Alzheimer’s disease is one of the most insidious neurodegenerative diseases, and the National Institute on Aging, part of the U.S. National Institutes of Health, reports that it is the sixth leading cause of death in the United States. Along with cancer and diabetes, it’s one of many great white whales in the pharmaceutical industry, but therapeutic candidates have generally been inefficacious at slowing or preventing disease onset.
Industry hopes had been high for one such candidate—aducanumab, developed by Biogen Inc.—but data analysis of the EMERGE and ENGAGE trials seemed to indicate that the drug would not meet its primary endpoints, leading Biogen to terminate ongoing trials. This was largely seen as the final nail in the coffin for the theory that amyloid beta was the ideal target for treating Alzheimer’s disease.
However, further analysis revealed that the earlier supposition was wrong, with EMERGE and ENGAGE patients showing therapeutic benefit, and Biogen reawakened its aducanumab program. DDN spoke with Dr. James Kupiec, chief medical officer at ProMIS Neurosciences, regarding the data for aducanumab and its impact on the drug development field for Alzheimer’s disease.
DDN Magazine: Aducanumab has obviously had a bit of a tumultuous journey up to this point, from reporting positive results in 2014 and 2015, to the announcement last year that all ongoing trials would be terminated. What kind of results did Biogen see in the EMERGE and ENGAGE trials to cause them to reopen the program?
Dr. James Kupiec: We’re looking at a potential landmark year in the search for Alzheimer’s disease (AD) treatment. Biogen announced on July 8, 2020, it had completed its rolling Biologics License Application (BLA) submission for aducanumab to the U.S. Food and Drug Administration (FDA). If Biogen’s aducanumab receives FDA approval, it will represent the first disease-modifying therapy for AD.
Approval will validate aducanumab’s target, amyloid-beta (Aß), the protein numerous scientific and clinical studies implicate in the development of AD. While data show aducanumab is only modestly effective in slowing progression of AD, its tumultuous reanimation from near-termination has already propelled the necessary innovation driving the next generation of therapies. These next-generation, improved therapies will incorporate the learnings and consensus of two decades of drug development struggles, including that of aducanumab.
As background, Biogen initiated in 2015 two large, identical Phase 3 studies named EMERGE and ENGAGE, with over 1,600 early AD participants in each 78-week study. Based on data available in December 2018, an interim “futility” analysis indicated the probability the two studies would successfully meet the primary endpoint in the final analysis was less than 20 percent. Biogen announced March 2019 their decision to halt the two studies, and this news was a great disappointment for trial participants, families of patients with AD and the entire AD research community.
However, between December 2018 and March 2019, the EMERGE and ENGAGE trial participants continued to be evaluated according to the experimental protocol. Additional “on-drug” data were thus generated and many trial participants, due to a 2017 protocol amendment, completed the trial at the 10 mg/kg highest dose during this three-month period. Biogen began to analyze the larger, final dataset for efficacy and safety, met with FDA to review their findings, and then announced in October 2019 the earlier conclusion drawn from their futility analysis was incorrect.
At the 12th Clinical Trials on Alzheimer’s Disease (CTAD) conference in December 2019, Biogen explained that the EMERGE and ENGAGE protocols were amended in 2017 to increase the maximum administered dose to 10 mg/kg for trial subjects having the apoE4 genotype. Carriers of apoE4 have a higher risk of Amyloid-Related Imaging Abnormalities–Edema (ARIA-E; i.e., patchy vasogenic brain edema) when administered anti-amyloid antibodies that bind amyloid plaque, and this caused Biogen scientists to initially limit the maximum available dose administered to these trial subjects. At CTAD, Biogen explained how the timing of the 2017 protocol amendment differentially impacted the two trials and increased more significantly the number of subjects in the EMERGE trial who received the maximum dose of 10 mg/kg for a prolonged period of time.
The EMERGE trial was unequivocally positive upon analysis of the final dataset and showed a statistically significant 23-percent reduction in cognitive decline on the primary endpoint (Clinical Dementia Rating–Sum of Boxes [CDR-SB]) at the 10 mg/kg dose. Secondary cognitive and functional endpoints were also statistically significant and Biogen’s biomarker analyses supported the claim that aducanumab beneficially affected the underlying AD neuropathology.
The ENGAGE trial did not show an overall treatment benefit like EMERGE because of the differential impact of the protocol amendment, but a post-hoc analysis showed that the subset of ENGAGE participants (n=790) who had consented to the high-dose protocol amendment early in their trial participation had a treatment benefit (-27 percent) on CDR-SB similar to that observed in the equivalent subset (n=887) of the EMERGE study (-30 percent).
Biogen concluded that trial subjects who demonstrated a reduction in their rate of clinical decline had consistently been administered the highest possible dose of aducanumab over a prolonged duration, and this result encouraged Biogen to meet with FDA and prepare their BLA.
DDN: Biogen has submitted a rolling BLA for aducanumab, which means a slightly longer path to approval. Beyond the obvious impact of the COVID-19 pandemic, why was this determined to be the best route for aducanumab?
Kupiec: The rolling submission/review process for a BLA is quite common, and it’s typically beneficial for both sponsor and FDA. The rolling aducanumab BLA allowed Biogen to submit various research reports and section modules in a series of waves, as opposed to one large final application. This gave FDA the option to commence preliminary review of the individual application components and also provided greater efficiency to ensure the BLA was complete and ready for FDA’s deep and integrated review. Submitting a rolling BLA and having the accompanying Fast Track designation facilitates more frequent communication with FDA scientists to ensure there are no major outstanding questions and the filing is electronically navigable. Thus, a rolling BLA helps avoid an FDA refusal of the application file due to an unexpected deficiency.
DDN: What kind of timeframe can be expected with regards to aducanumab’s regulatory review and, potentially, its approval?
Kupiec: In response to an option embedded in the Fast Track designation process, Biogen has requested Priority Review of the aducanumab BLA. Now that the BLA is complete, FDA has up to 60 days to accept the application filing, and then the review clock begins to tick. If the BLA is granted Priority Review, then I anticipate an advisory committee meeting in early 2021 and a potential approval as early as March 2021.
DDN: Given how many clinical candidates targeting amyloid have failed in clinical trials, some companies in the neurodegenerative field are pivoting to explore other targets for treating Alzheimer’s disease, such as the tau protein. From what you’ve seen, is the targeting of amyloid beta plaques still considered the primary approach for combating Alzheimer’s, or are other approaches generating greater interest or efficacy?
Kupiec: Great question. Aducanumab’s advancement clearly validates amyloid-beta (Aβ) as a target. However, the EMERGE and ENGAGE datasets argue Aβ plaque is not the correct molecular species to primarily target. This is a critical distinction. Copious data affirm that a therapeutic focus on Aβ plaque is outdated: since 2013, more than 2000 scientific papers have shown that soluble, toxic Aβ oligomers (AßOs), a structurally different molecular species, drive disease progression and cognitive decline in AD.
A greater awareness of the underlying neurobiology has resulted in next-generation drug candidates with superior selectivity for toxic AßOs. These early candidates demonstrate a high degree of binding to toxic oligomers without binding to the non-toxic, physiologically critical Aß monomer (another molecular species of amyloid-beta). Moreover, by avoiding binding to plaque, we can dose higher with greater potential clinical benefit and no ARIA-E, the brain-swelling side effect associated with aducanumab.
There remains significant interest in non-amyloid drugs to treat AD, including ones that can potentially modulate tau fibril formation and neuroinflammation, but there is not yet any clinical data to suggest these approaches will ultimately be successful.
DDN: Small-molecule drugs have comprised a large portion of the pharmaceutical field in recent years, but large-molecule compounds or biologics such as aducanumab are gaining popularity. In your experience, are these better suited for neurodegenerative diseases than small-molecule compounds?
Kupiec: The most advantageous therapeutic approach, be it small- or large-molecule, depends upon the targeted neurodegenerative (ND) disease, the clinical aspect of the disease one wishes to improve, and how well one understands the underlying neurobiology of that disease.
Small-molecule therapeutics with the right chemical characteristics and the ability to avoid significant efflux transport at the blood brain barrier (BBB) do work well to inhibit brain enzymes or membrane transporters that impact neurotransmitters (e.g., donepezil inhibits acetylcholinesterase). The development challenge is to design and deliver such small molecules to brain tissue, because an extremely large percentage of small molecules are pumped out of the brain by protective transport mechanisms at the BBB.
However, small molecules are more prone to produce off-target safety issues depending upon their binding specificity and affinity, as well as their metabolism. Although they can provide some symptomatic benefit to patients with ND disease, scientific teams continue their attempts to discover small molecules that can impact the underlying disease process.
Notwithstanding these attempts, large molecules, such as monoclonal antibodies, more precisely bind the targeted epitope, and only the targeted epitope It is thus not surprising that large amounts of monoclonal antibodies can be administered without such side effects (e.g., crenezumab was administered at up to 60 mg/kg to trial subjects with AD).
We now know many ND diseases, such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), are caused by toxic misfolded protein oligomers that aggregate and propagate in a prion-like fashion. Although a small molecule could potentially inhibit the formation of such oligomers, we do not currently have a clear understanding of the biochemical processes that induce misfolding and oligomerization of the pertinent proteins. Designing such a drug can be a frustrating hit or miss.
Alternatively, rational drug design of a highly specific monoclonal antibody can successfully and precisely promote immune system removal of the offending oligomer before cell-to-cell propagation contributes to neuropathology. Monoclonal antibodies administered intravenously can penetrate the BBB. Although this route of administration provides brain concentrations of 0.1 percent to 0.5 percent the concentration measured in blood, the very long half-life of antibodies ensures they can impact neuropathology over a prolonged duration. Nevertheless, a number of companies are working on chemical approaches to augment transport of immunoglobulins more efficiently across the BBB.
Approaches other than monoclonal antibodies also suggest that large molecules are better suited for ND disease in comparison to small molecules.
Antisense oligonucleotide (ASO) therapies have demonstrated their value in genetically driven ND diseases. For example, nusinersen is approved for the treatment of spinal muscular atrophy in children, BIIB067 (Biogen) is in Phase 3 to evaluate its effect on disease progression in patients with ALS caused by superoxide dismutase 1 (SOD1) mutation, and tominserin is being evaluated by Roche in a Phase 3 trial in patients with Huntington’s disease. ASOs at this point must be administered intraventricularly or intrathecally, but the new BBB transport drug-delivery techniques in development could simplify drug administration in the years ahead.
Finally, genomic editing via CRISPR, vectorized small interfering RNAs and vectorized antibodies (i.e., intrabodies) represent revolutionary large molecule approaches for the future treatment of ND diseases. In ALS, for example, cytoplasmic accumulation and aggregation of misfolded TDP-43 may require an intrabody approach with a highly selective therapeutic in order to adequately deliver an exquisitely precise therapy that avoids binding to the critical physiologic molecular species. Indeed, such future approaches are now on the horizon.
DDN: Should it gain FDA approval, aducanumab is set to become the first approved disease-modifying therapy for Alzheimer’s disease. Obviously, this is a treatment, not a cure, but do you think this is something of a turning point in terms of the industry’s understanding of Alzheimer’s disease and the potential for additional treatments—or even preventative therapies?
Kupiec: Absolutely! Aducanumab’s approval, which I anticipate, will be nothing short of a landmark decision with astounding impact on AD patients and their families. However, I believe its most powerful effect will be on research and development efforts guiding future treatments. This will continue regardless of aducanumab’s regulatory success, as its clinical validation alone has re-energized innovation supporting next-generation therapies. Researchers are now blending supercomputing, biology and physics to create potential new medicines with very precise targeting for only the toxic protein forms that drive AD and other ND diseases, nothing more. Scientists engaged in next-generation drug research will also benefit from revolutionary advances in ultrasensitive blood-based biomarkers to bring these treatments to patients faster.
While aducanumab captures media headlines, scientists armed with the knowledge of two decades of AD drug research have been quietly and diligently working to bring new, better therapies to patients, faster and more efficiently. FDA approval of aducanumab would certainly impact financial investment in and enthusiasm for next-generation therapies, pushing the research community to make even more meaningful strides against this terrible disease at long last.
Prior to his position at ProMIS Neurosciences, Kupiec served as vice president, global clinical leader for Parkinson’s disease and clinical head of the Neuroscience Research Unit in Cambridge for Prizer Inc. He also worked at Sanofi-Synthelabo and has held faculty positions at the University of Rochester School of Medicine and the SUNY Upstate Medical University, with more than 25 years of early- and late-stage work in the fields of neurologic and psychiatric disorders.