Photo by Chad McNeeley

The European Commission has granted orphan designation to OMS721 for use in the setting of hematopoietic stem cell transplant (HSCT).

OMS721 is a monoclonal antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system.

Omeros Corporation is developing OMS721 as a treatment for HSCT-associated thrombotic microangiopathy (TMA) and other conditions.

OMS721 is currently under evaluation in a phase 2 trial (NCT02222545) of patients with HSCT-TMA, and Omeros released some results from this study in February.

Results were reported for 18 adults with HSCT-TMA persisting for at least 2 weeks following immunosuppressive regimen modification or more than 30 days post-transplant.

The patients received weekly OMS721 treatments for 4 to 8 weeks at the discretion of the investigator.

These patients had a significantly longer median overall survival than historical controls—347 days and 21 days, respectively (P<0.0001).

Omeros also reported that markers of TMA activity significantly improved following OMS721 treatment.

The mean platelet count increased from 18,100 x 10⁶/mL at baseline to 52,300 x 10⁶/mL (P=0.017). The mean LDH decreased from 591 U/L to 250 U/L (P<0.001). And the mean haptoglobin increased from 8 mg/dL to 141 mg/dL (P=0.003).

Mean creatinine remained stable—at approximately 120 μmol/L—but a majority of patients had co-existing conditions for which they were receiving nephrotoxic medications. These conditions included graft-versus-host disease, cytomegalovirus and human herpes virus 6 infections, prior sepsis, diffuse alveolar hemorrhage, and residual underlying malignancies.

The most commonly reported adverse events in this trial were diarrhea and neutropenia.

Four deaths occurred. One of these—due to acute renal and respiratory failure—was considered possibly related to OMS721.

The other deaths were due to progression of acute myeloid leukemia (n=1) and neutropenic sepsis (n=2).

About orphan designation

Orphan designation from the European Commission is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union.

The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the European Union after product approval, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and access to centralized marketing authorization.

Photo by Chad McNeeley

The European Commission has granted orphan designation to OMS721 for use in the setting of hematopoietic stem cell transplant (HSCT).

OMS721 is a monoclonal antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system.

Omeros Corporation is developing OMS721 as a treatment for HSCT-associated thrombotic microangiopathy (TMA) and other conditions.

OMS721 is currently under evaluation in a phase 2 trial (NCT02222545) of patients with HSCT-TMA, and Omeros released some results from this study in February.

Results were reported for 18 adults with HSCT-TMA persisting for at least 2 weeks following immunosuppressive regimen modification or more than 30 days post-transplant.

The patients received weekly OMS721 treatments for 4 to 8 weeks at the discretion of the investigator.

These patients had a significantly longer median overall survival than historical controls—347 days and 21 days, respectively (P<0.0001).

Omeros also reported that markers of TMA activity significantly improved following OMS721 treatment.

The mean platelet count increased from 18,100 x 10⁶/mL at baseline to 52,300 x 10⁶/mL (P=0.017). The mean LDH decreased from 591 U/L to 250 U/L (P<0.001). And the mean haptoglobin increased from 8 mg/dL to 141 mg/dL (P=0.003).

Mean creatinine remained stable—at approximately 120 μmol/L—but a majority of patients had co-existing conditions for which they were receiving nephrotoxic medications. These conditions included graft-versus-host disease, cytomegalovirus and human herpes virus 6 infections, prior sepsis, diffuse alveolar hemorrhage, and residual underlying malignancies.

The most commonly reported adverse events in this trial were diarrhea and neutropenia.

Four deaths occurred. One of these—due to acute renal and respiratory failure—was considered possibly related to OMS721.

The other deaths were due to progression of acute myeloid leukemia (n=1) and neutropenic sepsis (n=2).

About orphan designation

Orphan designation from the European Commission is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union.

The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the European Union after product approval, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and access to centralized marketing authorization.

Photo by Chad McNeeley

The European Commission has granted orphan designation to OMS721 for use in the setting of hematopoietic stem cell transplant (HSCT).

OMS721 is a monoclonal antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system.

Omeros Corporation is developing OMS721 as a treatment for HSCT-associated thrombotic microangiopathy (TMA) and other conditions.

OMS721 is currently under evaluation in a phase 2 trial (NCT02222545) of patients with HSCT-TMA, and Omeros released some results from this study in February.

Results were reported for 18 adults with HSCT-TMA persisting for at least 2 weeks following immunosuppressive regimen modification or more than 30 days post-transplant.

The patients received weekly OMS721 treatments for 4 to 8 weeks at the discretion of the investigator.

These patients had a significantly longer median overall survival than historical controls—347 days and 21 days, respectively (P<0.0001).

Omeros also reported that markers of TMA activity significantly improved following OMS721 treatment.

The mean platelet count increased from 18,100 x 10⁶/mL at baseline to 52,300 x 10⁶/mL (P=0.017). The mean LDH decreased from 591 U/L to 250 U/L (P<0.001). And the mean haptoglobin increased from 8 mg/dL to 141 mg/dL (P=0.003).

Mean creatinine remained stable—at approximately 120 μmol/L—but a majority of patients had co-existing conditions for which they were receiving nephrotoxic medications. These conditions included graft-versus-host disease, cytomegalovirus and human herpes virus 6 infections, prior sepsis, diffuse alveolar hemorrhage, and residual underlying malignancies.

The most commonly reported adverse events in this trial were diarrhea and neutropenia.

Four deaths occurred. One of these—due to acute renal and respiratory failure—was considered possibly related to OMS721.

The other deaths were due to progression of acute myeloid leukemia (n=1) and neutropenic sepsis (n=2).

About orphan designation

Orphan designation from the European Commission is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union.

The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the European Union after product approval, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and access to centralized marketing authorization.

Image by Spencer Phillips

Measurement of circulating tumor DNA (ctDNA) could be a new and useful tool for predicting survival outcomes and response to therapy in patients with diffuse large B-cell lymphoma (DLBCL), according to researchers.

Pretreatment ctDNA levels predicted 24-month event-free survival as well as overall survival in a prospective study.

Changes in ctDNA during treatment were prognostic for outcomes as early as 21 days into therapy.

Ash A. Alizadeh, MD, PhD, of Stanford University in California, and his colleagues reported these findings in the Journal of Clinical Oncology.

ctDNA was detected in 98% of the 217 patients evaluated, which demonstrated the “potentially universal applicability” of this approach, the researchers wrote.

In an evaluation of pretreatment ctDNA levels, the researchers found a 2.5 log haploid genome equivalents per milliliter threshold stratified patient outcomes. Event-free survival was significantly inferior at 24 months in patients with ctDNA above that threshold, with hazard ratios of 2.6 (P=0.007) for frontline treatment and 2.9 (P=0.01) for salvage therapy.

On-treatment ctDNA levels were favorably prognostic for outcomes in patients receiving frontline therapy.

An early molecular response (EMR), defined as a 2-log decrease in ctDNA levels after one cycle of treatment, was associated with a 24-month event-free survival of 83% versus 50% for no EMR (P=0.0015).

Major molecular response (MMR), defined as a 2.5-log drop in ctDNA after two cycles of treatment, was associated with a 24-month event-free survival of 82% versus 46% for no MMR in patients on frontline therapy (P<0.001).

In one cohort of patients receiving salvage therapy, EMR also predicted superior 24-month event-free survival.

The EMR measure was also favorably prognostic for overall survival in both the frontline and salvage settings.

The prognostic value of measuring ctDNA was independent of International Prognostic Index and interim PET/CT studies, results of multivariable analyses showed.

Patients had “excellent outcomes” if they had both molecular response and favorable interim PET results, according to researchers. Conversely, patients were at “extremely high risk” for treatment failure if they had no molecular response and a positive PET scan.

“The identification of patients at exceptionally high risk (i.e., interim PET/CT positive and not achieving EMR/MMR) could provide an opportunity for early intervention with alternative treatments, including autologous bone marrow transplantation or chimeric antigen receptor T cells,” the researchers wrote.

Patients in the study were all treated with combination immunochemotherapy according to local standards.

Dr. Alizadeh reported disclosures related to CiberMed, Forty Seven, Janssen Oncology, Celgene, Roche/Genentech, and Gilead, as well as patent filings on ctDNA detection assigned to Stanford University.

Image by Spencer Phillips

Measurement of circulating tumor DNA (ctDNA) could be a new and useful tool for predicting survival outcomes and response to therapy in patients with diffuse large B-cell lymphoma (DLBCL), according to researchers.

Pretreatment ctDNA levels predicted 24-month event-free survival as well as overall survival in a prospective study.

Changes in ctDNA during treatment were prognostic for outcomes as early as 21 days into therapy.

Ash A. Alizadeh, MD, PhD, of Stanford University in California, and his colleagues reported these findings in the Journal of Clinical Oncology.

ctDNA was detected in 98% of the 217 patients evaluated, which demonstrated the “potentially universal applicability” of this approach, the researchers wrote.

In an evaluation of pretreatment ctDNA levels, the researchers found a 2.5 log haploid genome equivalents per milliliter threshold stratified patient outcomes. Event-free survival was significantly inferior at 24 months in patients with ctDNA above that threshold, with hazard ratios of 2.6 (P=0.007) for frontline treatment and 2.9 (P=0.01) for salvage therapy.

On-treatment ctDNA levels were favorably prognostic for outcomes in patients receiving frontline therapy.

An early molecular response (EMR), defined as a 2-log decrease in ctDNA levels after one cycle of treatment, was associated with a 24-month event-free survival of 83% versus 50% for no EMR (P=0.0015).

Major molecular response (MMR), defined as a 2.5-log drop in ctDNA after two cycles of treatment, was associated with a 24-month event-free survival of 82% versus 46% for no MMR in patients on frontline therapy (P<0.001).

In one cohort of patients receiving salvage therapy, EMR also predicted superior 24-month event-free survival.

The EMR measure was also favorably prognostic for overall survival in both the frontline and salvage settings.

The prognostic value of measuring ctDNA was independent of International Prognostic Index and interim PET/CT studies, results of multivariable analyses showed.

Patients had “excellent outcomes” if they had both molecular response and favorable interim PET results, according to researchers. Conversely, patients were at “extremely high risk” for treatment failure if they had no molecular response and a positive PET scan.

“The identification of patients at exceptionally high risk (i.e., interim PET/CT positive and not achieving EMR/MMR) could provide an opportunity for early intervention with alternative treatments, including autologous bone marrow transplantation or chimeric antigen receptor T cells,” the researchers wrote.

Patients in the study were all treated with combination immunochemotherapy according to local standards.

Dr. Alizadeh reported disclosures related to CiberMed, Forty Seven, Janssen Oncology, Celgene, Roche/Genentech, and Gilead, as well as patent filings on ctDNA detection assigned to Stanford University.

Image by Spencer Phillips

Measurement of circulating tumor DNA (ctDNA) could be a new and useful tool for predicting survival outcomes and response to therapy in patients with diffuse large B-cell lymphoma (DLBCL), according to researchers.

Pretreatment ctDNA levels predicted 24-month event-free survival as well as overall survival in a prospective study.

Changes in ctDNA during treatment were prognostic for outcomes as early as 21 days into therapy.

Ash A. Alizadeh, MD, PhD, of Stanford University in California, and his colleagues reported these findings in the Journal of Clinical Oncology.

ctDNA was detected in 98% of the 217 patients evaluated, which demonstrated the “potentially universal applicability” of this approach, the researchers wrote.

In an evaluation of pretreatment ctDNA levels, the researchers found a 2.5 log haploid genome equivalents per milliliter threshold stratified patient outcomes. Event-free survival was significantly inferior at 24 months in patients with ctDNA above that threshold, with hazard ratios of 2.6 (P=0.007) for frontline treatment and 2.9 (P=0.01) for salvage therapy.

On-treatment ctDNA levels were favorably prognostic for outcomes in patients receiving frontline therapy.

An early molecular response (EMR), defined as a 2-log decrease in ctDNA levels after one cycle of treatment, was associated with a 24-month event-free survival of 83% versus 50% for no EMR (P=0.0015).

Major molecular response (MMR), defined as a 2.5-log drop in ctDNA after two cycles of treatment, was associated with a 24-month event-free survival of 82% versus 46% for no MMR in patients on frontline therapy (P<0.001).

In one cohort of patients receiving salvage therapy, EMR also predicted superior 24-month event-free survival.

The EMR measure was also favorably prognostic for overall survival in both the frontline and salvage settings.

The prognostic value of measuring ctDNA was independent of International Prognostic Index and interim PET/CT studies, results of multivariable analyses showed.

Patients had “excellent outcomes” if they had both molecular response and favorable interim PET results, according to researchers. Conversely, patients were at “extremely high risk” for treatment failure if they had no molecular response and a positive PET scan.

“The identification of patients at exceptionally high risk (i.e., interim PET/CT positive and not achieving EMR/MMR) could provide an opportunity for early intervention with alternative treatments, including autologous bone marrow transplantation or chimeric antigen receptor T cells,” the researchers wrote.

Patients in the study were all treated with combination immunochemotherapy according to local standards.

Dr. Alizadeh reported disclosures related to CiberMed, Forty Seven, Janssen Oncology, Celgene, Roche/Genentech, and Gilead, as well as patent filings on ctDNA detection assigned to Stanford University.

The China Drug Administration is reviewing the Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib for the treatment of relapsed/refractory mantle cell lymphoma (MCL).

The U.S. Food and Drug Administration recently granted the drug fast track designation for the treatment of patients with Waldenström’s macroglobulinemia.

The application in China is supported by results from a phase 2, single-arm trial of 86 patients with relapsed/refractory MCL who received 160 mg zanubrutinib orally twice daily. The overall response rate was 84%, which included 59% of patients with a complete response. At 8.3 months of follow-up, the median duration of response had not been reached, according to the drug’s sponsor BeiGene.

Zanubrutinib is being studied in several ongoing trials, including for the treatment of untreated chronic lymphocytic leukemia (CLL), for relapsed/refractory follicular lymphoma in combination with obinutuzumab, and comparing it to ibrutinib in Waldenström’s macroglobulinemia and CLL/small lymphocytic lymphoma.

[email protected]

The China Drug Administration is reviewing the Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib for the treatment of relapsed/refractory mantle cell lymphoma (MCL).

The U.S. Food and Drug Administration recently granted the drug fast track designation for the treatment of patients with Waldenström’s macroglobulinemia.

The application in China is supported by results from a phase 2, single-arm trial of 86 patients with relapsed/refractory MCL who received 160 mg zanubrutinib orally twice daily. The overall response rate was 84%, which included 59% of patients with a complete response. At 8.3 months of follow-up, the median duration of response had not been reached, according to the drug’s sponsor BeiGene.

Zanubrutinib is being studied in several ongoing trials, including for the treatment of untreated chronic lymphocytic leukemia (CLL), for relapsed/refractory follicular lymphoma in combination with obinutuzumab, and comparing it to ibrutinib in Waldenström’s macroglobulinemia and CLL/small lymphocytic lymphoma.

[email protected]

The China Drug Administration is reviewing the Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib for the treatment of relapsed/refractory mantle cell lymphoma (MCL).

The U.S. Food and Drug Administration recently granted the drug fast track designation for the treatment of patients with Waldenström’s macroglobulinemia.

The application in China is supported by results from a phase 2, single-arm trial of 86 patients with relapsed/refractory MCL who received 160 mg zanubrutinib orally twice daily. The overall response rate was 84%, which included 59% of patients with a complete response. At 8.3 months of follow-up, the median duration of response had not been reached, according to the drug’s sponsor BeiGene.

Zanubrutinib is being studied in several ongoing trials, including for the treatment of untreated chronic lymphocytic leukemia (CLL), for relapsed/refractory follicular lymphoma in combination with obinutuzumab, and comparing it to ibrutinib in Waldenström’s macroglobulinemia and CLL/small lymphocytic lymphoma.

[email protected]

LAKE TAHOE, CALIF. – Several years ago, David H. Darrow, MD, DDS, began to notice a pattern in the conversation threads on websites dedicated to support for parents of children with facial port-wine stains (PWS).

Parents were reporting that dental problems arose earlier on their child’s side of face with the PWS, and that the alveolar ridge was lower on the side of the face that harbored the lesion. “Most importantly, parents were concerned that dentists were not touching their children because they were concerned about bleeding,” Dr. Darrow said at the annual meeting of the Society for Pediatric Dermatology. A search in the medical literature for port-wine stains and oral cavity changes, did not turn up much except for a few articles on bleeding. “One said that port-wine stains or capillary malformations rarely present major problems for the oral and maxillofacial surgeon. The other said that periodontal probing should not be done, as even gentle probing can result in uncontrolled bleeding,” he noted.

This prompted Dr. Darrow, who directs the Center for Hemangiomas and Vascular Birthmarks at the Eastern Virginia Medical School, Norfolk, and coinvestigators, Megan B. Dowling, MD, and Yueqin Zhao, PhD, to characterize manifestations of PWS in the oral cavity via an anonymous paired survey of volunteers with facial PWS and their dentists who were recruited from birthmarks.com and 10 collaborating physician practices (J Am Acad Dermatol 2012;67:687-93). Volunteers ranged in age from 1 to 62 years; mean age was 29 years. A total of 30 patients participated, and most (67%) were female.

The five most common oral manifestations reported by the patients were lip hyperplasia (53%), stained gingiva (47%), malocclusion (30%), bleeding gingiva (27%), and spacing between teeth (23%). Only 3% reported bleeding from dental procedures. When the researchers evaluated the orodental findings in the paired patient-physician responses, “most of the time there was good agreement between the patient and the dentist,” Dr. Darrow said. “The only one that fell out of agreement was lip hyperplasia. That’s probably because most dentists look right past the lips and into the oral cavity.”

When the researchers examined patients who had stained gingiva versus those who did not, they found that early-stage lesions demonstrated a reddish blush of the oral mucosa and gingiva, while late-stage lesions demonstrated increased blush of the oral tissues, as well as hyperplasia of the soft tissue or bone in the affected area. “Based on our review of the literature, bleeding of gums is rarely prolonged and dental procedures are safe,” Dr. Darrow said.

The findings are important, he continued, because capillary malformations of the oral cavity may result in periodontal disease associated with gingival overgrowth. The depth of the gingival pocket should be no more than 2-3 mm. “When you have areas of inflammation and deep-pocket formation, plaque and bacteria slowly erode the connection between the tooth and the soft tissue,” he explained. “At some point, that pocket becomes so deep that it reaches down into the bone in which the tooth is anchored. As that bone is eroded, the teeth loosen and begin to fall out. The goals of therapy are prevention of periodontal disease with meticulous oral hygiene.”

Soft tissue hyperplasia may be exacerbated by medications such as calcium channel blockers, cyclosporine, and phenytoin and phenobarbital, which are sometimes used by patients with Sturge-Weber syndrome, he said.

Dr. Darrow reported having no financial disclosures.

[email protected]

LAKE TAHOE, CALIF. – Several years ago, David H. Darrow, MD, DDS, began to notice a pattern in the conversation threads on websites dedicated to support for parents of children with facial port-wine stains (PWS).

Parents were reporting that dental problems arose earlier on their child’s side of face with the PWS, and that the alveolar ridge was lower on the side of the face that harbored the lesion. “Most importantly, parents were concerned that dentists were not touching their children because they were concerned about bleeding,” Dr. Darrow said at the annual meeting of the Society for Pediatric Dermatology. A search in the medical literature for port-wine stains and oral cavity changes, did not turn up much except for a few articles on bleeding. “One said that port-wine stains or capillary malformations rarely present major problems for the oral and maxillofacial surgeon. The other said that periodontal probing should not be done, as even gentle probing can result in uncontrolled bleeding,” he noted.

This prompted Dr. Darrow, who directs the Center for Hemangiomas and Vascular Birthmarks at the Eastern Virginia Medical School, Norfolk, and coinvestigators, Megan B. Dowling, MD, and Yueqin Zhao, PhD, to characterize manifestations of PWS in the oral cavity via an anonymous paired survey of volunteers with facial PWS and their dentists who were recruited from birthmarks.com and 10 collaborating physician practices (J Am Acad Dermatol 2012;67:687-93). Volunteers ranged in age from 1 to 62 years; mean age was 29 years. A total of 30 patients participated, and most (67%) were female.

The five most common oral manifestations reported by the patients were lip hyperplasia (53%), stained gingiva (47%), malocclusion (30%), bleeding gingiva (27%), and spacing between teeth (23%). Only 3% reported bleeding from dental procedures. When the researchers evaluated the orodental findings in the paired patient-physician responses, “most of the time there was good agreement between the patient and the dentist,” Dr. Darrow said. “The only one that fell out of agreement was lip hyperplasia. That’s probably because most dentists look right past the lips and into the oral cavity.”

When the researchers examined patients who had stained gingiva versus those who did not, they found that early-stage lesions demonstrated a reddish blush of the oral mucosa and gingiva, while late-stage lesions demonstrated increased blush of the oral tissues, as well as hyperplasia of the soft tissue or bone in the affected area. “Based on our review of the literature, bleeding of gums is rarely prolonged and dental procedures are safe,” Dr. Darrow said.

The findings are important, he continued, because capillary malformations of the oral cavity may result in periodontal disease associated with gingival overgrowth. The depth of the gingival pocket should be no more than 2-3 mm. “When you have areas of inflammation and deep-pocket formation, plaque and bacteria slowly erode the connection between the tooth and the soft tissue,” he explained. “At some point, that pocket becomes so deep that it reaches down into the bone in which the tooth is anchored. As that bone is eroded, the teeth loosen and begin to fall out. The goals of therapy are prevention of periodontal disease with meticulous oral hygiene.”

Soft tissue hyperplasia may be exacerbated by medications such as calcium channel blockers, cyclosporine, and phenytoin and phenobarbital, which are sometimes used by patients with Sturge-Weber syndrome, he said.

Dr. Darrow reported having no financial disclosures.

[email protected]

LAKE TAHOE, CALIF. – Several years ago, David H. Darrow, MD, DDS, began to notice a pattern in the conversation threads on websites dedicated to support for parents of children with facial port-wine stains (PWS).

Parents were reporting that dental problems arose earlier on their child’s side of face with the PWS, and that the alveolar ridge was lower on the side of the face that harbored the lesion. “Most importantly, parents were concerned that dentists were not touching their children because they were concerned about bleeding,” Dr. Darrow said at the annual meeting of the Society for Pediatric Dermatology. A search in the medical literature for port-wine stains and oral cavity changes, did not turn up much except for a few articles on bleeding. “One said that port-wine stains or capillary malformations rarely present major problems for the oral and maxillofacial surgeon. The other said that periodontal probing should not be done, as even gentle probing can result in uncontrolled bleeding,” he noted.

This prompted Dr. Darrow, who directs the Center for Hemangiomas and Vascular Birthmarks at the Eastern Virginia Medical School, Norfolk, and coinvestigators, Megan B. Dowling, MD, and Yueqin Zhao, PhD, to characterize manifestations of PWS in the oral cavity via an anonymous paired survey of volunteers with facial PWS and their dentists who were recruited from birthmarks.com and 10 collaborating physician practices (J Am Acad Dermatol 2012;67:687-93). Volunteers ranged in age from 1 to 62 years; mean age was 29 years. A total of 30 patients participated, and most (67%) were female.

The five most common oral manifestations reported by the patients were lip hyperplasia (53%), stained gingiva (47%), malocclusion (30%), bleeding gingiva (27%), and spacing between teeth (23%). Only 3% reported bleeding from dental procedures. When the researchers evaluated the orodental findings in the paired patient-physician responses, “most of the time there was good agreement between the patient and the dentist,” Dr. Darrow said. “The only one that fell out of agreement was lip hyperplasia. That’s probably because most dentists look right past the lips and into the oral cavity.”

When the researchers examined patients who had stained gingiva versus those who did not, they found that early-stage lesions demonstrated a reddish blush of the oral mucosa and gingiva, while late-stage lesions demonstrated increased blush of the oral tissues, as well as hyperplasia of the soft tissue or bone in the affected area. “Based on our review of the literature, bleeding of gums is rarely prolonged and dental procedures are safe,” Dr. Darrow said.

The findings are important, he continued, because capillary malformations of the oral cavity may result in periodontal disease associated with gingival overgrowth. The depth of the gingival pocket should be no more than 2-3 mm. “When you have areas of inflammation and deep-pocket formation, plaque and bacteria slowly erode the connection between the tooth and the soft tissue,” he explained. “At some point, that pocket becomes so deep that it reaches down into the bone in which the tooth is anchored. As that bone is eroded, the teeth loosen and begin to fall out. The goals of therapy are prevention of periodontal disease with meticulous oral hygiene.”

Soft tissue hyperplasia may be exacerbated by medications such as calcium channel blockers, cyclosporine, and phenytoin and phenobarbital, which are sometimes used by patients with Sturge-Weber syndrome, he said.

Dr. Darrow reported having no financial disclosures.

[email protected]

Higher pretreatment drug concentrations close to a resistance breakpoint for susceptibility were associated with greater relapse risk in TB, based on data from 54 patients who relapsed and 63 who were treated and cured.

iLexx/Thinkstock

“We postulated that drug-susceptible Mycobacterium tuberculosis might have a graded spectrum of susceptibilities that could be used to determine the risk of relapse,” wrote Roberto Colangeli, PhD, of Rutgers University, Newark, N.J., and his colleagues.

In a study published in the New England Journal of Medicine, the researchers examined pretreatment bacterial isolates from adults with TB who had experienced relapse and those who were cured. Using these isolates, they identified the minimum inhibitory concentration (MIC) – the lowest concentration of the drug that prevents visible bacterial growth in culture – for isoniazid and rifampin.

Overall, after controlling for other potential relapse risk factors, higher pretreatment MIC values for both isoniazid and rifampin were associated with an increased relapse risk. For isoniazid, the average MIC below the breakpoint was 0.0334 mcg/mL for relapsed patients and 0.0286 mcg/mL for cured patients. For rifampin, the average MIC below the breakpoint was 0.0695 mcg/mL for relapsed patients and 0.0453 mcg/mL for cured patients. The higher values for the relapsed versus cured patients were represented by factors of 1.17 and 1.53 for isoniazid and rifampin, respectively.

The average age of the patients was 41 years; 83% were men, and 35% were non-Hispanic white.

The study findings were limited by several factors, including the small sample size, retrospective design, and inability to test MIC values from primary cultures versus subcultures, the researchers wrote. However, the results suggest an impact of MIC values on treatment outcomes, and “additional studies that are performed in larger, well-defined prospective cohorts and that include MIC testing of pretreatment culture isolates will be useful to better validate these findings,”

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Colangeli reported no financial conflicts. Dr. Alland disclosed funding from Cepheid and several current and pending patents in the United States and Europe, with some royalties paid to Cepheid.

SOURCE: Colangeli R et al. N Engl J Med. 2018;379:823-33.

Higher pretreatment drug concentrations close to a resistance breakpoint for susceptibility were associated with greater relapse risk in TB, based on data from 54 patients who relapsed and 63 who were treated and cured.

iLexx/Thinkstock

“We postulated that drug-susceptible Mycobacterium tuberculosis might have a graded spectrum of susceptibilities that could be used to determine the risk of relapse,” wrote Roberto Colangeli, PhD, of Rutgers University, Newark, N.J., and his colleagues.

In a study published in the New England Journal of Medicine, the researchers examined pretreatment bacterial isolates from adults with TB who had experienced relapse and those who were cured. Using these isolates, they identified the minimum inhibitory concentration (MIC) – the lowest concentration of the drug that prevents visible bacterial growth in culture – for isoniazid and rifampin.

Overall, after controlling for other potential relapse risk factors, higher pretreatment MIC values for both isoniazid and rifampin were associated with an increased relapse risk. For isoniazid, the average MIC below the breakpoint was 0.0334 mcg/mL for relapsed patients and 0.0286 mcg/mL for cured patients. For rifampin, the average MIC below the breakpoint was 0.0695 mcg/mL for relapsed patients and 0.0453 mcg/mL for cured patients. The higher values for the relapsed versus cured patients were represented by factors of 1.17 and 1.53 for isoniazid and rifampin, respectively.

The average age of the patients was 41 years; 83% were men, and 35% were non-Hispanic white.

The study findings were limited by several factors, including the small sample size, retrospective design, and inability to test MIC values from primary cultures versus subcultures, the researchers wrote. However, the results suggest an impact of MIC values on treatment outcomes, and “additional studies that are performed in larger, well-defined prospective cohorts and that include MIC testing of pretreatment culture isolates will be useful to better validate these findings,”

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Colangeli reported no financial conflicts. Dr. Alland disclosed funding from Cepheid and several current and pending patents in the United States and Europe, with some royalties paid to Cepheid.

SOURCE: Colangeli R et al. N Engl J Med. 2018;379:823-33.

Higher pretreatment drug concentrations close to a resistance breakpoint for susceptibility were associated with greater relapse risk in TB, based on data from 54 patients who relapsed and 63 who were treated and cured.

iLexx/Thinkstock

“We postulated that drug-susceptible Mycobacterium tuberculosis might have a graded spectrum of susceptibilities that could be used to determine the risk of relapse,” wrote Roberto Colangeli, PhD, of Rutgers University, Newark, N.J., and his colleagues.

In a study published in the New England Journal of Medicine, the researchers examined pretreatment bacterial isolates from adults with TB who had experienced relapse and those who were cured. Using these isolates, they identified the minimum inhibitory concentration (MIC) – the lowest concentration of the drug that prevents visible bacterial growth in culture – for isoniazid and rifampin.

Overall, after controlling for other potential relapse risk factors, higher pretreatment MIC values for both isoniazid and rifampin were associated with an increased relapse risk. For isoniazid, the average MIC below the breakpoint was 0.0334 mcg/mL for relapsed patients and 0.0286 mcg/mL for cured patients. For rifampin, the average MIC below the breakpoint was 0.0695 mcg/mL for relapsed patients and 0.0453 mcg/mL for cured patients. The higher values for the relapsed versus cured patients were represented by factors of 1.17 and 1.53 for isoniazid and rifampin, respectively.

The average age of the patients was 41 years; 83% were men, and 35% were non-Hispanic white.

The study findings were limited by several factors, including the small sample size, retrospective design, and inability to test MIC values from primary cultures versus subcultures, the researchers wrote. However, the results suggest an impact of MIC values on treatment outcomes, and “additional studies that are performed in larger, well-defined prospective cohorts and that include MIC testing of pretreatment culture isolates will be useful to better validate these findings,”

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Colangeli reported no financial conflicts. Dr. Alland disclosed funding from Cepheid and several current and pending patents in the United States and Europe, with some royalties paid to Cepheid.

SOURCE: Colangeli R et al. N Engl J Med. 2018;379:823-33.

Epilepsy occurred in approximately two-thirds of infants with congenital Zika virus infection in a study of 141 children.

copyright Devonyu/Thinkstock

“When ZIKV [Zika virus] infection is acquired in utero, it may be associated with epilepsy, and we characterized aspects of this complication in a study performed at our referral center,” wrote Hélio van der Linden Jr., MD, of Dr. Henrique Santillo Rehabilitation and Readaptation Center in Goiânia, Brazil, and colleagues in a letter to the editor published in the New England Journal of Medicine.

The researchers reviewed data from 141 infants aged 1-14 months with a median age of 9 months and Zika virus infection confirmed by laboratory analysis; 55% were girls.

The prevalence of epilepsy was 67%, with a mean age at onset of 4.9 months. Based on data provided by parents, 74% of the children experienced seizures at 6 months of age or younger.

Overall, 77% of the infants experienced a single type of seizure. Epileptic spasms, the most common type, occurred in 72% of infants, followed by focal motor seizure (21%) and tonic seizures (4%).

All 95 epileptic infants were treated with antiepileptic medications and 62 (65%) achieved remission. Of those in remission, 24 (39%) received monotherapy and 38 (61%) received polytherapy. The drugs most associated with seizure control were vigabatrin, levetiracetam, valproate, and phenobarbital.

The prevalence of epilepsy in this study was higher than that seen in previous studies, and most patients had early-onset, drug-resistant epilepsy, the researchers noted. However, burst-suppression patterns and hypsarrhythmia on EEG predicted more severe disease and suggest that epilepsy might complicate cases of congenital Zika infection, they said.

The researchers had no financial conflicts to disclose.

SOURCE: van der Linden H et al. N Engl J Med. 2018 Aug 30. doi: 10.1056/NEJMc1716070.

Epilepsy occurred in approximately two-thirds of infants with congenital Zika virus infection in a study of 141 children.

copyright Devonyu/Thinkstock

“When ZIKV [Zika virus] infection is acquired in utero, it may be associated with epilepsy, and we characterized aspects of this complication in a study performed at our referral center,” wrote Hélio van der Linden Jr., MD, of Dr. Henrique Santillo Rehabilitation and Readaptation Center in Goiânia, Brazil, and colleagues in a letter to the editor published in the New England Journal of Medicine.

The researchers reviewed data from 141 infants aged 1-14 months with a median age of 9 months and Zika virus infection confirmed by laboratory analysis; 55% were girls.

The prevalence of epilepsy was 67%, with a mean age at onset of 4.9 months. Based on data provided by parents, 74% of the children experienced seizures at 6 months of age or younger.

Overall, 77% of the infants experienced a single type of seizure. Epileptic spasms, the most common type, occurred in 72% of infants, followed by focal motor seizure (21%) and tonic seizures (4%).

All 95 epileptic infants were treated with antiepileptic medications and 62 (65%) achieved remission. Of those in remission, 24 (39%) received monotherapy and 38 (61%) received polytherapy. The drugs most associated with seizure control were vigabatrin, levetiracetam, valproate, and phenobarbital.

The prevalence of epilepsy in this study was higher than that seen in previous studies, and most patients had early-onset, drug-resistant epilepsy, the researchers noted. However, burst-suppression patterns and hypsarrhythmia on EEG predicted more severe disease and suggest that epilepsy might complicate cases of congenital Zika infection, they said.

The researchers had no financial conflicts to disclose.

SOURCE: van der Linden H et al. N Engl J Med. 2018 Aug 30. doi: 10.1056/NEJMc1716070.

Epilepsy occurred in approximately two-thirds of infants with congenital Zika virus infection in a study of 141 children.

copyright Devonyu/Thinkstock

“When ZIKV [Zika virus] infection is acquired in utero, it may be associated with epilepsy, and we characterized aspects of this complication in a study performed at our referral center,” wrote Hélio van der Linden Jr., MD, of Dr. Henrique Santillo Rehabilitation and Readaptation Center in Goiânia, Brazil, and colleagues in a letter to the editor published in the New England Journal of Medicine.

The researchers reviewed data from 141 infants aged 1-14 months with a median age of 9 months and Zika virus infection confirmed by laboratory analysis; 55% were girls.

The prevalence of epilepsy was 67%, with a mean age at onset of 4.9 months. Based on data provided by parents, 74% of the children experienced seizures at 6 months of age or younger.

Overall, 77% of the infants experienced a single type of seizure. Epileptic spasms, the most common type, occurred in 72% of infants, followed by focal motor seizure (21%) and tonic seizures (4%).

All 95 epileptic infants were treated with antiepileptic medications and 62 (65%) achieved remission. Of those in remission, 24 (39%) received monotherapy and 38 (61%) received polytherapy. The drugs most associated with seizure control were vigabatrin, levetiracetam, valproate, and phenobarbital.

The prevalence of epilepsy in this study was higher than that seen in previous studies, and most patients had early-onset, drug-resistant epilepsy, the researchers noted. However, burst-suppression patterns and hypsarrhythmia on EEG predicted more severe disease and suggest that epilepsy might complicate cases of congenital Zika infection, they said.

The researchers had no financial conflicts to disclose.

SOURCE: van der Linden H et al. N Engl J Med. 2018 Aug 30. doi: 10.1056/NEJMc1716070.

MIAMI—As a treatment for Parkinson’s disease psychosis, pimavanserin is associated with significantly improved outcomes, compared with quetiapine and other therapies, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. “The data suggest that use of pimavanserin is associated with significantly improved treatment outcomes, both within and beyond six months of treatment,” said Conrad Tenenbaum, PhD, Senior Associate at BluePrint Research Group in Princeton, New Jersey, and colleagues.

More than half of patients with Parkinson’s disease develop related psychosis. According to Dr. Tenenbaum and colleagues, most clinicians prescribe quetiapine for Parkinson’s disease psychosis, but clinicians report that pimavanserin is more likely to provide adequate control of symptoms. To probe this discrepancy, Dr. Tenenbaum and colleagues investigated current treatments and outcomes for patients with Parkinson’s disease psychosis to improve disease management.

A Retrospective Chart Review

The researchers collected 1,800 anonymized patient charts from 200 physicians who each managed at least eight pharmacologically treated patients with Parkinson’s disease psychosis during the previous six months. Each physician contributed abbreviated charts for his or her six most recently treated patients. The charts contained information about demographics, symptoms, and treatment. The physicians also provided three detailed charts that included expanded demographic information, full treatment history, and physician-rated control of symptoms. The investigators weighted the data by physician specialty and volume of patients with Parkinson’s disease psychosis.

Of the participating physicians, 101 were neurologists, 46 were movement disorder specialists, 38 were psychiatrists, and 15 were geriatric psychiatrists. The physicians provided 1,200 abbreviated charts and 600 detailed charts.

More Than Half of Patients Received Quetiapine

Approximately 90% of treated patients with Parkinson’s disease psychosis received an antipsychotic agent as first-line therapy. More than 50% of treated patients received quetiapine, 18% received pimavanserin, and 31% received another antipsychotic or other type of treatment (eg, an antidepressant or antidementia agent). Among patients who received quetiapine as a first-line therapy, 68% received a low dose (ie, less than 100 mg/day), and 32% received a high dose (ie, more than 100 mg/day). The discontinuation rate was 15% for quetiapine and 1% for pimavanserin.

The participating physicians reported that the symptoms of Parkinson’s disease psychosis were significantly better controlled among patients treated with 34 mg of pimavanserin, compared with a low dose of quetiapine. About 60% of patients treated with pimavanserin achieved adequate symptom control within six months of treatment, compared with 38% of patients receiving low-dose quetiapine. Patients who received pimavanserin for more than six months achieved significantly better symptom control than patients who received any dose of quetiapine.

“Despite the widespread use of quetiapine as a first-line treatment of Parkinson’s disease psychosis, we find that patients treated with 34 mg of pimavanserin achieve significantly better physician-reported control of … symptoms, especially compared with those who receive low-dose quetiapine,” said Dr. Tenenbaum and colleagues. “Increased use of 34 mg of pimavanserin as a first-line pharmacologic treatment for Parkinson’s disease psychosis is suggested to improve outcomes and overall control of symptoms.”

The group of investigators included Doral Fredericks, PharmD, Vice President of Medical Affairs at Acadia Pharmaceuticals in San Diego. Acadia Pharmaceuticals markets Nuplazid, a formulation of pimavanserin.

—Erik Greb

Suggested Reading

Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson disease. Arch Neurol. 2010;67(8):996-1001.

MIAMI—As a treatment for Parkinson’s disease psychosis, pimavanserin is associated with significantly improved outcomes, compared with quetiapine and other therapies, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. “The data suggest that use of pimavanserin is associated with significantly improved treatment outcomes, both within and beyond six months of treatment,” said Conrad Tenenbaum, PhD, Senior Associate at BluePrint Research Group in Princeton, New Jersey, and colleagues.

More than half of patients with Parkinson’s disease develop related psychosis. According to Dr. Tenenbaum and colleagues, most clinicians prescribe quetiapine for Parkinson’s disease psychosis, but clinicians report that pimavanserin is more likely to provide adequate control of symptoms. To probe this discrepancy, Dr. Tenenbaum and colleagues investigated current treatments and outcomes for patients with Parkinson’s disease psychosis to improve disease management.

A Retrospective Chart Review

The researchers collected 1,800 anonymized patient charts from 200 physicians who each managed at least eight pharmacologically treated patients with Parkinson’s disease psychosis during the previous six months. Each physician contributed abbreviated charts for his or her six most recently treated patients. The charts contained information about demographics, symptoms, and treatment. The physicians also provided three detailed charts that included expanded demographic information, full treatment history, and physician-rated control of symptoms. The investigators weighted the data by physician specialty and volume of patients with Parkinson’s disease psychosis.

Of the participating physicians, 101 were neurologists, 46 were movement disorder specialists, 38 were psychiatrists, and 15 were geriatric psychiatrists. The physicians provided 1,200 abbreviated charts and 600 detailed charts.

More Than Half of Patients Received Quetiapine

Approximately 90% of treated patients with Parkinson’s disease psychosis received an antipsychotic agent as first-line therapy. More than 50% of treated patients received quetiapine, 18% received pimavanserin, and 31% received another antipsychotic or other type of treatment (eg, an antidepressant or antidementia agent). Among patients who received quetiapine as a first-line therapy, 68% received a low dose (ie, less than 100 mg/day), and 32% received a high dose (ie, more than 100 mg/day). The discontinuation rate was 15% for quetiapine and 1% for pimavanserin.

The participating physicians reported that the symptoms of Parkinson’s disease psychosis were significantly better controlled among patients treated with 34 mg of pimavanserin, compared with a low dose of quetiapine. About 60% of patients treated with pimavanserin achieved adequate symptom control within six months of treatment, compared with 38% of patients receiving low-dose quetiapine. Patients who received pimavanserin for more than six months achieved significantly better symptom control than patients who received any dose of quetiapine.

“Despite the widespread use of quetiapine as a first-line treatment of Parkinson’s disease psychosis, we find that patients treated with 34 mg of pimavanserin achieve significantly better physician-reported control of … symptoms, especially compared with those who receive low-dose quetiapine,” said Dr. Tenenbaum and colleagues. “Increased use of 34 mg of pimavanserin as a first-line pharmacologic treatment for Parkinson’s disease psychosis is suggested to improve outcomes and overall control of symptoms.”

The group of investigators included Doral Fredericks, PharmD, Vice President of Medical Affairs at Acadia Pharmaceuticals in San Diego. Acadia Pharmaceuticals markets Nuplazid, a formulation of pimavanserin.

—Erik Greb

Suggested Reading

Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson disease. Arch Neurol. 2010;67(8):996-1001.

MIAMI—As a treatment for Parkinson’s disease psychosis, pimavanserin is associated with significantly improved outcomes, compared with quetiapine and other therapies, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. “The data suggest that use of pimavanserin is associated with significantly improved treatment outcomes, both within and beyond six months of treatment,” said Conrad Tenenbaum, PhD, Senior Associate at BluePrint Research Group in Princeton, New Jersey, and colleagues.

More than half of patients with Parkinson’s disease develop related psychosis. According to Dr. Tenenbaum and colleagues, most clinicians prescribe quetiapine for Parkinson’s disease psychosis, but clinicians report that pimavanserin is more likely to provide adequate control of symptoms. To probe this discrepancy, Dr. Tenenbaum and colleagues investigated current treatments and outcomes for patients with Parkinson’s disease psychosis to improve disease management.

A Retrospective Chart Review

The researchers collected 1,800 anonymized patient charts from 200 physicians who each managed at least eight pharmacologically treated patients with Parkinson’s disease psychosis during the previous six months. Each physician contributed abbreviated charts for his or her six most recently treated patients. The charts contained information about demographics, symptoms, and treatment. The physicians also provided three detailed charts that included expanded demographic information, full treatment history, and physician-rated control of symptoms. The investigators weighted the data by physician specialty and volume of patients with Parkinson’s disease psychosis.

Of the participating physicians, 101 were neurologists, 46 were movement disorder specialists, 38 were psychiatrists, and 15 were geriatric psychiatrists. The physicians provided 1,200 abbreviated charts and 600 detailed charts.

More Than Half of Patients Received Quetiapine

Approximately 90% of treated patients with Parkinson’s disease psychosis received an antipsychotic agent as first-line therapy. More than 50% of treated patients received quetiapine, 18% received pimavanserin, and 31% received another antipsychotic or other type of treatment (eg, an antidepressant or antidementia agent). Among patients who received quetiapine as a first-line therapy, 68% received a low dose (ie, less than 100 mg/day), and 32% received a high dose (ie, more than 100 mg/day). The discontinuation rate was 15% for quetiapine and 1% for pimavanserin.

The participating physicians reported that the symptoms of Parkinson’s disease psychosis were significantly better controlled among patients treated with 34 mg of pimavanserin, compared with a low dose of quetiapine. About 60% of patients treated with pimavanserin achieved adequate symptom control within six months of treatment, compared with 38% of patients receiving low-dose quetiapine. Patients who received pimavanserin for more than six months achieved significantly better symptom control than patients who received any dose of quetiapine.

“Despite the widespread use of quetiapine as a first-line treatment of Parkinson’s disease psychosis, we find that patients treated with 34 mg of pimavanserin achieve significantly better physician-reported control of … symptoms, especially compared with those who receive low-dose quetiapine,” said Dr. Tenenbaum and colleagues. “Increased use of 34 mg of pimavanserin as a first-line pharmacologic treatment for Parkinson’s disease psychosis is suggested to improve outcomes and overall control of symptoms.”

The group of investigators included Doral Fredericks, PharmD, Vice President of Medical Affairs at Acadia Pharmaceuticals in San Diego. Acadia Pharmaceuticals markets Nuplazid, a formulation of pimavanserin.

—Erik Greb

Suggested Reading

Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson disease. Arch Neurol. 2010;67(8):996-1001.

Treatment with nusinersen (Spinraza) produced significant improvements in motor function in children with spinal muscular atrophy type 1 even if treatment was initiated at a later age, new research has suggested.

In a paper published online Aug. 29 in Neurology, researchers presented the results of a prospective cohort study in 33 children who ranged in age from 8.3 months to 9.4 years and had spinal muscular atrophy type 1. In this study, the children were treated with the antisense oligonucleotide nusinersen, which increases production of functional survival motor neuron (SMN) protein. The patients participated in the trial as a part of an Expanded Access Program for nusinersen that’s operated by its manufacturer, Biogen.

FamVeld/Thinkstock

All previous trials of nusinersen have enrolled patients younger than 7 months, wrote Karolina Aragon-Gawinska, MD, of the Institute I-motion at Armand Trousseau Hospital, Paris, and her coauthors. The benefits of the drug in older patients were unknown.

The disease has a median survival of 8-13.5 months of age, yet all patients in the study were alive at 6 months after starting the treatment. Researchers saw a 1.5-point median improvement in motor milestones – measured using the Hammersmith Infant Neurologic Examination (HINE) Part 2 – and five patients were able to sit up without support for more than 30 seconds.

On the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale, which assesses the motor skills of infants with spinal muscular atrophy, there was a median improvement of four points at 6 months.

There were no significant changes in the need for nutritional support. However, eight patients showed worsening respiratory condition at 6 months, compared with baseline. Three patients – all of whom had a more severe form of the disease by virtue of only having two copies of the nearly identical SMN2 gene – showed no significant motor progress and were placed on full-time ventilation.

Overall, the number of copies of SMN2 gene did not appear to affect the need for ventilator or nutritional support.

“The response to treatment was highly variable, but new motor acquisitions were attained even in 8-year-old patients,” the authors wrote. “In some patients, respiratory worsening was observed despite motor improvement, suggesting a slower action of nusinersen on the respiratory symptoms and the possible intercurrent infections that might destabilize these weak patients.”

They noted that while previous studies had included patients with only two copies of the SMN2 gene – and hence more severe disease – around half the patients in this study had three copies, which may explain why even older patients showed significant responses to treatment.

“Patients with three SMN2 copies were older and had a longer disease duration than patients with two SMN2 copies, which may partially explain the absence of copy number effect.”

The study was funded by the Institute of Myology and AFM-Telethon. Eight authors reported involvement with pharmaceutical-sponsored trials, consultancies, or other funding from the pharmaceutical industry, including Biogen. No other conflicts of interest were declared.

SOURCE: Aragon-Gawinska K et al. Neurology. 2018 Aug 29. doi: 10.1212/WNL.0000000000006281.

Treatment with nusinersen (Spinraza) produced significant improvements in motor function in children with spinal muscular atrophy type 1 even if treatment was initiated at a later age, new research has suggested.

In a paper published online Aug. 29 in Neurology, researchers presented the results of a prospective cohort study in 33 children who ranged in age from 8.3 months to 9.4 years and had spinal muscular atrophy type 1. In this study, the children were treated with the antisense oligonucleotide nusinersen, which increases production of functional survival motor neuron (SMN) protein. The patients participated in the trial as a part of an Expanded Access Program for nusinersen that’s operated by its manufacturer, Biogen.

FamVeld/Thinkstock

All previous trials of nusinersen have enrolled patients younger than 7 months, wrote Karolina Aragon-Gawinska, MD, of the Institute I-motion at Armand Trousseau Hospital, Paris, and her coauthors. The benefits of the drug in older patients were unknown.

The disease has a median survival of 8-13.5 months of age, yet all patients in the study were alive at 6 months after starting the treatment. Researchers saw a 1.5-point median improvement in motor milestones – measured using the Hammersmith Infant Neurologic Examination (HINE) Part 2 – and five patients were able to sit up without support for more than 30 seconds.

On the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale, which assesses the motor skills of infants with spinal muscular atrophy, there was a median improvement of four points at 6 months.

There were no significant changes in the need for nutritional support. However, eight patients showed worsening respiratory condition at 6 months, compared with baseline. Three patients – all of whom had a more severe form of the disease by virtue of only having two copies of the nearly identical SMN2 gene – showed no significant motor progress and were placed on full-time ventilation.

Overall, the number of copies of SMN2 gene did not appear to affect the need for ventilator or nutritional support.

“The response to treatment was highly variable, but new motor acquisitions were attained even in 8-year-old patients,” the authors wrote. “In some patients, respiratory worsening was observed despite motor improvement, suggesting a slower action of nusinersen on the respiratory symptoms and the possible intercurrent infections that might destabilize these weak patients.”

They noted that while previous studies had included patients with only two copies of the SMN2 gene – and hence more severe disease – around half the patients in this study had three copies, which may explain why even older patients showed significant responses to treatment.

“Patients with three SMN2 copies were older and had a longer disease duration than patients with two SMN2 copies, which may partially explain the absence of copy number effect.”

The study was funded by the Institute of Myology and AFM-Telethon. Eight authors reported involvement with pharmaceutical-sponsored trials, consultancies, or other funding from the pharmaceutical industry, including Biogen. No other conflicts of interest were declared.

SOURCE: Aragon-Gawinska K et al. Neurology. 2018 Aug 29. doi: 10.1212/WNL.0000000000006281.

Treatment with nusinersen (Spinraza) produced significant improvements in motor function in children with spinal muscular atrophy type 1 even if treatment was initiated at a later age, new research has suggested.

In a paper published online Aug. 29 in Neurology, researchers presented the results of a prospective cohort study in 33 children who ranged in age from 8.3 months to 9.4 years and had spinal muscular atrophy type 1. In this study, the children were treated with the antisense oligonucleotide nusinersen, which increases production of functional survival motor neuron (SMN) protein. The patients participated in the trial as a part of an Expanded Access Program for nusinersen that’s operated by its manufacturer, Biogen.

FamVeld/Thinkstock

All previous trials of nusinersen have enrolled patients younger than 7 months, wrote Karolina Aragon-Gawinska, MD, of the Institute I-motion at Armand Trousseau Hospital, Paris, and her coauthors. The benefits of the drug in older patients were unknown.

The disease has a median survival of 8-13.5 months of age, yet all patients in the study were alive at 6 months after starting the treatment. Researchers saw a 1.5-point median improvement in motor milestones – measured using the Hammersmith Infant Neurologic Examination (HINE) Part 2 – and five patients were able to sit up without support for more than 30 seconds.

On the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale, which assesses the motor skills of infants with spinal muscular atrophy, there was a median improvement of four points at 6 months.

There were no significant changes in the need for nutritional support. However, eight patients showed worsening respiratory condition at 6 months, compared with baseline. Three patients – all of whom had a more severe form of the disease by virtue of only having two copies of the nearly identical SMN2 gene – showed no significant motor progress and were placed on full-time ventilation.

Overall, the number of copies of SMN2 gene did not appear to affect the need for ventilator or nutritional support.

“The response to treatment was highly variable, but new motor acquisitions were attained even in 8-year-old patients,” the authors wrote. “In some patients, respiratory worsening was observed despite motor improvement, suggesting a slower action of nusinersen on the respiratory symptoms and the possible intercurrent infections that might destabilize these weak patients.”

They noted that while previous studies had included patients with only two copies of the SMN2 gene – and hence more severe disease – around half the patients in this study had three copies, which may explain why even older patients showed significant responses to treatment.

“Patients with three SMN2 copies were older and had a longer disease duration than patients with two SMN2 copies, which may partially explain the absence of copy number effect.”

The study was funded by the Institute of Myology and AFM-Telethon. Eight authors reported involvement with pharmaceutical-sponsored trials, consultancies, or other funding from the pharmaceutical industry, including Biogen. No other conflicts of interest were declared.

SOURCE: Aragon-Gawinska K et al. Neurology. 2018 Aug 29. doi: 10.1212/WNL.0000000000006281.

A combination of capmatinib and gefitinib shows promise for patients with EGFR-mutated, MET-dysregulated non–small-cell lung cancer (NSCLC) after EGFR inhibitor failure, investigators said.

Patients with MET-amplified disease had the most robust responses, reported lead author Yi-Long Wu, MD, of the Guangdong Lung Cancer Institute in Guangzhou, China, and his colleagues.

“Patients with EGFR-mutated NSCLC usually relapse within a year, despite high response rates to EGFR-TKIs,” the authors wrote in the Journal of Clinical Oncology. MET amplification is responsible for resistance in 5%-26% of NSCLC cases with EGFR inhibitor resistance.

Capmatinib is a highly specific MET inhibitor that has been effective in preclinical models as a single agent and in combination with first- or third-generation EGFR-TKIs. It also promotes apoptosis and restores erlotinib sensitivity in erlotinib-resistant NSCLC. Gefitinib, like erlotinib, is an EGFR-TKI.

The phase 1b/2 study involved 161 patients with EGFR-mutated, MET-dysregulated (amplified/overexpressed) NSCLC who had disease progression during EGFR-TKI therapy. In the dose escalating, phase 1b portion of the study, 61 patients received capmatinib 100-800 mg daily or 200-600 mg twice daily, plus gefitinib 250 mg daily. During phase 2, 100 patients received capmatinib 400 mg twice daily plus gefitinib 250 mg daily. The primary endpoint was overall response rate (ORR).

Across both phases of the study, approximately one-quarter of the patients responded to the drug combination (ORR = 27%). In patients with a high level of MET amplification (MET gene copy number greater than or equal to 6), responses were more common, with almost half of the patients responding (ORR = 47%).

The treatment regimen was generally well tolerated. The most common adverse events were nausea (28%), peripheral edema (22%), reduced appetite (21%), and rash (20%). Grade 3 or higher adverse events were uncommon; increased lipase and increased amylase occurred most frequently (6% for each).

“The combination of capmatinib with gefitinib has been shown to be both feasible and rational,” the authors concluded, “and the data from this study suggest that the combination of capmatinib with an EGFR-TKI may be a promising treatment option for patients with EGFR-mutated, MET-dysregulated NSCLC and particularly for patients with MET-amplified tumors.”

Novartis funded the study. The authors reported affiliations with Novartis and others.

SOURCE: Wu et al. J Clin Oncol. Aug 29. doi: 10.1200/JCO.2018.77.7326.

A combination of capmatinib and gefitinib shows promise for patients with EGFR-mutated, MET-dysregulated non–small-cell lung cancer (NSCLC) after EGFR inhibitor failure, investigators said.

Patients with MET-amplified disease had the most robust responses, reported lead author Yi-Long Wu, MD, of the Guangdong Lung Cancer Institute in Guangzhou, China, and his colleagues.

“Patients with EGFR-mutated NSCLC usually relapse within a year, despite high response rates to EGFR-TKIs,” the authors wrote in the Journal of Clinical Oncology. MET amplification is responsible for resistance in 5%-26% of NSCLC cases with EGFR inhibitor resistance.

Capmatinib is a highly specific MET inhibitor that has been effective in preclinical models as a single agent and in combination with first- or third-generation EGFR-TKIs. It also promotes apoptosis and restores erlotinib sensitivity in erlotinib-resistant NSCLC. Gefitinib, like erlotinib, is an EGFR-TKI.

The phase 1b/2 study involved 161 patients with EGFR-mutated, MET-dysregulated (amplified/overexpressed) NSCLC who had disease progression during EGFR-TKI therapy. In the dose escalating, phase 1b portion of the study, 61 patients received capmatinib 100-800 mg daily or 200-600 mg twice daily, plus gefitinib 250 mg daily. During phase 2, 100 patients received capmatinib 400 mg twice daily plus gefitinib 250 mg daily. The primary endpoint was overall response rate (ORR).

Across both phases of the study, approximately one-quarter of the patients responded to the drug combination (ORR = 27%). In patients with a high level of MET amplification (MET gene copy number greater than or equal to 6), responses were more common, with almost half of the patients responding (ORR = 47%).

The treatment regimen was generally well tolerated. The most common adverse events were nausea (28%), peripheral edema (22%), reduced appetite (21%), and rash (20%). Grade 3 or higher adverse events were uncommon; increased lipase and increased amylase occurred most frequently (6% for each).

“The combination of capmatinib with gefitinib has been shown to be both feasible and rational,” the authors concluded, “and the data from this study suggest that the combination of capmatinib with an EGFR-TKI may be a promising treatment option for patients with EGFR-mutated, MET-dysregulated NSCLC and particularly for patients with MET-amplified tumors.”

Novartis funded the study. The authors reported affiliations with Novartis and others.

SOURCE: Wu et al. J Clin Oncol. Aug 29. doi: 10.1200/JCO.2018.77.7326.

A combination of capmatinib and gefitinib shows promise for patients with EGFR-mutated, MET-dysregulated non–small-cell lung cancer (NSCLC) after EGFR inhibitor failure, investigators said.

Patients with MET-amplified disease had the most robust responses, reported lead author Yi-Long Wu, MD, of the Guangdong Lung Cancer Institute in Guangzhou, China, and his colleagues.

“Patients with EGFR-mutated NSCLC usually relapse within a year, despite high response rates to EGFR-TKIs,” the authors wrote in the Journal of Clinical Oncology. MET amplification is responsible for resistance in 5%-26% of NSCLC cases with EGFR inhibitor resistance.

Capmatinib is a highly specific MET inhibitor that has been effective in preclinical models as a single agent and in combination with first- or third-generation EGFR-TKIs. It also promotes apoptosis and restores erlotinib sensitivity in erlotinib-resistant NSCLC. Gefitinib, like erlotinib, is an EGFR-TKI.

The phase 1b/2 study involved 161 patients with EGFR-mutated, MET-dysregulated (amplified/overexpressed) NSCLC who had disease progression during EGFR-TKI therapy. In the dose escalating, phase 1b portion of the study, 61 patients received capmatinib 100-800 mg daily or 200-600 mg twice daily, plus gefitinib 250 mg daily. During phase 2, 100 patients received capmatinib 400 mg twice daily plus gefitinib 250 mg daily. The primary endpoint was overall response rate (ORR).

Across both phases of the study, approximately one-quarter of the patients responded to the drug combination (ORR = 27%). In patients with a high level of MET amplification (MET gene copy number greater than or equal to 6), responses were more common, with almost half of the patients responding (ORR = 47%).

The treatment regimen was generally well tolerated. The most common adverse events were nausea (28%), peripheral edema (22%), reduced appetite (21%), and rash (20%). Grade 3 or higher adverse events were uncommon; increased lipase and increased amylase occurred most frequently (6% for each).

“The combination of capmatinib with gefitinib has been shown to be both feasible and rational,” the authors concluded, “and the data from this study suggest that the combination of capmatinib with an EGFR-TKI may be a promising treatment option for patients with EGFR-mutated, MET-dysregulated NSCLC and particularly for patients with MET-amplified tumors.”

Novartis funded the study. The authors reported affiliations with Novartis and others.

SOURCE: Wu et al. J Clin Oncol. Aug 29. doi: 10.1200/JCO.2018.77.7326.

Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which state public health departments use to screen newborns for genetic disorders.

Secretary of the Department of Health and Human Services (HHS) Alex M. Azar II formally added SMA to the panel on July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.

“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis—information that often is required to determine whether their child is eligible to participate in clinical trials.”

Adding SMA to the RUSP does not mean that states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested a wide variation in resources, infrastructure, funding, and time to implementation among states.

Drug Approval Raised Ethical Questions

An estimated one in 11,000 newborns has SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brainstem and spinal cord, thus leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the FDA approved nusinersen for the disorder in December 2016. The drug’s approval has raised ethical questions.^1–3

After reviewing the evidence at its February 8 meeting, the advisory committee recommended adding SMA screening to the RUSP in a March 8 letter from committee chair Joseph A. Bocchini Jr, MD, Professor and Chair of Pediatrics at Louisiana State University Health in Shreveport.

According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”

“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”

Symptom Onset Distinguishes the Types of SMA

Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.

A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.

The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.

Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.

Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”

Long-Term Data on Nusinersen Are Lacking

Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.²

Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.²

Yet evidence to date is favorable in children with early onset SMA. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”

Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify the disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.

“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past age 1 are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of four million births.

At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs of $1 or less per screen.

The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University in Durham, North Carolina. No disclosures were provided for evidence review group members.

—Tara Haelle

References

1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9):534-538.

2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.

3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.

Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which state public health departments use to screen newborns for genetic disorders.

Secretary of the Department of Health and Human Services (HHS) Alex M. Azar II formally added SMA to the panel on July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.

“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis—information that often is required to determine whether their child is eligible to participate in clinical trials.”

Adding SMA to the RUSP does not mean that states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested a wide variation in resources, infrastructure, funding, and time to implementation among states.

Drug Approval Raised Ethical Questions

An estimated one in 11,000 newborns has SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brainstem and spinal cord, thus leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the FDA approved nusinersen for the disorder in December 2016. The drug’s approval has raised ethical questions.^1–3

After reviewing the evidence at its February 8 meeting, the advisory committee recommended adding SMA screening to the RUSP in a March 8 letter from committee chair Joseph A. Bocchini Jr, MD, Professor and Chair of Pediatrics at Louisiana State University Health in Shreveport.

According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”

“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”

Symptom Onset Distinguishes the Types of SMA

Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.

A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.

The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.

Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.

Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”

Long-Term Data on Nusinersen Are Lacking

Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.²

Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.²

Yet evidence to date is favorable in children with early onset SMA. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”

Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify the disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.

“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past age 1 are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of four million births.

At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs of $1 or less per screen.

The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University in Durham, North Carolina. No disclosures were provided for evidence review group members.

—Tara Haelle

References

1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9):534-538.

2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.

3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.

Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which state public health departments use to screen newborns for genetic disorders.

Secretary of the Department of Health and Human Services (HHS) Alex M. Azar II formally added SMA to the panel on July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.

“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis—information that often is required to determine whether their child is eligible to participate in clinical trials.”

Adding SMA to the RUSP does not mean that states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested a wide variation in resources, infrastructure, funding, and time to implementation among states.

Drug Approval Raised Ethical Questions

An estimated one in 11,000 newborns has SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brainstem and spinal cord, thus leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the FDA approved nusinersen for the disorder in December 2016. The drug’s approval has raised ethical questions.^1–3

After reviewing the evidence at its February 8 meeting, the advisory committee recommended adding SMA screening to the RUSP in a March 8 letter from committee chair Joseph A. Bocchini Jr, MD, Professor and Chair of Pediatrics at Louisiana State University Health in Shreveport.

According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”

“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”

Symptom Onset Distinguishes the Types of SMA

Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.

A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.

The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.

Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.

Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”

Long-Term Data on Nusinersen Are Lacking

Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.²

Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.²

Yet evidence to date is favorable in children with early onset SMA. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”

Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify the disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.

“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past age 1 are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of four million births.

At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs of $1 or less per screen.

The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University in Durham, North Carolina. No disclosures were provided for evidence review group members.

—Tara Haelle

References

1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9):534-538.

2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.

3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.