Doubtful clinical efficacy, despite risky side effects. Deep divisions among clinicians, patients and regulators. A price that practically dares public and private payers to limit access.

That’s not an enviable set of circumstances for the teams charged with creating promotional and market-access communications for any new drug. Yet it’s what the marketers working on Biogen’s recently approved Alzheimer’s drug, Aduhelm, are facing as they gear up to launch the first new medication for the disease in 18 years.

Controversy was sparked almost immediately after the Food and Drug Administration gave Aduhelm the green light on June 7. Its impact may be felt, to a large extent, in the area of market access. 

“Payers want to know who is an appropriate patient for a medication given the data that’s available,” explained one agency executive who has experience working on market-access communications for drugs that, like Aduhelm, were approved via FDA’s accelerated-approval program. 

Accelerated approval allows products to reach the market if they treat serious conditions and fill an unmet medical need. Medicines that go this regulatory route need only meet a “surrogate endpoint” such as shrinking tumor size, rather than a primary one such as prolonging life.

“An endpoint that doesn’t tie directly to the clinical data per se is a harder conversation to be having from an access perspective,” the executive added.

In this case, the FDA sanctioned Aduhelm (aducanumab) based on its ability to clear amyloid, the sticky protein that clumps into plaques in the brain. It’s reasonably likely, regulators said, that clearing plaque may delay patients’ clinical decline, even though scores of other plaque-clearing drugs failed to show such a benefit and internal documents reveal the agency’s own statistician had recommended against approving Aduhelm

The FDA also granted the drug a broad label. Anyone with Alzheimer’s can get it, even though people with advanced disease were not studied in the Biogen trials. 

The drugmaker stoked concerns over affordability when, hours after the approval, it set a list price of $56,000 a year. That was almost five times what analysts had been forecasting. Combined with the high disease prevalence of Alzheimer’s – 5.3 million people in the U.S. over 65 suffer from the disease – market access became front and center. 

The drugmaker expects patients on Medicare to comprise 80% of Aduhelm’s U.S. patient population. Medicare beneficiaries must bear 20% of a prescription drug’s cost themselves, which in this case amounts to $11,200. That’s not to mention the pricey diagnostic imaging that will be needed to qualify for the drug and monitor side effects.

The Alzheimer’s Association, which had enthusiastically welcomed Aduhelm’s arrival and had funded a pro-approval ad campaign during the run-up to the decision date, switched gears and criticized the price. It vowed to work with payers and to attempt to convince Biogen to lower the price tag so that patients aren’t overwhelmed by out-of-pocket costs.

Biogen had anticipated some of the fallout, announcing it would lock in the price for four years and that it would look to craft a value-based agreement with private insurer Cigna. Since it’s not yet known whether amyloid causes Alzheimer’s, as the surrogate endpoint is not yet well understood, that could make it difficult for the parties to mutually align on an outcomes-based measurement.

“Oftentimes customers have their own data sets available that they can use to pull real-world evidence,” said the agency executive. “From that perspective, you can enter into a value-based agreement,” one which would be based on biomarkers rather than clinical benefit.

Would payers be comfortable enough with that to extend coverage? Possibly, as long as the biomarker helps identify appropriate candidates for the drug, the expert said. Value-based contracts may help ensure coverage from both private and public payers – but sustainability of the healthcare system is another matter.

As an infusion drug, Aduhelm would be covered under Medicare Part B. Even the $7 billion in Aduhelm revenue analysts initially projected is more than twice the annual cost of the current highest-spend drugs in Part B. That’s according to an analysis by Kaiser Family Foundation, which said the brand’s actual revenue could approach $112 billion. Healthcare policy shop Altarum forecast Aduhelm would raise prescription drug spending by more than 8% in the next few years.

The scale of spend could be too big to ignore, spurring payers to put up limits. Even Medicare could tighten the pursestrings. The Centers for Medicare and Medicaid Services (CMS) could launch a National Coverage Decision (NCD) to specify the circumstances under which the program will provide reimbursement. 

A CMS decision to allow coverage with evidence development could compel Biogen to collect more efficacy data postmarket as a condition of coverage. States, too, could feel pressure to limit access, despite the threat of legal action.

Policy makers most likely don’t want to curtail access to effective medicines. But if CMS uses the NCD process to protect Medicare beneficiaries from getting a treatment whose risks outweigh its benefits, that would effectively decouple CMS reimbursement from FDA approval – which would be unprecedented. 

Patients, meanwhile, seem willing to take the risk. The FDA’s Peter Stein, who directs the Office of New Drugs, said during a press conference that the FDA “heard very clearly from patients that they’re willing to accept some uncertainty to have access to a drug that could provide meaningful benefit in preventing the progression of this disease – which, as we all know, can have very devastating consequences.”

Per the FDA, Aduhelm is the first treatment in clinical trials to show “proof of concept” in an early-stage trial that reducing amyloid could slow decline, a finding that was bolstered by an analysis of a subset (those taking a higher dose) of one of the company’s late-stage trials. Patients in Biogen’s second Phase III trial, though, failed to show benefit.

The FDA held a “listening session” with patients in January following a November advisory committee meeting and public hearing, during which several patients also had their say. The advisory committee eventually ruled that the failed trial could not be separated from a successful study, and that there was no overwhelming evidence of efficacy, voting 10-0 against approval.

Patients are realistic about Aduhelm’s efficacy. “I don’t see any patient advocates saying, ‘This is a cure.’ They’re saying, ‘This is a glimmer of hope,’” said Jack Barrette, founder of Wego Health, a network of patient influencers. “Folks who are leaders themselves are very aware that in some ways this is a real-time trial of the drug and are aware that if it doesn’t work, we’ll all find that out, too.”

In addition to the Alzheimer’s Association, other patient advocacy groups that pushed for approval included USAgainstAlzheimer’s, which had argued that patients cannot afford to wait any longer for a treatment.

On the professional side, the American Geriatrics Society argued that approval was “premature,” in part because the clinical trials were incomplete and the relevance of a positive finding “ambiguous.” And three physician members of the FDA’s advisory committee have since abdicated their committee seats, with one characterizing the approval as the agency’s “worst decision.”

That said, a subsequent poll of U.S. neurologists by investment bank Jefferies found that many stand ready to prescribe the drug. Findings suggest at least 300,000 patients could wind up on the drug, equating to $10 billion to $15 billion in peak Aduhelm sales from the U.S. alone. Biogen, for its part, has said it will not promote Aduhelm outside of the patient population studied in trials, which translates to about 1.5 million people. 

At the end of the day, Alzheimer’s patients and caregivers who, as one of Wego’s members put it, “have the misfortune of real-life experience,” are understandably thrilled to have some positive news to counter the brutality of this disease. 

“We need to move forward,” said Barrette. “Hope is not a scientific construct. But in the patient community, it’s an outcome.”

So it stands that the first newly approved drug for Alzheimer’s since 2003, which should be a glamour assignment for marketers, isn’t. The approval of a drug with uncertain clinical value and a price much higher than many felt was justified, combined with the scale and budgetary impact of Aduhelm, has caused controversy that will reverberate for the rest of this year, and likely beyond.