Aduhelm, a medication to treat mild stages of Alzheimer's disease, was launched by Biogen in June 2021. The approval was highly controversial and a cascade of events took place which resulted in the discontinuation of its commercialization in May 2022. This articles describes the story of Aduhelm from discovery to the end, and reflects on strategic decision making in drug development.
I have been working for many years in Alzheimer's disease drug discovery and followed with high interest the development of Aduhelm both from the clinical science as well as the business perspective. I have already written last year an article that reflects on the go-to-market strategy for Aduhelm and what can go wrong. This is now the entire story about Aduhelm: the initial promising clinical science, the controversial approval and the unfortunate end.
Alzheimer’s disease (AD) is the leading causes of dementia in the elderly, affecting over 50 million people worldwide. There is no cure for this type of dementia, although researchers are constantly looking for new ways to treat it. The most common known avenue is the development of new drugs that target specific proteins in the brain known as amyloid-beta peptides. As we age, our brains produce more of these peptides, which in case of AD causes the formation of amyloid plaques. Biogen, a drug company, has developed the drug Aduhelm against these amyloid plaques.
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Biogen’s Aduhelm and How it Started
Aduhelm is a medication to treat Alzheimer’s disease with the active ingredient aducanumab. It is a fully human IgG1 monoclonal anti-amyloid antibody that removes aggregated forms of amyloid beta (Aβ) found in the brains of people with Alzheimer's disease. Aduhelm is administered as a monthly injection to patients with mild cognitive impairment or mild dementia.
The long history of Aduhelm started, when Swiss-based Neurimmune Therapeutics AG in collaboration with the University of Zurich, identified protective anti-amyloid antibodies in healthy elderly people and patients with slowly progressing dementia. This research led to the discovery of aducanumab. Neurimmune licensed aducanumab for the treatment of Alzheimer’s disease to Biogen in 2007, which further developed it jointly with Eisai since 2012. The Japanese company Eisai has introduced Aricept (donepezil) the first drug for AD back in 1996.
The Mechanism of Action of Aduhelm
Beta-amyloid is a protein that is normally present in the brain. In Alzheimer’s disease, it clumps into amyloid plaques. Therefore, medical research has for a long time focused on removing amyloid plaques. Aduhelm binds to these amyloid plaques, specifically at a confirmational epitope, and triggers the immune system to destroy the plaques. The disputed amyloid hypothesis assumes, that once the plaques are removed, the brain cells will stop dying and cognitive function will stop deteriorating. Treatment with Aduhelm aims at slowing down the progression of the disease, particularly in patients in the early stages of Alzheimer’s disease. However, Aduhelm does not reverse the damage that has already been done.
Figure 1. Data were collected from public sources such as Clinicaltrial.org, press releases and media reports (e.g., FiercePharma.com). Dates for the clinical trials as posted on Clinicaltrial, which may not always be consistent with media announcements or the actual start of patient enrollment. Similarly for dates extracted from media reports.
Clinical Development of Aduhelm from 2011 to 2019
Aduhelm in Phase 1: Reduced levels of Amyloid β
In 2011, Biogen launched the first Phase I clinical trial with Aduhelm in patients with mild to moderate Alzheimer’s disease. The first study enrolled 18 patients who had already been treated with another Alzheimer’s disease drug, Aricept (donepezil). Patients who received Aduhelm had improved cognitive function by a median of 9% compared to a placebo group. This as such is not overwhelming, but promising in the light of a Phase I safety and pharmacokinetic study design. The dose ranged from 0.3 to 30 mg/kg and because of the mild side-effects, the dose was increased to even 60 mg/kg since (this corresponds to 4,2 g for a 70 kg person).
A year later, another Phase I study, called PRIME, was started as multi-center, multiple-dose study in 166 patients. Patients were analysed next to cognitive and mental tests with amyloid PET and MRI scans (positron emission tomography and magnetic resonance imaging). A significant reduction of cortical amyloid in a dose-dependent manner was observed showing efficacy against the drug target of Aduhelm.
Aduhelm in Phase 2: Limited evidence for slowing cognitive impairment
Biogen reported results of Phase 2 trials in late 2018. Those studies evaluated the safety of continued dosing of Aduhelm, in addition to checking for a reduction of amyloid plaques and a slowing down of cognitive decline in participants with early stage and symptomatic Alzheimer’s disease. Unfortunately, Aduhelm failed its primary goal of showing slower cognitive decline at the 12-month mark. The data were reviewed after 18 months and positive effects were observed in the highest dose. The highest dose was shown to reduce the amyloid plaques in the brain, as well as positive responses on cognition.
A note on the at first glance non-chronological dates: some of the studies used a roll-over design such as the PRIME study, which was continued for three years as long-term open-label extension phase. Consequently, data were not always reported at the end of the study.
Aduhelm in Phase 3: Reduction of Aβ-load but weak evidence for slowing cognitive decline
In 2015, Biogen initiated two Phase 3 trials, called ENGAGE and EMERGE, which enrolled approximately 3,300 participants with relatively mild Alzheimer’s disease in North America, Australia, Europe, and Asia. The primary outcome measures were cognitive and functional decline per the CDR-SB Test. The secondary outcomes included further cognitive tests such as the MMSE (see table below for details).
Test Acronym | Test | Methodology |
CDR-SB | Clinical Dementia Rating Scale-sum of Boxes quantifies the severity of symptoms of dementia on a scale from 0 -18 | Structured-interview protocol to assess a patient's cognitive and functional performance in six areas. |
MMSE | Minimal Mental State Examination | 30-point questionnaire including problem solving. |
ADAS-cog13 | Alzheimer's Disease Assessment Scale | Tasks to assess mood and behavioural changes |
ADCS-ADL | Alzheimer's Disease Cooperative study Score -Activities of Daily Living | Questionaire with ~23 tasks a patient can handle indepently or requires assistance |
In 2019 Biogen and Eisai stopped the two Phase 3 studies, because Aduhelm did not appear to be working as intended and would miss the primary endpoints. However, seven months later, Biogen announced in October 2019, that a reanalysis of larger data sets indicated that at high doses the medicine appeared to reduce cognitive decline in a subset of patients: In the EMERGE trial, patients on the highest dose, 10 mg/kg, had a significant reduction in decline on the primary endpoint, the CDR-SB. This group also scored better on secondary endpoints MMSE, ADAS-Cog, and ADCS-ADL-MCI. Although the ENGAGE trial did not meet the primary endpoint, again an exploratory analysis suggested that a subgroup of patients who had received 10 or more 10 mg/kg doses declined more slowly, similar to comparable EMERGE participants.
To cut the story of all clinical studies with Aduhelm short:
A significant dose-dependent reduction of amyloid load was achieved through administration of Aduhelm.
Evidence for a consistent reduction of cognitive impairment or slowing down of progression was weak and only significant in sub-populations of patients. Nevertheless, Biogen decided to apply for regulatory approval.
Approval and Launch of Aduhelm in 2021
In October 2019, Biogen applied for regulatory approval for Aduhelm (aducanumab) at the FDA and later, in 2020, in the European Union as well as Japan. Notably, an FDA advisory committee voted against approval in November 2020 because of the weak efficacy data.
Surprisingly, on June 7 in 2021, the FDA approved Aduhelm under the agency's accelerated approval pathway, although the FDA advisory committee renewed its thumb down (1). The accelerated approval program is intended for drugs that fulfill an unmet medical need to enter the market early based on surrogate, or biomarker data. In case of Aduhelm, it requires substantial evidence of effect on an intermediate marker (amyloid removal, which was shown), reasonable likelihood of a meaningful clinical benefit (such as slowing down cognitive impairment, which was controversial), and a Phase 4 trial, which provides evidence for such a benefit (consequently, yet another clinical trial, ENVISION, is on its way). A success for Biogen, but it is not the end of the story.
The Beginning of the End from 2021 to 2022
There has not been any new drug for treating Alzheimer's disease approved since 2003. This is why Aduhelm was such a hopeful medication to many patients, care givers and doctors. The following will read as excitingly from a business perspective but keep in mind that after nearly two decades of intensive pharma research and development again no new therapeutic option for AD is in sight! The following cascade of regulatory, commercial and organisational events took place.
Aftermath at the FDA and Disapproval of Aduhelm in Europe and Japan
The decision for approval of Aduhelm has raised a controversy and shortly after the approval, three FDA advisors resigned. The FDA launched an independent investigation into Aduhelm's approval on July 9, 2021. This also brought the accelerated approval program under scrutiny, which will affect e.g., Eli Lilly's accelerated approval request for donanemab, an antibody that also targets amyloid plaques. In December 2021, the EMA and the PMDA rejected Aduhelm in Europe and respectively Japan.
After an intensive discussion over the reimbursement of Aduhelm, which should be sold at a much criticized list price of $ 56,000 per year, Biogen decided to half the price to $ 28,200 in December 2021. In fact, Centers for Medicaid & Medicare Services (CMS) decided in April 2022 to restrict medical coverage of Aduhelm to only those participating in an approved clinical trial. To put it simply, no reimbursement for this drug.
Sales of Aduhelm never really kicked-off and remained sluggish
Biogen launched Aduhelm in June 2021. Third-quarter sales reported a meager $ 300,000 (non-consolidated) instead of the originally forecasted $ 14 million for this period. Fourth-quarter results reported an increase to $ 1 million and the sales for the first quarter in 2022 were just $ 2.8 million. These numbers are far of from forecasted consensus peak sales around $ 9 billion in 2026.
In March 2022, Eisai decided to abandon Aduhelm and leave the decision making and commercialization right to Biogen (still securing a tiered royalty based on sales of Aduhelm between 2 and 8%).
Consequences for Biogen and Restructuring
Biogen offers next to Aduhelm a significant drug portfolio for treating multiple sclerosis, spinal muscular atrophy and other indications. Total sales in 2021 were around $ 9 billion, which is in the order of forecasted peak sales for just Aduhelm alone. Consequently, the expectations were high: starting from a share price of around $ 270 before the approval in June 2021, the share price jumped to nearly $ 415 on June 10. Since then, the share price fell steadily below $ 200 in May 2022.
The domino-effect after the unlucky launch also resulted in a number of changes within the organisation. The Head of R&D, Al Sandrock, retired in November 2021, two board members left in January 2022. Biogen announced in May 2022 that its CEO, Michel Vounatsos, will step down. To which extend these changes might be related to the failure of Aduhelm, or just by coincidence, a "natural event" as termed by Vounatsos, is not the scope of this article. But a clear consequence of the slow uptake in revenues is the restructuring plan of $ 500 million in annual cost cutting including lay-off as many as 1,000 employees, which was announced by Biogen In December 2021.
In May 2022, Biogen decided to discontinue its marketing efforts for Aduhelm (3).
Figure 2. Impression of Aduhelm's efficacy to illustrate the dilemma of: (1) inconsistent, weak reduction of the cognitive impairment as clinical endpoint versus (2) significant, dose-dependent change in amyloid plaque load on the molecular level.
Data extracted from the briefing document for the FDA Advisory Committee (Nov 2020). Data from the 78 week mark of the Phase 3 studies EMERGE (derived from Table 3; Figure 5 and Figure 6; here, condensed data presented as wide bars) and ENGAGE (derived from Table 10 and Figure 13; here, condensed data presented as slim bars) (2).
The conclusion of the reviewers: "The totality of the data does not seem to provide sufficient evidence to support the efficacy of the high dose." "... a study fully completed ... is needed ... ." (8. Appendix 2: chapter 5.3 on page 341).
Reflections and Conclusions
The launch of a drug, here Aduhelm, failed. The reason, insufficient efficacy data meaning no obvious benefits for the patient. Share prices dropped. Nothing new in the bio-pharma business, it is actual the normal. Well, the story of Aduhelm is fascinating. The discovery was promising in the early 2000s, the first clinical trials encouraging, and with the first new treatment for Alzheimer's disease at the horizon, the approval was pushed through. But then the launch and subsequent events were disastrous. What can we learn from the long journey with Aduhelm for nearly two decades? From a business strategic perspective two things:
What counts is the benefit for the user
Target the right market segment or niche
Pretty fundamental, nothing really new and yet easier said then done! How to apply this wisdom to the complex environment of health care?
"Firstly, you have to show that your innovation works ..."
Let's acknowledge, Biogen has done a number of things very well. It has chosen a drug target (amyloid plaques), which is and actually still is considered as key target in Alzheimer's disease. Biogen has developed an antibody against this target and demonstrated in numerous clinical trials with sophisticated analysis methodologies, that the drug is capable of substantially reducing the amyloid plaque load. The drug does on the molecular level, what it has been designed for.
"... secondly, that it has benefits for the user ..."
The issue was, the drug has not convincingly enough improved the condition of AD patients such as slowing down cognitive impairment. In general terms, the feature of the product has not translated into a clear benefit for the user. And here, questions arise, why Biogen has pushed this drug for so long. Let's take a step back. The amyloid plaque hypothesis is highly controversial and a number of clinical trials with other drug candidates have failed. On the other hand, there are still drugs in the pipeline e.g., Eli Lilly's donanemab or Biogen/ Eisai's own lecanemab. Also, the clinical data are not black or white. In certain patients of the EMERGE trail, cognition was improved and correlated with a reduced amyloid plaque load. For every innovative approach endless reasons can be thought of, why it is supposedly unlikely to work.
So, how to take proper decisions? How to drive the project? On data relevant for the user! First evidences, that Aduhelm did not perform on the clinical endpoints as desired and only in subgroups of patients were early visible already in the Phase II and Phase III trials (around 2015 and then in 2019). Whether the amyloid plaques hypothesis holds or not, the drug under investigation simply did not perform well enough.
Cognition is a highly complex mental action and assessing a diseased person is not a simple task. Remember the clinical protocols were relying on questionnaires. Imagine how to quantify them, not to mention, how to harmonize data coming from multiple trial centers. Maybe it would be naive to belief, there is a drug capable to switch on cognition, like a caffeine boost in the morning or re-studying for a failed exam. And therefore Biogen was right to re-analyse their data at later time points to allow the brain of the patients to accommodate. But also here, it appears to me, that Biogen possibly relied to much on biomarker analysis, which is obviously better controllable. And again, when Biogen presented the extended data analysis from ENGAGE and EMERGE in March 2022, much emphasis was laid on the underlying molecular mechanism (amyloid reduction). But this was actually not really questioned.
"... and be ready to pivot your strategy based on data, if it does not work!"
Biogen has differentiated the patients in sub-cohorts to identify patients that benefited from long-term treatment with Aduhelm and reported those data. But here, we get to the second point - find the right market niche. If Biogen did not want to abandon Aduhelm, because it did not show a substantial benefit to most patients, why did it still nurse the next blockbuster story for AD? Maybe, it would have been better to accept, that Aduhelm is not the on-fits for all treatment, but could still be valuable for specific patient sub-populations.
It may have taken a kind of precision medicine approach and established an effective diagnostics scheme to identify those, who would with a higher likelihood respond to Aduhelm. And in fact, interesting details can be found in the characterization of patients in those trials such as assessing p-tau181 levels (the Tau protein is another protein involved in AD) or identifying APOE e4 carriers (APOE e4 is a risk factor for AD) as they responded differently from other patients to Aduhelm. But, this was rather used to defend the therapeutic approach (amyloid plaque reduction) than to revise and pivot the strategy.
Changing strategy does not come with ease: Stakeholders put pressure on time lines and budgets. Medical science in general takes long and data are not always clear-cut and conclusive. But there is no point in continuing forcefully the wrong path. To often and for too long organisations try to rescue a project, instead of turning the wheel. And this case study shows clearly what happens, if critical decisions are not taken. Because in the end it is always the market that mercilessly decides whether or not a product is successful.
It appears to me that the following issues contributed to the fate of Aduhelm:
not or only selectively responding to the data,
not taking bold decisions to revise the clinical approach and
not pivoting the business and marketing strategy.
It needs to been seen, whether Biogen will continue to put effort into Aduhelm and go through with its phase 4 ENVISION trial. But for the time being, the focus will be shifted to its next AD drug, lecanemab (3). It is again an antibody against amyloid plaques, which has shown less side-effects. Well, at least the ongoing phase 3 clinical trial, CLARITY AD, is geared towards discovering the therapy's clinical benefit.
Addendum 31. January 2024:
Today, Biogen announced to abandon its Aduhelm efforts. Story closed.
DISCLAIMER:
The author has no relationship with Biogen. This is a business case using publicly available sources, avoiding media hype and trying to be neutral. Drug discovery & development is a long and complex process. Most drug candidates fail and only a fraction will ever see the market. It is inherent to the bio-pharmaceutical world and not to Biogen particularly. The intention of this business case is to tell the long and difficult road of drug development using Aduhelm as an example and to discuss, what can be learnt to improve on business decisions in the healthcare environment. Therefore, study results, sequence of events and debates have been partially simplified, condensed, or left out.
Furthermore, this article does not contain any medical advise and shall not be used to construct any recommendation for or against taking Aduhelm.
(1) https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
Photo by Robina Weermeijer on Unsplash