serious adverse event.

In-stent restenosis occurred more often in the lerodalcibep group than in the placebo group (5.4% vs 2.0%).

The study drug was associated with low levels of transient and sporadic antidrug antibodies and a low rate of neutralizing antidrug antibodies (0.9%), which were not associated with restenosis, a reduction in free PCSK9 levels, or the ability of lerodalcibep to lower LDL cholesterol levels.

A version of this article first appeared on Medscape.com.

CHICAGO — Surgical resection is the standard of care for small colorectal liver metastases, but the results of a phase 3 trial reported at the American Society of Clinical Oncology (ASCO) 2024 annual meeting may prompt a change.

At nearly 30 months of follow-up, European investigators found no difference in overall and progression-free survival with thermal ablation instead of surgery, as well as better local control, fewer adverse events, shorter hospital stays, and no treatment-related deaths.

The benefit of thermal ablation was so substantial that the trial was stopped early with about 300 of the planned 600 patients randomized.

Numerous retrospective studies have compared the two approaches, and some have reported better survival with surgery. As a result, although a large number of lesions are amenable to either approach, “the majority of colorectal liver mets [are] still being” resected, said lead investigator and presenter Martijn R. Meijerink, MD, PhD, an interventional radiologist at the Amsterdam University Medical Center, Amsterdam, the Netherlands.

Dr. Meijerink said many of the previous reviews were unreliable due to selection bias because patients only had ablation if their lesions couldn’t be removed surgically. In contrast, all patients in the COLLISION trial were eligible for resection.

“Thermal ablation in experienced centers seems to be at least as good as surgical resection for small liver tumors.” Patients would benefit if it replaced surgery as the standard of care with no compromise in survival, Dr. Meijerink added.

The 296 COLLISION patients were treated at 14 centers in the Netherlands, Belgium, and Italy. They had no more than 12 liver lesions 3 cm or smaller with a median of two lesions. Participants were split equally between the ablation and surgical arms of the trial.

Almost half of the surgeries were laparoscopic, and nearly 60% of the ablations were percutaneous. Recent technological advances were used in the ablation cases, including software to confirm the complete eradication of targeted metastases.

At 28.8 months, there was no difference in overall survival between treatment arms (hazard ratio [HR], 1.051; P = .813) and no difference in local (HR, 0.817; P = .53) and distant (HR, 1.03; P = .836) progression-free survival. Local control — meaning treated lesions didn’t grow back — favored thermal ablation (HR, 0.092; P = .024).

The results held across number subgroup analyses, including by stage, molecular profile, and number of lesions.

“Interestingly, the majority of ablation site recurrences were somehow retreated, and most of them successfully, [while] the majority of resection plane recurrences were not retreated,” Dr. Meijerink said.

Patients with ablation vs surgery spent a median of 1 day vs 4 days in the hospital. Almost 20% of patients in the surgery group had grade 3/4 treatment-related adverse events vs 6% of those in the ablation group, which isn’t surprising, Dr. Meijerink said, because “the needle is less invasive than a knife.”

Three patients (2.1%) died of surgical complications, but there were no treatment-related deaths with ablation.

Major Kenneth Lee, MD, PhD, a gastrointestinal surgeon at the University of Pennsylvania, Philadelphia, who was the study discussant, emphasized the importance of gathering prospective data to compare the two approaches fairly.

“Ablation appears equivalent to resection for small, ideally located colorectal liver mets,” he said. Still, longer follow-up is needed to ensure that cure rates with ablation match those with surgery.

The study was funded by Medtronic-Covidien, a maker of thermal ablation equipment. Among other industry ties, Dr. Meijerink reported receiving honoraria and research funding from Medtronic and advising the company. Dr. Lee didn’t have any disclosures.

A version of this article appeared on Medscape.com.

CHICAGO — Surgical resection is the standard of care for small colorectal liver metastases, but the results of a phase 3 trial reported at the American Society of Clinical Oncology (ASCO) 2024 annual meeting may prompt a change.

At nearly 30 months of follow-up, European investigators found no difference in overall and progression-free survival with thermal ablation instead of surgery, as well as better local control, fewer adverse events, shorter hospital stays, and no treatment-related deaths.

The benefit of thermal ablation was so substantial that the trial was stopped early with about 300 of the planned 600 patients randomized.

Numerous retrospective studies have compared the two approaches, and some have reported better survival with surgery. As a result, although a large number of lesions are amenable to either approach, “the majority of colorectal liver mets [are] still being” resected, said lead investigator and presenter Martijn R. Meijerink, MD, PhD, an interventional radiologist at the Amsterdam University Medical Center, Amsterdam, the Netherlands.

Dr. Meijerink said many of the previous reviews were unreliable due to selection bias because patients only had ablation if their lesions couldn’t be removed surgically. In contrast, all patients in the COLLISION trial were eligible for resection.

“Thermal ablation in experienced centers seems to be at least as good as surgical resection for small liver tumors.” Patients would benefit if it replaced surgery as the standard of care with no compromise in survival, Dr. Meijerink added.

The 296 COLLISION patients were treated at 14 centers in the Netherlands, Belgium, and Italy. They had no more than 12 liver lesions 3 cm or smaller with a median of two lesions. Participants were split equally between the ablation and surgical arms of the trial.

Almost half of the surgeries were laparoscopic, and nearly 60% of the ablations were percutaneous. Recent technological advances were used in the ablation cases, including software to confirm the complete eradication of targeted metastases.

At 28.8 months, there was no difference in overall survival between treatment arms (hazard ratio [HR], 1.051; P = .813) and no difference in local (HR, 0.817; P = .53) and distant (HR, 1.03; P = .836) progression-free survival. Local control — meaning treated lesions didn’t grow back — favored thermal ablation (HR, 0.092; P = .024).

The results held across number subgroup analyses, including by stage, molecular profile, and number of lesions.

“Interestingly, the majority of ablation site recurrences were somehow retreated, and most of them successfully, [while] the majority of resection plane recurrences were not retreated,” Dr. Meijerink said.

Patients with ablation vs surgery spent a median of 1 day vs 4 days in the hospital. Almost 20% of patients in the surgery group had grade 3/4 treatment-related adverse events vs 6% of those in the ablation group, which isn’t surprising, Dr. Meijerink said, because “the needle is less invasive than a knife.”

Three patients (2.1%) died of surgical complications, but there were no treatment-related deaths with ablation.

Major Kenneth Lee, MD, PhD, a gastrointestinal surgeon at the University of Pennsylvania, Philadelphia, who was the study discussant, emphasized the importance of gathering prospective data to compare the two approaches fairly.

“Ablation appears equivalent to resection for small, ideally located colorectal liver mets,” he said. Still, longer follow-up is needed to ensure that cure rates with ablation match those with surgery.

The study was funded by Medtronic-Covidien, a maker of thermal ablation equipment. Among other industry ties, Dr. Meijerink reported receiving honoraria and research funding from Medtronic and advising the company. Dr. Lee didn’t have any disclosures.

A version of this article appeared on Medscape.com.

CHICAGO — Surgical resection is the standard of care for small colorectal liver metastases, but the results of a phase 3 trial reported at the American Society of Clinical Oncology (ASCO) 2024 annual meeting may prompt a change.

At nearly 30 months of follow-up, European investigators found no difference in overall and progression-free survival with thermal ablation instead of surgery, as well as better local control, fewer adverse events, shorter hospital stays, and no treatment-related deaths.

The benefit of thermal ablation was so substantial that the trial was stopped early with about 300 of the planned 600 patients randomized.

Numerous retrospective studies have compared the two approaches, and some have reported better survival with surgery. As a result, although a large number of lesions are amenable to either approach, “the majority of colorectal liver mets [are] still being” resected, said lead investigator and presenter Martijn R. Meijerink, MD, PhD, an interventional radiologist at the Amsterdam University Medical Center, Amsterdam, the Netherlands.

Dr. Meijerink said many of the previous reviews were unreliable due to selection bias because patients only had ablation if their lesions couldn’t be removed surgically. In contrast, all patients in the COLLISION trial were eligible for resection.

“Thermal ablation in experienced centers seems to be at least as good as surgical resection for small liver tumors.” Patients would benefit if it replaced surgery as the standard of care with no compromise in survival, Dr. Meijerink added.

The 296 COLLISION patients were treated at 14 centers in the Netherlands, Belgium, and Italy. They had no more than 12 liver lesions 3 cm or smaller with a median of two lesions. Participants were split equally between the ablation and surgical arms of the trial.

Almost half of the surgeries were laparoscopic, and nearly 60% of the ablations were percutaneous. Recent technological advances were used in the ablation cases, including software to confirm the complete eradication of targeted metastases.

At 28.8 months, there was no difference in overall survival between treatment arms (hazard ratio [HR], 1.051; P = .813) and no difference in local (HR, 0.817; P = .53) and distant (HR, 1.03; P = .836) progression-free survival. Local control — meaning treated lesions didn’t grow back — favored thermal ablation (HR, 0.092; P = .024).

The results held across number subgroup analyses, including by stage, molecular profile, and number of lesions.

“Interestingly, the majority of ablation site recurrences were somehow retreated, and most of them successfully, [while] the majority of resection plane recurrences were not retreated,” Dr. Meijerink said.

Patients with ablation vs surgery spent a median of 1 day vs 4 days in the hospital. Almost 20% of patients in the surgery group had grade 3/4 treatment-related adverse events vs 6% of those in the ablation group, which isn’t surprising, Dr. Meijerink said, because “the needle is less invasive than a knife.”

Three patients (2.1%) died of surgical complications, but there were no treatment-related deaths with ablation.

Major Kenneth Lee, MD, PhD, a gastrointestinal surgeon at the University of Pennsylvania, Philadelphia, who was the study discussant, emphasized the importance of gathering prospective data to compare the two approaches fairly.

“Ablation appears equivalent to resection for small, ideally located colorectal liver mets,” he said. Still, longer follow-up is needed to ensure that cure rates with ablation match those with surgery.

The study was funded by Medtronic-Covidien, a maker of thermal ablation equipment. Among other industry ties, Dr. Meijerink reported receiving honoraria and research funding from Medtronic and advising the company. Dr. Lee didn’t have any disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

An experimental pancreatic gene therapy given to a mouse model of obesity as a one-time, single-dose treatment showed improvements in body composition and fasting glucose comparable with those achieved with the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide, without the reversal of fat-loss and glycemia improvements that are a key concern with the withdrawal of GLP-1 receptor agonist drugs.

METHODOLOGY:

• The adeno-associated virus–based GLP-1 pancreatic gene therapy is designed to induce durable islet production of GLP-1 peptides that could, in theory, negate the need for regular injections or dosing of conventional GLP-1 receptor agonist drugs.
• With initial preclinical research showing benefits in Yucatan pigs, the authors tested the pancreatic gene therapy in mice representing a validated model of diet-induced obesity.
• The mice were randomized to receive either a single-dose administration of the pancreatic gene therapy (n = 10), daily subcutaneous semaglutide injections (n = 10; 10 nmol/kg/d for 4 weeks), pancreatic gene therapy placebo (n = 8), or a semaglutide placebo (n = 8).
• The gene therapy is designed to be delivered directly to the pancreas with a needle puncture, using a proprietary endoscopic delivery method that is similar to procedures commonly performed by gastrointestinal endoscopists, limiting systemic exposure.
• At 4 weeks, semaglutide was discontinued, and 5 of the 10 mice in that group were randomized to the gene therapy, while the other 5 received placebo.

TAKEAWAY:

• At week 4, the pancreatic gene therapy arm had a reduction in fat mass of 21%, compared with 16% with semaglutide (P < .05; both P < .0001 vs placebo)
• The pancreatic gene therapy and semaglutide groups each preserved lean mass, with a loss of only 5% of body weight (both P < .0001 vs placebo).
• At week 8, mice withdrawn from semaglutide had nearly a full reversal of the fat and lean mass losses observed at 4 weeks, returning to within 1% and 2% below baseline, respectively, while the semaglutide-withdrawn mice treated with gene therapy maintained a fat reduction of 17% (P < .01) and lean mass of 5% (P < .0001).
• Significant improvements in fasting glucose were observed in the gene therapy and semaglutide-treated mice at week 4 (both 18%; P < .0001).
• While semaglutide-withdrawal resulted in a rebound of fasting glucose to baseline at week 8, those who had initially received gene therapy or were switched over to the therapy maintained fasting glucose reductions of 21% and 22% at 8 weeks (P < .0001 and P < .001), respectively.
• No indications of pancreatic inflammation or injury were observed in any of the groups.

IN PRACTICE:

The results suggest the therapy could represent “a reliable, ‘off ramp’ from chronic GLP-1 drugs that allows people to maintain the weight loss and blood sugar benefits, even as they stop taking these medicines,” said first author Harith Rajagopalan, MD, PhD, cofounder and chief executive officer of Fractyl Health, which is developing the gene therapy, in a press statement issued by the company.

The therapy is being developed as a candidate for the treatment of type 2 diabetes and plans are underway for the first in-human study in type 2 diabetes in 2025, Dr. Rajagopalan noted while presenting the results at the American Diabetes Association (ADA)’s 84th scientific sessions.
 

SOURCE:

The study was presented on June 23, 2024, at the annual meeting of the ADA’s 84th scientific sessions (Abstract #261-OR).

LIMITATIONS:

The pancreatic gene therapy is in early development and has not been assessed by any regulatory body for investigational or commercial use.

Asked by an audience member at the ADA presentation if the therapy would be reversible if complications were to arise, Dr. Rajagopalan responded that “there are ways to tune this effect in order to prevent complications from occurring, which we will discuss in due course.”

Also asked about the potential for a positive feedback loop with GLP-1 signaling and insulin signaling, Dr. Rajagopalan noted that “I don’t believe that we have seen any evidence of that risk so far. One could hypothesize, but we have not seen anything [in that regard] that would be a cause for concern.”
 

DISCLOSURES:

The study was funded by Fractyl Health, and Dr. Rajagopalan and the authors declared being employees and stockholders/shareholders of the company.

A version of this article first appeared on Medscape.com.

TOPLINE:

An experimental pancreatic gene therapy given to a mouse model of obesity as a one-time, single-dose treatment showed improvements in body composition and fasting glucose comparable with those achieved with the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide, without the reversal of fat-loss and glycemia improvements that are a key concern with the withdrawal of GLP-1 receptor agonist drugs.

METHODOLOGY:

• The adeno-associated virus–based GLP-1 pancreatic gene therapy is designed to induce durable islet production of GLP-1 peptides that could, in theory, negate the need for regular injections or dosing of conventional GLP-1 receptor agonist drugs.
• With initial preclinical research showing benefits in Yucatan pigs, the authors tested the pancreatic gene therapy in mice representing a validated model of diet-induced obesity.
• The mice were randomized to receive either a single-dose administration of the pancreatic gene therapy (n = 10), daily subcutaneous semaglutide injections (n = 10; 10 nmol/kg/d for 4 weeks), pancreatic gene therapy placebo (n = 8), or a semaglutide placebo (n = 8).
• The gene therapy is designed to be delivered directly to the pancreas with a needle puncture, using a proprietary endoscopic delivery method that is similar to procedures commonly performed by gastrointestinal endoscopists, limiting systemic exposure.
• At 4 weeks, semaglutide was discontinued, and 5 of the 10 mice in that group were randomized to the gene therapy, while the other 5 received placebo.

TAKEAWAY:

• At week 4, the pancreatic gene therapy arm had a reduction in fat mass of 21%, compared with 16% with semaglutide (P < .05; both P < .0001 vs placebo)
• The pancreatic gene therapy and semaglutide groups each preserved lean mass, with a loss of only 5% of body weight (both P < .0001 vs placebo).
• At week 8, mice withdrawn from semaglutide had nearly a full reversal of the fat and lean mass losses observed at 4 weeks, returning to within 1% and 2% below baseline, respectively, while the semaglutide-withdrawn mice treated with gene therapy maintained a fat reduction of 17% (P < .01) and lean mass of 5% (P < .0001).
• Significant improvements in fasting glucose were observed in the gene therapy and semaglutide-treated mice at week 4 (both 18%; P < .0001).
• While semaglutide-withdrawal resulted in a rebound of fasting glucose to baseline at week 8, those who had initially received gene therapy or were switched over to the therapy maintained fasting glucose reductions of 21% and 22% at 8 weeks (P < .0001 and P < .001), respectively.
• No indications of pancreatic inflammation or injury were observed in any of the groups.

IN PRACTICE:

The results suggest the therapy could represent “a reliable, ‘off ramp’ from chronic GLP-1 drugs that allows people to maintain the weight loss and blood sugar benefits, even as they stop taking these medicines,” said first author Harith Rajagopalan, MD, PhD, cofounder and chief executive officer of Fractyl Health, which is developing the gene therapy, in a press statement issued by the company.

The therapy is being developed as a candidate for the treatment of type 2 diabetes and plans are underway for the first in-human study in type 2 diabetes in 2025, Dr. Rajagopalan noted while presenting the results at the American Diabetes Association (ADA)’s 84th scientific sessions.
 

SOURCE:

The study was presented on June 23, 2024, at the annual meeting of the ADA’s 84th scientific sessions (Abstract #261-OR).

LIMITATIONS:

The pancreatic gene therapy is in early development and has not been assessed by any regulatory body for investigational or commercial use.

Asked by an audience member at the ADA presentation if the therapy would be reversible if complications were to arise, Dr. Rajagopalan responded that “there are ways to tune this effect in order to prevent complications from occurring, which we will discuss in due course.”

Also asked about the potential for a positive feedback loop with GLP-1 signaling and insulin signaling, Dr. Rajagopalan noted that “I don’t believe that we have seen any evidence of that risk so far. One could hypothesize, but we have not seen anything [in that regard] that would be a cause for concern.”
 

DISCLOSURES:

The study was funded by Fractyl Health, and Dr. Rajagopalan and the authors declared being employees and stockholders/shareholders of the company.

A version of this article first appeared on Medscape.com.

TOPLINE:

An experimental pancreatic gene therapy given to a mouse model of obesity as a one-time, single-dose treatment showed improvements in body composition and fasting glucose comparable with those achieved with the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide, without the reversal of fat-loss and glycemia improvements that are a key concern with the withdrawal of GLP-1 receptor agonist drugs.

METHODOLOGY:

• The adeno-associated virus–based GLP-1 pancreatic gene therapy is designed to induce durable islet production of GLP-1 peptides that could, in theory, negate the need for regular injections or dosing of conventional GLP-1 receptor agonist drugs.
• With initial preclinical research showing benefits in Yucatan pigs, the authors tested the pancreatic gene therapy in mice representing a validated model of diet-induced obesity.
• The mice were randomized to receive either a single-dose administration of the pancreatic gene therapy (n = 10), daily subcutaneous semaglutide injections (n = 10; 10 nmol/kg/d for 4 weeks), pancreatic gene therapy placebo (n = 8), or a semaglutide placebo (n = 8).
• The gene therapy is designed to be delivered directly to the pancreas with a needle puncture, using a proprietary endoscopic delivery method that is similar to procedures commonly performed by gastrointestinal endoscopists, limiting systemic exposure.
• At 4 weeks, semaglutide was discontinued, and 5 of the 10 mice in that group were randomized to the gene therapy, while the other 5 received placebo.

TAKEAWAY:

• At week 4, the pancreatic gene therapy arm had a reduction in fat mass of 21%, compared with 16% with semaglutide (P < .05; both P < .0001 vs placebo)
• The pancreatic gene therapy and semaglutide groups each preserved lean mass, with a loss of only 5% of body weight (both P < .0001 vs placebo).
• At week 8, mice withdrawn from semaglutide had nearly a full reversal of the fat and lean mass losses observed at 4 weeks, returning to within 1% and 2% below baseline, respectively, while the semaglutide-withdrawn mice treated with gene therapy maintained a fat reduction of 17% (P < .01) and lean mass of 5% (P < .0001).
• Significant improvements in fasting glucose were observed in the gene therapy and semaglutide-treated mice at week 4 (both 18%; P < .0001).
• While semaglutide-withdrawal resulted in a rebound of fasting glucose to baseline at week 8, those who had initially received gene therapy or were switched over to the therapy maintained fasting glucose reductions of 21% and 22% at 8 weeks (P < .0001 and P < .001), respectively.
• No indications of pancreatic inflammation or injury were observed in any of the groups.

IN PRACTICE:

The results suggest the therapy could represent “a reliable, ‘off ramp’ from chronic GLP-1 drugs that allows people to maintain the weight loss and blood sugar benefits, even as they stop taking these medicines,” said first author Harith Rajagopalan, MD, PhD, cofounder and chief executive officer of Fractyl Health, which is developing the gene therapy, in a press statement issued by the company.

The therapy is being developed as a candidate for the treatment of type 2 diabetes and plans are underway for the first in-human study in type 2 diabetes in 2025, Dr. Rajagopalan noted while presenting the results at the American Diabetes Association (ADA)’s 84th scientific sessions.
 

SOURCE:

The study was presented on June 23, 2024, at the annual meeting of the ADA’s 84th scientific sessions (Abstract #261-OR).

LIMITATIONS:

The pancreatic gene therapy is in early development and has not been assessed by any regulatory body for investigational or commercial use.

Asked by an audience member at the ADA presentation if the therapy would be reversible if complications were to arise, Dr. Rajagopalan responded that “there are ways to tune this effect in order to prevent complications from occurring, which we will discuss in due course.”

Also asked about the potential for a positive feedback loop with GLP-1 signaling and insulin signaling, Dr. Rajagopalan noted that “I don’t believe that we have seen any evidence of that risk so far. One could hypothesize, but we have not seen anything [in that regard] that would be a cause for concern.”
 

DISCLOSURES:

The study was funded by Fractyl Health, and Dr. Rajagopalan and the authors declared being employees and stockholders/shareholders of the company.

A version of this article first appeared on Medscape.com.

Adults older than 50 years who report experiencing persistently high levels of loneliness have a 56% increased risk for stroke, a new study showed.

The increased stroke risk did not apply to individuals who reported experiencing situational loneliness, a finding that investigators believe bolsters the hypothesis that chronic loneliness is driving the association.

“Our findings suggest that individuals who experience chronic loneliness are at higher risk for incident stroke,” lead investigator Yenee Soh, ScD, research associate of social and behavioral sciences in the Harvard T.H. Chan School of Public Health, Boston, told this news organization. “It is important to routinely assess loneliness, as the consequences may be worse if unidentified and/or ignored.”

The findings were published online in eClinicalMedicine.
 

Significant, Chronic Health Consequences

Exacerbated by the COVID-19 pandemic, loneliness is at an all-time high. A 2023 Surgeon General’s report highlighted the fact that loneliness and social isolation are linked to significant and chronic health consequences.

Previous research has linked loneliness to cardiovascular disease, yet few studies have examined the association between loneliness and stroke risk. The current study is one of the first to examine the association between changes in loneliness and stroke risk over time.

Using data from the 2006-2018 Health and Retirement Study, researchers assessed the link between loneliness and incident stroke over time. Between 2006 and 2008, 12,161 study participants, who were all older than 50 years with no history of stroke, responded to questions from the Revised UCLA Loneliness Scale. From these responses, researchers created summary loneliness scores.

Four years later, from 2010 to 2012, the 8936 remaining study participants responded to the same 20 questions again. Based on loneliness scores across the two time points, participants were divided into four groups:

• Consistently low (those who scored low on the loneliness scale at both baseline and follow-up).
• Remitting (those who scored high at baseline and low at follow-up).
• Recent onset (those who scored low at baseline and high at follow-up).
• Consistently high (those who scored high at both baseline and follow-up).

Incident stroke was determined by participant report and medical record data.

Among participants whose loneliness was measured at baseline only, 1237 strokes occurred during the 2006-2018 follow-up period. Among those who provided two loneliness assessments over time, 601 strokes occurred during the follow-up period.

Even after adjusting for social isolation, depressive symptoms, physical activity, body mass index, and other health conditions, investigators found that participants who reported being lonely at baseline only had a 25% increased stroke risk, compared with those who did not report being lonely at baseline (hazard ratio [HR], 1.25; 95% confidence interval (CI), 1.06-1.47).

Participants who reported having consistently high loneliness across both time points had a 56% increased risk for incident stroke vs those who did not report loneliness at both time points after adjusting for social isolation and depression (HR, 1.56; 95% CI, 1.11-2.18).

The researchers did not investigate any of the underlying issues that may contribute to the association between loneliness and stroke risk, but speculated there may be physiological factors at play. These could include inflammation caused by increased hypothalamic pituitary-adrenocortical activity, behavioral factors such as poor medication adherence, smoking and/or alcohol use, and psychosocial issues.

Those who experience chronic loneliness may represent individuals that are unable to develop or maintain satisfying social relationships, which may result in longer-term interpersonal difficulties, Dr. Soh noted.

“Since loneliness is a highly subjective experience, seeking help to address and intervene to address a patient’s specific personal needs is important. It’s important to distinguish loneliness from social isolation,” said Dr. Soh.

She added that “by screening for loneliness and providing care or referring patients to relevant behavioral healthcare providers, clinicians can play a crucial role in addressing loneliness and its associated health risks early on to help reduce the population burden of loneliness.”
 

Progressive Research

Commenting on the findings for this news organization, Elaine Jones, MD, medical director of Access TeleCare, who was not involved in the research, applauded the investigators for “advancing the topic by looking at the chronicity aspect of loneliness.”

She said more research is needed to investigate loneliness as a stroke risk factor and noted that there may be something inherently different among respondents who reported loneliness at both study time points.

“Personality types may play a role here. We know people with positive attitudes and outlooks can do better in challenging health situations than people who are negative in their attitudes, regardless of depression. Perhaps those who feel lonely initially decided to do something about it and join groups, take up a hobby, or re-engage with family or friends. Perhaps the people who are chronically lonely don’t, or can’t, do this,” Dr. Jones said.

Chronic loneliness can cause stress, she added, “and we know that stress chemicals and hormones can be harmful to health over long durations of time.”

The study was funded by the National Institute on Aging. There were no conflicts of interest noted.

A version of this article first appeared on Medscape.com.

Adults older than 50 years who report experiencing persistently high levels of loneliness have a 56% increased risk for stroke, a new study showed.

The increased stroke risk did not apply to individuals who reported experiencing situational loneliness, a finding that investigators believe bolsters the hypothesis that chronic loneliness is driving the association.

“Our findings suggest that individuals who experience chronic loneliness are at higher risk for incident stroke,” lead investigator Yenee Soh, ScD, research associate of social and behavioral sciences in the Harvard T.H. Chan School of Public Health, Boston, told this news organization. “It is important to routinely assess loneliness, as the consequences may be worse if unidentified and/or ignored.”

The findings were published online in eClinicalMedicine.
 

Significant, Chronic Health Consequences

Exacerbated by the COVID-19 pandemic, loneliness is at an all-time high. A 2023 Surgeon General’s report highlighted the fact that loneliness and social isolation are linked to significant and chronic health consequences.

Previous research has linked loneliness to cardiovascular disease, yet few studies have examined the association between loneliness and stroke risk. The current study is one of the first to examine the association between changes in loneliness and stroke risk over time.

Using data from the 2006-2018 Health and Retirement Study, researchers assessed the link between loneliness and incident stroke over time. Between 2006 and 2008, 12,161 study participants, who were all older than 50 years with no history of stroke, responded to questions from the Revised UCLA Loneliness Scale. From these responses, researchers created summary loneliness scores.

Four years later, from 2010 to 2012, the 8936 remaining study participants responded to the same 20 questions again. Based on loneliness scores across the two time points, participants were divided into four groups:

• Consistently low (those who scored low on the loneliness scale at both baseline and follow-up).
• Remitting (those who scored high at baseline and low at follow-up).
• Recent onset (those who scored low at baseline and high at follow-up).
• Consistently high (those who scored high at both baseline and follow-up).

Incident stroke was determined by participant report and medical record data.

Among participants whose loneliness was measured at baseline only, 1237 strokes occurred during the 2006-2018 follow-up period. Among those who provided two loneliness assessments over time, 601 strokes occurred during the follow-up period.

Even after adjusting for social isolation, depressive symptoms, physical activity, body mass index, and other health conditions, investigators found that participants who reported being lonely at baseline only had a 25% increased stroke risk, compared with those who did not report being lonely at baseline (hazard ratio [HR], 1.25; 95% confidence interval (CI), 1.06-1.47).

Participants who reported having consistently high loneliness across both time points had a 56% increased risk for incident stroke vs those who did not report loneliness at both time points after adjusting for social isolation and depression (HR, 1.56; 95% CI, 1.11-2.18).

The researchers did not investigate any of the underlying issues that may contribute to the association between loneliness and stroke risk, but speculated there may be physiological factors at play. These could include inflammation caused by increased hypothalamic pituitary-adrenocortical activity, behavioral factors such as poor medication adherence, smoking and/or alcohol use, and psychosocial issues.

Those who experience chronic loneliness may represent individuals that are unable to develop or maintain satisfying social relationships, which may result in longer-term interpersonal difficulties, Dr. Soh noted.

“Since loneliness is a highly subjective experience, seeking help to address and intervene to address a patient’s specific personal needs is important. It’s important to distinguish loneliness from social isolation,” said Dr. Soh.

She added that “by screening for loneliness and providing care or referring patients to relevant behavioral healthcare providers, clinicians can play a crucial role in addressing loneliness and its associated health risks early on to help reduce the population burden of loneliness.”
 

Progressive Research

Commenting on the findings for this news organization, Elaine Jones, MD, medical director of Access TeleCare, who was not involved in the research, applauded the investigators for “advancing the topic by looking at the chronicity aspect of loneliness.”

She said more research is needed to investigate loneliness as a stroke risk factor and noted that there may be something inherently different among respondents who reported loneliness at both study time points.

“Personality types may play a role here. We know people with positive attitudes and outlooks can do better in challenging health situations than people who are negative in their attitudes, regardless of depression. Perhaps those who feel lonely initially decided to do something about it and join groups, take up a hobby, or re-engage with family or friends. Perhaps the people who are chronically lonely don’t, or can’t, do this,” Dr. Jones said.

Chronic loneliness can cause stress, she added, “and we know that stress chemicals and hormones can be harmful to health over long durations of time.”

The study was funded by the National Institute on Aging. There were no conflicts of interest noted.

A version of this article first appeared on Medscape.com.

Adults older than 50 years who report experiencing persistently high levels of loneliness have a 56% increased risk for stroke, a new study showed.

The increased stroke risk did not apply to individuals who reported experiencing situational loneliness, a finding that investigators believe bolsters the hypothesis that chronic loneliness is driving the association.

“Our findings suggest that individuals who experience chronic loneliness are at higher risk for incident stroke,” lead investigator Yenee Soh, ScD, research associate of social and behavioral sciences in the Harvard T.H. Chan School of Public Health, Boston, told this news organization. “It is important to routinely assess loneliness, as the consequences may be worse if unidentified and/or ignored.”

The findings were published online in eClinicalMedicine.
 

Significant, Chronic Health Consequences

Exacerbated by the COVID-19 pandemic, loneliness is at an all-time high. A 2023 Surgeon General’s report highlighted the fact that loneliness and social isolation are linked to significant and chronic health consequences.

Previous research has linked loneliness to cardiovascular disease, yet few studies have examined the association between loneliness and stroke risk. The current study is one of the first to examine the association between changes in loneliness and stroke risk over time.

Using data from the 2006-2018 Health and Retirement Study, researchers assessed the link between loneliness and incident stroke over time. Between 2006 and 2008, 12,161 study participants, who were all older than 50 years with no history of stroke, responded to questions from the Revised UCLA Loneliness Scale. From these responses, researchers created summary loneliness scores.

Four years later, from 2010 to 2012, the 8936 remaining study participants responded to the same 20 questions again. Based on loneliness scores across the two time points, participants were divided into four groups:

• Consistently low (those who scored low on the loneliness scale at both baseline and follow-up).
• Remitting (those who scored high at baseline and low at follow-up).
• Recent onset (those who scored low at baseline and high at follow-up).
• Consistently high (those who scored high at both baseline and follow-up).

Incident stroke was determined by participant report and medical record data.

Among participants whose loneliness was measured at baseline only, 1237 strokes occurred during the 2006-2018 follow-up period. Among those who provided two loneliness assessments over time, 601 strokes occurred during the follow-up period.

Even after adjusting for social isolation, depressive symptoms, physical activity, body mass index, and other health conditions, investigators found that participants who reported being lonely at baseline only had a 25% increased stroke risk, compared with those who did not report being lonely at baseline (hazard ratio [HR], 1.25; 95% confidence interval (CI), 1.06-1.47).

Participants who reported having consistently high loneliness across both time points had a 56% increased risk for incident stroke vs those who did not report loneliness at both time points after adjusting for social isolation and depression (HR, 1.56; 95% CI, 1.11-2.18).

The researchers did not investigate any of the underlying issues that may contribute to the association between loneliness and stroke risk, but speculated there may be physiological factors at play. These could include inflammation caused by increased hypothalamic pituitary-adrenocortical activity, behavioral factors such as poor medication adherence, smoking and/or alcohol use, and psychosocial issues.

Those who experience chronic loneliness may represent individuals that are unable to develop or maintain satisfying social relationships, which may result in longer-term interpersonal difficulties, Dr. Soh noted.

“Since loneliness is a highly subjective experience, seeking help to address and intervene to address a patient’s specific personal needs is important. It’s important to distinguish loneliness from social isolation,” said Dr. Soh.

She added that “by screening for loneliness and providing care or referring patients to relevant behavioral healthcare providers, clinicians can play a crucial role in addressing loneliness and its associated health risks early on to help reduce the population burden of loneliness.”
 

Progressive Research

Commenting on the findings for this news organization, Elaine Jones, MD, medical director of Access TeleCare, who was not involved in the research, applauded the investigators for “advancing the topic by looking at the chronicity aspect of loneliness.”

She said more research is needed to investigate loneliness as a stroke risk factor and noted that there may be something inherently different among respondents who reported loneliness at both study time points.

“Personality types may play a role here. We know people with positive attitudes and outlooks can do better in challenging health situations than people who are negative in their attitudes, regardless of depression. Perhaps those who feel lonely initially decided to do something about it and join groups, take up a hobby, or re-engage with family or friends. Perhaps the people who are chronically lonely don’t, or can’t, do this,” Dr. Jones said.

Chronic loneliness can cause stress, she added, “and we know that stress chemicals and hormones can be harmful to health over long durations of time.”

The study was funded by the National Institute on Aging. There were no conflicts of interest noted.

A version of this article first appeared on Medscape.com.

Halifax, Nova Scotia; American Samoa; Queens, New York; Lansing, Michigan; Gurugram, India. I often ask patients where they’re from. Practicing in San Diego, the answers are a geography lesson. People from around the world come here. I sometimes add the more interesting question: How’d you end up here? Many took the three highways to San Diego: the Navy, the defense industry (like General Dynamics), or followed a partner. My Queens patient had a better answer: Super Bowl XXII. On Sunday, Jan. 31st, 1988, the Redskins played the Broncos in San Diego. John Elway and the Broncos lost, but it didn’t matter. “I was scrapin’ the ice off my windshield that Monday morning when I thought, that’s it. I’m done! I drove to the garage where I worked and quit on the spot. Then I drove home and packed my bags.”

In a paper on how to make life decisions, this guy would be Exhibit A: “Don’t overthink it.” That approach might not be suitable for everyone, or for every decision. It might actually be an example of how not to make life decisions (more on that later). But, is there a best way to go about making big life decisions?

The first treatise on this subject was a paper by one Franklin, Ben in 1772. Providing advice to a friend on how to make a career decision, Franklin argued: “My way is to divide half a sheet of paper by a line into two columns; writing over the one Pro and over the other Con.” This “moral algebra” as he called it was a framework to put rigor to a messy, organic problem.

Jeffrey Benabio, MD, MBA

The flaw in this method is that in the end you have two lists. Then what? Do the length of the lists decide? What if some factors are more important? Well, let’s add tools to help. You could use a spreadsheet and assign weights to each variable. Then sum the values and choose based on that. So if “not scraping ice off your windshield” is twice as important as “doubling your rent,” then you’ve got your answer. But what if you aren’t good at estimating how important things are? Actually, most of us are pretty awful at assigning weights to life variables – having bags of money is the consummate example. Seems important, but because of habituation, it turns out to not be sustainable. Note Exhibit B, our wealthy neighbor who owns a Lambo and G-Wagen (AMG squared, of course), who just parked a Cybertruck in his driveway. Realizing the risk of depending on peoples’ flawed judgment, companies instead use statistical modeling called bootstrap aggregating to “vote” on the weights for variables in a prediction. If you aren’t sure how important a new Rivian or walking to the beach would be, a model can answer that for you! It’s a bit disconcerting, I know. I mean, how can a model know what we’d like? Wait, isn’t that how Netflix picks stuff for you? Exactly.

Ok, so why don’t we just ask our friendly personal AI? “OK, ChatGPT, given what you know about me, where can I have it all?” Alas, here we slam into a glass wall. It seems the answer is out there but even our life-changing magical AI tools fail us. Mathematically, it is impossible to have it all. An illustrative example of this is called the economic “impossible trinity problem.” Even the most sophisticated algorithm cannot find an optional solution to some trinities such as fixed foreign exchange rate, free capital movement, and an independent monetary policy. Economists have concluded you must trade off one to have the other two. Impossible trinities are common in economics and in life. Armistead Maupin in his “Tales of the City” codifies it as Mona’s Law, the essence of which is: You cannot have the perfect job, the perfect partner, and the perfect house at the same time. (See Exhibit C, one Tom Brady).

This brings me to my final point, hard decisions are matters of the heart and experiencing life is the best way to understand its beautiful chaos. If making rash judgments is ill-advised and using technology cannot solve all problems (try asking your AI buddy for the square root of 2 as a fraction) what tools can we use? Maybe try reading more novels. They allow us to experience multiple lifetimes in a short time, which is what we need to learn what matters. Reading Dorothea’s choice at the end of “Middlemarch” is a nice example. Should she give up Lowick Manor and marry the penniless Ladislaw or keep it and use her wealth to help others? Seeing her struggle helps us understand how to answer questions like: Should I give up my academic practice or marry that guy or move to Texas? These cannot be reduced to arithmetic. The only way to know is to know as much of life as possible.

My last visit with my Queens patient was our last together. He’s divorced and moving from San Diego to Gallatin, Tennessee. “I’ve paid my last taxes to California, Doc. I decided that’s it, I’m done!” Perhaps he should have read “The Grapes of Wrath” before he set out for California in the first place.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

Halifax, Nova Scotia; American Samoa; Queens, New York; Lansing, Michigan; Gurugram, India. I often ask patients where they’re from. Practicing in San Diego, the answers are a geography lesson. People from around the world come here. I sometimes add the more interesting question: How’d you end up here? Many took the three highways to San Diego: the Navy, the defense industry (like General Dynamics), or followed a partner. My Queens patient had a better answer: Super Bowl XXII. On Sunday, Jan. 31st, 1988, the Redskins played the Broncos in San Diego. John Elway and the Broncos lost, but it didn’t matter. “I was scrapin’ the ice off my windshield that Monday morning when I thought, that’s it. I’m done! I drove to the garage where I worked and quit on the spot. Then I drove home and packed my bags.”

In a paper on how to make life decisions, this guy would be Exhibit A: “Don’t overthink it.” That approach might not be suitable for everyone, or for every decision. It might actually be an example of how not to make life decisions (more on that later). But, is there a best way to go about making big life decisions?

The first treatise on this subject was a paper by one Franklin, Ben in 1772. Providing advice to a friend on how to make a career decision, Franklin argued: “My way is to divide half a sheet of paper by a line into two columns; writing over the one Pro and over the other Con.” This “moral algebra” as he called it was a framework to put rigor to a messy, organic problem.

Jeffrey Benabio, MD, MBA

The flaw in this method is that in the end you have two lists. Then what? Do the length of the lists decide? What if some factors are more important? Well, let’s add tools to help. You could use a spreadsheet and assign weights to each variable. Then sum the values and choose based on that. So if “not scraping ice off your windshield” is twice as important as “doubling your rent,” then you’ve got your answer. But what if you aren’t good at estimating how important things are? Actually, most of us are pretty awful at assigning weights to life variables – having bags of money is the consummate example. Seems important, but because of habituation, it turns out to not be sustainable. Note Exhibit B, our wealthy neighbor who owns a Lambo and G-Wagen (AMG squared, of course), who just parked a Cybertruck in his driveway. Realizing the risk of depending on peoples’ flawed judgment, companies instead use statistical modeling called bootstrap aggregating to “vote” on the weights for variables in a prediction. If you aren’t sure how important a new Rivian or walking to the beach would be, a model can answer that for you! It’s a bit disconcerting, I know. I mean, how can a model know what we’d like? Wait, isn’t that how Netflix picks stuff for you? Exactly.

Ok, so why don’t we just ask our friendly personal AI? “OK, ChatGPT, given what you know about me, where can I have it all?” Alas, here we slam into a glass wall. It seems the answer is out there but even our life-changing magical AI tools fail us. Mathematically, it is impossible to have it all. An illustrative example of this is called the economic “impossible trinity problem.” Even the most sophisticated algorithm cannot find an optional solution to some trinities such as fixed foreign exchange rate, free capital movement, and an independent monetary policy. Economists have concluded you must trade off one to have the other two. Impossible trinities are common in economics and in life. Armistead Maupin in his “Tales of the City” codifies it as Mona’s Law, the essence of which is: You cannot have the perfect job, the perfect partner, and the perfect house at the same time. (See Exhibit C, one Tom Brady).

This brings me to my final point, hard decisions are matters of the heart and experiencing life is the best way to understand its beautiful chaos. If making rash judgments is ill-advised and using technology cannot solve all problems (try asking your AI buddy for the square root of 2 as a fraction) what tools can we use? Maybe try reading more novels. They allow us to experience multiple lifetimes in a short time, which is what we need to learn what matters. Reading Dorothea’s choice at the end of “Middlemarch” is a nice example. Should she give up Lowick Manor and marry the penniless Ladislaw or keep it and use her wealth to help others? Seeing her struggle helps us understand how to answer questions like: Should I give up my academic practice or marry that guy or move to Texas? These cannot be reduced to arithmetic. The only way to know is to know as much of life as possible.

My last visit with my Queens patient was our last together. He’s divorced and moving from San Diego to Gallatin, Tennessee. “I’ve paid my last taxes to California, Doc. I decided that’s it, I’m done!” Perhaps he should have read “The Grapes of Wrath” before he set out for California in the first place.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

Halifax, Nova Scotia; American Samoa; Queens, New York; Lansing, Michigan; Gurugram, India. I often ask patients where they’re from. Practicing in San Diego, the answers are a geography lesson. People from around the world come here. I sometimes add the more interesting question: How’d you end up here? Many took the three highways to San Diego: the Navy, the defense industry (like General Dynamics), or followed a partner. My Queens patient had a better answer: Super Bowl XXII. On Sunday, Jan. 31st, 1988, the Redskins played the Broncos in San Diego. John Elway and the Broncos lost, but it didn’t matter. “I was scrapin’ the ice off my windshield that Monday morning when I thought, that’s it. I’m done! I drove to the garage where I worked and quit on the spot. Then I drove home and packed my bags.”

In a paper on how to make life decisions, this guy would be Exhibit A: “Don’t overthink it.” That approach might not be suitable for everyone, or for every decision. It might actually be an example of how not to make life decisions (more on that later). But, is there a best way to go about making big life decisions?

The first treatise on this subject was a paper by one Franklin, Ben in 1772. Providing advice to a friend on how to make a career decision, Franklin argued: “My way is to divide half a sheet of paper by a line into two columns; writing over the one Pro and over the other Con.” This “moral algebra” as he called it was a framework to put rigor to a messy, organic problem.

Jeffrey Benabio, MD, MBA

The flaw in this method is that in the end you have two lists. Then what? Do the length of the lists decide? What if some factors are more important? Well, let’s add tools to help. You could use a spreadsheet and assign weights to each variable. Then sum the values and choose based on that. So if “not scraping ice off your windshield” is twice as important as “doubling your rent,” then you’ve got your answer. But what if you aren’t good at estimating how important things are? Actually, most of us are pretty awful at assigning weights to life variables – having bags of money is the consummate example. Seems important, but because of habituation, it turns out to not be sustainable. Note Exhibit B, our wealthy neighbor who owns a Lambo and G-Wagen (AMG squared, of course), who just parked a Cybertruck in his driveway. Realizing the risk of depending on peoples’ flawed judgment, companies instead use statistical modeling called bootstrap aggregating to “vote” on the weights for variables in a prediction. If you aren’t sure how important a new Rivian or walking to the beach would be, a model can answer that for you! It’s a bit disconcerting, I know. I mean, how can a model know what we’d like? Wait, isn’t that how Netflix picks stuff for you? Exactly.

Ok, so why don’t we just ask our friendly personal AI? “OK, ChatGPT, given what you know about me, where can I have it all?” Alas, here we slam into a glass wall. It seems the answer is out there but even our life-changing magical AI tools fail us. Mathematically, it is impossible to have it all. An illustrative example of this is called the economic “impossible trinity problem.” Even the most sophisticated algorithm cannot find an optional solution to some trinities such as fixed foreign exchange rate, free capital movement, and an independent monetary policy. Economists have concluded you must trade off one to have the other two. Impossible trinities are common in economics and in life. Armistead Maupin in his “Tales of the City” codifies it as Mona’s Law, the essence of which is: You cannot have the perfect job, the perfect partner, and the perfect house at the same time. (See Exhibit C, one Tom Brady).

This brings me to my final point, hard decisions are matters of the heart and experiencing life is the best way to understand its beautiful chaos. If making rash judgments is ill-advised and using technology cannot solve all problems (try asking your AI buddy for the square root of 2 as a fraction) what tools can we use? Maybe try reading more novels. They allow us to experience multiple lifetimes in a short time, which is what we need to learn what matters. Reading Dorothea’s choice at the end of “Middlemarch” is a nice example. Should she give up Lowick Manor and marry the penniless Ladislaw or keep it and use her wealth to help others? Seeing her struggle helps us understand how to answer questions like: Should I give up my academic practice or marry that guy or move to Texas? These cannot be reduced to arithmetic. The only way to know is to know as much of life as possible.

My last visit with my Queens patient was our last together. He’s divorced and moving from San Diego to Gallatin, Tennessee. “I’ve paid my last taxes to California, Doc. I decided that’s it, I’m done!” Perhaps he should have read “The Grapes of Wrath” before he set out for California in the first place.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

A hot topic of PsA research is whether treating psoriasis patients with biologics reduces the risk of developing PsA. Floris and colleagues analyzed data from 1023 patients with psoriasis aged 18 years or older, of whom 29.6% received biologics at least once and 21.0% had PsA. They observed that patients treated at least once vs never treated with biologics had a significantly lower risk for PsA. The "protective" effect of biologics against PsA persisted irrespective of the class of biologic used. However, the study has many built-in biases; it was not a prospective study of psoriasis patients without PsA, but rather a retrospective analysis of data collected at enrollment. Nevertheless, effective psoriasis therapies may indeed reduce the risk for PsA; prospective interventional studies are required and are currently underway.

Development of radiographic damage indicates severe PsA and affects quality of life and physical function. Identifying patients at risk for joint damage may help treatment stratification. Using data from a real-world cohort of 476 patients with early PsA, of whom 14% demonstrated progressive radiographic damage, Koc and colleagues found that female sex was a protective factor whereas old age and initial radiographic damage were risk factors for radiographic progression. These results are consistent with previous studies. Male sex, older age, and presence of radiographic damage at first visit should prompt more aggressive management to prevent further joint damage.

Regarding newer treatments, Gossec and colleagues demonstrated that bimekizumab, a monoclonal antibody targeting both interleukin (IL)-17A and IL-17F, improved disease effects in a rapid and sustained manner in patients with PsA who had not used biologic disease-modifying antirheumatic drugs or had prior inadequate response to tumor necrosis factor inhibitors. Bimekizumab is a welcome addition to the drugs available to manage PsA. Its comparative efficacy against other targeted therapies, especially other IL-17 inhibitors, is yet to be determined.

Finally, a study from the Greek multicenter PsA registry by Vassilakis and colleagues showed that, of 467 patients with PsA, 16.5% had D2T PsA. Compared with non–D2T patients, those with D2T disease were more likely to have extensive psoriasis at diagnosis, higher body mass index, and a history of inflammatory bowel disease (IBD). Treatment-resistant disease is increasingly prevalent in PsA. Certain diseases and comorbidities, such as IBD and obesity, are associated with D2T PsA. A uniform definition of D2T PsA and prospective studies to identify risk factors, as well as new strategies to manage D2T PsA, are required.

A hot topic of PsA research is whether treating psoriasis patients with biologics reduces the risk of developing PsA. Floris and colleagues analyzed data from 1023 patients with psoriasis aged 18 years or older, of whom 29.6% received biologics at least once and 21.0% had PsA. They observed that patients treated at least once vs never treated with biologics had a significantly lower risk for PsA. The "protective" effect of biologics against PsA persisted irrespective of the class of biologic used. However, the study has many built-in biases; it was not a prospective study of psoriasis patients without PsA, but rather a retrospective analysis of data collected at enrollment. Nevertheless, effective psoriasis therapies may indeed reduce the risk for PsA; prospective interventional studies are required and are currently underway.

Development of radiographic damage indicates severe PsA and affects quality of life and physical function. Identifying patients at risk for joint damage may help treatment stratification. Using data from a real-world cohort of 476 patients with early PsA, of whom 14% demonstrated progressive radiographic damage, Koc and colleagues found that female sex was a protective factor whereas old age and initial radiographic damage were risk factors for radiographic progression. These results are consistent with previous studies. Male sex, older age, and presence of radiographic damage at first visit should prompt more aggressive management to prevent further joint damage.

Regarding newer treatments, Gossec and colleagues demonstrated that bimekizumab, a monoclonal antibody targeting both interleukin (IL)-17A and IL-17F, improved disease effects in a rapid and sustained manner in patients with PsA who had not used biologic disease-modifying antirheumatic drugs or had prior inadequate response to tumor necrosis factor inhibitors. Bimekizumab is a welcome addition to the drugs available to manage PsA. Its comparative efficacy against other targeted therapies, especially other IL-17 inhibitors, is yet to be determined.

Finally, a study from the Greek multicenter PsA registry by Vassilakis and colleagues showed that, of 467 patients with PsA, 16.5% had D2T PsA. Compared with non–D2T patients, those with D2T disease were more likely to have extensive psoriasis at diagnosis, higher body mass index, and a history of inflammatory bowel disease (IBD). Treatment-resistant disease is increasingly prevalent in PsA. Certain diseases and comorbidities, such as IBD and obesity, are associated with D2T PsA. A uniform definition of D2T PsA and prospective studies to identify risk factors, as well as new strategies to manage D2T PsA, are required.

A hot topic of PsA research is whether treating psoriasis patients with biologics reduces the risk of developing PsA. Floris and colleagues analyzed data from 1023 patients with psoriasis aged 18 years or older, of whom 29.6% received biologics at least once and 21.0% had PsA. They observed that patients treated at least once vs never treated with biologics had a significantly lower risk for PsA. The "protective" effect of biologics against PsA persisted irrespective of the class of biologic used. However, the study has many built-in biases; it was not a prospective study of psoriasis patients without PsA, but rather a retrospective analysis of data collected at enrollment. Nevertheless, effective psoriasis therapies may indeed reduce the risk for PsA; prospective interventional studies are required and are currently underway.

Development of radiographic damage indicates severe PsA and affects quality of life and physical function. Identifying patients at risk for joint damage may help treatment stratification. Using data from a real-world cohort of 476 patients with early PsA, of whom 14% demonstrated progressive radiographic damage, Koc and colleagues found that female sex was a protective factor whereas old age and initial radiographic damage were risk factors for radiographic progression. These results are consistent with previous studies. Male sex, older age, and presence of radiographic damage at first visit should prompt more aggressive management to prevent further joint damage.

Regarding newer treatments, Gossec and colleagues demonstrated that bimekizumab, a monoclonal antibody targeting both interleukin (IL)-17A and IL-17F, improved disease effects in a rapid and sustained manner in patients with PsA who had not used biologic disease-modifying antirheumatic drugs or had prior inadequate response to tumor necrosis factor inhibitors. Bimekizumab is a welcome addition to the drugs available to manage PsA. Its comparative efficacy against other targeted therapies, especially other IL-17 inhibitors, is yet to be determined.

Finally, a study from the Greek multicenter PsA registry by Vassilakis and colleagues showed that, of 467 patients with PsA, 16.5% had D2T PsA. Compared with non–D2T patients, those with D2T disease were more likely to have extensive psoriasis at diagnosis, higher body mass index, and a history of inflammatory bowel disease (IBD). Treatment-resistant disease is increasingly prevalent in PsA. Certain diseases and comorbidities, such as IBD and obesity, are associated with D2T PsA. A uniform definition of D2T PsA and prospective studies to identify risk factors, as well as new strategies to manage D2T PsA, are required.

A hot topic of PsA research is whether treating psoriasis patients with biologics reduces the risk of developing PsA. Floris and colleagues analyzed data from 1023 patients with psoriasis aged 18 years or older, of whom 29.6% received biologics at least once and 21.0% had PsA. They observed that patients treated at least once vs never treated with biologics had a significantly lower risk for PsA. The "protective" effect of biologics against PsA persisted irrespective of the class of biologic used. However, the study has many built-in biases; it was not a prospective study of psoriasis patients without PsA, but rather a retrospective analysis of data collected at enrollment. Nevertheless, effective psoriasis therapies may indeed reduce the risk for PsA; prospective interventional studies are required and are currently underway.

Development of radiographic damage indicates severe PsA and affects quality of life and physical function. Identifying patients at risk for joint damage may help treatment stratification. Using data from a real-world cohort of 476 patients with early PsA, of whom 14% demonstrated progressive radiographic damage, Koc and colleagues found that female sex was a protective factor whereas old age and initial radiographic damage were risk factors for radiographic progression. These results are consistent with previous studies. Male sex, older age, and presence of radiographic damage at first visit should prompt more aggressive management to prevent further joint damage.

Regarding newer treatments, Gossec and colleagues demonstrated that bimekizumab, a monoclonal antibody targeting both interleukin (IL)-17A and IL-17F, improved disease effects in a rapid and sustained manner in patients with PsA who had not used biologic disease-modifying antirheumatic drugs or had prior inadequate response to tumor necrosis factor inhibitors. Bimekizumab is a welcome addition to the drugs available to manage PsA. Its comparative efficacy against other targeted therapies, especially other IL-17 inhibitors, is yet to be determined.

Finally, a study from the Greek multicenter PsA registry by Vassilakis and colleagues showed that, of 467 patients with PsA, 16.5% had D2T PsA. Compared with non–D2T patients, those with D2T disease were more likely to have extensive psoriasis at diagnosis, higher body mass index, and a history of inflammatory bowel disease (IBD). Treatment-resistant disease is increasingly prevalent in PsA. Certain diseases and comorbidities, such as IBD and obesity, are associated with D2T PsA. A uniform definition of D2T PsA and prospective studies to identify risk factors, as well as new strategies to manage D2T PsA, are required.

A hot topic of PsA research is whether treating psoriasis patients with biologics reduces the risk of developing PsA. Floris and colleagues analyzed data from 1023 patients with psoriasis aged 18 years or older, of whom 29.6% received biologics at least once and 21.0% had PsA. They observed that patients treated at least once vs never treated with biologics had a significantly lower risk for PsA. The "protective" effect of biologics against PsA persisted irrespective of the class of biologic used. However, the study has many built-in biases; it was not a prospective study of psoriasis patients without PsA, but rather a retrospective analysis of data collected at enrollment. Nevertheless, effective psoriasis therapies may indeed reduce the risk for PsA; prospective interventional studies are required and are currently underway.

Development of radiographic damage indicates severe PsA and affects quality of life and physical function. Identifying patients at risk for joint damage may help treatment stratification. Using data from a real-world cohort of 476 patients with early PsA, of whom 14% demonstrated progressive radiographic damage, Koc and colleagues found that female sex was a protective factor whereas old age and initial radiographic damage were risk factors for radiographic progression. These results are consistent with previous studies. Male sex, older age, and presence of radiographic damage at first visit should prompt more aggressive management to prevent further joint damage.

Regarding newer treatments, Gossec and colleagues demonstrated that bimekizumab, a monoclonal antibody targeting both interleukin (IL)-17A and IL-17F, improved disease effects in a rapid and sustained manner in patients with PsA who had not used biologic disease-modifying antirheumatic drugs or had prior inadequate response to tumor necrosis factor inhibitors. Bimekizumab is a welcome addition to the drugs available to manage PsA. Its comparative efficacy against other targeted therapies, especially other IL-17 inhibitors, is yet to be determined.

Finally, a study from the Greek multicenter PsA registry by Vassilakis and colleagues showed that, of 467 patients with PsA, 16.5% had D2T PsA. Compared with non–D2T patients, those with D2T disease were more likely to have extensive psoriasis at diagnosis, higher body mass index, and a history of inflammatory bowel disease (IBD). Treatment-resistant disease is increasingly prevalent in PsA. Certain diseases and comorbidities, such as IBD and obesity, are associated with D2T PsA. A uniform definition of D2T PsA and prospective studies to identify risk factors, as well as new strategies to manage D2T PsA, are required.

A hot topic of PsA research is whether treating psoriasis patients with biologics reduces the risk of developing PsA. Floris and colleagues analyzed data from 1023 patients with psoriasis aged 18 years or older, of whom 29.6% received biologics at least once and 21.0% had PsA. They observed that patients treated at least once vs never treated with biologics had a significantly lower risk for PsA. The "protective" effect of biologics against PsA persisted irrespective of the class of biologic used. However, the study has many built-in biases; it was not a prospective study of psoriasis patients without PsA, but rather a retrospective analysis of data collected at enrollment. Nevertheless, effective psoriasis therapies may indeed reduce the risk for PsA; prospective interventional studies are required and are currently underway.

Development of radiographic damage indicates severe PsA and affects quality of life and physical function. Identifying patients at risk for joint damage may help treatment stratification. Using data from a real-world cohort of 476 patients with early PsA, of whom 14% demonstrated progressive radiographic damage, Koc and colleagues found that female sex was a protective factor whereas old age and initial radiographic damage were risk factors for radiographic progression. These results are consistent with previous studies. Male sex, older age, and presence of radiographic damage at first visit should prompt more aggressive management to prevent further joint damage.

Regarding newer treatments, Gossec and colleagues demonstrated that bimekizumab, a monoclonal antibody targeting both interleukin (IL)-17A and IL-17F, improved disease effects in a rapid and sustained manner in patients with PsA who had not used biologic disease-modifying antirheumatic drugs or had prior inadequate response to tumor necrosis factor inhibitors. Bimekizumab is a welcome addition to the drugs available to manage PsA. Its comparative efficacy against other targeted therapies, especially other IL-17 inhibitors, is yet to be determined.

Finally, a study from the Greek multicenter PsA registry by Vassilakis and colleagues showed that, of 467 patients with PsA, 16.5% had D2T PsA. Compared with non–D2T patients, those with D2T disease were more likely to have extensive psoriasis at diagnosis, higher body mass index, and a history of inflammatory bowel disease (IBD). Treatment-resistant disease is increasingly prevalent in PsA. Certain diseases and comorbidities, such as IBD and obesity, are associated with D2T PsA. A uniform definition of D2T PsA and prospective studies to identify risk factors, as well as new strategies to manage D2T PsA, are required.

MONTREAL – Levels of neurofilament light chain (Nfl) may be a biomarker of chemotherapy-induced peripheral neurotoxicity (CIPN), new research suggests.

Investigators found Nfl levels increased in cancer patients following a first infusion of the medication paclitaxel and corresponded to neuropathy severity 6-12 months post-treatment, suggesting the blood protein may provide an early CIPN biomarker.

“Nfl after a single cycle could detect axonal degeneration,” said lead investigator Masarra Joda, a researcher and PhD candidate at the University of Sydney in Australia. She added that “quantification of Nfl may provide a clinically useful marker of emerging neurotoxicity in patients vulnerable to CIPN.”

The findings were presented at the Peripheral Nerve Society (PNS) 2024 annual meeting.
 

Common, Burdensome Side Effect

A common side effect of chemotherapy, CIPN manifests as sensory neuropathy and causes degeneration of the peripheral axons. A protein biomarker of axonal degeneration, Nfl has previously been investigated as a way of identifying patients at risk of CIPN.

The goal of the current study was to identify the potential link between Nfl with neurophysiological markers of axon degeneration in patients receiving the neurotoxin chemotherapy paclitaxel.

The study included 93 cancer patients. All were assessed at the beginning, middle, and end of treatment. CIPN was assessed using blood samples of Nfl and the Total Neuropathy Score (TNS), the Common Terminology Criteria for Adverse Events (CTCAE) neuropathy scale, and patient-reported measures using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy Module (EORTC-CIPN20).

Axonal degeneration was measured with neurophysiological tests including sural nerve compound sensory action potential (CSAP) for the lower limbs, and sensory median nerve CSAP, as well as stimulus threshold testing, for the upper limbs. 

Almost all of study participants (97%) were female. The majority (66%) had breast cancer and 30% had gynecological cancer. Most (73%) were receiving a weekly regimen of paclitaxel, and the remainder were treated with taxanes plus platinum once every 3 weeks. By the end of treatment, 82% of the patients had developed CIPN, which was mild in 44% and moderate/severe in 38%. 

Nfl levels increased significantly from baseline to after the first dose of chemotherapy (P < .001), “highlighting that nerve damage occurs from the very beginning of treatment,” senior investigator Susanna Park, PhD, told this news organization. 

In addition, “patients with higher Nfl levels after a single paclitaxel treatment had greater neuropathy at the end of treatment (higher EORTC scores [P ≤ .026], and higher TNS scores [P ≤ .00]),” added Dr. Park, who is associate professor at the University of Sydney.

“Importantly, we also looked at long-term outcomes beyond the end of chemotherapy, because chronic neuropathy produces a significant burden in cancer survivors,” said Dr. Park. 

“Among a total of 44 patients who completed the 6- to 12-month post-treatment follow-up, NfL levels after a single treatment were linked to severity of nerve damage quantified with neurophysiological tests, and greater Nfl levels at mid-treatment were correlated with worse patient and neurologically graded neuropathy at 6-12 months.”

Dr. Park said the results suggest that NfL may provide a biomarker of long-term axon damage and that Nfl assays “may enable clinicians to evaluate the risk of long-term toxicity early during paclitaxel treatment to hopefully provide clinically significant information to guide better treatment titration.” 

Currently, she said, CIPN is a prominent cause of dose reduction and early chemotherapy cessation. 

“For example, in early breast cancer around 25% of patients experience a dose reduction due to the severity of neuropathy symptoms.” But, she said, “there is no standardized way of identifying which patients are at risk of long-term neuropathy and therefore, may benefit more from dose reduction. In this setting, a biomarker such as Nfl could provide oncologists with more information about the risk of long-term toxicity and take that into account in dose decision-making.” 

For some cancers, she added, there are multiple potential therapy options.

“A biomarker such as NfL could assist in determining risk-benefit profile in terms of switching to alternate therapies. However, further studies will be needed to fully define the utility of NfL as a biomarker of paclitaxel neuropathy.” 
 

Promising Research

Commenting on the research for this news organization, Maryam Lustberg, MD, associate professor, director of the Center for Breast Cancer at Smilow Cancer Hospital and Yale Cancer Center, and chief of Breast Medical Oncology at Yale Cancer Center, in New Haven, Connecticut, said the study “builds on a body of work previously reported by others showing that neurofilament light chains as detected in the blood can be associated with early signs of neurotoxic injury.” 

She added that the research “is promising, since existing clinical and patient-reported measures tend to under-detect chemotherapy-induced neuropathy until more permanent injury might have occurred.” 

Dr. Lustberg, who is immediate past president of the Multinational Association of Supportive Care in Cancer, said future studies are needed before Nfl testing can be implemented in routine practice, but that “early detection will allow earlier initiation of supportive care strategies such as physical therapy and exercise, as well as dose modifications, which may be helpful for preventing permanent damage and improving quality of life.” 

The investigators and Dr. Lustberg report no relevant financial relationships.

A version of this article appeared on Medscape.com.

MONTREAL – Levels of neurofilament light chain (Nfl) may be a biomarker of chemotherapy-induced peripheral neurotoxicity (CIPN), new research suggests.

Investigators found Nfl levels increased in cancer patients following a first infusion of the medication paclitaxel and corresponded to neuropathy severity 6-12 months post-treatment, suggesting the blood protein may provide an early CIPN biomarker.

“Nfl after a single cycle could detect axonal degeneration,” said lead investigator Masarra Joda, a researcher and PhD candidate at the University of Sydney in Australia. She added that “quantification of Nfl may provide a clinically useful marker of emerging neurotoxicity in patients vulnerable to CIPN.”

The findings were presented at the Peripheral Nerve Society (PNS) 2024 annual meeting.
 

Common, Burdensome Side Effect

A common side effect of chemotherapy, CIPN manifests as sensory neuropathy and causes degeneration of the peripheral axons. A protein biomarker of axonal degeneration, Nfl has previously been investigated as a way of identifying patients at risk of CIPN.

The goal of the current study was to identify the potential link between Nfl with neurophysiological markers of axon degeneration in patients receiving the neurotoxin chemotherapy paclitaxel.

The study included 93 cancer patients. All were assessed at the beginning, middle, and end of treatment. CIPN was assessed using blood samples of Nfl and the Total Neuropathy Score (TNS), the Common Terminology Criteria for Adverse Events (CTCAE) neuropathy scale, and patient-reported measures using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy Module (EORTC-CIPN20).

Axonal degeneration was measured with neurophysiological tests including sural nerve compound sensory action potential (CSAP) for the lower limbs, and sensory median nerve CSAP, as well as stimulus threshold testing, for the upper limbs. 

Almost all of study participants (97%) were female. The majority (66%) had breast cancer and 30% had gynecological cancer. Most (73%) were receiving a weekly regimen of paclitaxel, and the remainder were treated with taxanes plus platinum once every 3 weeks. By the end of treatment, 82% of the patients had developed CIPN, which was mild in 44% and moderate/severe in 38%. 

Nfl levels increased significantly from baseline to after the first dose of chemotherapy (P < .001), “highlighting that nerve damage occurs from the very beginning of treatment,” senior investigator Susanna Park, PhD, told this news organization. 

In addition, “patients with higher Nfl levels after a single paclitaxel treatment had greater neuropathy at the end of treatment (higher EORTC scores [P ≤ .026], and higher TNS scores [P ≤ .00]),” added Dr. Park, who is associate professor at the University of Sydney.

“Importantly, we also looked at long-term outcomes beyond the end of chemotherapy, because chronic neuropathy produces a significant burden in cancer survivors,” said Dr. Park. 

“Among a total of 44 patients who completed the 6- to 12-month post-treatment follow-up, NfL levels after a single treatment were linked to severity of nerve damage quantified with neurophysiological tests, and greater Nfl levels at mid-treatment were correlated with worse patient and neurologically graded neuropathy at 6-12 months.”

Dr. Park said the results suggest that NfL may provide a biomarker of long-term axon damage and that Nfl assays “may enable clinicians to evaluate the risk of long-term toxicity early during paclitaxel treatment to hopefully provide clinically significant information to guide better treatment titration.” 

Currently, she said, CIPN is a prominent cause of dose reduction and early chemotherapy cessation. 

“For example, in early breast cancer around 25% of patients experience a dose reduction due to the severity of neuropathy symptoms.” But, she said, “there is no standardized way of identifying which patients are at risk of long-term neuropathy and therefore, may benefit more from dose reduction. In this setting, a biomarker such as Nfl could provide oncologists with more information about the risk of long-term toxicity and take that into account in dose decision-making.” 

For some cancers, she added, there are multiple potential therapy options.

“A biomarker such as NfL could assist in determining risk-benefit profile in terms of switching to alternate therapies. However, further studies will be needed to fully define the utility of NfL as a biomarker of paclitaxel neuropathy.” 
 

Promising Research

Commenting on the research for this news organization, Maryam Lustberg, MD, associate professor, director of the Center for Breast Cancer at Smilow Cancer Hospital and Yale Cancer Center, and chief of Breast Medical Oncology at Yale Cancer Center, in New Haven, Connecticut, said the study “builds on a body of work previously reported by others showing that neurofilament light chains as detected in the blood can be associated with early signs of neurotoxic injury.” 

She added that the research “is promising, since existing clinical and patient-reported measures tend to under-detect chemotherapy-induced neuropathy until more permanent injury might have occurred.” 

Dr. Lustberg, who is immediate past president of the Multinational Association of Supportive Care in Cancer, said future studies are needed before Nfl testing can be implemented in routine practice, but that “early detection will allow earlier initiation of supportive care strategies such as physical therapy and exercise, as well as dose modifications, which may be helpful for preventing permanent damage and improving quality of life.” 

The investigators and Dr. Lustberg report no relevant financial relationships.

A version of this article appeared on Medscape.com.

MONTREAL – Levels of neurofilament light chain (Nfl) may be a biomarker of chemotherapy-induced peripheral neurotoxicity (CIPN), new research suggests.

Investigators found Nfl levels increased in cancer patients following a first infusion of the medication paclitaxel and corresponded to neuropathy severity 6-12 months post-treatment, suggesting the blood protein may provide an early CIPN biomarker.

“Nfl after a single cycle could detect axonal degeneration,” said lead investigator Masarra Joda, a researcher and PhD candidate at the University of Sydney in Australia. She added that “quantification of Nfl may provide a clinically useful marker of emerging neurotoxicity in patients vulnerable to CIPN.”

The findings were presented at the Peripheral Nerve Society (PNS) 2024 annual meeting.
 

Common, Burdensome Side Effect

A common side effect of chemotherapy, CIPN manifests as sensory neuropathy and causes degeneration of the peripheral axons. A protein biomarker of axonal degeneration, Nfl has previously been investigated as a way of identifying patients at risk of CIPN.

The goal of the current study was to identify the potential link between Nfl with neurophysiological markers of axon degeneration in patients receiving the neurotoxin chemotherapy paclitaxel.

The study included 93 cancer patients. All were assessed at the beginning, middle, and end of treatment. CIPN was assessed using blood samples of Nfl and the Total Neuropathy Score (TNS), the Common Terminology Criteria for Adverse Events (CTCAE) neuropathy scale, and patient-reported measures using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy Module (EORTC-CIPN20).

Axonal degeneration was measured with neurophysiological tests including sural nerve compound sensory action potential (CSAP) for the lower limbs, and sensory median nerve CSAP, as well as stimulus threshold testing, for the upper limbs. 

Almost all of study participants (97%) were female. The majority (66%) had breast cancer and 30% had gynecological cancer. Most (73%) were receiving a weekly regimen of paclitaxel, and the remainder were treated with taxanes plus platinum once every 3 weeks. By the end of treatment, 82% of the patients had developed CIPN, which was mild in 44% and moderate/severe in 38%. 

Nfl levels increased significantly from baseline to after the first dose of chemotherapy (P < .001), “highlighting that nerve damage occurs from the very beginning of treatment,” senior investigator Susanna Park, PhD, told this news organization. 

In addition, “patients with higher Nfl levels after a single paclitaxel treatment had greater neuropathy at the end of treatment (higher EORTC scores [P ≤ .026], and higher TNS scores [P ≤ .00]),” added Dr. Park, who is associate professor at the University of Sydney.

“Importantly, we also looked at long-term outcomes beyond the end of chemotherapy, because chronic neuropathy produces a significant burden in cancer survivors,” said Dr. Park. 

“Among a total of 44 patients who completed the 6- to 12-month post-treatment follow-up, NfL levels after a single treatment were linked to severity of nerve damage quantified with neurophysiological tests, and greater Nfl levels at mid-treatment were correlated with worse patient and neurologically graded neuropathy at 6-12 months.”

Dr. Park said the results suggest that NfL may provide a biomarker of long-term axon damage and that Nfl assays “may enable clinicians to evaluate the risk of long-term toxicity early during paclitaxel treatment to hopefully provide clinically significant information to guide better treatment titration.” 

Currently, she said, CIPN is a prominent cause of dose reduction and early chemotherapy cessation. 

“For example, in early breast cancer around 25% of patients experience a dose reduction due to the severity of neuropathy symptoms.” But, she said, “there is no standardized way of identifying which patients are at risk of long-term neuropathy and therefore, may benefit more from dose reduction. In this setting, a biomarker such as Nfl could provide oncologists with more information about the risk of long-term toxicity and take that into account in dose decision-making.” 

For some cancers, she added, there are multiple potential therapy options.

“A biomarker such as NfL could assist in determining risk-benefit profile in terms of switching to alternate therapies. However, further studies will be needed to fully define the utility of NfL as a biomarker of paclitaxel neuropathy.” 
 

Promising Research

Commenting on the research for this news organization, Maryam Lustberg, MD, associate professor, director of the Center for Breast Cancer at Smilow Cancer Hospital and Yale Cancer Center, and chief of Breast Medical Oncology at Yale Cancer Center, in New Haven, Connecticut, said the study “builds on a body of work previously reported by others showing that neurofilament light chains as detected in the blood can be associated with early signs of neurotoxic injury.” 

She added that the research “is promising, since existing clinical and patient-reported measures tend to under-detect chemotherapy-induced neuropathy until more permanent injury might have occurred.” 

Dr. Lustberg, who is immediate past president of the Multinational Association of Supportive Care in Cancer, said future studies are needed before Nfl testing can be implemented in routine practice, but that “early detection will allow earlier initiation of supportive care strategies such as physical therapy and exercise, as well as dose modifications, which may be helpful for preventing permanent damage and improving quality of life.” 

The investigators and Dr. Lustberg report no relevant financial relationships.

A version of this article appeared on Medscape.com.