Research Blog for the month of November
FDA Committee Votes Do Not Support Aducanumab as Effective Treatment
An advisory arm of the U.S. Food and Drug Administration (FDA) is recommending that available clinical data on Aducanumab (BIIB037) does not support the effectiveness of this investigational therapy in treating Alzheimer’s disease.
In votes, eight of the committee’s 11 members found Phase 3 EMERGE data did not provide “strong evidence” of efficacy, and seven members did not agree that aducanumab’s initial PRIME study, a Phase 1b trial, showed evidence supporting effectiveness (the other four members cast “uncertain” votes), according to a press release.
Aducanumab is an antibody designed to clear toxic clumps of beta-amyloid protein, which are thought to damage the brain in people with Alzheimer’s.
Biogen sponsored two Phase 3 clinical trials testing Aducanumab in people with early Alzheimer’s disease: ENGAGE (NCT02477800) and EMERGE (NCT02484547). Both trials were terminated last year after an independent monitoring committee analyzing 18-month data determined that aducanumab was not likely to produce meaningful benefits for patients.
However, an analysis that included an additional three months of data that became available after the trials stopped showed that EMERGE met its primary endpoint (or main efficacy measure): relative to a placebo, aducanumab resulted in improvements in cognition and function, including memory, orientation, and language, as well as activities of daily living.
Based on these findings, Biogen and Eisai submitted a request for approval to the FDA in July, and filed a similar request with the European Medicines Agency that is now under EMA review.
FDA Advisory Committees provide non-binding recommendations to the regulatory agency for consideration. FDA officials will now continue to review the biologics license application for aducanumab, with a final decision expected by March 7, 2021. The FDA, in arriving at its final decision on aducanumab and its possible commercial use, is expected to consider the committee’s votes but is not bound to agree with them.
EMA Agrees to Review Biogen, Eisai Request for Aducanumab’s Approval
The European Medicines Agency (EMA) has agreed to review Biogen and Eisai’s application requesting the approval of Aducanumab (BIIB037) for the treatment of Alzheimer’s disease.
The companies’ approval request will be analyzed by the EMA following the usual review timetable for new medications, which can take up to 210 days. If approved, the investigational treatment will become the first therapy for Alzheimer’s that has the potential to lower patients’ clinical decline and alter the course of the disease.
Developed by Biogen in collaboration with Eisai, Aducanumab is a man-made antibody that is designed to bind to the toxic clumps of beta-amyloid protein that are thought to be the underlying cause of neurodegeneration in Alzheimer’s.
Earlier this year, the companies submitted a similar request for approval — in the form of a biologics license application — to the U.S. Food and Drug Administration (FDA). The agency is reviewing Aducanumab’s application under priority review, and has set an action date of March 7, 2021, to come to a final decision on whether to approve the therapy to treat Alzheimer’s patients.
However, a Nov. 6 meeting cast a future FDA approval in doubt as an advisory committee suggested that current data from trials are not sufficient to prove aducanumab’s effectiveness. Advisory committees provide recommendations for the FDA to consider in reviewing potential therapies, and the agency will continue to review aducanumab ahead of the March 7 deadline.
“There are no treatments available that impact the progression of Alzheimer’s disease by addressing the underlying disease pathology. The potential that aducanumab may hold to effectively reduce the clinical decline brings new hope to people and families living with this devastating disease,” said Haruo Naito, CEO of Eisai.
FDA Clears Neuraly to Begin Phase 2 Trial of NLY01 in Alzheimer’s Patients
The U.S. Food and Drug Administration has given clearance for a Phase 2B clinical trial to evaluate the safety, tolerability, and efficacy of Neuraly as investigational therapy NLY01 in people with Alzheimer’s disease.
The randomized, double-blinded, placebo-controlled trial is expected to enroll more than 500 people with mild cognitive impairment due to Alzheimer’s disease at more than 100 sites in the U.S., Canada, and Europe. Results from the trial are expected by the end of 2023.
NLY01, which was initially developed by researchers at Johns Hopkins University, works by activating a protein called glucagon-like peptide-1 receptor. This protein is highly expressed on microglia — a type of immune cell in the brain that plays a central role in controlling brain inflammation.
Neuroinflammation is thought to be involved in the progression of numerous neurological diseases, including Alzheimer’s, Parkinson’s disease, and amyotrophic lateral sclerosis. Preclinical research has suggested that NLY01 can lessen this inflammation, which may ease symptoms in turn.
Neuraly previously funded a first-in-human Phase 1 clinical trial (NCT03672604) in which NLY01 was given via under-the-skin (subcutaneous) injections to healthy volunteers. The treatment was found to be well-tolerated in the study.
Neuraly is also currently conducting a Phase 2 clinical trial of the investigational medication in people with early untreated Parkinson’s disease. The trial (NCT04154072) aims to enroll about 240 patients, age 30–80, in the U.S. and Canada. Enrollment is currently ongoing at multiple sites in the U.S.; more information is available here.
Co-occurance of apathy and impulse control disorders in Parkinson disease
Objective To empirically test whether apathy and impulse control disorders (ICDs) represent independent, opposite ends of a motivational spectrum.
In this single-center, cross-sectional study, the researchers obtained retrospective demographics and clinical data for 887 patients with idiopathic Parkinson disease (PD) seen at a tertiary care center. Mood and motivation disturbances were classified using recommended cutoff scores from self-reported measures of apathy, Impulse Control Disorder (ICD), anxiety, and depression.
Results Prevalence rates included 29.0% of patients with PD with depression, 40.7% with anxiety, 41.3% with apathy, 27.6% with ICDs, and 17.0% with both apathy and ICD. The majority (61.6%) of people reporting clinically significant ICDs also reported clinically significant apathy, and more than a third of patients with apathy (41.3%) also reported elevated ICD. Anxiety and depression were highest in patients with both apathy and ≥1 ICDs. Dopamine agonist use was higher in people with only ICD compared to people with only apathy. Mood significantly interacted with demographic variables to predict motivational disturbances.
Conclusions Motivational disturbances are common comorbid conditions in patients with PD. In addition, these complex behavioral syndromes interact with mood in clinically important ways that may influence the design of future clinical trials and the development of novel therapies. This study challenges the concept of apathy and ICD in PD as opposite ends of a spectrum.
Genetic risk scores and hallucinations in patients with Parkinson disease
Objective To examine the hypothesized overlap of genetic architecture for Alzheimer disease (AD), schizophrenia (SZ), and Parkinson disease (PD) through the use of polygenic risk scores (PRSs) with the occurrence of hallucinations in PD.
The researchers used 2 population-based studies (ParkWest, Norway, and Parkinson's Environment and Gene, USA) providing them with 399 patients with PD with European ancestry and a PD diagnosis after age 55 years to assess the associations between 4 PRSs and hallucinations after 5 years of mean disease duration. Based on the existing genome-wide association study of other large consortia, 4 PRSs were created: one each using AD, SZ, and PD cohorts and another PRS for height, which served as a negative control.
Results A higher prevalence of hallucinations was observed with each SD increase of the AD-PRS. This effect was mainly driven by APOE. In addition, a suggestive decrease and increase, respectively, in hallucination prevalence were observed with the SZ-PRS and the PD-PRS.
Conclusions These results suggest that mechanisms for hallucinations in PD may in part be driven by the same genetic architecture that leads to cognitive decline in AD, especially by APOE.
It's a Triple Threat: Loneliness, Parkinson's and COVID-19
Loneliness, Parkinson's disease (PD) and COVID-19 have all been described as pandemics, each deleterious effects on health and quality of life. For some patients with PD, COVID-19 is just one of the three pandemics they are currently living through.
Some studies show that loneliness is as bad for you as smoking half a pack of cigarettes a day or being obese.
Indu Subramanian, MD, director of the Veterans Administration (VA) Southwest Parkinson's Disease Research, Education and Clinical Center had been working with her colleague Laurie K. Mischley, ND, PhD, MPH, on the Complementary and Alternative Medicine in PD (CAM Care PD) study since 2013. This is a prospective, observational, web-based study to explore the assoication between modifiable lifestyle variables and self-reported PD symptoms. A few years ago, they added questions about loneliness into the analysis.
The paper used Patient-Reported Outcomes in PD (PRO-PD) and questions from PROMIS Global related to social health to measure patient responses. "Individuals who reported being lonely experienced a 55 percent greater symptom severity than those who were not lonely. Individuals who documented having a lot of friends had 21 percent fewer symptoms than those with few or no friends," Dr. Subramanian and colleagues wrote. Although causation could not be determined due to the nature of the findings, there could still be important implications for neurologists.
Dr. Subramanian suggests, "social prescribing" - the practice of having clinicians prescribe resources or activites in the community (in-person or virtual) to help patients with social connection - could be the way forward. There's a huge stigma around loneliness, she said, because people think it reflects poorly on them and their likability.
For caregives of persons living with PD and related disorders, it is important to know there are tremendous resources online, asynchronous classes and webinars that people can watch on their own time, virtual support groups, fitness classes. So many of these things are achieved so they can join live or they can join after the fact, but to know that they're not alone, to know that there are resources out there, that's one of the best gifts that we can give caregivers.
For those patients who have difficulty with or distrust technology, it is better for families to pick up the phone, write letters or postcards, send photo albums - anything to remind their person in care that they are not alone.
Gum Disease Bacteria Found in Most Alzheimer’s Patients in Atuzaginstat Trial
Most of the mild to moderate Alzheimer’s patients enrolled in atuzaginstat (COR388) Phase 2/3 trial show evidence of systemic infection due to Porphyromonas gingivalis, a bacteria linked to periodontal disease whose toxic enzymes are thought to contribute to Alzheimer’s and are targets for this candidate therapy.
Data was presented during the oral session “Phase 2/3 GAIN trial of COR388 (atuzaginstat), a novel bacterial virulence factor inhibitor for the treatment of Alzheimer’s disease: Update and baseline Data,” at the 13th Clinical Trials on Alzheimer’s Disease Conference (CTAD), held online Nov. 4–7.
Atuzaginstat is a small molecule inhibitor of gingipains, the enzymes produced and released by P. gingivalis that have been found in more than 90% of post-mortem patient brain samples. These toxic enzymes are also known to trigger Alzheimer’s in animal models.
By blocking these enzymes, which are also thought to contribute to disease progression, atuzaginstat may be able to slow, or stop, the continuous neurodegeneration observed in patients.
GAIN, a Phase 2/3 trial, is assessing the safety, tolerability, and efficacy of two doses of oral atuzaginstat — 80 or 40 mg capsules taken twice daily — compared with a matched placebo, in adults with mild to moderate Alzheimer’s.
At the conference, the company presented data from an analysis of baseline patient characteristics covering 40–50% of all those enrolled (data available as of Oct. 15), and showing a majority had an adequate profile for responding to atuzaginstat.
Specifically, 75% had an amyloid beta (Aβ) 42/40 — a biomarker of Alzheimer’s, and around 88% had a low Aβ 42/40 ratio associated with the presence of amyloid plaques in a positron emission tomography (PET) scan. Most of these patients also had high levels of tau (89%) and phosphorylated tau protein (86%), two other CSF biomarkers of Alzheimer’s.
More than half (65%) were found to carry at least one copy of the ApoE4 gene variant, a known genetic risk factor for Alzheimer’s.
Data from GAIN’s gum disease sub-study also showed that more than 90% of patients evaluated had moderate to severe gum disease at the time of enrollment.
Last Participant Finishes PEGASUS Clinical Trial, Results Expected Next Year
The last participant has completed the planned 24 weeks in the Phase 2 PEGASUS clinical trial, which is assessing the safety and biological activity of Amylyx Pharmaceuticals‘ investigational therapy AMX0035 in people with Alzheimer’s disease.
AMX0035 is an oral formulation of sodium phenylbutyrate (PB) and tauroursodeoxycholic-acid (TUDCA). PB helps stop proteins from unfolding — protein unfolding is associated with the toxic accumulation of proteins in nerve cells. TUDCA helps to limit the loss of cellular energy, which is involved in the progression of neurological diseases like Alzheimer’s.
Amylyx reported encouraging results of the Phase 2 CENTAUR trial (NCT03127514), which assessed the compound’s safety and tolerability among 137 people with sporadic or familial amyotrophic lateral sclerosis, in 2019.
PEGASUS (NCT03533257) is testing the investigational medication’s safety and tolerability among people with late mild cognitive impairment or early dementia due to Alzheimer’s.
Participants in the trial were randomized to receive either AMX0035 or a placebo for 24 weeks (roughly six months). The study’s main goal is to investigate the treatment’s safety and tolerability, as assessed by reported adverse events. A battery of imaging-based markers, neurobiological changes, functional measures, and cognitive outcomes will also be assessed.
The researchers look forward to sharing the topline results of the trial in the first half of 2021.
Compiled by Padmaja Genesh, Learning Specialist