LONDON—The Alzheimer’s Biomarkers in Daily Practice (ABIDE) project may help neurologists to choose diagnostic tests, select proper treatment, and effectively communicate with patients who have suspected Alzheimer’s disease, according to an overview presented at the 2017 Alzheimer’s Association International Conference. Furthermore, biomarkers may enable neurologists to predict individual progression, target underlying proteinopathy, and measure progression.

“Ultimately, biomarkers will help us to prevent Alzheimer’s disease if we start as soon as possible,” said Phillip Scheltens, MD, PhD, Director of the Alzheimer Center at the VU University Medical Center in Amsterdam.

The advent of MRI and the discovery of CSF biomarkers and amyloid PET are among the greatest successes in Alzheimer’s disease research, allowing diagnosis at an earlier stage of the disease, Dr. Scheltens said. Established and promising biomarkers for Alzheimer’s disease include Abeta_1–42, total tau, p-tau₁₈₁, NF-L, neurogranin, and VILIP-1. Further research has characterized probable Alzheimer’s disease in its prodromal stage, defined different phenotypes of Alzheimer’s disease, and offered insights into the rate of decline based on biomarker profiles.

Despite a wealth of literature on Alzheimer’s disease biomarkers, there remains a gap between the scientific value and the actual utilization of biomarkers in daily clinical practice. “Translating research findings to individual patients in daily practice is difficult, as the prognostic value of each biomarker may vary with, for example, age, gender, and cognitive status,” said Dr. Scheltens and colleagues. “Moreover, when combining biomarkers, interpretation becomes complicated, especially when they are not clearly positive, negative, or even conflicting.” Also, little is known about patients’ preferences towards diagnostic testing and the best ways to communicate test results to patients and caregivers.

ABIDE Study and New App

To address these concerns, Dr. Scheltens and colleagues started the ABIDE study, an ongoing four-year project with a goal of determining what biomarkers mean for clinical practice, what patients think about biomarkers, and how to engage patients to determine which biomarkers to use.

In one of the ABIDE substudies, researchers are using retrospective data to develop personalized risk estimates for patients with mild cognitive impairment (MCI). In addition, investigators are using quantitative and qualitative research methods to collect MRI and CSF data from 200 patients from local memory clinics and amyloid PET from 500 patients in tertiary settings. Ultimately, the study will help to create practical tools for clinicians and improve interpretation and communication of results. The investigation also focuses on the impact of disclosing amyloid positivity or negativity with patients. For this study, the researchers used an anxiety–uncertainty questionnaire and found that anxiety level did not change after disclosure of PET results. “Even if the result is not positive, patients felt less uncertain and somewhat assured,” Dr. Scheltens said.

The researchers used what they have learned thus far to develop the Addapt app, a new tool based on statistical and predictive modeling to help clinicians determine the most useful tests and imaging to perform and which biomarkers are most informative for a given patient. “You can look at the results of the individual, and it can help you to decide, for example, if it will be helpful to do a CSF or to do another PET scan,” said Dr. Scheltens.

A Need for New Criteria

The evolution of biomarker research has resulted in new diagnostic criteria and proposed guidelines. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have developed the 2018 NIA-AA Research Framework to Investigate the Alzheimer’s Disease Continuum. By incorporating new scientific insights and technological advances, the new guidelines aim to improve current diagnosis, strengthen autopsy reporting of Alzheimer’s brain changes, and establish a research agenda for future progress in earlier detection and greater diagnostic accuracy.

Three of the new guidelines focus on three stages of Alzheimer’s disease: dementia due to Alzheimer’s disease, MCI due to Alzheimer’s disease, and preclinical (ie, presymptomatic) Alzheimer’s disease. The fourth guideline updates criteria for documenting and reporting Alzheimer’s disease-related changes observed during an autopsy. Unlike previous guidelines, the 2018 criteria will not require clinical symptoms to diagnose Alzheimer’s disease. In addition, the new guidelines state that the presence of both amyloid and tau protein pathology is indicative of Alzheimer’s disease.

New Research and the Future of Biomarkers

Despite all the advances in biomarker research, there is still work to do, said Dr. Scheltens. Analytical issues, clinical validation, clinical utility, ethical issues, and reimbursement still need to be addressed, he added. “We have to educate not only the patients, but more importantly, the physicians, on how to work with biomarkers, how to interpret biomarkers, and when to use them and when not to use them,” said Dr. Scheltens. “Hopefully we will experience patients who survive Alzheimer’s disease if we have the right drugs at the right doses at the right moment.”

—Erica Tricarico

Suggested Reading

de Wilde A, van Maurik IS, Kunneman M, et al. Alzheimer’s biomarkers in daily practice (ABIDE) project: Rationale and design. Alzhiemers Dement (Amst). 2017;6:143-151.

Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol. 2017;16(8):661-676.

Morbelli S, Bauckneht M, Scheltens P. Imaging biomarkers in Alzheimer’s disease: added value in the clinical setting. Q J Nucl Med Mol Imaging. 2017 Jul 17 [Epub ahead of print].

van Maurik IS, Zwan MD, Tijms BM, et al. Interpreting biomarker results in individual MCI patients - the ABIDE project. JAMA Neurol. In press.

LONDON—The Alzheimer’s Biomarkers in Daily Practice (ABIDE) project may help neurologists to choose diagnostic tests, select proper treatment, and effectively communicate with patients who have suspected Alzheimer’s disease, according to an overview presented at the 2017 Alzheimer’s Association International Conference. Furthermore, biomarkers may enable neurologists to predict individual progression, target underlying proteinopathy, and measure progression.

“Ultimately, biomarkers will help us to prevent Alzheimer’s disease if we start as soon as possible,” said Phillip Scheltens, MD, PhD, Director of the Alzheimer Center at the VU University Medical Center in Amsterdam.

The advent of MRI and the discovery of CSF biomarkers and amyloid PET are among the greatest successes in Alzheimer’s disease research, allowing diagnosis at an earlier stage of the disease, Dr. Scheltens said. Established and promising biomarkers for Alzheimer’s disease include Abeta_1–42, total tau, p-tau₁₈₁, NF-L, neurogranin, and VILIP-1. Further research has characterized probable Alzheimer’s disease in its prodromal stage, defined different phenotypes of Alzheimer’s disease, and offered insights into the rate of decline based on biomarker profiles.

Despite a wealth of literature on Alzheimer’s disease biomarkers, there remains a gap between the scientific value and the actual utilization of biomarkers in daily clinical practice. “Translating research findings to individual patients in daily practice is difficult, as the prognostic value of each biomarker may vary with, for example, age, gender, and cognitive status,” said Dr. Scheltens and colleagues. “Moreover, when combining biomarkers, interpretation becomes complicated, especially when they are not clearly positive, negative, or even conflicting.” Also, little is known about patients’ preferences towards diagnostic testing and the best ways to communicate test results to patients and caregivers.

ABIDE Study and New App

To address these concerns, Dr. Scheltens and colleagues started the ABIDE study, an ongoing four-year project with a goal of determining what biomarkers mean for clinical practice, what patients think about biomarkers, and how to engage patients to determine which biomarkers to use.

In one of the ABIDE substudies, researchers are using retrospective data to develop personalized risk estimates for patients with mild cognitive impairment (MCI). In addition, investigators are using quantitative and qualitative research methods to collect MRI and CSF data from 200 patients from local memory clinics and amyloid PET from 500 patients in tertiary settings. Ultimately, the study will help to create practical tools for clinicians and improve interpretation and communication of results. The investigation also focuses on the impact of disclosing amyloid positivity or negativity with patients. For this study, the researchers used an anxiety–uncertainty questionnaire and found that anxiety level did not change after disclosure of PET results. “Even if the result is not positive, patients felt less uncertain and somewhat assured,” Dr. Scheltens said.

The researchers used what they have learned thus far to develop the Addapt app, a new tool based on statistical and predictive modeling to help clinicians determine the most useful tests and imaging to perform and which biomarkers are most informative for a given patient. “You can look at the results of the individual, and it can help you to decide, for example, if it will be helpful to do a CSF or to do another PET scan,” said Dr. Scheltens.

A Need for New Criteria

The evolution of biomarker research has resulted in new diagnostic criteria and proposed guidelines. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have developed the 2018 NIA-AA Research Framework to Investigate the Alzheimer’s Disease Continuum. By incorporating new scientific insights and technological advances, the new guidelines aim to improve current diagnosis, strengthen autopsy reporting of Alzheimer’s brain changes, and establish a research agenda for future progress in earlier detection and greater diagnostic accuracy.

Three of the new guidelines focus on three stages of Alzheimer’s disease: dementia due to Alzheimer’s disease, MCI due to Alzheimer’s disease, and preclinical (ie, presymptomatic) Alzheimer’s disease. The fourth guideline updates criteria for documenting and reporting Alzheimer’s disease-related changes observed during an autopsy. Unlike previous guidelines, the 2018 criteria will not require clinical symptoms to diagnose Alzheimer’s disease. In addition, the new guidelines state that the presence of both amyloid and tau protein pathology is indicative of Alzheimer’s disease.

New Research and the Future of Biomarkers

Despite all the advances in biomarker research, there is still work to do, said Dr. Scheltens. Analytical issues, clinical validation, clinical utility, ethical issues, and reimbursement still need to be addressed, he added. “We have to educate not only the patients, but more importantly, the physicians, on how to work with biomarkers, how to interpret biomarkers, and when to use them and when not to use them,” said Dr. Scheltens. “Hopefully we will experience patients who survive Alzheimer’s disease if we have the right drugs at the right doses at the right moment.”

—Erica Tricarico

Suggested Reading

de Wilde A, van Maurik IS, Kunneman M, et al. Alzheimer’s biomarkers in daily practice (ABIDE) project: Rationale and design. Alzhiemers Dement (Amst). 2017;6:143-151.

Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol. 2017;16(8):661-676.

Morbelli S, Bauckneht M, Scheltens P. Imaging biomarkers in Alzheimer’s disease: added value in the clinical setting. Q J Nucl Med Mol Imaging. 2017 Jul 17 [Epub ahead of print].

van Maurik IS, Zwan MD, Tijms BM, et al. Interpreting biomarker results in individual MCI patients - the ABIDE project. JAMA Neurol. In press.

LONDON—The Alzheimer’s Biomarkers in Daily Practice (ABIDE) project may help neurologists to choose diagnostic tests, select proper treatment, and effectively communicate with patients who have suspected Alzheimer’s disease, according to an overview presented at the 2017 Alzheimer’s Association International Conference. Furthermore, biomarkers may enable neurologists to predict individual progression, target underlying proteinopathy, and measure progression.

“Ultimately, biomarkers will help us to prevent Alzheimer’s disease if we start as soon as possible,” said Phillip Scheltens, MD, PhD, Director of the Alzheimer Center at the VU University Medical Center in Amsterdam.

The advent of MRI and the discovery of CSF biomarkers and amyloid PET are among the greatest successes in Alzheimer’s disease research, allowing diagnosis at an earlier stage of the disease, Dr. Scheltens said. Established and promising biomarkers for Alzheimer’s disease include Abeta_1–42, total tau, p-tau₁₈₁, NF-L, neurogranin, and VILIP-1. Further research has characterized probable Alzheimer’s disease in its prodromal stage, defined different phenotypes of Alzheimer’s disease, and offered insights into the rate of decline based on biomarker profiles.

Despite a wealth of literature on Alzheimer’s disease biomarkers, there remains a gap between the scientific value and the actual utilization of biomarkers in daily clinical practice. “Translating research findings to individual patients in daily practice is difficult, as the prognostic value of each biomarker may vary with, for example, age, gender, and cognitive status,” said Dr. Scheltens and colleagues. “Moreover, when combining biomarkers, interpretation becomes complicated, especially when they are not clearly positive, negative, or even conflicting.” Also, little is known about patients’ preferences towards diagnostic testing and the best ways to communicate test results to patients and caregivers.

ABIDE Study and New App

To address these concerns, Dr. Scheltens and colleagues started the ABIDE study, an ongoing four-year project with a goal of determining what biomarkers mean for clinical practice, what patients think about biomarkers, and how to engage patients to determine which biomarkers to use.

In one of the ABIDE substudies, researchers are using retrospective data to develop personalized risk estimates for patients with mild cognitive impairment (MCI). In addition, investigators are using quantitative and qualitative research methods to collect MRI and CSF data from 200 patients from local memory clinics and amyloid PET from 500 patients in tertiary settings. Ultimately, the study will help to create practical tools for clinicians and improve interpretation and communication of results. The investigation also focuses on the impact of disclosing amyloid positivity or negativity with patients. For this study, the researchers used an anxiety–uncertainty questionnaire and found that anxiety level did not change after disclosure of PET results. “Even if the result is not positive, patients felt less uncertain and somewhat assured,” Dr. Scheltens said.

The researchers used what they have learned thus far to develop the Addapt app, a new tool based on statistical and predictive modeling to help clinicians determine the most useful tests and imaging to perform and which biomarkers are most informative for a given patient. “You can look at the results of the individual, and it can help you to decide, for example, if it will be helpful to do a CSF or to do another PET scan,” said Dr. Scheltens.

A Need for New Criteria

The evolution of biomarker research has resulted in new diagnostic criteria and proposed guidelines. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have developed the 2018 NIA-AA Research Framework to Investigate the Alzheimer’s Disease Continuum. By incorporating new scientific insights and technological advances, the new guidelines aim to improve current diagnosis, strengthen autopsy reporting of Alzheimer’s brain changes, and establish a research agenda for future progress in earlier detection and greater diagnostic accuracy.

Three of the new guidelines focus on three stages of Alzheimer’s disease: dementia due to Alzheimer’s disease, MCI due to Alzheimer’s disease, and preclinical (ie, presymptomatic) Alzheimer’s disease. The fourth guideline updates criteria for documenting and reporting Alzheimer’s disease-related changes observed during an autopsy. Unlike previous guidelines, the 2018 criteria will not require clinical symptoms to diagnose Alzheimer’s disease. In addition, the new guidelines state that the presence of both amyloid and tau protein pathology is indicative of Alzheimer’s disease.

New Research and the Future of Biomarkers

Despite all the advances in biomarker research, there is still work to do, said Dr. Scheltens. Analytical issues, clinical validation, clinical utility, ethical issues, and reimbursement still need to be addressed, he added. “We have to educate not only the patients, but more importantly, the physicians, on how to work with biomarkers, how to interpret biomarkers, and when to use them and when not to use them,” said Dr. Scheltens. “Hopefully we will experience patients who survive Alzheimer’s disease if we have the right drugs at the right doses at the right moment.”

—Erica Tricarico

Suggested Reading

de Wilde A, van Maurik IS, Kunneman M, et al. Alzheimer’s biomarkers in daily practice (ABIDE) project: Rationale and design. Alzhiemers Dement (Amst). 2017;6:143-151.

Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol. 2017;16(8):661-676.

Morbelli S, Bauckneht M, Scheltens P. Imaging biomarkers in Alzheimer’s disease: added value in the clinical setting. Q J Nucl Med Mol Imaging. 2017 Jul 17 [Epub ahead of print].

van Maurik IS, Zwan MD, Tijms BM, et al. Interpreting biomarker results in individual MCI patients - the ABIDE project. JAMA Neurol. In press.

HILTON HEAD, SC—Many new treatments for Parkinson’s disease are in the pipeline, according to a lecture given at the 40th Annual Contemporary Clinical Neurology Symposium. Researchers are examining potential symptomatic therapies and neuroprotective agents.

A “Niche Therapy” Emerges

Rapidly acting abortive agents have emerged as “a niche therapy” for Parkinson’s disease, said Thomas L. Davis, MD, Professor of Neurology at Vanderbilt University in Nashville. The purpose of these drugs is to reduce motor fluctuations and unpredictable off periods that sometimes limit patients’ social activities. The only approved treatment of this kind is an autoinjector that delivers apomorphine subcutaneously. The device allows the patient to adjust the dose and delivers it reliably. Many patients dislike giving themselves injections, however.

Several other rapidly acting abortive agents under investigation may soon become available. A sublingual formulation of apomorphine is currently in phase III trials. These self-dissolving strips avoid the potential inconvenience of self-injection, but one challenge is the possibility that patients may swallow the strips before they dissolve fully. These formulations also do not permit fine control of the dose. The phase III trials are almost complete, and this drug could be available in the near future, said Dr. Davis.

Studies of an inhalable formulation of levodopa also are nearing completion. This formulation has a quicker onset of action than an oral formulation. Delivering a consistent dose over various administrations can be challenging for inhaled formulations, said Dr. Davis. A patient in an off period might have trouble breathing deeply enough to get an adequate dose, he added. The therapy has shown promise, however, and may come to market soon.

In addition, researchers are studying two pumps designed to provide continuous dopaminergic stimulation throughout the day. One device delivers apomorphine through a subcutaneous pump and has been available in Europe for several years. The other pump delivers a solubilized form of levodopa methylester salt subcutaneously. A pump provides continuous administration and allows for control over the dose. The volume of medication that a pump can deliver is limited, however, and pumps sometimes irritate the skin.

Downstream Therapies Heighten Levodopa’s Effects

Levodopa acts on the striatum, but investigators also are studying drugs that act at points further downstream in the CNS. Adenosine A_2A inhibitors are one potential class of downstream therapies. They heighten the downstream effects of levodopa and may increase on time without causing dyskinesia. They also may reduce freezing of gait. Current symptomatic therapies for Parkinson’s disease lower blood pressure and cause somnolence. Adenosine A_2A inhibitors, however, increase blood pressure and act as stimulants.

Caffeine, istradefylline, and tozadenant all inhibit adenosine A_2A receptors. Istradefylline has regulatory approval in Japan for the treatment of motor fluctuations and freezing of gait, but study results in the United States did not convince the FDA that the drug was effective. Tozadenant is currently under investigation in the US.

Anecdotal evidence suggests that marijuana reduces tremor, but “it is not really hard to stop tremor if you do not mind making somebody high,” said Dr. Davis. “The problem is that your balance gets worse and your cognition gets worse.” Data indicate that nabilone, a cannabinoid receptor agonist, might decrease dyskinesia, but trials of other cannabinoid receptor agonists and antagonists have been negative. In short, evidence that marijuana is beneficial in Parkinson’s disease is lacking, said Dr. Davis.

Researchers Seek Neuroprotective Agents

Other research in Parkinson’s disease aims to find neuroprotective therapies that could slow disease progression. One obstacle is the lack of a biomarker of disease progression. In a sampling study, investigators are measuring alpha synuclein in various tissues to determine whether synuclein levels could be a biomarker of disease progression.

Structural MRI based on voxel-based morphometric analysis may emerge as a reliable biomarker, said Dr. Davis. Atrophy of certain brain regions over time may be the most sensitive means of observing disease progression. “The resolution of MRI has increased to the point that with computer calculations, you can detect relatively small changes in volume reliably,” he added. Researchers also are studying SPECT ligands, PET ligands, and ultrasound of the midbrain as potential biomarkers.

Despite the lack of a validated biomarker, the NIH Exploratory Trials in Parkinson Disease (NET-PD) program has screened and tested various potential neuroprotective agents. The program has examined creatine, minocycline, CoQ₁₀, nicotine, and pioglitazone, but all of these drugs failed to slow disease progression.

The NET-PD program recently completed recruitment for a study of inosine. The study follows an epidemiologic observation that patients with a higher level of urate, a natural antioxidant and free-radical scavenger, had slower progression of Parkinson’s disease. Because inosine increases the level of urate, the program is studying the drug in a phase III trial.

Alpha Synuclein Receives Renewed Attention

The past year has witnessed a renewed interest in alpha synuclein, said Dr. Davis. In Parkinson’s disease, the protein forms abnormal polymers and accumulates in Lewy bodies. Removing abnormal or dysfunctional alpha synuclein might reduce symptoms or modify the disease course. One way to effect this removal is to increase autophagy, the body’s mechanism for clearing dysfunctional proteins.

Nilotinib, a tyrosine kinase inhibitor approved for the treatment of Philadelphia-positive chronic myelocytic leukemia, increases autophagy clearance of alpha synuclein in rodent models. In 2016, researchers randomized 12 patients with either Parkinson’s disease dementia or dementia with Lewy bodies to 150 mg/day or 300 mg/day of nilotinib for 24 weeks. The drug appeared to be safe and well tolerated, and the results suggested possible motor and cognitive benefits of treatment. CSF levels of homovanillic acid, the end metabolite of dopamine, were significantly increased at week 24, compared with baseline, suggesting an increase in dopamine production. The trial was open label.

Other research is examining whether active immunization would produce antibodies and help clear misfolded alpha synuclein. Initial trials of this strategy included 28 participants, most of whom developed antibodies. The antibodies were short-lived, and the researchers administered booster shots at one year. The method appeared to be safe, and the vaccine is scheduled to enter phase II trials. One potential problem with active immunization is that it would be delivered mainly to older individuals, whose immune response likely would be less vigorous than that of younger people, said Dr. Davis. In addition, physicians would have little control over the magnitude of the immune response, and an excessive response could cause encephalitis.

An alternative technique is passive immunity, which entails the delivery of humanized monoclonal antibodies against alpha synuclein. Investigators studied this strategy in a phase Ib trial of 80 participants with Parkinson’s disease. The treatment was safe and well tolerated, and levels of free serum alpha synuclein decreased by as much as 97% with vaccination. The challenge with humanized monoclonal antibodies is that less than 1% of the therapy crosses the blood–brain barrier, said Dr. Davis. “The hope is that you can give so much systemically that even that small amount would be therapeutic.” Further trials of this strategy are under way.

Exercise May Improve Outcomes

Researchers continue to find evidence that exercise is helpful in Parkinson’s disease. Exercise induces the production of neurotrophic factors, reduces oxidative stress, decreases neuroinflammation, and improves cerebral blood flow. For these reasons, exercise might provide neuroprotection.

Improvements in activity-monitoring technology have made tracking activity easier and data collection quicker. Also, sample sizes required for exercise studies have decreased.

The National Parkinson’s Foundation is sponsoring the Parkinson’s Outcome Project, a longitudinal registry that collects outcomes data on 9,000 international participants annually. “Early in the course of this [project], it became clear that patients who exercised did better,” said Dr. Davis. Whether exercise caused improved outcomes was uncertain, however. Physicians have begun encouraging the sedentary study participants to exercise, and the rate of decline has slowed for the patients who began exercising.

“We do not have enough information now to give people exercise prescriptions,” said Dr. Davis. “But activity in general is so much better than inactivity that we just tell patients to find something that they like and do it.”

—Erik Greb

Suggested Reading

Alkadhi KA. Exercise as a positive modulator of brain function. Mol Neurobiol. 2017 May 2 [Epub ahead of print].

Pagan F, Hebron M, Valadez EH, et al. Nilotinib effects in Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis. 2016;6(3):503-517.

Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218.

HILTON HEAD, SC—Many new treatments for Parkinson’s disease are in the pipeline, according to a lecture given at the 40th Annual Contemporary Clinical Neurology Symposium. Researchers are examining potential symptomatic therapies and neuroprotective agents.

A “Niche Therapy” Emerges

Rapidly acting abortive agents have emerged as “a niche therapy” for Parkinson’s disease, said Thomas L. Davis, MD, Professor of Neurology at Vanderbilt University in Nashville. The purpose of these drugs is to reduce motor fluctuations and unpredictable off periods that sometimes limit patients’ social activities. The only approved treatment of this kind is an autoinjector that delivers apomorphine subcutaneously. The device allows the patient to adjust the dose and delivers it reliably. Many patients dislike giving themselves injections, however.

Several other rapidly acting abortive agents under investigation may soon become available. A sublingual formulation of apomorphine is currently in phase III trials. These self-dissolving strips avoid the potential inconvenience of self-injection, but one challenge is the possibility that patients may swallow the strips before they dissolve fully. These formulations also do not permit fine control of the dose. The phase III trials are almost complete, and this drug could be available in the near future, said Dr. Davis.

Studies of an inhalable formulation of levodopa also are nearing completion. This formulation has a quicker onset of action than an oral formulation. Delivering a consistent dose over various administrations can be challenging for inhaled formulations, said Dr. Davis. A patient in an off period might have trouble breathing deeply enough to get an adequate dose, he added. The therapy has shown promise, however, and may come to market soon.

In addition, researchers are studying two pumps designed to provide continuous dopaminergic stimulation throughout the day. One device delivers apomorphine through a subcutaneous pump and has been available in Europe for several years. The other pump delivers a solubilized form of levodopa methylester salt subcutaneously. A pump provides continuous administration and allows for control over the dose. The volume of medication that a pump can deliver is limited, however, and pumps sometimes irritate the skin.

Downstream Therapies Heighten Levodopa’s Effects

Levodopa acts on the striatum, but investigators also are studying drugs that act at points further downstream in the CNS. Adenosine A_2A inhibitors are one potential class of downstream therapies. They heighten the downstream effects of levodopa and may increase on time without causing dyskinesia. They also may reduce freezing of gait. Current symptomatic therapies for Parkinson’s disease lower blood pressure and cause somnolence. Adenosine A_2A inhibitors, however, increase blood pressure and act as stimulants.

Caffeine, istradefylline, and tozadenant all inhibit adenosine A_2A receptors. Istradefylline has regulatory approval in Japan for the treatment of motor fluctuations and freezing of gait, but study results in the United States did not convince the FDA that the drug was effective. Tozadenant is currently under investigation in the US.

Anecdotal evidence suggests that marijuana reduces tremor, but “it is not really hard to stop tremor if you do not mind making somebody high,” said Dr. Davis. “The problem is that your balance gets worse and your cognition gets worse.” Data indicate that nabilone, a cannabinoid receptor agonist, might decrease dyskinesia, but trials of other cannabinoid receptor agonists and antagonists have been negative. In short, evidence that marijuana is beneficial in Parkinson’s disease is lacking, said Dr. Davis.

Researchers Seek Neuroprotective Agents

Other research in Parkinson’s disease aims to find neuroprotective therapies that could slow disease progression. One obstacle is the lack of a biomarker of disease progression. In a sampling study, investigators are measuring alpha synuclein in various tissues to determine whether synuclein levels could be a biomarker of disease progression.

Structural MRI based on voxel-based morphometric analysis may emerge as a reliable biomarker, said Dr. Davis. Atrophy of certain brain regions over time may be the most sensitive means of observing disease progression. “The resolution of MRI has increased to the point that with computer calculations, you can detect relatively small changes in volume reliably,” he added. Researchers also are studying SPECT ligands, PET ligands, and ultrasound of the midbrain as potential biomarkers.

Despite the lack of a validated biomarker, the NIH Exploratory Trials in Parkinson Disease (NET-PD) program has screened and tested various potential neuroprotective agents. The program has examined creatine, minocycline, CoQ₁₀, nicotine, and pioglitazone, but all of these drugs failed to slow disease progression.

The NET-PD program recently completed recruitment for a study of inosine. The study follows an epidemiologic observation that patients with a higher level of urate, a natural antioxidant and free-radical scavenger, had slower progression of Parkinson’s disease. Because inosine increases the level of urate, the program is studying the drug in a phase III trial.

Alpha Synuclein Receives Renewed Attention

The past year has witnessed a renewed interest in alpha synuclein, said Dr. Davis. In Parkinson’s disease, the protein forms abnormal polymers and accumulates in Lewy bodies. Removing abnormal or dysfunctional alpha synuclein might reduce symptoms or modify the disease course. One way to effect this removal is to increase autophagy, the body’s mechanism for clearing dysfunctional proteins.

Nilotinib, a tyrosine kinase inhibitor approved for the treatment of Philadelphia-positive chronic myelocytic leukemia, increases autophagy clearance of alpha synuclein in rodent models. In 2016, researchers randomized 12 patients with either Parkinson’s disease dementia or dementia with Lewy bodies to 150 mg/day or 300 mg/day of nilotinib for 24 weeks. The drug appeared to be safe and well tolerated, and the results suggested possible motor and cognitive benefits of treatment. CSF levels of homovanillic acid, the end metabolite of dopamine, were significantly increased at week 24, compared with baseline, suggesting an increase in dopamine production. The trial was open label.

Other research is examining whether active immunization would produce antibodies and help clear misfolded alpha synuclein. Initial trials of this strategy included 28 participants, most of whom developed antibodies. The antibodies were short-lived, and the researchers administered booster shots at one year. The method appeared to be safe, and the vaccine is scheduled to enter phase II trials. One potential problem with active immunization is that it would be delivered mainly to older individuals, whose immune response likely would be less vigorous than that of younger people, said Dr. Davis. In addition, physicians would have little control over the magnitude of the immune response, and an excessive response could cause encephalitis.

An alternative technique is passive immunity, which entails the delivery of humanized monoclonal antibodies against alpha synuclein. Investigators studied this strategy in a phase Ib trial of 80 participants with Parkinson’s disease. The treatment was safe and well tolerated, and levels of free serum alpha synuclein decreased by as much as 97% with vaccination. The challenge with humanized monoclonal antibodies is that less than 1% of the therapy crosses the blood–brain barrier, said Dr. Davis. “The hope is that you can give so much systemically that even that small amount would be therapeutic.” Further trials of this strategy are under way.

Exercise May Improve Outcomes

Researchers continue to find evidence that exercise is helpful in Parkinson’s disease. Exercise induces the production of neurotrophic factors, reduces oxidative stress, decreases neuroinflammation, and improves cerebral blood flow. For these reasons, exercise might provide neuroprotection.

Improvements in activity-monitoring technology have made tracking activity easier and data collection quicker. Also, sample sizes required for exercise studies have decreased.

The National Parkinson’s Foundation is sponsoring the Parkinson’s Outcome Project, a longitudinal registry that collects outcomes data on 9,000 international participants annually. “Early in the course of this [project], it became clear that patients who exercised did better,” said Dr. Davis. Whether exercise caused improved outcomes was uncertain, however. Physicians have begun encouraging the sedentary study participants to exercise, and the rate of decline has slowed for the patients who began exercising.

“We do not have enough information now to give people exercise prescriptions,” said Dr. Davis. “But activity in general is so much better than inactivity that we just tell patients to find something that they like and do it.”

—Erik Greb

Suggested Reading

Alkadhi KA. Exercise as a positive modulator of brain function. Mol Neurobiol. 2017 May 2 [Epub ahead of print].

Pagan F, Hebron M, Valadez EH, et al. Nilotinib effects in Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis. 2016;6(3):503-517.

Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218.

HILTON HEAD, SC—Many new treatments for Parkinson’s disease are in the pipeline, according to a lecture given at the 40th Annual Contemporary Clinical Neurology Symposium. Researchers are examining potential symptomatic therapies and neuroprotective agents.

A “Niche Therapy” Emerges

Rapidly acting abortive agents have emerged as “a niche therapy” for Parkinson’s disease, said Thomas L. Davis, MD, Professor of Neurology at Vanderbilt University in Nashville. The purpose of these drugs is to reduce motor fluctuations and unpredictable off periods that sometimes limit patients’ social activities. The only approved treatment of this kind is an autoinjector that delivers apomorphine subcutaneously. The device allows the patient to adjust the dose and delivers it reliably. Many patients dislike giving themselves injections, however.

Several other rapidly acting abortive agents under investigation may soon become available. A sublingual formulation of apomorphine is currently in phase III trials. These self-dissolving strips avoid the potential inconvenience of self-injection, but one challenge is the possibility that patients may swallow the strips before they dissolve fully. These formulations also do not permit fine control of the dose. The phase III trials are almost complete, and this drug could be available in the near future, said Dr. Davis.

Studies of an inhalable formulation of levodopa also are nearing completion. This formulation has a quicker onset of action than an oral formulation. Delivering a consistent dose over various administrations can be challenging for inhaled formulations, said Dr. Davis. A patient in an off period might have trouble breathing deeply enough to get an adequate dose, he added. The therapy has shown promise, however, and may come to market soon.

In addition, researchers are studying two pumps designed to provide continuous dopaminergic stimulation throughout the day. One device delivers apomorphine through a subcutaneous pump and has been available in Europe for several years. The other pump delivers a solubilized form of levodopa methylester salt subcutaneously. A pump provides continuous administration and allows for control over the dose. The volume of medication that a pump can deliver is limited, however, and pumps sometimes irritate the skin.

Downstream Therapies Heighten Levodopa’s Effects

Levodopa acts on the striatum, but investigators also are studying drugs that act at points further downstream in the CNS. Adenosine A_2A inhibitors are one potential class of downstream therapies. They heighten the downstream effects of levodopa and may increase on time without causing dyskinesia. They also may reduce freezing of gait. Current symptomatic therapies for Parkinson’s disease lower blood pressure and cause somnolence. Adenosine A_2A inhibitors, however, increase blood pressure and act as stimulants.

Caffeine, istradefylline, and tozadenant all inhibit adenosine A_2A receptors. Istradefylline has regulatory approval in Japan for the treatment of motor fluctuations and freezing of gait, but study results in the United States did not convince the FDA that the drug was effective. Tozadenant is currently under investigation in the US.

Anecdotal evidence suggests that marijuana reduces tremor, but “it is not really hard to stop tremor if you do not mind making somebody high,” said Dr. Davis. “The problem is that your balance gets worse and your cognition gets worse.” Data indicate that nabilone, a cannabinoid receptor agonist, might decrease dyskinesia, but trials of other cannabinoid receptor agonists and antagonists have been negative. In short, evidence that marijuana is beneficial in Parkinson’s disease is lacking, said Dr. Davis.

Researchers Seek Neuroprotective Agents

Other research in Parkinson’s disease aims to find neuroprotective therapies that could slow disease progression. One obstacle is the lack of a biomarker of disease progression. In a sampling study, investigators are measuring alpha synuclein in various tissues to determine whether synuclein levels could be a biomarker of disease progression.

Structural MRI based on voxel-based morphometric analysis may emerge as a reliable biomarker, said Dr. Davis. Atrophy of certain brain regions over time may be the most sensitive means of observing disease progression. “The resolution of MRI has increased to the point that with computer calculations, you can detect relatively small changes in volume reliably,” he added. Researchers also are studying SPECT ligands, PET ligands, and ultrasound of the midbrain as potential biomarkers.

Despite the lack of a validated biomarker, the NIH Exploratory Trials in Parkinson Disease (NET-PD) program has screened and tested various potential neuroprotective agents. The program has examined creatine, minocycline, CoQ₁₀, nicotine, and pioglitazone, but all of these drugs failed to slow disease progression.

The NET-PD program recently completed recruitment for a study of inosine. The study follows an epidemiologic observation that patients with a higher level of urate, a natural antioxidant and free-radical scavenger, had slower progression of Parkinson’s disease. Because inosine increases the level of urate, the program is studying the drug in a phase III trial.

Alpha Synuclein Receives Renewed Attention

The past year has witnessed a renewed interest in alpha synuclein, said Dr. Davis. In Parkinson’s disease, the protein forms abnormal polymers and accumulates in Lewy bodies. Removing abnormal or dysfunctional alpha synuclein might reduce symptoms or modify the disease course. One way to effect this removal is to increase autophagy, the body’s mechanism for clearing dysfunctional proteins.

Nilotinib, a tyrosine kinase inhibitor approved for the treatment of Philadelphia-positive chronic myelocytic leukemia, increases autophagy clearance of alpha synuclein in rodent models. In 2016, researchers randomized 12 patients with either Parkinson’s disease dementia or dementia with Lewy bodies to 150 mg/day or 300 mg/day of nilotinib for 24 weeks. The drug appeared to be safe and well tolerated, and the results suggested possible motor and cognitive benefits of treatment. CSF levels of homovanillic acid, the end metabolite of dopamine, were significantly increased at week 24, compared with baseline, suggesting an increase in dopamine production. The trial was open label.

Other research is examining whether active immunization would produce antibodies and help clear misfolded alpha synuclein. Initial trials of this strategy included 28 participants, most of whom developed antibodies. The antibodies were short-lived, and the researchers administered booster shots at one year. The method appeared to be safe, and the vaccine is scheduled to enter phase II trials. One potential problem with active immunization is that it would be delivered mainly to older individuals, whose immune response likely would be less vigorous than that of younger people, said Dr. Davis. In addition, physicians would have little control over the magnitude of the immune response, and an excessive response could cause encephalitis.

An alternative technique is passive immunity, which entails the delivery of humanized monoclonal antibodies against alpha synuclein. Investigators studied this strategy in a phase Ib trial of 80 participants with Parkinson’s disease. The treatment was safe and well tolerated, and levels of free serum alpha synuclein decreased by as much as 97% with vaccination. The challenge with humanized monoclonal antibodies is that less than 1% of the therapy crosses the blood–brain barrier, said Dr. Davis. “The hope is that you can give so much systemically that even that small amount would be therapeutic.” Further trials of this strategy are under way.

Exercise May Improve Outcomes

Researchers continue to find evidence that exercise is helpful in Parkinson’s disease. Exercise induces the production of neurotrophic factors, reduces oxidative stress, decreases neuroinflammation, and improves cerebral blood flow. For these reasons, exercise might provide neuroprotection.

Improvements in activity-monitoring technology have made tracking activity easier and data collection quicker. Also, sample sizes required for exercise studies have decreased.

The National Parkinson’s Foundation is sponsoring the Parkinson’s Outcome Project, a longitudinal registry that collects outcomes data on 9,000 international participants annually. “Early in the course of this [project], it became clear that patients who exercised did better,” said Dr. Davis. Whether exercise caused improved outcomes was uncertain, however. Physicians have begun encouraging the sedentary study participants to exercise, and the rate of decline has slowed for the patients who began exercising.

“We do not have enough information now to give people exercise prescriptions,” said Dr. Davis. “But activity in general is so much better than inactivity that we just tell patients to find something that they like and do it.”

—Erik Greb

Suggested Reading

Alkadhi KA. Exercise as a positive modulator of brain function. Mol Neurobiol. 2017 May 2 [Epub ahead of print].

Pagan F, Hebron M, Valadez EH, et al. Nilotinib effects in Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis. 2016;6(3):503-517.

Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218.

The Affordable Care Act – Obamacare – is not a disaster. It is not a long-term solution, but it is fixable. Now that repeal and/or replace efforts have failed, Congress should intelligently debate which solutions make the most sense and move forward with legislation to fix the health care system.

Before that can happen, Democrats and Republicans need to make certain acknowledgments.

Democrats should acknowledge that the ACA is flawed. Whereas many experts believe a single-payer system is ultimately going to be the best long-term answer, for our country, we’re just not there yet.

1. Incentivize or persuade more states to expand Medicaid.

2. Create a public option or “public fallback plan” in every state that would compete alongside private plans in the marketplaces.

3. Possibly implement a Cadillac tax on high-cost private plans as recommended by economists.

4. Provide vigorous outreach to the millions of uninsured Americans who are eligible for but not enrolled in Medicaid or the Children’s Health Insurance Program.

5. Invest generously in parent-centered, equitable, high-quality early interventions such as Individuals with Disabilities and Education Act (IDEA) Part C, early childhood special education such as IDEA Part B, and early learning/preschool for young children. High-quality birth-to-5 programs yield $13 for every $1 invested and substantially lower health risks down the road of life.

6. Consider implementing a nationwide sugar tax. Evidence exists that taxing sugary drinks could improve the overall health of the U.S. population which could help to reduce the federal deficit over time.

7. Implement a six-point plan (as originally recommended by Sen. Bernie Sanders [I-Vt.]) to lower prescription drug prices. “Americans pay, by far, the highest prices for prescription drugs in the entire world,” Sen. Sanders notes on his website. He calls for negotiating better deals with drug manufacturers, reimporting prescriptions from Canada, restoring discounts for low-income seniors, prohibiting deals that block generic medications from entering the market, enacting stronger penalties for fraud, and requiring pricing and cost transparency.

8. Expand the role of nurses to filter out which patients need to be seen urgently, and which patients do not need an expensive trip to doctor’s office, urgent care, or emergency department. With appropriate training, nurses can manage behavior change and medication adjustment for chronic conditions; can lead care management teams for patients who are high utilizers of care; and manage transitions of care between the medical home, specialist outpatient, and hospital settings, according to primary care and nursing faculty leaders at the University of California, San Francisco.

9. Bring better accountability to health care by using bundled payments, global payments, and accountable care organizations, while simultaneously improving access and care coordination efforts for people with chronic conditions like mental health disorders and substance abuse, as recommended by the Commonwealth Fund.

10. Expand palliative care programs so far fewer people needlessly suffer and then die in very expensive intensive care units.

11. Enact common-sense tort reform. The overuse of tests and procedures because of fear of malpractice litigation, known as defensive medicine, is indirectly estimated to cost the United States $46 billion annually. According to a 2014 JAMA article, 28% of orders and 13% of costs were judged to be at least partially defensive, and 2.9% of total costs were completely defensive. Most costs were from potentially unnecessary hospitalizations. Survey studies show that greater than 90% of doctors practice defensive medicine, but what separates this perception from careful practice or patient expectations/demands remains controversial.

The main point is this – the Affordable Care Act is indeed fixable. We should not “let Obamacare implode, then deal” as the President tweeted. Whether politicians and other Americans can overcome their hyperpartisan beliefs and expectations remains to be seen.

Kevin P. Marks, MD, is a pediatrician in Eugene, Ore., and a clinical assistant professor at the Oregon Health and Science University, Portland.

The Affordable Care Act – Obamacare – is not a disaster. It is not a long-term solution, but it is fixable. Now that repeal and/or replace efforts have failed, Congress should intelligently debate which solutions make the most sense and move forward with legislation to fix the health care system.

Before that can happen, Democrats and Republicans need to make certain acknowledgments.

Democrats should acknowledge that the ACA is flawed. Whereas many experts believe a single-payer system is ultimately going to be the best long-term answer, for our country, we’re just not there yet.

1. Incentivize or persuade more states to expand Medicaid.

2. Create a public option or “public fallback plan” in every state that would compete alongside private plans in the marketplaces.

3. Possibly implement a Cadillac tax on high-cost private plans as recommended by economists.

4. Provide vigorous outreach to the millions of uninsured Americans who are eligible for but not enrolled in Medicaid or the Children’s Health Insurance Program.

5. Invest generously in parent-centered, equitable, high-quality early interventions such as Individuals with Disabilities and Education Act (IDEA) Part C, early childhood special education such as IDEA Part B, and early learning/preschool for young children. High-quality birth-to-5 programs yield $13 for every $1 invested and substantially lower health risks down the road of life.

6. Consider implementing a nationwide sugar tax. Evidence exists that taxing sugary drinks could improve the overall health of the U.S. population which could help to reduce the federal deficit over time.

7. Implement a six-point plan (as originally recommended by Sen. Bernie Sanders [I-Vt.]) to lower prescription drug prices. “Americans pay, by far, the highest prices for prescription drugs in the entire world,” Sen. Sanders notes on his website. He calls for negotiating better deals with drug manufacturers, reimporting prescriptions from Canada, restoring discounts for low-income seniors, prohibiting deals that block generic medications from entering the market, enacting stronger penalties for fraud, and requiring pricing and cost transparency.

8. Expand the role of nurses to filter out which patients need to be seen urgently, and which patients do not need an expensive trip to doctor’s office, urgent care, or emergency department. With appropriate training, nurses can manage behavior change and medication adjustment for chronic conditions; can lead care management teams for patients who are high utilizers of care; and manage transitions of care between the medical home, specialist outpatient, and hospital settings, according to primary care and nursing faculty leaders at the University of California, San Francisco.

9. Bring better accountability to health care by using bundled payments, global payments, and accountable care organizations, while simultaneously improving access and care coordination efforts for people with chronic conditions like mental health disorders and substance abuse, as recommended by the Commonwealth Fund.

10. Expand palliative care programs so far fewer people needlessly suffer and then die in very expensive intensive care units.

11. Enact common-sense tort reform. The overuse of tests and procedures because of fear of malpractice litigation, known as defensive medicine, is indirectly estimated to cost the United States $46 billion annually. According to a 2014 JAMA article, 28% of orders and 13% of costs were judged to be at least partially defensive, and 2.9% of total costs were completely defensive. Most costs were from potentially unnecessary hospitalizations. Survey studies show that greater than 90% of doctors practice defensive medicine, but what separates this perception from careful practice or patient expectations/demands remains controversial.

The main point is this – the Affordable Care Act is indeed fixable. We should not “let Obamacare implode, then deal” as the President tweeted. Whether politicians and other Americans can overcome their hyperpartisan beliefs and expectations remains to be seen.

Kevin P. Marks, MD, is a pediatrician in Eugene, Ore., and a clinical assistant professor at the Oregon Health and Science University, Portland.

The Affordable Care Act – Obamacare – is not a disaster. It is not a long-term solution, but it is fixable. Now that repeal and/or replace efforts have failed, Congress should intelligently debate which solutions make the most sense and move forward with legislation to fix the health care system.

Before that can happen, Democrats and Republicans need to make certain acknowledgments.

Democrats should acknowledge that the ACA is flawed. Whereas many experts believe a single-payer system is ultimately going to be the best long-term answer, for our country, we’re just not there yet.

1. Incentivize or persuade more states to expand Medicaid.

2. Create a public option or “public fallback plan” in every state that would compete alongside private plans in the marketplaces.

3. Possibly implement a Cadillac tax on high-cost private plans as recommended by economists.

4. Provide vigorous outreach to the millions of uninsured Americans who are eligible for but not enrolled in Medicaid or the Children’s Health Insurance Program.

5. Invest generously in parent-centered, equitable, high-quality early interventions such as Individuals with Disabilities and Education Act (IDEA) Part C, early childhood special education such as IDEA Part B, and early learning/preschool for young children. High-quality birth-to-5 programs yield $13 for every $1 invested and substantially lower health risks down the road of life.

6. Consider implementing a nationwide sugar tax. Evidence exists that taxing sugary drinks could improve the overall health of the U.S. population which could help to reduce the federal deficit over time.

7. Implement a six-point plan (as originally recommended by Sen. Bernie Sanders [I-Vt.]) to lower prescription drug prices. “Americans pay, by far, the highest prices for prescription drugs in the entire world,” Sen. Sanders notes on his website. He calls for negotiating better deals with drug manufacturers, reimporting prescriptions from Canada, restoring discounts for low-income seniors, prohibiting deals that block generic medications from entering the market, enacting stronger penalties for fraud, and requiring pricing and cost transparency.

8. Expand the role of nurses to filter out which patients need to be seen urgently, and which patients do not need an expensive trip to doctor’s office, urgent care, or emergency department. With appropriate training, nurses can manage behavior change and medication adjustment for chronic conditions; can lead care management teams for patients who are high utilizers of care; and manage transitions of care between the medical home, specialist outpatient, and hospital settings, according to primary care and nursing faculty leaders at the University of California, San Francisco.

9. Bring better accountability to health care by using bundled payments, global payments, and accountable care organizations, while simultaneously improving access and care coordination efforts for people with chronic conditions like mental health disorders and substance abuse, as recommended by the Commonwealth Fund.

10. Expand palliative care programs so far fewer people needlessly suffer and then die in very expensive intensive care units.

11. Enact common-sense tort reform. The overuse of tests and procedures because of fear of malpractice litigation, known as defensive medicine, is indirectly estimated to cost the United States $46 billion annually. According to a 2014 JAMA article, 28% of orders and 13% of costs were judged to be at least partially defensive, and 2.9% of total costs were completely defensive. Most costs were from potentially unnecessary hospitalizations. Survey studies show that greater than 90% of doctors practice defensive medicine, but what separates this perception from careful practice or patient expectations/demands remains controversial.

The main point is this – the Affordable Care Act is indeed fixable. We should not “let Obamacare implode, then deal” as the President tweeted. Whether politicians and other Americans can overcome their hyperpartisan beliefs and expectations remains to be seen.

Kevin P. Marks, MD, is a pediatrician in Eugene, Ore., and a clinical assistant professor at the Oregon Health and Science University, Portland.

In 2012, the IHS National Prescription Drug Workgroup began focusing its attention on the ongoing threat posed by the opioid epidemic. The Workgroup was tasked with promoting appropriate and effective pain management, reducing prescription pain medication misuse and overdose deaths, focusing efforts on pregnant women with opioid use disorder, and improving access to culturally appropriate treatment.

From that platform, IHS established the multidisciplinary IHS National Committee on Heroin, Opioid, and Pain Efforts (HOPE Committee) in March. The committee will address 6 elements: establishing policies, training health care providers, ensuring effective pain management, increasing access to naloxone, expanding medication-assisted treatment, and reducing the inappropriate use of methadone. Among other things, that has meant updating the Indian Health Manual chapter on chronic non-cancer pain to align with the CDC Guideline for Prescribing Opioids for Chronic Pain.

The IHS also also instituted a mandatory no-cost training course, “IHS Essential Training on Pain and Addiction,” and to date has trained 96% of providers required to attend, including many tribal and urban Indian providers.

Since December 2015, when IHS signed a memorandum of agreement with the Bureau of Indian Affairs to increase access to naloxone, 284 BIA law enforcement officers have been trained and provided with emergency naloxone kits.

IHS is also “actively working” to reduce the use of methadone for pain management, which is associated with a high number of overdose deaths, compared with other opioid pain relievers. IHS policy states that methadone should not be used as a first-line pain management therapy. In an ongoing partnership with the University of New Mexico Pain Center, IHS also offers IHS, tribal, and urban Indian providers weekly real-time consultation with pain-management experts and additional web-based educational services. To help providers provide effective and optimal pain management, IHS maintains 2 websites: on Pain Management (https://www.ihs.gov/painmanagement) and Opioid Use Disorder management (https://www.ihs.gov/odm).

In 2012, the IHS National Prescription Drug Workgroup began focusing its attention on the ongoing threat posed by the opioid epidemic. The Workgroup was tasked with promoting appropriate and effective pain management, reducing prescription pain medication misuse and overdose deaths, focusing efforts on pregnant women with opioid use disorder, and improving access to culturally appropriate treatment.

From that platform, IHS established the multidisciplinary IHS National Committee on Heroin, Opioid, and Pain Efforts (HOPE Committee) in March. The committee will address 6 elements: establishing policies, training health care providers, ensuring effective pain management, increasing access to naloxone, expanding medication-assisted treatment, and reducing the inappropriate use of methadone. Among other things, that has meant updating the Indian Health Manual chapter on chronic non-cancer pain to align with the CDC Guideline for Prescribing Opioids for Chronic Pain.

The IHS also also instituted a mandatory no-cost training course, “IHS Essential Training on Pain and Addiction,” and to date has trained 96% of providers required to attend, including many tribal and urban Indian providers.

Since December 2015, when IHS signed a memorandum of agreement with the Bureau of Indian Affairs to increase access to naloxone, 284 BIA law enforcement officers have been trained and provided with emergency naloxone kits.

IHS is also “actively working” to reduce the use of methadone for pain management, which is associated with a high number of overdose deaths, compared with other opioid pain relievers. IHS policy states that methadone should not be used as a first-line pain management therapy. In an ongoing partnership with the University of New Mexico Pain Center, IHS also offers IHS, tribal, and urban Indian providers weekly real-time consultation with pain-management experts and additional web-based educational services. To help providers provide effective and optimal pain management, IHS maintains 2 websites: on Pain Management (https://www.ihs.gov/painmanagement) and Opioid Use Disorder management (https://www.ihs.gov/odm).

In 2012, the IHS National Prescription Drug Workgroup began focusing its attention on the ongoing threat posed by the opioid epidemic. The Workgroup was tasked with promoting appropriate and effective pain management, reducing prescription pain medication misuse and overdose deaths, focusing efforts on pregnant women with opioid use disorder, and improving access to culturally appropriate treatment.

From that platform, IHS established the multidisciplinary IHS National Committee on Heroin, Opioid, and Pain Efforts (HOPE Committee) in March. The committee will address 6 elements: establishing policies, training health care providers, ensuring effective pain management, increasing access to naloxone, expanding medication-assisted treatment, and reducing the inappropriate use of methadone. Among other things, that has meant updating the Indian Health Manual chapter on chronic non-cancer pain to align with the CDC Guideline for Prescribing Opioids for Chronic Pain.

The IHS also also instituted a mandatory no-cost training course, “IHS Essential Training on Pain and Addiction,” and to date has trained 96% of providers required to attend, including many tribal and urban Indian providers.

Since December 2015, when IHS signed a memorandum of agreement with the Bureau of Indian Affairs to increase access to naloxone, 284 BIA law enforcement officers have been trained and provided with emergency naloxone kits.

IHS is also “actively working” to reduce the use of methadone for pain management, which is associated with a high number of overdose deaths, compared with other opioid pain relievers. IHS policy states that methadone should not be used as a first-line pain management therapy. In an ongoing partnership with the University of New Mexico Pain Center, IHS also offers IHS, tribal, and urban Indian providers weekly real-time consultation with pain-management experts and additional web-based educational services. To help providers provide effective and optimal pain management, IHS maintains 2 websites: on Pain Management (https://www.ihs.gov/painmanagement) and Opioid Use Disorder management (https://www.ihs.gov/odm).

A historic trial to test safety and efficacy of an experimental HIV vaccine is under way at 15 sites in South Africa, where more than 1,000 people become infected with HIV every day, says the NIH.

The Phase2b/3 study, HVTN 702, is the first HIV vaccine efficacy study in 8 years. The regimen involves a new version of the only HIV vaccine candidate ever shown to provide some protection against the virus. That vaccine, tested in the 2009 RV144 clinical trial in Thailand, led by the U.S. military HIV Research program and the Thai Ministry of Health, delivered “landmark results.”

RV144 found for the first time that a vaccine could prevent HIV infection, “albeit modestly.” The vaccine was 31.2% effective at preventing infection over the nearly 4-year follow-up. HVTN 702, researchers hope, will provide more sustained protection; the components of the RV144 regimen have been modified to try to increase the magnitude and duration of immune responses. Recently, interim results were reported for HVTN 100, the predecessor clinical trial, which found the new vaccine regimen was safe for the 252 study participants and induced immune responses comparable with those in RV144.

Researchers aim to enroll 5,400 men and women in HVTN 702, which will make it the largest and most advanced HIV vaccine clinical trial to take place in South Africa. “If an HIV vaccine were found to work in South Africa, it could dramatically alter the course of the pandemic,” said HVTN 702 Protocol Chair Glenda Gray, MBBCH, FC Paed (SA).

“[A] safe and effective vaccine could be the final nail in the coffin for HIV,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, a cofunder of the study. Results from HVTN 702 are expected in 2020.

Source:
First new HIV vaccine efficacy study in seven years has begun [news release]. National Institute of Allergy and Infectious Disease; November 27, 2016.  https://www.niaid.nih.gov/news-events/first-new-hiv-vaccine-efficacy-study-seven-years-has-begun. Accessed August 23, 2017.

A historic trial to test safety and efficacy of an experimental HIV vaccine is under way at 15 sites in South Africa, where more than 1,000 people become infected with HIV every day, says the NIH.

The Phase2b/3 study, HVTN 702, is the first HIV vaccine efficacy study in 8 years. The regimen involves a new version of the only HIV vaccine candidate ever shown to provide some protection against the virus. That vaccine, tested in the 2009 RV144 clinical trial in Thailand, led by the U.S. military HIV Research program and the Thai Ministry of Health, delivered “landmark results.”

RV144 found for the first time that a vaccine could prevent HIV infection, “albeit modestly.” The vaccine was 31.2% effective at preventing infection over the nearly 4-year follow-up. HVTN 702, researchers hope, will provide more sustained protection; the components of the RV144 regimen have been modified to try to increase the magnitude and duration of immune responses. Recently, interim results were reported for HVTN 100, the predecessor clinical trial, which found the new vaccine regimen was safe for the 252 study participants and induced immune responses comparable with those in RV144.

Researchers aim to enroll 5,400 men and women in HVTN 702, which will make it the largest and most advanced HIV vaccine clinical trial to take place in South Africa. “If an HIV vaccine were found to work in South Africa, it could dramatically alter the course of the pandemic,” said HVTN 702 Protocol Chair Glenda Gray, MBBCH, FC Paed (SA).

“[A] safe and effective vaccine could be the final nail in the coffin for HIV,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, a cofunder of the study. Results from HVTN 702 are expected in 2020.

Source:
First new HIV vaccine efficacy study in seven years has begun [news release]. National Institute of Allergy and Infectious Disease; November 27, 2016.  https://www.niaid.nih.gov/news-events/first-new-hiv-vaccine-efficacy-study-seven-years-has-begun. Accessed August 23, 2017.

A historic trial to test safety and efficacy of an experimental HIV vaccine is under way at 15 sites in South Africa, where more than 1,000 people become infected with HIV every day, says the NIH.

The Phase2b/3 study, HVTN 702, is the first HIV vaccine efficacy study in 8 years. The regimen involves a new version of the only HIV vaccine candidate ever shown to provide some protection against the virus. That vaccine, tested in the 2009 RV144 clinical trial in Thailand, led by the U.S. military HIV Research program and the Thai Ministry of Health, delivered “landmark results.”

RV144 found for the first time that a vaccine could prevent HIV infection, “albeit modestly.” The vaccine was 31.2% effective at preventing infection over the nearly 4-year follow-up. HVTN 702, researchers hope, will provide more sustained protection; the components of the RV144 regimen have been modified to try to increase the magnitude and duration of immune responses. Recently, interim results were reported for HVTN 100, the predecessor clinical trial, which found the new vaccine regimen was safe for the 252 study participants and induced immune responses comparable with those in RV144.

Researchers aim to enroll 5,400 men and women in HVTN 702, which will make it the largest and most advanced HIV vaccine clinical trial to take place in South Africa. “If an HIV vaccine were found to work in South Africa, it could dramatically alter the course of the pandemic,” said HVTN 702 Protocol Chair Glenda Gray, MBBCH, FC Paed (SA).

“[A] safe and effective vaccine could be the final nail in the coffin for HIV,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, a cofunder of the study. Results from HVTN 702 are expected in 2020.

Source:
First new HIV vaccine efficacy study in seven years has begun [news release]. National Institute of Allergy and Infectious Disease; November 27, 2016.  https://www.niaid.nih.gov/news-events/first-new-hiv-vaccine-efficacy-study-seven-years-has-begun. Accessed August 23, 2017.

and Drug Administration

The risk of death from breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is less than 1 in a million, according to a study published in Aesthetic Surgery Journal.

Researchers analyzed data on breast implants and estimated the risk of death from BIA-ALCL to be 0.4 micromorts for a woman with bilateral, textured implants.

One micromort means a person’s risk of dying is 1 in a million. For context, a person who drives a car for 1 hour per day is said to have a micromort of 2, which is 5 times the BIA-ALCL micromort.

The researchers noted that there are no documented cases of BIA-ALCL in patients who have only received smooth-surface breast implants. Therefore, the risk of death from BIA-ALCL in a woman with smooth breast implants is “essentially 0.”

“We conducted this micromort study to bring real-life perspective for all existing and potential breast augmentation patients who might have reservations about implants based on the recent media coverage indicating that breast implants can be fatal—a sensationalized take on a very rare and very treatable condition,” said study author William P. Adams, Jr, MD, a professor in the Department of Plastic Surgery at the University of Texas Southwestern in Dallas.

“This analysis resonates with patients. They get it when you explain to a patient that their micromort risk from skiing for 1 day is 2 times higher than the micromort risk of having a textured breast implant for their lifetime—or that traveling 8 hours by car carries a 40-times higher micromort risk than having 2 textured breast implants for their lifetime.”

Dr Adams and his co-author analyzed data from the International Society of Aesthetic Plastic Surgery, the American Society of Plastic Surgeons, the American Society for Aesthetic Plastic Surgery, and the Austrian Breast Implant Register, as well as studies by Allergan and Sientra.

This led to a “conservative estimate” that approximately 30 million patients have textured breast implants worldwide (not including breast reconstructions).

This figure and the report of 12 deaths from BIA-ALCL worldwide suggest the risk of death from BIA-ALCL is 0.4 micromorts per patient (with 2 textured implants) or 0.2 micromorts per textured implant.

“The findings of this study are very important for patient education,” said study author David A. Sieber, MD, a plastic surgeon in private practice in San Francisco, California.

“The clear lymphoproliferative nature of BIA-ALCL, along with the calculated risks associated with its diagnosis, should be used for discussion during new consultations or at the time of presentation for evaluation of delayed-onset seromas.”

and Drug Administration

The risk of death from breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is less than 1 in a million, according to a study published in Aesthetic Surgery Journal.

Researchers analyzed data on breast implants and estimated the risk of death from BIA-ALCL to be 0.4 micromorts for a woman with bilateral, textured implants.

One micromort means a person’s risk of dying is 1 in a million. For context, a person who drives a car for 1 hour per day is said to have a micromort of 2, which is 5 times the BIA-ALCL micromort.

The researchers noted that there are no documented cases of BIA-ALCL in patients who have only received smooth-surface breast implants. Therefore, the risk of death from BIA-ALCL in a woman with smooth breast implants is “essentially 0.”

“We conducted this micromort study to bring real-life perspective for all existing and potential breast augmentation patients who might have reservations about implants based on the recent media coverage indicating that breast implants can be fatal—a sensationalized take on a very rare and very treatable condition,” said study author William P. Adams, Jr, MD, a professor in the Department of Plastic Surgery at the University of Texas Southwestern in Dallas.

“This analysis resonates with patients. They get it when you explain to a patient that their micromort risk from skiing for 1 day is 2 times higher than the micromort risk of having a textured breast implant for their lifetime—or that traveling 8 hours by car carries a 40-times higher micromort risk than having 2 textured breast implants for their lifetime.”

Dr Adams and his co-author analyzed data from the International Society of Aesthetic Plastic Surgery, the American Society of Plastic Surgeons, the American Society for Aesthetic Plastic Surgery, and the Austrian Breast Implant Register, as well as studies by Allergan and Sientra.

This led to a “conservative estimate” that approximately 30 million patients have textured breast implants worldwide (not including breast reconstructions).

This figure and the report of 12 deaths from BIA-ALCL worldwide suggest the risk of death from BIA-ALCL is 0.4 micromorts per patient (with 2 textured implants) or 0.2 micromorts per textured implant.

“The findings of this study are very important for patient education,” said study author David A. Sieber, MD, a plastic surgeon in private practice in San Francisco, California.

“The clear lymphoproliferative nature of BIA-ALCL, along with the calculated risks associated with its diagnosis, should be used for discussion during new consultations or at the time of presentation for evaluation of delayed-onset seromas.”

and Drug Administration

The risk of death from breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is less than 1 in a million, according to a study published in Aesthetic Surgery Journal.

Researchers analyzed data on breast implants and estimated the risk of death from BIA-ALCL to be 0.4 micromorts for a woman with bilateral, textured implants.

One micromort means a person’s risk of dying is 1 in a million. For context, a person who drives a car for 1 hour per day is said to have a micromort of 2, which is 5 times the BIA-ALCL micromort.

The researchers noted that there are no documented cases of BIA-ALCL in patients who have only received smooth-surface breast implants. Therefore, the risk of death from BIA-ALCL in a woman with smooth breast implants is “essentially 0.”

“We conducted this micromort study to bring real-life perspective for all existing and potential breast augmentation patients who might have reservations about implants based on the recent media coverage indicating that breast implants can be fatal—a sensationalized take on a very rare and very treatable condition,” said study author William P. Adams, Jr, MD, a professor in the Department of Plastic Surgery at the University of Texas Southwestern in Dallas.

“This analysis resonates with patients. They get it when you explain to a patient that their micromort risk from skiing for 1 day is 2 times higher than the micromort risk of having a textured breast implant for their lifetime—or that traveling 8 hours by car carries a 40-times higher micromort risk than having 2 textured breast implants for their lifetime.”

Dr Adams and his co-author analyzed data from the International Society of Aesthetic Plastic Surgery, the American Society of Plastic Surgeons, the American Society for Aesthetic Plastic Surgery, and the Austrian Breast Implant Register, as well as studies by Allergan and Sientra.

This led to a “conservative estimate” that approximately 30 million patients have textured breast implants worldwide (not including breast reconstructions).

This figure and the report of 12 deaths from BIA-ALCL worldwide suggest the risk of death from BIA-ALCL is 0.4 micromorts per patient (with 2 textured implants) or 0.2 micromorts per textured implant.

“The findings of this study are very important for patient education,” said study author David A. Sieber, MD, a plastic surgeon in private practice in San Francisco, California.

“The clear lymphoproliferative nature of BIA-ALCL, along with the calculated risks associated with its diagnosis, should be used for discussion during new consultations or at the time of presentation for evaluation of delayed-onset seromas.”

Image by Andre E.X. Brown

Researchers have gained “important mechanistic insights” into how von Willebrand factor (VWF) controls bleeding, according to an article published in Nature Communications.

Fluorescence imaging and microfluidic tools allowed the researchers to capture images of individual VWF molecules on camera while manipulating the molecules with life-like mechanical forces emulating natural blood flow.

This revealed that VWF undergoes a 2-step, shape-shifting transformation to activate blood clotting.

This transformation is triggered when VWF senses certain changes in blood flow that are indicative of injury.

“Under normal circumstances, VWF molecules are compact and globular in shape,” said study author Hongxia Fu, PhD, of Boston Children’s Hospital in Massachusetts.

“But we found that, when blood flow rate increases, VWF rapidly elongates, stretching out more and more in response to higher shear stress.”

However, elongating is not sufficient to activate blood clotting. It’s only when the tensile forces generated in the elongated VWF hit critical levels that the shape-shifter’s transformation becomes complete.

The tensile forces activate “sticky” sites along VWF, allowing it to adhere to circulating platelets.

Normally, the rush of blood needed to reach these critically high tensile forces can only occur at sites of injury inside blood vessels. This specificity enables VWF to sense blood loss and activate rapidly and locally, without activating elsewhere in the body.

“This experiment really represents a new platform for seeing and measuring what’s happening in the blood on a molecular level,” said study author Wesley P. Wong, PhD, of Boston Children’s Hospital.

“Through the use of novel microfluidic technologies that allow us to mimic the body’s vasculature in combination with single-molecule imaging techniques, we are finally able to capture striking images that uncover the mystery of nature’s forces at work in our bodies.”

Yan Jiang, PhD, of Boston Children’s Hospital, said the new findings could inspire smart drugs that are designed to treat obstructive clotting, like deep vein thrombosis, at only diseased areas of the body.

“When you’re putting a generic drug into the circulatory system, it’s taking effect everywhere, even in places that can cause detriment,” Dr Jiang said. “But what if we could design a smart drug that can mimic the 2-step shape-shifting of VWF and only takes effect in areas where clotting is likely to occur?”

Image by Andre E.X. Brown

Researchers have gained “important mechanistic insights” into how von Willebrand factor (VWF) controls bleeding, according to an article published in Nature Communications.

Fluorescence imaging and microfluidic tools allowed the researchers to capture images of individual VWF molecules on camera while manipulating the molecules with life-like mechanical forces emulating natural blood flow.

This revealed that VWF undergoes a 2-step, shape-shifting transformation to activate blood clotting.

This transformation is triggered when VWF senses certain changes in blood flow that are indicative of injury.

“Under normal circumstances, VWF molecules are compact and globular in shape,” said study author Hongxia Fu, PhD, of Boston Children’s Hospital in Massachusetts.

“But we found that, when blood flow rate increases, VWF rapidly elongates, stretching out more and more in response to higher shear stress.”

However, elongating is not sufficient to activate blood clotting. It’s only when the tensile forces generated in the elongated VWF hit critical levels that the shape-shifter’s transformation becomes complete.

The tensile forces activate “sticky” sites along VWF, allowing it to adhere to circulating platelets.

Normally, the rush of blood needed to reach these critically high tensile forces can only occur at sites of injury inside blood vessels. This specificity enables VWF to sense blood loss and activate rapidly and locally, without activating elsewhere in the body.

“This experiment really represents a new platform for seeing and measuring what’s happening in the blood on a molecular level,” said study author Wesley P. Wong, PhD, of Boston Children’s Hospital.

“Through the use of novel microfluidic technologies that allow us to mimic the body’s vasculature in combination with single-molecule imaging techniques, we are finally able to capture striking images that uncover the mystery of nature’s forces at work in our bodies.”

Yan Jiang, PhD, of Boston Children’s Hospital, said the new findings could inspire smart drugs that are designed to treat obstructive clotting, like deep vein thrombosis, at only diseased areas of the body.

“When you’re putting a generic drug into the circulatory system, it’s taking effect everywhere, even in places that can cause detriment,” Dr Jiang said. “But what if we could design a smart drug that can mimic the 2-step shape-shifting of VWF and only takes effect in areas where clotting is likely to occur?”

Image by Andre E.X. Brown

Researchers have gained “important mechanistic insights” into how von Willebrand factor (VWF) controls bleeding, according to an article published in Nature Communications.

Fluorescence imaging and microfluidic tools allowed the researchers to capture images of individual VWF molecules on camera while manipulating the molecules with life-like mechanical forces emulating natural blood flow.

This revealed that VWF undergoes a 2-step, shape-shifting transformation to activate blood clotting.

This transformation is triggered when VWF senses certain changes in blood flow that are indicative of injury.

“Under normal circumstances, VWF molecules are compact and globular in shape,” said study author Hongxia Fu, PhD, of Boston Children’s Hospital in Massachusetts.

“But we found that, when blood flow rate increases, VWF rapidly elongates, stretching out more and more in response to higher shear stress.”

However, elongating is not sufficient to activate blood clotting. It’s only when the tensile forces generated in the elongated VWF hit critical levels that the shape-shifter’s transformation becomes complete.

The tensile forces activate “sticky” sites along VWF, allowing it to adhere to circulating platelets.

Normally, the rush of blood needed to reach these critically high tensile forces can only occur at sites of injury inside blood vessels. This specificity enables VWF to sense blood loss and activate rapidly and locally, without activating elsewhere in the body.

“This experiment really represents a new platform for seeing and measuring what’s happening in the blood on a molecular level,” said study author Wesley P. Wong, PhD, of Boston Children’s Hospital.

“Through the use of novel microfluidic technologies that allow us to mimic the body’s vasculature in combination with single-molecule imaging techniques, we are finally able to capture striking images that uncover the mystery of nature’s forces at work in our bodies.”

Yan Jiang, PhD, of Boston Children’s Hospital, said the new findings could inspire smart drugs that are designed to treat obstructive clotting, like deep vein thrombosis, at only diseased areas of the body.

“When you’re putting a generic drug into the circulatory system, it’s taking effect everywhere, even in places that can cause detriment,” Dr Jiang said. “But what if we could design a smart drug that can mimic the 2-step shape-shifting of VWF and only takes effect in areas where clotting is likely to occur?”

Antihemophilic factor

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for emicizumab.

The BLA is for emicizumab as once-weekly prophylaxis for adults, adolescents, and children with hemophilia A and factor VIII inhibitors.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the BLA for emicizumab by February 23, 2018.

About emicizumab

Emicizumab (formerly ACE910) is an investigational, bispecific monoclonal antibody designed to bring together factors IXa and X, proteins required to activate the natural coagulation cascade and restore the blood clotting process.

The drug is administered by subcutaneous injection of a ready-to-use solution. It was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche, and Genentech.

The BLA for emicizumab is based on results from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July. Interim results from HAVEN 2 were presented at ISTH as well.

HAVEN 1

HAVEN 1 is a randomized, phase 3 study in which researchers evaluated the efficacy, safety, and pharmacokinetics of emicizumab prophylaxis compared to on-demand bypassing agents (BPAs; no prophylaxis) in adults and adolescents (12 years of age and older) with hemophilia A and inhibitors to factor VIII.

The study included 109 patients who were previously treated with BPAs on-demand or as prophylaxis.

There was a significant reduction in treated bleeds of 87% (risk rate=0.13, P<0.0001) with emicizumab compared with no prophylaxis.

Adverse events occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of the BPA activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

HAVEN 2

HAVEN 2 is a single-arm, phase 3 study in which researchers are evaluating the efficacy, safety, and pharmacokinetics of once-weekly emicizumab in children (younger than 12 years of age) with hemophilia A and inhibitors to factor VIII who require treatment with BPAs.

The interim analysis included 19 children. After a median observation time of 12 weeks, 1 of the 19 children had a treated bleed. There were no reported joint or muscle bleeds.

The most common adverse events were mild injection site reactions and nasopharyngitis. No TEs or TMA events were observed.

Antihemophilic factor

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for emicizumab.

The BLA is for emicizumab as once-weekly prophylaxis for adults, adolescents, and children with hemophilia A and factor VIII inhibitors.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the BLA for emicizumab by February 23, 2018.

About emicizumab

Emicizumab (formerly ACE910) is an investigational, bispecific monoclonal antibody designed to bring together factors IXa and X, proteins required to activate the natural coagulation cascade and restore the blood clotting process.

The drug is administered by subcutaneous injection of a ready-to-use solution. It was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche, and Genentech.

The BLA for emicizumab is based on results from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July. Interim results from HAVEN 2 were presented at ISTH as well.

HAVEN 1

HAVEN 1 is a randomized, phase 3 study in which researchers evaluated the efficacy, safety, and pharmacokinetics of emicizumab prophylaxis compared to on-demand bypassing agents (BPAs; no prophylaxis) in adults and adolescents (12 years of age and older) with hemophilia A and inhibitors to factor VIII.

The study included 109 patients who were previously treated with BPAs on-demand or as prophylaxis.

There was a significant reduction in treated bleeds of 87% (risk rate=0.13, P<0.0001) with emicizumab compared with no prophylaxis.

Adverse events occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of the BPA activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

HAVEN 2

HAVEN 2 is a single-arm, phase 3 study in which researchers are evaluating the efficacy, safety, and pharmacokinetics of once-weekly emicizumab in children (younger than 12 years of age) with hemophilia A and inhibitors to factor VIII who require treatment with BPAs.

The interim analysis included 19 children. After a median observation time of 12 weeks, 1 of the 19 children had a treated bleed. There were no reported joint or muscle bleeds.

The most common adverse events were mild injection site reactions and nasopharyngitis. No TEs or TMA events were observed.

Antihemophilic factor

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for emicizumab.

The BLA is for emicizumab as once-weekly prophylaxis for adults, adolescents, and children with hemophilia A and factor VIII inhibitors.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the BLA for emicizumab by February 23, 2018.

About emicizumab

Emicizumab (formerly ACE910) is an investigational, bispecific monoclonal antibody designed to bring together factors IXa and X, proteins required to activate the natural coagulation cascade and restore the blood clotting process.

The drug is administered by subcutaneous injection of a ready-to-use solution. It was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche, and Genentech.

The BLA for emicizumab is based on results from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July. Interim results from HAVEN 2 were presented at ISTH as well.

HAVEN 1

HAVEN 1 is a randomized, phase 3 study in which researchers evaluated the efficacy, safety, and pharmacokinetics of emicizumab prophylaxis compared to on-demand bypassing agents (BPAs; no prophylaxis) in adults and adolescents (12 years of age and older) with hemophilia A and inhibitors to factor VIII.

The study included 109 patients who were previously treated with BPAs on-demand or as prophylaxis.

There was a significant reduction in treated bleeds of 87% (risk rate=0.13, P<0.0001) with emicizumab compared with no prophylaxis.

Adverse events occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of the BPA activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

HAVEN 2

HAVEN 2 is a single-arm, phase 3 study in which researchers are evaluating the efficacy, safety, and pharmacokinetics of once-weekly emicizumab in children (younger than 12 years of age) with hemophilia A and inhibitors to factor VIII who require treatment with BPAs.

The interim analysis included 19 children. After a median observation time of 12 weeks, 1 of the 19 children had a treated bleed. There were no reported joint or muscle bleeds.

The most common adverse events were mild injection site reactions and nasopharyngitis. No TEs or TMA events were observed.

Clinical Question: What is the frequency of short-term corticosteroid prescriptions and adverse events associated with their use?

Background: Long-term corticosteroid use is usually avoided given risks of complications. Less is known about the risk and frequency of short-term corticosteroid use.

Study Design: Retrospective cohort study and self-controlled case series.

Setting: National U.S. dataset of private insurance claims.

Dr. Gray is assistant professor in the University of Kentucky division of hospital medicine and the Lexington VA Medical Center.

Clinical Question: What is the frequency of short-term corticosteroid prescriptions and adverse events associated with their use?

Background: Long-term corticosteroid use is usually avoided given risks of complications. Less is known about the risk and frequency of short-term corticosteroid use.

Study Design: Retrospective cohort study and self-controlled case series.

Setting: National U.S. dataset of private insurance claims.

Dr. Gray is assistant professor in the University of Kentucky division of hospital medicine and the Lexington VA Medical Center.

Clinical Question: What is the frequency of short-term corticosteroid prescriptions and adverse events associated with their use?

Background: Long-term corticosteroid use is usually avoided given risks of complications. Less is known about the risk and frequency of short-term corticosteroid use.

Study Design: Retrospective cohort study and self-controlled case series.

Setting: National U.S. dataset of private insurance claims.

Dr. Gray is assistant professor in the University of Kentucky division of hospital medicine and the Lexington VA Medical Center.

NASHVILLE, TENN. – Axillary thermometry outperformed both rectal and temporal artery thermometry in 205 newborns aged 12-72 hours in a study performed at the University of North Carolina at Chapel Hill.

The infants had two temperatures taken by each method over a period of 15 minutes, for a total of six readings per child and 1,230 measurements overall. Axillary thermometry proved both accurate and reliable. Rectal thermometry was accurate but less reliable, and temporal thermometry was reliable but less accurate.

M. Alexander Otto/Frontline Medical News

[email protected]

NASHVILLE, TENN. – Axillary thermometry outperformed both rectal and temporal artery thermometry in 205 newborns aged 12-72 hours in a study performed at the University of North Carolina at Chapel Hill.

The infants had two temperatures taken by each method over a period of 15 minutes, for a total of six readings per child and 1,230 measurements overall. Axillary thermometry proved both accurate and reliable. Rectal thermometry was accurate but less reliable, and temporal thermometry was reliable but less accurate.

M. Alexander Otto/Frontline Medical News

[email protected]

NASHVILLE, TENN. – Axillary thermometry outperformed both rectal and temporal artery thermometry in 205 newborns aged 12-72 hours in a study performed at the University of North Carolina at Chapel Hill.

The infants had two temperatures taken by each method over a period of 15 minutes, for a total of six readings per child and 1,230 measurements overall. Axillary thermometry proved both accurate and reliable. Rectal thermometry was accurate but less reliable, and temporal thermometry was reliable but less accurate.

M. Alexander Otto/Frontline Medical News

[email protected]