Advances in Alzheimer’s, but Knowledge Gaps Remain

The Regulatory Affairs Professionals Society (RAPS) held its annual conference, the RAPS Regulatory Convergence, from September 17-20 in San Jose, CA. Clarivate Analytics Medical/Regulatory Writer Meg Egan Auderset attended; she wrote the following is based on a session about Alzheimer’s disease, Delivering the Next Generation of Alzheimer’s Treatments: Are We Prepared?

At a session on the “next generation” of treatments for Alzheimer’s disease, Timothy Franson, MD, chief medical officer of the consulting firm YourEncore, bemoaned the existence of “zombies” in the field: practices and approaches to Alzheimer’s drug development that should be “dead” but that persist, draining energy and resources.

“What we have here is not the walking dead, but the walking debt,” Franson quipped. The reason for it, he said, is lack of understanding about the causes of Alzheimer’s and the factors that impact its progression—and about the best way to move the field forward. Innovation will ensure the future of the field, Franson said.

Alzheimer’s disease is an “epidemic,” according to session moderator George Vradenburg, chairman of UsAgainstAlzheimer’s and co-convener of the Global CEO Initiative on Alzheimer’s Disease. Worldwide, nearly 50 million people live with dementia, and that number is expected to triple by 2050, Vradenburg said. Within the US, approximately 5.4 million people have the disease, according to the Alzheimer’s Association.

The Alzheimer’s field is “desperately ready” for new innovation, “but I don’t think we’re prepared,” said Carlos Garner, PhD, senior director for Global Regulatory Affairs at Eli Lilly and Company. First, the field must fill in the knowledge gaps, he said. European colleague Enrica Alteri, head of the Human Medicines R&D Support Division at the European Medicines Agency, agreed. While basic information on the cause of Alzheimer’s and its pathways is evolving, it remains incomplete, she said. Consequently, drug companies have developed potential treatments based on assumptions about the disease; some of those assumptions have been false, resulting in failed therapeutic efforts. The field has also not yet identified reliable biomarkers, she said.

Both speakers expressed hope, however. Garner anticipates “profound” scientific, medical, and regulatory advances in the next few years. Regulatory advances will be increasingly important as the field fills the holes in scientific understanding. To date, many drug developers have been unable to take advantage of regulatory tools like breakthrough therapy designation, accelerated approval, and priority review, because the science has not been strong enough to support their use. “We need to be ready,” Garner said.

According to Garner, more than a dozen new disease-modifying drugs “could” become available to patients over the next 5 years. Vradenburg referred to 57 compounds currently in phase 2 development; approximately 40% of them have multiple mechanisms of action, according to materials he shared from UsAgainstAlzheimer’s. Of the phase 2 drugs, 22 are either repurposed drugs or nutritional supplements. (Note: in November 2016, Eli Lilly and Company announced that it would no longer “pursue regulatory submissions” for its phase 3 drug, solanezumab, after patients treated with the compound failed to show statistically significant slowing in cognitive decline when compared to placebo. Solanezumab was being developed to treat mild dementia due to Alzheimer’s.)


Drugs in Phase 3 Development for Alzheimer’s
Anticipated to Launch by the End of 2021
Compound Sponsor
aducanumab Biogen
ALZ-801 Alzheon, Inc
ALZT-OP1 AZTherapies, Inc
aripiprazole Otsuka Pharmaceutical Co, Ltd
AVP-786 Avanir Pharmaceuticals, Inc
azeliragon vTv Therapeutics
brexpiprazole Otsuka Pharmaceutical Co, Ltd; H Lundbeck A/S
gantenerumab F Hoffmann-La Roche Ltd
idalopirdine Otsuka Pharmaceutical Co, Ltd; H Lundbeck A/S
intepirdine Axovant Sciences Ltd
masitinib AB Sciences
nilvadipine Astellas Pharma Inc; Archer Pharmaceuticals, Inc
pioglitazone Takeda Pharmaceuticals USA; Zinfandel Pharmaceuticals Inc
sodium oligo-mannurarate Shanghai Greenvalley Pharmaceutical Co, Ltd
TRx0237 TauRx Therapeutics
verubecestat Merck & Co, Inc
Source: UsAgainstAlzheimer’s


Session speakers repeatedly called for increased collaboration. Alteri advocated for new mechanisms to foster data sharing among drug developers, for example, and cited a need to share information on surrogate and intermediate clinical endpoints (ICEs). Drug developers should also exchange information on biomarkers, she said, particularly to identify pre-symptomatic patients and those whose disease is likely to progress, and to predict likely clinical outcomes of interventions.

Noting his frustration over the current number of “disparate efforts,” Franson called for collaboration across all stakeholders. While it is important to share best practices, it is even more important to share information about failures, he said. Franson also advised redefining the benefit-risk balance in Alzheimer’s disease, suggesting that caregivers should have a voice in such discussions.

Garner stressed the importance of involving patients and advised finding new ways to engage them. In particular, researchers must keep in touch with potential study subjects, even when current trials are not suitable for them, he said. Researchers must learn to maintain patient motivation, and that requires active engagement.

Alteri mentioned efforts by the FDA and EMA to align their respective guidelines on drug development in Alzheimer’s. She reported “very good” FDA-EMA agreement on underlying concepts, as well as plans to compare revised and finalized documents currently in development.

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