Case Study: Learning From The Aducanumab Story

The Most Controversial Approval In Recent History:

In January 2024, Biogen announced that it had discontinued the development and commercialisation of Aducanumab and handed back the asset rights to Neurimmune, who initially discovered the monoclonal antibody.
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This announcement finally marks the end of the Aducanumab saga at Biogen (saying that, given I thought something very similar during the ENGAGE and EMERGE results, you never really know). It thus allows for a brief overview of what went wrong for Biogen and what lessons development teams can take away.

Before I continue, it's essential to recognise and celebrate the ambition demonstrated by the Aducanumab team in pursuing an indication of the importance and unmet need of Alzheimer's disease. This short takeaway isn't a criticism of the development team nor another contribution to the (unending) debate about the veracity of the amyloid hypothesis. Instead, this is a short case study on what lessons development teams across all therapeutic areas can draw from this unique story.
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Given the unique circumstances surrounding the program and the broader ecosystem, I would suggest its likely that many teams may have ended up making similar decisions to Biogen.

An Unconventional Development Strategy:

The development of Aducanumab began with its discovery by the Swiss biotech company Neurimmune through its reverse translational medicine platform. Biogen later acquired the rights to develop aducanumab, and the Japanese drug maker Eisai joined efforts in 2017.

The 2012 PRIME randomised phase 1b study, which evaluated the safety and tolerability of aducanumab in 197 patients with mild Alzheimer's disease at four doses, showed dose-and duration-dependent reduction of amyloid plaque through PET scans and provided suggestive evidence that the drug reduced the rate of cognitive decline.

Based on this promising early data and in collaboration with the FDA, Biogen elected to initiate two identically designed phase III trials in 2015 (ENGAGE and EMERGE), recruiting patients with early Alzheimer's disease with confirmed amyloid pathology. These studies were designed to test the efficacy of aducanumab at two different doses using a clinical dementia rating scale as the primary endpoint.

The Ides of March:

In March 2019, Biogen and Eisai announced the termination of both phase III studies due to recommendations from a DMC after a pre-specified futility analysis, which suggested the trials were unlikely to meet their primary endpoints. The companies also terminated an ongoing Phase II safety study and the long-term extension of the PRIME Phase1b study. The announcement from Biogen highlighted the complexities of Alzheimer's disease and emphasised the need "to further advance knowledge in neuroscience."

Following this announcement, Biogen stock plummeted by 29%, representing its worst trading day since 2005, due to analysts' expectations that aducanumab could have eventually reached sales of $12B.
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A quote from SVB Leerink analyst Geoffrey Porges summarised market sentiment at the time: "…We cannot find any near-term catalysts that would help the stock recover…" Little did Geoffrey or anyone else know what would happen just seven months later.

The Lazarus Event:

On October 22, 2019, Biogen announced that, after consulting with the FDA, the company planned to seek regulatory approval for Aducanumab and submit a BLA in 2020.

The company reported that The Phase 3 EMERGE Study had met its primary endpoint and showed a significant reduction in clinical decline. Despite the identical ENGAGE study failing to achieve the same, a subset of patients in the study who received high-dose aducanumab supported the findings from EMERGE. The filing package included pooled results from both studies as well as results from the phase 1/1b studies.
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Biogen believed that the difference between these studies was that more patients on ENGAGE were exposed to higher doses for a longer period than EMERGE. These differences in dosing were hypothesised to be due to a protocol amendment that increased the number of patients on high-dose aducanumab (10mg/kg), which led to differences in relative enrolment.

A presentation from the company also showed that before the announcement, the company had two type C meetings with the FDA, indicating close regulatory collaboration.

The news was well received by wall street causing the stock to gain approximately 43% during premarket trading.

The response among clinicians and drug developers was divided. Despite significant scepticism, a sizeable number of experts awaited detailed data, which the company was due to present at an upcoming medical conference (CTAD).

During the scientific presentation, Biogen argued that the differences in the Phase III studies were driven by a protocol amendment that caused an imbalance in recruitment rates of patients on the highest dose across both studies.

The company showed that in the primary analysis of EMERGE, patients saw a reduction in clinical decline of 14% and 23% on the low and high doses of aducanumab, respectively, in comparison to placebo. Importantly, statistical significance was only achieved in the high-dose group. In the ENGAGE study, the reduction was reported as 12% on the low dose and paradoxically an increase of 2% on the high.

Biogen showed that ENGAGE had enrolled 200 more patients than EMERGE before the protocol amendment. The company argued that this had impacted the number of patients who received high-dose aducanumab.

Without accounting for the protocol amendment, 29% of patients in EMERGE and 22% in ENGAGE received the 10mg/kg dose for the full 14-week period. However, looking only post-amendment, this increased to 51% of patients in EMERGE and 47% of patients in ENGAGE.
The company argued that once this had been considered, patients in EMERGE saw a 24% reduction in their clinical decline at the low dose and 30% at the high dose, while patients in the ENGAGE study saw a decrease of 20% and 27% at the same dosing.

The Advisory Board:

In August 2020, the FDA announced it had accepted Biogen's submission and would evaluate Aducanumab under priority review (without Biogen having to submit a PRV).

The agency subsequently convened an advisory committee to provide non-binding advice to the FDA on approving Aducanumab. The advisory group, which included patient advocates, clinicians, and scientists, walked through the data and was asked to vote on a pre-specified set of questions.

The overwhelming sentiment towards Aducanumab (and the FDA) was negative, with criticisms centred around biostatistical discrepancies in the analysis, the drug's clinical effectiveness potential, and the way in which the agency presented the data.

When it was all said and done, the final question was whether it was reasonable to consider the EMERGE study as providing primary evidence of the effectiveness of Aducanumab, given the context of the whole briefing pack. 10 of the 11 external advisors voted no, with the remaining participant voting that they were uncertain.

One of the participants stated that they were "very, very disturbed" by the agency's interpretation of the clinical data and the way the advisory board had been structured.

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The Regulatory Payor Paradox:

In June 2021, the FDA granted conditional approval for Aducanumab based on the drug's ability to clear beta-amyloid. Furthermore, the label was surprisingly broad and indicated the drug was for use in all patients with Alzheimer's disease, but was subsequently narrowed to "in patients with mild cognitive impairment or mild dementia stage of the disease."

Following the approval, three of the FDA advisory panel resigned in protest and in January 2022, CMS announced it would provide coverage for the drug only to patients who had been enrolled on trials, arguing the drug didn't have sufficient evidence of being safe and effective, effectively denying to cover the drug.

Furthermore, a survey of 25 large private insurers in the US found that they viewed aducanumab as not medically necessary, with many classifying the drug as experimental or investigational. Further adding to the perilous emerging commercial picture, several large academic centres, including Johns Hopkins, UCSF, and UCLA, indicated they would not prescribe the drug.
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The Final Result:

Despite initial estimates that Aducanumab would be one of the most significant launches of all time, revenue from the drug was a mere $3 million in 2021 and $4.8 million in 2022. In 2023, Biogen stopped reporting Aducanumab sales separately in its quarterly updates. The company announced that in 2024, it had started a strategic review of the business, and after not being able to find external partners or financing for the program, the company was discontinuing the development and commercialisation of the drug.

What Can Drug Developers Learn From This Episode:

The Aducanumab story highlights the complex interplay between regulatory and commercial aspects of drug development. While the company was successful in gaining approval for the drug, its core stakeholders, insurers, prescribers, and patients, weren't convinced about its value.

While there is a pricing element to this story, with Biogen first electing to charge $50k per year for the drug before substantially cutting the list price, I would contend that this only magnified the issues in the drug's core development strategy.

Biogen found itself on a path to regulatory approval without a clear understanding of the impact of the evidence gaps within its program. Continuous gap identification and prioritisation is a core element of any clinical development program. It allows the development and strategy team to determine what critical questions need to be answered in order to best position the drug.

There is an unfortunate tendency in drug development to focus on evidence gaps related to regulatory approval at the expense of those pertaining to payers or supporting physicians to prescribe the drug with the (erroneous) understanding that these can be easily addressed through post-marketing studies. This may have played a role in the Aducanumab decision-making process.

Takeaways

1. Early and regular interactions with regulatory agencies are an invaluable opportunity to gain feedback on the acceptability of a development program.
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2. Integrated evidence planning is a genuine force multiplier for any drug development program, its essential to ensure that gaps are identified and prioritised holistically and that regulatory needs are consistent with those of other stakeholders.
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3. Transparency with clear and consistent communication strategies are essential throughout the life cycle of a development program.

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References:

https://www.cnbc.com/2019/03/21/biogen-shares-plunge-more-than-25percent-after-ending-trial-for-alzheimers-drug-aducanumab.html

https://investors.biogen.com/static-files/5a31a1e3-4fbb-4165-921a-f0ccb1d64b65

https://www.statnews.com/2019/10/22/biogen-to-submit-aducanumab/

https://www.statnews.com/2021/06/07/fda-grants-historic-approval-to-alzheimers-drug-designed-to-slow-cognitive-decline/

https://www.statnews.com/2021/06/07/twist-fda-alzheimers-decision-no-limits-on-patients/

https://www.statnews.com/2022/12/29/biogen-set-unjustifiably-high-price-for-alzheimers-treatment-investigation-finds/

https://www.bloomberg.com/news/articles/2021-11-18/insurers-balk-at-paying-for-biogen-alzheimer-s-treatment?embedded-checkout=true&leadSource=uverify%20wall

https://www.pbs.org/newshour/health/insurers-view-new-alzheimers-drug-as-experimental-wont-cover-treatment-for-some-customers

https://www.reuters.com/business/healthcare-pharmaceuticals/biogen-alzheimers-drug-hits-roadblocks-with-some-hospitals-insurers-2021-07-15/

https://endpts.com/private-insurers-decline-to-cover-biogens-new-alzheimers-drug-in-escalating-standoff-report/

https://www.fiercehealthcare.com/payers/unitedhealthcare-adopts-limited-coverage-policy-aduhelm

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193636/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8926483/

https://pubmed.ncbi.nlm.nih.gov/35542991/

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000TOC.cfm

https://investors.biogen.com/news-releases/news-release-details/fda-grants-accelerated-approval-aduhelmtm-first-and-only

https://link.springer.com/article/10.1007/s40265-021-01569-z

https://link.springer.com/article/10.14283/jpad.2022.30

https://investors.biogen.com/static-files/e4a90dde-5b3a-4167-887b-96267a6550f1

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