The US approval of Biogen’s aducanumab in June marked the first new Alzheimer’s disease (AD) treatment to be greenlit by regulators in almost 20 years. While the development was celebrated by many as an important step towards fighting the incurable disease, the move also sparked outrage in the medical community and saw a number of FDA experts resign from their posts in protest.

Critics of the drug have said, both prior to and after its approval, that there is insufficient evidence the medicine will have any benefit for Alzheimer’s patients, and it could cause serious side effects such as brain swelling. Aducanumab, which Biogen developed in partnership with Japanese drugmaker Eisai, is designed to target the amyloid-beta (A-beta) plaques in the brain believed to be the underlying cause of AD, but experts have argued that removing plaques hasn’t yet been proven to improve cognition in those with the disease. The drug’s hefty $56,000 price tag has also been subject to much criticism.

Despite an FDA advisory panel voting almost unanimously against aducanumab’s approval, marketed as Aduhelm, the regulator made the unusual decision to overrule the committee and authorise the treatment through an accelerated pathway.

Now, the EU’s Committee for Medicinal Products for Human Use (CHMP) has handed Biogen a negative trend vote on its marketing authorisation application for aducanumab, indicating that Europe is unlikely to follow the US in granting regulatory approval.

Almost six months on from Aduhelm’s US greenlight, and after a string of setbacks for its maker, how much more is known about the efficacy of aducanumab – and have opinions of the controversial drug changed?

Aduhelm: commercial failure?

The fallout from aducanumab’s approval saw the drug get off to a rocky start in the US, and things don’t appear to have improved in the months since. In the three-month period from July to September, Biogen made just $300,000 in Aduhelm sales, a dramatic drop from the $1.6m reported in the company’s second quarter.

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The drug’s disappointing commercial performance has not been helped by the US Department of Veterans Affairs’ (VA) decision earlier this year to leave Aduhelm off its national formulary. The VA, a federal government department responsible for providing healthcare to military veterans, rejected Aduhelm due to concerns about adverse events and a lack of evidence for its efficacy.

According to Biogen, only 120 sites across the US are offering Aduhelm to patients – and commercial insurers are awaiting direction from Medicare before they cover the pricey drug. The health insurance programme recently announced next year’s monthly premium for Medicare Part B will rise by $21.60 – the largest increase in its history – in part to set aside money in the event Aduhelm is covered.

In a development sure to exacerbate concerns about aducanumab’s safety, Biogen this month launched a probe into the death of a patient who had taken the treatment. The 75-year-old was hospitalised after receiving Aduhelm and was found to have brain swelling – a known side-effect of the drug.

The CHMP’s recent recommendation against Aduhelm is yet another in a series of blows for Biogen; if Europe rejects the company’s market application, up to 40% of future revenue for the product could be lost, RBC Capital Markets analyst Brian Abrahams has said.

Biogen’s stock dipped 4% this month after the company announced its R&D head Alfred W. Sandrock would be retiring – and the European regulator’s recent down vote for Aduhelm saw yet another 4% drop.

New data for aducanumab

Much of the criticism directed at aducanumab has centred on a lack of data to show, convincingly, that the drug could meaningfully improve cognition in AD patients. In a rare positive for Aduhelm, recently announced Phase III data has shown the drug successfully reduced plasma p-tau, another protein that accumulates and causes ‘tangles’ in the brains of people with AD, resulting in less functional and cognitive decline.

Biogen said the analysis also demonstrated a correlation between reduction of the protein and lowering of amyloid beta plaque, a defining feature of Alzheimer’s and a key target of aducanumab.

R&D head Sandrock commented: “We now have robust and concordant data that Aduhelm has effect on two core defining pathologies of Alzheimer’s disease, and substantial evidence of treatment correlation between changes in plasma p-tau181 and the slowing of disease progression.”

It remains to be seen whether the promising study findings, arriving alongside a potentially Aduhelm-related death, will do much to improve Aduhelm’s reputation among sceptical doctors and experts.

AD treatment: other promising candidates

Though aducanumab’s approval marked the first new AD treatment in many years, a host of other late-stage pipeline treatment candidates are also aiming to address the high unmet need for effective Alzheimer’s treatments.

Perhaps fortunately for Biogen and Eisai, aducanumab isn’t the companies’ only stab at tackling AD; another jointly developed anti-amyloid candidate, lecanemab, was granted breakthrough therapy designation by the FDA in June. Phase IIb study results announced earlier this month indicate the drug is effective at clearing brain amyloid and slowing of cognitive decline in patients with early AD.

No doubt spurred on by aducanumab’s approval, pharma giants Roche and Eli Lilly are also developing potential rivals to Aduhelm, with both companies’ candidates receiving FDA breakthrough designation this year.

Analyses of the Phase II trial for Lilly’s donanemab showed the drug “induced rapid amyloid plaque reduction” in participants with early AD and significantly reduced plasma p-tau. Clinical studies of Roche’s amyloid-targeting gantenerumab “showed beta-amyloid plaque lowering” in patients with the more common type of AD not directly caused by gene mutations, but the drug failed to demonstrate a significant slowing of cognitive decline in patients with early-onset, inherited AD.

Both drugs are currently in Phase III safety and efficacy studies.