Biogen CEO Michel Vounatsos

Aducanumab, the Alzheimer’s disease candidate Biogen has co-developed with Eisai, today won accelerated approval from the FDA—which hinged its authorization of the drug on a new clinical trial.

The FDA hopes the trial will resolve longstanding questions over aducanumab’s effectiveness—questions that prompted an advisory committee of the agency last year to recommend against approving the drug. But the committee was not asked to evaluate whether the drug warranted an accelerated pathway approval.

“That is one way the FDA appears able to come up with a different path of action here” from the committee, Jefferies analyst Michael Yee wrote in a research note.

Biogen plans to market aducanumab under the name Aduhelm (aducanumab-avwa).

The FDA approved Aduhelm via its accelerated approval pathway, which the agency can use for a drug for a serious or life-threatening illness that provides a “meaningful” therapeutic advantage over existing treatments.

However, as part of that accelerated approval, the FDA will require Biogen to conduct a new randomized, controlled clinical trial to verify the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA said, it may initiate proceedings to withdraw approval of the drug.

Withdrawal of an FDA approval is rare; one of the most dramatic examples came in 2011, when the agency revoked the agency’s 2008 approval of an indication for Avastin (bevacizumab) with the chemo drug paclitaxel for the treatment of women with HER2-negative metastatic breast cancer (MBC) in the United States., concluding that the drug had not been shown to be safe and effective for that use.

Brad Loncar, CEO of Loncar Investments, tweeted today that the FDA’s accelerated approval “is probably a reasonable middle ground here. Though good luck taking the drug off the market if future data doesn’t support the its [sic] efficacy.”

The FDA’s accelerated approval pathway authorized Aduhelm based on the surrogate endpoint of reduction of amyloid beta plaque in the brain. Amyloid beta plaque was quantified using positron emission tomography (PET) imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology.

“Predicting a specific outcome was always difficult in this case due to the controversy surrounding this resurrected product. But, we are not particularly surprised by the FDA’s reliance on a surrogate marker, which we had specifically pointed to as the only silver lining as a fallback for the agency to approve adu after the scathingly negative Advisory Committee meeting,” Sumant Kulkarni, an analyst with Canaccord Genuity, wrote in a research note.

By winning FDA approval, Aduhelm became the first therapy indicated for reducing clinical decline in people with Alzheimer’s disease, and the first therapy to tie improved clinical outcomes to removing amyloid beta. Aduhelm is the first treatment approved with an Alzheimer’s indication since 2003.

A decade of development

“This historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease,” Biogen CEO Michel Vounatsos said in a statement released minutes after the FDA approval.

“We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come. We are grateful for the contributions of thousands of patients and caregivers who participated in our clinical trials, as well as for the dedication of our scientists and researchers,” Vounatsos stated. “Together with the healthcare community, we are ready to bring this new medicine to patients and begin to address this growing global health crisis.”

Investors appeared to share Biogen’s optimism about aducanumab and brush off concerns about the confirmatory trial potentially not succeeding. After a halt in trading around the FDA announcement, shares of Biogen rocketed 60% to $458.10 at 1:31 p.m., a minute after trading resumed, before the share price slid to $395.85, still 38% above Friday’s close of $286.14.

“We have always assumed on approval that the stock would trade in the $400 range,” Marc Goodman, managing director, neuroscience and a senior research analyst with SVB Leerink, wrote earlier today in a research note. “This is long awaited good news for Biogen and for the Alzheimer’s space given the significant unmet need.”

SVB maintained its “outperform” rating on Biogen.

Yee of Jefferies also expressed optimism, writing that the approval was “consistent with our positive thesis that FDA was willing to analyze the totality of the data, take everything into consideration (including high unmet need), and realize risk/benefit was positive enough to approve this.”

As for the confirmatory trial, he added: “We’re confident the Street [investors] will not be overly concerned on this, and it would be done in a way that would not have significant jeopardy to stakeholders, in our view.”

Jefferies rates Biogen a “Buy,” and has set a one-year price target of $450 a share.

Trials halted, committee balks

Biogen surprised analysts in October 2019 by planning to file for FDA approval of aducanumab despite halting two failed Phase III studies of the drug seven months earlier. Biogen and Eisai asserted that one of those trials, Study 301 or ENGAGE (NCT02484547) met its primary endpoint showing a significant reduction in clinical decline—a result the companies later said was supported by results from a subset of patients in the other halted Phase III trial, Study 302 or EMERGE (NCT02477800).

The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee agreed in November 2020 that aducanumab’s U.S. sponsor Biogen presented strong evidence of a pharmacodynamic effect on Alzheimer’s disease pathophysiology in a Phase I proof of concept trial known as Study 103 or PRIME (NCT01677572), in a 5–0 vote with six members uncertain.

But in three other votes, the advisory committee balked at endorsing aducanumab:

  • By an 8–1 vote (two members uncertain), the panel agreed that EMERGE, viewed independently from ENGAGE, did not provide strong evidence supporting the effectiveness of aducanumab for the treatment of Alzheimer’s disease.
  • In a 100 vote (with one member uncertain), the committee also voted that it was not “reasonable to consider EMERGE as primary evidence of effectiveness of aducanumab for Alzheimer’s.”
  • The panel also concurred 7–0 (with four uncertain) that the PRIME trial failed to provide evidence supporting the effectiveness of aducanumab as an Alzheimer’s treatment.

The three trials assessing Aduhelm’s efficacy recruited a total of 3,482 patients. In the three trials, Aduhelm showed a dose- and time-dependent effect on the lowering of amyloid beta plaques—by 59% in ENGAGE, 71% in EMERGE, and 61% in PRIME.

As for safety, Biogen said, the most frequently reported adverse event was radiographic detection of events termed Amyloid Related Imaging Abnormalities (ARIA). ARIA -E and/or -H was seen in 41% of patients treated with Aduhelm 10 mg/kg compared to 10% of patients on placebo. Clinical symptoms were seen in 24% of patients treated with Aduhelm 10 mg/kg who had an observation of ARIA -E and/or -H, compared to 5% of placebo patients.

A warning for ARIA is included in the prescribing label for Aduhelm. According to the FDA, ARIA most commonly presents as temporary swelling in areas of the brain that usually resolves over time and does not cause symptoms, though some patients may show symptoms such as headache, confusion, dizziness, vision changes, or nausea. The label for Aduhelm also warns for a risk of hypersensitivity reactions, including angioedema and urticaria.

The most common side effects of Aduhelm were ARIA, headache, fall, diarrhea, and confusion/delirium/altered mental status/disorientation, the FDA added.

Kulkarni observed that the label did not limit Aduhelm’s use by stage of Alzheimer’s disease or by genetic markers (APOE4 carrier status, for example), and struck what he called “a lenient tone” by hinging continued approval on the confirmatory trial.

120 drugs in Alzheimer’s pipeline

Aducanumab is the first of several Alzheimer’s drugs that will become available in the next five to 10 years, said Howard Fillit, MD, founding executive director and CSO at the Alzheimer’s Drug Discovery Foundation (ADDF).

“The robust Alzheimer’s research pipeline, complemented by a growing number of biomarkers and other important research tools, means that the clinical trials underway today are more rigorous and more promising than ever.”

According to the ADDF, 120 drugs against Alzheimer’s are under study in clinical trials. Twenty percent of the drugs in clinical development for Alzheimer’s disease have received support from the ADDF, which has awarded more than $168 million to fund over 650 Alzheimer’s drug discovery programs and clinical trials in 19 countries since it was founded in 1998 by co-chairmen Leonard A. and Ronald S. Lauder.

$56,000 yearly list price

Biogen announced a list price or “wholesale acquisition cost (WAC) for Aduhelm of $4,312 per monthly infusion for a patient of 74 kg (163 pounds)—the average weight of a U.S. patient with mild cognitive impairment (MCI) or mild dementia. That would add up to $51,744 per year. At the maintenance dose (10 mg/kg), the yearly cost would increase to $56,000—but will be lower during the first year of treatment, Biogen said, due to the titration period.

Those list prices are too high, contends the nonprofit Institute of Clinical and Economic Review (ICER), which analyzes evidence on the effectiveness and value of drugs and other medical services. ICER has calculated a fair annual price to lie between $2,500–$8,300. In a best-case scenario, it added, aducanumab’s health gains would support an annual price between $11,100–$23,100.

“Only a hypothetical drug that halts dementia entirely would merit this pricing level. The evidence on aducanumab suggests that, at best, the drug is not nearly this effective,” ICER said in a statement.

However, Biogen and Eisai said they had committed to not increasing the price of Aduhelm for the next four years, and noted that access programs through private and public payers may reduce costs for some patients to zero. Soon after the approval, however, Biogen and Eisai announced a range of programs intended to support access for all qualified patients, including traditionally underserved populations:

  • Biogen said personal “Support Service Coordinators” were now available to patients and their families to provide one-on-one support, answer questions about Alzheimer’s and Aduhelm, assess financial assistance options, and locate healthcare providers and infusion sites.
  • Biogen and Eisai have partnered with Labcorp and Mayo Clinic Laboratories to help physicians and patients access cerebrospinal fluid (CSF) diagnostic lab testing to aid in the diagnosis of Alzheimer’s.
  • The Veterans Health Administration (VHA) is working with Biogen to finalize a multi-year agreement designed to support access for veterans. The VHA is the nation’s largest integrated health system with nine million enrolled veterans, about 48% of which are over age 65.
  • CVS Health has agreed, also partnering with Biogen, to offer cognitive screenings through its Project Health, designed to address care disparities for uninsured and underinsured Americans, particularly in racially and ethnically diverse communities. The program is scheduled to begin in September in the Atlanta, Boston/Providence, Charlotte, Charleston/Columbia, Chicago, Dallas/Fort Worth, Detroit, Houston, Jackson/Memphis, Los Angeles, Miami, New York City, Philadelphia, and Washington DC, regions.
  • Biogen said it intended to develop a program with the National Association of Free and Charitable Clinics (NAFC), a nationwide network of 1,400 clinics serving medically underserved Americans, that will support brain health and “culturally competent” Alzheimer’s disease education for patients and network healthcare providers.

Eisai joined Biogen in partnering on aducanumab in 2017—10 years after Biogen (then called Biogen Idec) began developing the drug under license from its original developer, Zurich-based Neurimmune.

Biogen and Eisai have succeeded where numerous other drug developers have failed in the long struggle to create successful new drugs for Alzheimer’s disease. Only a handful of drug successes have ever reached the market, and even they have merely slowed progression of symptoms by 6 to 12 months.

2014 Cleveland Clinic study found a 99.6% failure rate of clinical trials for Alzheimer’s disease drug candidates between 2002 and 2012. That study found high attrition rates for Alzheimer’s disease treatments, with 72% of agents failing in Phase I, 92% failing in Phase II, and 98% failing in Phase III.

“Eisai has been working on the creation of new treatments for Alzheimer’s disease since the early 80s through our relentless pursuit to understand the root causes of this disease, and we have spent more than a quarter of a century with people living with Alzheimer’s disease to understand their needs,” Eisai CEO Haruo Naito added. “We are very pleased to be able to open a new chapter in the history of Alzheimer’s disease treatment with the approval of Aduhelm.”