It is the best of times and the worst of times for the Alzheimer's space as 2023 is off to an eventful start.
Successful treatments are so tantalizingly close to making a difference for patients, but roadblocks are still aplenty, whether they come from trial design, regulatory ambiguity or even alleged tampering of the approval process. The situation has the field on the edge of greatness with several pharma companies vying for that first unobstructed step forward.
The ramshackle launch of Biogen and Eisai's Aduhelm in 2021 exposed the pitfalls of navigating the regulatory process with less-than-perfect clinical results. And an eagerness to swiftly bring the first disease-modifying candidate to patients may have caused more skepticism in an area already prone to disagreement.
The FDA's approval process for Aduhelm was "rife with irregularities," according to a congressional investigation released just before the new year. The report showed "lapses in protocol" that raised "serious concerns" for both the regulatory process and Biogen's price-setting after a year-and-a-half-long investigation.
Now, two more drug candidates — donanemab from Eli Lilly and lecanemab from the same partnership between Eisai and Biogen — are on the immediate horizon. One thing is clear: The approval processes for these molecules need to be flawless and transparent to avoid any of the confusion and false hope that befell Aduhelm.
An end in sight
After Aduhelm's rocky launch and ultimate market demise, Eisai and Biogen are back in the driver's seat for an imminent decision from the FDA on their follow-up drug lecanemab, which works the same way by clearing amyloid plaques in the brain.
That regulatory decision for potential accelerated approval — the same type that Aduhelm was granted — is expected this week. Eisai is taking the lead this time and has appeared to distance itself from partner Biogen in the matter, according to a November note from Mizuho analyst Salim Syed. In a presentation of results at the time, the Japanese company did not utter "Biogen" once.
“Moving into the slowing of progression for those that aren’t yet experiencing any symptoms is an exciting evolution for the field."
Global development leader of Alzheimer’s disease, Eli Lilly
But the results spoke for themselves, and lecanemab looks like a strong candidate, Syed said.
"The data overall continued to look great, and any 'holes' were in the subgroup analyses, none of which though are likely to tank the thesis that the drug will get approved and used, assuming reimbursement," Syed said.
The FDA is now in control with a Jan. 6 target PDUFA date, even as the investigation into previous dealings between the companies and the regulatory agency continues.
Failure and persistence
Lilly's donanemab is the further away from approval of the two newer amyloid-clearing molecules, with confirmatory phase 3 results due by the middle of 2023. Before that, there is also the potential for an accelerated approval by February.
For Lilly, it's a long time coming. Like its pharma giant peers, the company has suffered setbacks over the years, including the 2016 failure of its drug solanezumab. But unlike companies who left the arena — including Merck & Co. and Pfizer — Lilly stayed the course in Alzheimer's with donanemab to show for it.
Donanemab's most recent success came from a head-to-head trial against Aduhelm — an unusual target for a comparison trial given how fresh its approval was — in which Lilly's drug cleared amyloid plaque at a quicker rate than Biogen's beleaguered treatment after six months. The safety of the drugs has been shown to be similar, particularly in the characteristic brain swelling called ARIA.
John Sims, senior medical director of neurodegeneration at Lilly, has been working on donanemab for 13 years. Although he’s had a hand in other molecules as well, the Alzheimer's drug was his first at the company.
"We've had lots of failures along the way, but what's been key here is that we kept at it," Sims said in an interview. "We have to learn from each one of these and do each next stage a little bit better — many of us, including me, have had family members really suffering from this disease and who died from this disease, and it's been an unsolved pain in society that has needed some kind of persistence."
The company's Alzheimer's journey stretches back even further than Sims’ tenure, said Dawn Brooks, global development leader of Alzheimer's disease at Lilly.
"Lilly has tried to show an enduring commitment to this space through 30 years of investments, and all the ups and downs," Brooks said. "It's really gratifying and inspirational to see now that some of these investments and, for Lilly working on multiple fronts, are turning into positive results."
And with a milestone in sight, the company has learned much about the disease and its causes, Sims said. The theory that clearing amyloid plaques can lead to positive clinical outcomes has come under fire over the years as amyloid-targeting molecules have failed to pan out and other approaches like the clearing of tau tangles have arisen. But Lilly has stuck to the amyloid theory with donanemab.
"We've had a lot of people saying amyloid is not the problem — we've always been saying we're trying to solve two problems at the same time, which are trial design and molecules, and when one's not right you can't answer the other one very easily," Sims said. "Now we're starting to see reproduction, and that gives us a new tool — these drugs are new tools to understand the disease, and it will start to really open up this box scientifically."
Sims compared the competing Alzheimer's target theories to the decades-old debate over the cause of cardiovascular disease and whether cholesterol or thrombosis was more to blame.
"It's almost identical to the tau/amyloid arguments today, which are starting to now subside," Sims said. "Through many studies, we know that people with amyloid in their brains and those without amyloid in their brains are performing very differently on very sensitive tasks — so (we’re) learning which pathologies play a key role and when is the optimal time to intervene."
Lilly has also moved into patient populations who are much earlier in their disease state as a means to potentially treat Alzheimer's before it becomes cognitively apparent, Brooks said.
"Moving into the slowing of progression for those that aren't yet experiencing any symptoms is an exciting evolution for the field and the direction we want to be going," Brooks said.
The controversial nature of Alzheimer's has not been lost on the company, and the various ups and downs of scientific and public opinion have been a constant push and pull, requiring special attention to the potential launch of donanemab down the road.
"We observed what was happening in the external environment along with everybody else, and we've been trying to engage (the) CMS along the way, for example, and sharing our data to make sure there's an understanding of our program and our dataset," Brooks said.
When it comes to competition among Alzheimer's drug manufacturers, Brooks said there is room — and perhaps a need — for many treatments, and that the industry is united in some ways to bring these drugs to patients.
"It's the lifting of all boats to move the field forward," Brooks said.
What's most important is the science to dispel any rumors that Alzheimer's is too difficult to tackle, Sims said.
"There's a lot of skepticism in this field to begin with, and the more skepticism there is, the less you can take for granted — and here, the science is important," Sims said. "The key is to reproduce data, and in the absence of that, it's hard to win an argument. We've been laser focused on finishing this confirmatory trial and doing it in a very judicious fashion that will replicate the science and give us confidence."