Free Access To High-Cost Aducanumab May Incentivize Phase IV Trial Participants

GAP President John Dwyer spoke to Scrip Informa Pharma Intelligence about Biogen’s aducanumab, and how clinical trials are more important than ever since it’s FDA approval.

The requirement for Biogen, Inc. and Eisai Co., Ltd. to conduct a Phase IV clinical trialas a condition of Aduhelm’s accelerated approval raises the question of whether Alzheimer’s disease patients in the US will be willing to enroll in the trial – or in other companies’ large, late-stage studies – when the drug is broadly available following its 7 June US Food and Drug Administration approval.

However, experts who spoke with Scrip about the agency’s Aduhelm (aducanumab) decision noted that with millions of people diagnosed with Alzheimer’s disease in the US and because of the amyloid-clearing antibody’s list price of $56,000 per year, there are sure to be plenty of volunteers for the trial – where the drug would be provided at no cost.

Biogen/Eisai Win On Aduhelm Approval Bet And Wager Next On Price

The first disease modifying drug for Alzheimer’s disease will be priced at a $56,000 a year for an average weight patient, setting the drug up to be a mega blockbuster if Biogen can get it reimbursed.

The FDA granted accelerated approval based on Aduhelm’s ability to reduce levels of the amyloid beta protein in the brains of Alzheimer’s patients in the Phase III EMERGE and ENGAGE trials, but to obtain full approval Biogen and Eisai must show in a confirmatory trial that clearing amyloid with the drug results in a clinical benefit. The Phase IV study could clarify the mixed results of EMERGE and ENGAGE, which showed that treatment with Aduhelm resulted in a statistically significant slower rate of cognitive decline in only one of the studies.

Biogen and Eisai have not disclosed any details about their confirmatory study plans, so when they will begin enrollment, how many patients they plan to enroll, what the trial will look like and how long it will last are unknown.

Biogen executives said during an 8 June investor call to discuss Aduhelm’s approval and commercial launch that the company is discussing those details with the FDA and its advisors. They also noted that Biogen’s $2.3bn-$2.4bn in research and development spending for 2021 includes expenses related to the confirmatory trial.

“I think a key aspect of this is to ensure that the design of that trial is sufficient and implementable,” Peter Stein, director of the Office of New Drugs, part of the FDA’s Center for Drug Evaluation and Research, said during a 7 June press call to discuss Aduhelm’s approval.

“I also recognize, because this is a global disease, there will be sites in many regions of the world where [Aduhelm] would otherwise not be available,” Stein said. “We expect that this will be a trial that can be implemented and completed and, obviously, we will be tracking that very carefully.”

Patients Needed: For Aduhelm As Well As Competitors’ Studies

But in addition to the uncertainty of whether US patients will be willing to risk receiving a placebo instead of Aduhelm in the Phase IV trial, there is the possibility that potential Alzheimer’s trial participants will opt to enroll in the Biogen/Eisai study rather than a late-stage trial for another company’s potentially more effective treatment.

Competing Phase III Trials
Multiple later-stage clinical trial programs are under way in Alzheimer’s disease,
including several for therapies that target amyloid. Among the potential Aduhelm
– Roche Holding AG has completed enrollment in its Phase III GRADUATE-1 and GRADUATE-2 studies of the amyloid-targeting antibody gantenerumab with about 1,000 patients each trial and results expected in 2022.
– Lilly initiated TRAILBLAZER-ALZ 2 as a 500-plus-patient Phase IIb trial a year ago but increased the study to 1,500 patients and converted it to a Phase III trial in March.
– Alzheon Inc. is recruiting 300 patients with early Alzheimer’s disease and the APOE4/4 genotype for the Phase III APOLLOE4 study of ALZ-801, a prodrug of tramiprosate, which interferes with the association between glycosaminoglycans and amyloid beta.
– AZTherapies, Inc. said in November that it completed the Phase III COGNITE trial that tested ALZT-OP1 in more than 600 patients and planned to report the results in the first quarter of 2021. The drug is designed to inhibit beta-amyloid peptide polymerization and the neuro-inflammatory response.
– Biogen and Eisai are testing lecanemab (BAN2401), which targets amyloid protofibrils, in the fully enrolled 1,795-patient Phase III Clarity AD trial and the Phase III AHEAD 3-45 study, which will enroll 1,400 patients.

John Dwyer, president of the Global Alzheimer’s Platform Foundation (GAP), does not anticipate major problems enrolling the Aduhelm confirmatory study, but said other companies’ trials could feel an impact. GAP is a non-profit organization that works to bring new Alzheimer’s treatments to patients with reduced time and costs by facilitating access to high-quality medicines and clinical trial sites through its GAP Network. The organization has been involved in prior aducanumab studies and is involved in the pivotal Phase III TRAILBLAZER-ALZ 2 trial for Eli Lilly and Company’s donanemab, which targets a modified form of beta-amyloid called N3pG.

Dwyer said it is likely that Biogen/Eisai’s Phase IV study will be designed so that the placebo group will be given an opportunity, after a certain randomized period, to take Aduhelm in an open-label component of the trial.

“We’re looking at [more than] $50,000 a year to get the drug,” he noted. “If you can be in a trial for free, if that’s how the protocol is going to be written, I don’t think recruitment’s going to be a challenge. Some people will take the risk of being on placebo for a while to get the whole workup. There’s the MRI and the PET imaging; there’s a lot of upfront cost to patients to get on this therapy before Biogen charges you, so there can be a fair amount of cost to persuade patients to look at the trial carefully.”

Dwyer added that “we’re involved in almost all the leading studies now of comparable drug candidates,” and said that enrollment in some of those trials may be impacted by Aduhelm’s approval in the US as well as its confirmatory trial. Even so, he said it is not an impossible task to enroll the Biogen/Eisai trial and other studies that are or soon will be under way.

“Thank God this happened, because now we have momentum to give choice to patients and scientific approaches to patients,” Dwyer commented. “I think that it’s incumbent upon my organization and clinical trial sponsors to communicate why their study has more value to the patient or trial participant, why their molecule and theory could provide them with more benefits than aducanumab. And I think we’re going to have to work harder, but we should still [be able to] recruit.”

Clinical trial sponsors also should make an effort to enroll diverse populations, he said. GAP has made a commitment for its 1,000-patient BioHermes study, which is evaluating potential blood tests and digital tools that may predict the presence of amyloid in the brain, to make sure 20% of its trial participants are Black or Hispanic. Biopharmaceutical companies should make similar commitments in their Alzheimer’s clinical trials, Dwyer said, “especially if you’re going to charge somebody $50,000 for the drug, you should be pretty darn certain it works for everybody.”

Maria Carrillo, chief science officer at the Alzheimer’s Association, agreed in an interview with Scrip that the cost of Aduhelm may help drive enrollment in the confirmatory study for Aduhelm.

“I think it’s important to remember that even though there will be [Medicare and health insurance] coverage for this drug, there may be out-of-pocket costs that could be considerable for many Americans,” Carrillo said. “If you are participating in a clinical trial, you may have those costs covered and you may have access to actually higher-touch care, more frequent health care. So, there are lots of benefits to participating in clinical trial, and I think it’s going to be important for families just to make that decision and to see what works best for them.”

In addition to the cost of Aduhelm, there are plenty of patients clamoring for treatments that could slow or stop the progression of their disease and who may be willing to enroll in a clinical trial, Howard Fillit, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, told Scrip.

The need to enroll potentially thousands of patients in the future Aduhelm study “could possibly have an impact, but even now less than 5% of people with Alzheimer’s participate in clinical trials, and the Phase IV study may only require 1,000 to 3,000 patients around the country. You’re talking about 1,000 to 3,000 patients out of millions who are potentially eligible to get the drug, so I think there’ll be some people out there that might want to participate in the trial. I would hope so.”

Originally posted by Scrip Informa Pharma Intelligence on June 7, 2021.

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