If you thought that Eli Lilly's donanemab could ensure a smooth regulatory flight in the slipstream of Eisai and Biogen, the FDA has other ideas.
The decision to call a last-minute advisory committee meeting last month for the Alzheimer’s disease med came as a surprise to Lilly’s donanemab team. Not for the request to discuss the therapy’s safety and efficacy, but for the timing of it.
“It was unexpected for us, because if you've been following this space, we were kind of heading towards an action date,” said Dawn Brooks, Ph.D., global development leader for Lilly’s lead Alzheimer’s medicines donanemab and remternetug, in an interview with Fierce Biotech.
Lilly had hoped to be celebrating the approval of donanemab at the end of the first quarter, but the FDA threw a wrench into the plans with the decision to convene the Peripheral and Central Nervous System Drugs Advisory Committee to discuss a few key matters. Lilly announced the agency’s decision in early March.
The FDA specifically wants advice from the expert panel on the safety and efficacy of the med, including safety results in patients who received donanemab and the efficacy implications of the trial’s unique design.
Both recently approved Alzheimer’s meds—Biogen and Eisai’s Aduhelm (which has since been withdrawn) and Leqembi (granted full approval in July 2023)—were examined at a public advisory committee meeting. With the regulatory process nearing the Prescription Drug User Fee Act (PDUFA) action date, Lilly had thought donanemab was in the clear.
“We had gone very far through the regulatory review without a signal that we would also have an advisory committee,” Brooks said.
Fervent FDA watchers may note that the FDA typically warms to subsequent drugs in a class as they come in for review. But the Alzheimer’s space has never been like any other therapeutic area, so why would the regulatory process be any different?
Brooks said Lilly’s application for donanemab arrived at the FDA’s desk at a time when senior leadership there was questioning myriad regulatory matters—including the role of advisory committee meetings and accelerated approvals. Discussion about reforms to advisory meetings had spilled out into the public domain, with Commissioner Robert Califf, M.D., suggesting cutting the vote that caps off the hourslong marathon public sessions.
While Brooks does not know whether the FDA specifically had this in mind, she said it’s interesting timing.
“That's about all we know. We certainly don't have a direct insight into what they were thinking, but here we are,” Brooks said. “And, of course, we're preparing actively for that and look forward to having the broad stakeholder inputs, which now will incorporate the external experts as well as patients and advocacy groups.”
The fine print
Brooks says the two questions the FDA seems to be ruminating on have to do with the label donanemab will ultimately bear.
The first issue is the decision to allow patients to stop treatment once they achieve amyloid clearance. This previously derailed Lilly’s request for accelerated approval, as, at the time of submission, few patients had actually been on the drug for 12 months.
That hurdle has long since been cleared, according to John Sims, M.D., head of medical development for donanemab at Lilly: “We've had more people on dona in the program than any other amyloid therapy—even probably [than those treatments available] today, so we have lots of exposures now.”
Those exposures have generated the kind of data the FDA was looking for when it declined the accelerated approval request for donanemab last year. That's all been submitted to the agency as part of an updated data package.
At the advisory meeting, Brooks said the FDA wants to hear more about the limited duration dosing that is a break from standard in Alzheimer’s care.
“Because Lilly's been working on Alzheimer's for quite a while and learning from each trial, the irony is our science is way ahead of clinical practice at this point in time because there's been like, no treatments, right?” Sims said. “Clinical practice has not evolved at all in this space.”
Ultimately, the short dosing schedule is a good thing, according to Brooks. Patients can take the drug until they achieve amyloid clearance and then stop, meaning a lower burden for treatment and the healthcare system.
“We have a mechanism that specifically targets amyloid plaque, and so we stop treatment when it's gone,” Brooks said. “How to handle that in a label where we generally see them wanting to have class-based language across the label … that would be a place where they're perhaps wrestling with because it's unique for donanemab.”
Another issue flagged by the FDA is that Lilly screened patients for tau levels prior to entry in the trial. This is the other misfolded protein behind amyloid that can lead to the neurodegeneration in Alzheimer's.
“We understood what level each person had that participated in the trial, which allowed us to kind of build on the science and build on what we had learned in phase 2,” Brooks said.
The sprawling TRAILBLAZER program that tested donanemab showed benefit across tau levels. But this was a new approach, meaning the FDA may have been debating whether tau levels needed to be considered post-approval. Brooks says this was just a different trial design.
“We believe it's not something that needs to be required for labeling, even if they're considering it that—we're not sure—but it is something that since we showed benefit across the board, it has helped to improve the understanding in the field and we'll kind of remind and show that,” Brooks said.
If tau imaging were to be included on the label, Sims says such a barrier to treatment would run into the realities of clinical practice. Tau imaging is available at top-notch clinics like the Mayo Clinic or Harvard, but not in everyday practice. Availability is not going to expand overnight, and it doesn’t have to. Up to now, amyloid drugs have been offered to patients who have amyloid on PET scans and symptoms, and that’s still applicable for donanemab.
“To require tau imaging, everyone can't go to Mayo and Harvard at this point in time. And so it would put a huge burden,” Sims added. “I do think the FDA is good, they're always kind of looking into the future here, not trying to cut certain patients off from access and trying to keep the dialogue open.”
At the end of the day, Alzheimer’s drug development has been a tough road, and Lilly has been one of the companies at the forefront of the battle to bring new treatments to the market behind Eisai and Biogen. At the advisory meeting, Lilly will get to make its case to the general public that donanemab is a stronger drug. Normally, that information is presented at medical conferences far away from the public eye.
The FDA has yet to set a date for the advisory committee meeting, but it will be posted in the Federal Register when scheduled. Lilly has not yet revised its guidance on when donanemab will be launched and is still hoping for sometime this year. While the FDA has nixed its previous PDUFA schedule, Sims said the agency has promised to resolve the issues quickly.