In June 2021, Biogen and Esai’s Aduhelm became the first Alzheimer’s treatment targeting the pathophysiology of the disease – the accumulation of amyloid beta plaques in the brain – to be approved by the U.S. Food and Drug Administration (FDA). A bit over 2 years after this historic approval, on January 31st, Biogen announced that it would halt Aduhelm sales and development due to a realignment of its Alzheimer’s disease franchise. These resources will be reoriented towards Leqembi, Biogen and Esai’s new treatment that received FDA approval in 2023, while Aduhelm’s rights will be reverted to Neurimmune. How does Biogen intend to pivot from Aduhelm’s failure?
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Why did the FDA approve Aduhelm?
Aduhelm was approved through the FDA’s accelerated approval pathway, which is used for drugs that fill an urgent, unmet medical need. This pathway allows drugs to be approved based on surrogate endpoints that are thought to predict clinical benefits, rather than direct evidence of improved patient outcomes. The decision to approve Aduhelm under this pathway was partly due to the considerable burden the disease represents, with over 55 million people suffering from dementia in 2020 around the world, according to Alzheimer’s Disease International.
What is the controversy with the approval of Aduhelm?
This decision came despite quasi-unanimous advice against approval from an FDA independent advisory committee, which cited insufficient evidence that Aduhelm improved patients’ cognitive function. This committee had not considered the accelerated approval option during their deliberations, leading to a situation where the FDA granted approval based on a different premise than what was presented to the committee. Indeed, the drug’s approval relied on its ability to reduce amyloid-beta plaques in the brain. This change sparked concerns and led to the resignation of three committee members.
This controversy raised concerns about the accelerated approval pathway and even led the Office of Inspector General (OIG) at the U.S. Department of Health and Human Services to release a study. The OIG concluded that while the accelerated approval pathway holds promise for patients who face serious illnesses where adequate treatments are lacking, it can result in drugs staying on the market and being administered to patients for years without the predicted clinical benefit being verified.
Why did Biogen fail with Aduhelm?
Besides the controversy surrounding Adulhem’s approval in 2021, the high cost of the treatment, estimated at $56,000 per year for a patient, has also been a significant point of concern. This price point has led to debates over the drug’s affordability and the economic impact on insurance systems.
The concerns raised at the time of approval were later confirmed as the safety and efficacy of the drug did not surpass the controversy. The FDA based its approval on Aduhelm’s ability to reduce amyloid-beta plaques in the brain, a surrogate endpoint. However, the clinical benefit of plaque reduction in terms of slowing the progression of Alzheimer’s disease remained uncertain. Additionally, safety concerns arose due to brain swelling and bleeding observed in some patients during clinical trials.
Additionally, the deaths of patients treated with Aduhelm kept the controversies and the safety concerns alive even though there wasn’t sufficient evidence to link those events to the drug. Adding to its troubles, Biogen withdrew its application for marketing authorization of Aduhelm in Europe after the European Medicines Agency recommended refusing the authorization. The agency cited concerns that the drug’s clinical benefit had not been convincingly demonstrated and expressed worries about safety issues, including brain abnormalities suggestive of swelling or bleeding.
In the wake of Aduhelm’s challenges, Biogen and Eisai’s other drug, Lecanemab, is showing promise notably in phase 3 trials, potentially offering a more effective and safer alternative. Leqembi also targets amyloid-beta deposits but has demonstrated a clearer clinical benefit and a more favorable safety profile, raising questions about Aduhelm’s place in Alzheimer’s treatment moving forward. If questions on Aduhelm’s future in the global Alzheimer’s treatment can subsist, its fate in the Biogen portfolio is sealed as the drug’s rights will be reverted to Neurimmune.
Biogen’s move to halt Aduhelm’s development
We reached out to Logan DuBose, physician, and co-founder of Olera, a startup specializing in the care of older people including memory care. According to him, Biogen’s decision to pivot away from Aduhelm is likely related to contradicting phase III clinical trial results where the drug was tested in thousands of people with Alzheimer’s disease to see if it improved symptoms of cognitive decline. “The EMERGE and ENGAGE trials conducted in 2019-2020, evaluated Aduhelm’s ability to slow the cognitive decline caused by Alzheimer’s disease. However, both were stopped early because they did not show any benefits of clinical significance. Only after the trials were officially stopped, did follow-up on supplementary data from some patients in one of the two studies (EMERGE) show some statistically significant changes in cognitive testing. However, these changes didn’t meet standard clinical result thresholds. More concerning is that the other clinical trial (ENGAGE) didn’t show the benefits even after supplementary data post-stopping the trial was considered,” said DuBose.
“This ambiguity prompted skepticism from regulatory agencies like the FDA and reimbursement bodies like Medicare, which denied coverage due to this lack of effectiveness in trials and high costs to patients. The costs of taking this drug likely outweigh any mild benefits.”
If Dubose thinks Biogen’s decision to shift focus toward Leqembi makes sense he believes there are some lessons to learn from Aduhelm’s failure: “Biogen’s pivot away from Aduhelm underscores the importance of robust clinical evidence, not just statistical significance, and how practical clinical benefits in Alzheimer’s drug development determine if a drug is paid for by insurance or made available to the public. The challenges shown in these trials with Aduhelm highlight the need for a cautious and rigorous approach in evaluating potential treatments for this complex and devastating disease.”
Aduhelm: an important step for Alzheimer’s treatment
Neurimmune, who was initially licensing the rights to test Aduhelm in clinical trials, is now faced with how to move forward with these less-than-ideal clinical trial results. “Due to some positive indicators in the Emerge trial, as well as promising results in the pre-clinical phases, Neurimmune will likely push to work with researchers to further invest in clinical trials to reconcile these differences in Biogen’s results from Emerge and Engage trials and continue to attempt to establish the drug’s clinical significance,” said DuBose.
However, with Aduhelm’s reputation and its benefits that remain uncertain, Neurimmune will need to be cautious in the process.
Andrea Pfeifer, CEO at AC Immune, a company specializing in neurodegenerative diseases, puts Aduhelm’s failure into perspective: “The development of Aduhelm and all the other Abeta antibodies is a major step forward in the treatment of Alzheimer’s patients. It means amyloid has been validated as a clinical target for Alzheimer’s disease-modifying therapies and as such, is creating renewed interest and excitement in the field of neurodegeneration. It also represents validation of immunotherapy, in a passive sense, as an effective therapeutic modality.”
Although the marketing of Aduhelm has been stopped and is expected to be replaced by lecanemab and donanemab, the first generation of intravenously infused antibodies is in fact a new beginning to the story of treating Alzheimer’s disease.
“The next generation, active immunotherapies (vaccines) could take us so much further in addressing this scourge and saving brain function before it is lost, providing the possibility for significantly enhanced global access,” said Pfeifer.
“It is a natural process that early and important milestones are eclipsed by future, more advanced developments.”
Leqembi: Biogen’s new Alzheimer’s candidate
Leqembi represents a significant development in Alzheimer’s treatment for both Biogen and the broader Alzheimer’s community. The FDA granted traditional approval to Leqembi for the treatment of Alzheimer’s disease after a confirmatory trial verified its clinical benefit. This approval marks Leqembi as the first amyloid beta-directed antibody to transition from accelerated to traditional approval for Alzheimer’s disease treatment.
Leqembi is currently under review by the European Medicine Agency and the marketing authorization decision is expected at the end of June 2024. After the U.S. and Japan, China has also approved Leqembi for the treatment of Alzheimer’s disease. With an estimated 17 million Alzheimer’s patients in China, according to Esai, this marks a significant step into Leqembi’s market access journey.
How does Leqembi work?
Leqembi targets and affects the underlying disease process of Alzheimer’s, rather than merely treating the symptoms. It is designed to slow the progression of the disease in its early stages by targeting beta-amyloid plaques in the brain. While not a cure, Leqembi has demonstrated in clinical trials that 76% of patients showed no deterioration and 60% improved over 18 months. It’s important to note that Leqembi is administered as an intravenous infusion every two weeks and comes with a warning due to safety concerns, including risks of brain swelling and bleeding.
Biogen’s strategic shift with Leqembi: A path forward after Aduhelm
For Biogen, the development and approval of Leqembi, in collaboration with Eisai, signals a strategic shift towards advancing Alzheimer’s disease treatments with potential disease-modifying effects. This move could help Biogen rebuild its reputation and financial prospects in the Alzheimer’s market, especially after the controversies surrounding Aduhelm. Leqembi’s approval and its reception by the medical community and patients could play a crucial role in determining Biogen’s future success in the Alzheimer’s disease franchise.
It seems Leqembi’s journey will be clearer than Aduhelm’s in every way. While Leqembi’s $26,500 price tag may remind the controversy about Aduhelm’s affordability, Medicare announced that it would cover 80% of the treatment.
“Advances in the treatment or prevention of Alzheimer’s will be accompanied by huge economic benefits as the administration, logistics, and efficiency of treatment are all poised to improve significantly,” said Pfeifer.
What other diseases does Biogen focus on?
While the spotlight has been on Biogen’s Alzheimer’s portfolio and not always for the right reasons, the biotech giant has more than one string to its bow.
As we mentioned earlier, the company has been making significant shifts in its strategic focus and operations, particularly in response to the challenges and competitive landscape it faces in its key therapeutic areas. The company has been known for its contributions to neurology, including its work in multiple sclerosis (MS) treatments and the development of therapies for spinal muscular atrophy (SMA). However, recent years have seen Biogen navigating through complex waters.
Biogen has discontinued and paused several other programs, including BIIB093, a phase 3 asset for large hemispheric infarction, due to operational challenges and strategic considerations. Another notable change involves BIIB131, a small molecule in phase 2b development for acute ischemic stroke, with the initiation of its trial being paused. Additionally, development of the Ionis-partnered antisense oligonucleotide BIIB132 for spinocerebellar ataxia type 3 has been discontinued.
The company is gearing up for anticipated approvals for several products. Biogen recently received accelerated approval for Qalsody (tofersen) for superoxide dismutase 1 (SOD1) ALS and traditional approval for zuranolone to treat postpartum depression. Another interesting Biogen candidate, Tofidence, a tocilizumab biosimilar, received FDA approval in September 2023.
Additionally, Biogen completed the acquisition of Reata Pharmaceuticals in 2023, enhancing its rare disease portfolio with Skyclarys (omaveloxolone), the first FDA-approved treatment for Friedreich’s Ataxia in the U.S. This move strengthens Biogen’s position in the rare disease market, adding valuable assets to its portfolio. Biogen could be able to capitalize on this asset as Skyclaris received approval from the European Commission earlier this week.
What does the future hold for Biogen?
In a move to revitalize its growth trajectory, Biogen announced a substantial reduction in its workforce, aiming to cut about 1,000 jobs, which accounts for 11% of its global workforce. This decision is part of a broader strategy to reduce costs and reallocate resources towards more promising areas of its portfolio, particularly focusing on the launch of its recently approved Alzheimer’s drug, Leqembi. This cost-cutting measure is seen as a response to the slumping sales of its MS treatment, Tecfidera, due to competition from cheaper generic alternatives, and the uncertain future of its SMA drug, Spinraza, amidst intense competition.
Biogen’s CEO, Christopher Viehbacher, emphasized the necessity of these changes to align the company’s cost base with its current reality, reflecting the shift in its product fortunes and the competitive pressures it faces. The company has set a goal to reinvest approximately $300 million from the cost savings into drug launches and research and development efforts, aiming to achieve a net reduction of about $700 million in operating expenses by 2025. This strategic pivot underscores Biogen’s commitment to focusing on high-growth areas, including the advancement of its Alzheimer’s disease portfolio, while also exploring opportunities across rare diseases, immunology, and neuropsychiatry.
Biogen’s efforts to streamline its operations and focus on key growth drivers reflect a broader industry trend of biopharmaceutical companies realigning their strategies to adapt to changing market dynamics, regulatory challenges, and the evolving needs of patients. The company’s current pipeline and cash reserves position it to be selective in pursuing strategic deals that align with its core areas of focus.