by William Newton in Texas.

Biogen antibody aducanumab, if FDA-approved for mild Alzheimer’s disease (AD), will likely face significant barriers to coverage. Questionable efficacy, a high cost of USD 50,000 annually that could be incurred for more than a decade, and safety concerns all represent serious payer caveats.

As a result, high coinsurance requirements and stringent prior authorisation, including expensive testing to determine eligibility, could mean far less than 10% of eligible patients take aducanumab if it gains FDA approval.

The actual approval decision, however, has mixed expectations on the likely outcome. One former FDA official, who is now a healthcare regulatory consultant, said the “damning” FDA Advisory Committee (AdCom) meeting on 6 November leaves the FDA with no choice but to disapprove. A healthcare business consultant said strong external pressure from patient advocacy groups means it is more likely than not the FDA will still approve the drug. Most of the other experts this publication spoke to said they are uncertain due to an overwhelmingly positive FDA position combined with a very negative AdCom response.

The former FDA official said the FDA could reject aducanumab and require Biogen to complete a one-year study confirming its effect on reducing amyloid count. The FDA could then conditionally approve aducanumab while requiring an additional postmarket study to confirm the surrogate marker of reduced amyloid count is clinically meaningful, he added.

Two days after FDA scientists called evidence for aducanumab “exceptionally persuasive” in documents preceding the FDA AdCom, the FDA AdCom voted 8-1 against Biogen’s two Phase III studies – EMERGE (NCT02484547) and ENGAGE (NCT02477800) – showing evidence of efficacy. During the meeting, AdCom members took aim at both the data itself and the FDA’s approach to evaluating it. Aducanumab has a PDUFA date of 7 March 2021.

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Biogen, which has a market cap of $37.55bn, did not respond for comment. A GlobalData consensus forecasts peak sales for aducanumab of $6bn in the US and $8.4bn globally by 2026.

Significant barriers to coverage if Biogen antibody approved

If the FDA approves aducanumab, Medicare will be required to provide some form of access, explained the healthcare business consultant. However, the Centers for Medicare and Medicaid Services (CMS) will independently review the data when determining coverage and are not bound to the FDA’s conclusions regarding efficacy, the former FDA official added. Even if the FDA contradicts the AdCom in its approval decision, CMS officials are likely to pay close attention to AdCom member objections in making coverage decisions, including their questions regarding aducanumab’s efficacy, he added.

As a result, Medicare and private payers will most likely add stringent prior authorisation and coinsurance requirements to aducanumab, pricing the majority of potentially eligible candidates out, the consultant and the former FDA official agreed. Specifically, the consultant expects coinsurance requirements of 25–33% for the drug, which is set to cost $50,000 per year.

Without strong coverage, far less than 10% of eligible patients would actually be able to use aducanumab, said George Perry, PhD, Semmes Foundation Distinguished University chair in Neurobiology, University of Texas, San Antonio. Given aducanumab is targeted at patients with early-stage AD, many could take the drug for more than 10 years, amplifying the drug’s lifetime cost, he added.

Furthermore, in addition to the high cost of the drug itself, PET scans to determine amyloid count could pose additional barriers to uptake as they cost around $5,000 and are currently uncovered by Medicare, said Barry Greenberg, PhD, Director, Alzheimer’s Disease Translational Center. In aducanumab studies, patients were required to have high amyloid counts as determined by PET scans, according to Additionally, since aducanumab is administered via monthly infusions, the logistical challenges associated with getting patients to sites able to perform infusions could further complicate uptake, the former FDA official said.

Though there is some correlation between amyloid count and AD, it is not concrete, Perry said. As a result, it is unclear if Medicare would begin covering the PET scans likely necessary to determine aducanumab eligibility, he explained. Still, it is possible that more cost-effective blood biomarker tests of amyloid count in development will become available within two years, Greenberg noted.

Overall, if approved, aducanumab would offer bleaker coverage prospects than other recent controversial FDA approvals, including that of Sarepta Therapeutics’ Exondys 51 (eteplirsen) for Duchenne muscular dystrophy, the former FDA official said. With up to 5 million potentially eligible patients, aducanumab’s use would involve a much larger population than in orphan diseases where controversial approvals are more common, he added.

Additionally, aducanumab poses a serious risk of amyloid-related imaging abnormalities (ARIA), meaning its unclear efficacy profile is packaged with a much clearer safety concern, the former FDA official continued. Perry agreed, adding concerns over ARIA give aducanumab a distinct disadvantage when compared to other AD drugs, such as Allergan’s Namenda (memantine), with similarly questionable efficacy. Namenda is used to treat moderate-to-severe AD. In the Phase Ib PRIME study (NCT01677572), 41% of patients taking the highest 10mg/kg dose of aducanumab, the dose purportedly showing some signals of efficacy, had ARIA. In 547 EMERGE patients receiving that same dose, 36 permanently discontinued treatment due to ARIA, and in 558 ENGAGE patients receiving that dose, 41 permanently discontinued treatment due to ARIA.

Payers are likely to strongly weigh this well-established safety concern against the less clear efficacy benefit when determining coverage plans, the business consultant explained.

Approval prospects uncertain though potential for conditional approval

Overall, experts this publication spoke to have no clear consensus over the likelihood of FDA approval for aducanumab. One expert said there is less than a 10% chance of approval, another said it is more likely than not to gain approval, and the remaining three said it is impossible to predict.

As one potential path forward, the FDA could reject aducanumab’s approval but request a one-year study confirming that aducanumab can reduce amyloid count, the former FDA official said. If Biogen meets this requirement, the FDA could grant the drug conditional approval for its impact on a surrogate marker, amyloid count, he continued. Biogen would then be required to perform a postmarket study to confirm that the surrogate marker of amyloid decrease corresponds to clinically meaningful disease outcomes, he said. This path forward, he explained, could appease most parties by not overtly delaying approval with a requirement of a new Phase III trial that might take 3–4 years.

Perry agreed with the former FDA official that the strongest evidence Biogen demonstrated of aducanumab was leading to decreased amyloid count. Patients receiving the highest dose of 10mg/kg in EMERGE (n=14) had a standardised uptake value ratio (SUVR) difference from placebo in amyloid count of -0.278 after 78 weeks, and patients with the same dose in PRIME had an SUVR difference from placebo of -0.277 after 54 weeks, according to FDA AdCom briefing documents. However, Perry cautioned that it was unlikely removing amyloid would have an effect on disease outcome.

Nevertheless, the FDA’s approval decision could have long-lasting implications on AD drug development going forward, Perry and another AD researcher agreed. Rather than trying new approaches to treating AD, many companies would reopen and refocus on the amyloid approach to combatting the disease for the next decade, likely ushering in a number of studies of amyloid-approaches in even earlier patient populations. The other AD researcher agreed, adding that approval could open the door for less scientifically rigorous studies given a perceived lower bar of FDA standards.

However, Greenberg said he is unsure the FDA approval decision would actually shift how trials are run. Instead, it could delay trial recruitment timelines given some potential AD clinical trial candidates would be using aducanumab, he said.

William Newton is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.