Category: aducanumab

When Eli Lilly reported results for donanemab in Alzheimer’s disease earlier this week it was hailed as a rare win for the amyloid hypothesis, although there’s no shortage of candidates that have failed despite positive mid-stage trial results.

Some analysts have intimated that given the small size of the study at just over 270 patients, rival amyloid drug developers Biogen and Eisai could claim the biggest benefit from the data in positive sentiment ahead of an FDA decision later this year.

Goldman Sachs analyst Terence Flynn said the result was a “positive surprise” after Lilly revealed top-line data from the TRAILBLAZER-ALZ study showing that donanemab slowed cognitive decline by a third in people with early Alzheimer’s and completely resolved the amyloid beta plaques that are a hallmark of the disease.

Flynn also said the data was an “incremental positive” for Biogen, whose Eisai-partnered aducanumab is already filed for approval and awaiting an FDA decision by 7 March, as it lends further weight to the amyloid beta hypothesis of Alzheimer’s.

Biogen is nearest to market with aducanumab but a positive verdict from the US regulator is far from assured. In November, an FDA advisory committee voted ten to one against approval, saying the clinical data backing the drug was inconclusive, but that came on the back of a positive assessment by the FDA’s own reviewer.

Wolfe analyst Tim Anderson said in a research note issued ahead of the donanemab readout that the FDA could be influenced by the donanemab data and – if positive – that would raise the chances of a greenlight for aducanumab.

There’s an alternative view however that donanemab’s data might actually harm aducanumab’s prospects. Analysts at Jefferies told Barron’s this week that the FDA may have been minded to approve Biogen and Eisai’s drug because there were no other late-stage candidates in play, but Lilly’s drug could change that perception.

Donanemab is unlike most other amyloid-targeting drugs – including aducanumab – because it targets a pyroglutamated form of amyloid beta called N3pG that is found only in amyloid plaques and according to some research can stimulate misfolding of proteins.

Lilly’s hypothesis – as yet unproven – is that clearing those plaques has a direct association with cognitive benefits.

Lilly says TRAILBLAZER-ALZ met its primary endpoint, slowing decline on the Integrated Alzheimer’s Disease Rating Scale in the donanemab group by 32% compared to placebo, with trends towards improvement on secondary endpoints that didn’t hit statistical significance.

On safety, around 27% of the treatment arm showed ARIA-E – an inflammatory reactions also seen with other amyloid-targeting antibodies – but there’s little other data available yet.

Lilly started a 500-patient phase 2 trial called TRAILBLAZER-ALZ-2 last June that it suggests could serve as a confirmatory pivotal study and potentially support regulatory filings – dramatically shortening the development timeline for the drug. That’s due to read out in next year or later.

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Shots:

• The submission is based on P-lll EMERGE and ENGAGE study assessing aducanumab vs PBO in patients with AD. The studies evaluate the efficacy of monthly doses of aducanumab in reducing cognitive and functional impairment
• The secondary objectives of the study were to assess the effect of monthly doses of aducanumab on the clinical decline as measured by MMSE, ADAS-Cog 13 & ADCS-ADL-MCI. MHLW will review the application through the standard review process
• Aducanumab is an investigational mAb that is under the US FDA’s PR with an anticipated PDUFA date as Mar 7, 2021 and is also under review with the EMA

Click here ­to­ read full press release/ article | Ref: GlobeNewswire | Image: Barron’s

The post Biogen Reports NDA Submission of Aducanumab (BIIB037) to the MHLW for Alzheimer’s Disease first appeared on PharmaShots.

The FDA may have been minded to approve Biogen and Eisai’s Alzheimer’s candidate aducanumab, but its clinical advisors have little doubt that the evidence for the drug is lacking.

The much-anticipated advisory committee meeting held on Friday to discuss the marketing application for aducanumab proved to be a fractious affair, with both the companies’ data – and some of the FDA’s interpretation of it – under fire by panellists.

After hours of debate, the verdict from the experts was pretty unequivocal – 10 panellists voted against the main study supporting the drug, with just one saying they were uncertain about the data. Not one was convinced that the clinical trial results proved that the drug was effective.

The resounding rejection of the clinical data submitted in support of the marketing application for aducanumab came after the FDA published briefing documents that indicated the agency’s clinical reviewer was in favour of approval, calling the results “persuasive” despite a fairly damning assessment by the agency’s statistical expert in an appendix.

Aducanumab is vying to become the first Alzheimer’s drug designed to tackle an underlying cause of the disease, and the first new treatment for the neurodegenerative disease in almost two decades.

The FDA has been working closely with Biogen on the application and could still decide to approve the drug despite its experts’ reservations. That said, the balance of the votes makes that outcome unlikely – despite impassioned testimony during the virtual meeting by patient organizations.

The agency is due to make a decision by 7 March, and a review is also underway at the European Medicines Agency (EMA). Analysts have predicted it could become a multibillion-dollar blockbuster if approved, although at the moment that looks unlikely without another clinical trial.

An approval could also be seen as vindication for the hypothesis that tackling the amyloid plaques that are seen in the brains of people with the disease helps to slow the onset of symptoms. Many people had given up on the hypothesis after dozens of failed studies involving anti-amyloid drugs.

Biogen ran two identically-designed phase 3 studies of aducanumab – EMERGE (Study 302) and ENGAGE (Study 301) – to try to demonstrate that the anti-amyloid antibody could slow down the loss of cognitive function in people with mild cognitive impairment due to Alzheimer’s.

Last year, it called a halt to the studies after a futility analysis found it unlikely that aducanumab would show an effect on cognitive decline, but a few months later said that EMERGE was positive after all, and would form the basis of a marketing application with a phase 1b extension study – called PRIME – used as supportive evidence.

After a positive discussion of the results from Billy Dunn, acting director of the FDA’s office of neuroscience, the panel voted on three aspects of the data set.

In the first, they came down 8 to 1, with 2 uncertain, that the EMERGE trial could not be viewed on its own as providing strong evidence supporting aducanumab’s efficacy without taking into account the negative ENGAGE data.

They then voted 7 against and 4 uncertain on a question asking whether PRIME provide supportive evidence of the effectiveness of aducanumab in Alzheimer’s, before rejecting the premise that EMERGE could serve as primary evidence supporting the efficacy of the antibody.

Overall, the conclusion was that a negative interpretation of the data is just as likely as the positive one put forward by the trial sponsors, with one suggesting Biogen had shot first, and painted a bullseye later.

Biogen issued a short statement after the meeting in which CEO Michel Vounatsos said: “We appreciated the opportunity to share our data with the advisory committee, and we will continue to work with the FDA as it completes its review of our application.”

Trading in the biotech’s stock was halted ahead of the advisory committee meeting, but looks likely to be under considerable pressure when it resumes as it has been fluctuating wildly in reflection of the fortunes of aducanumab.

Biogen has a lot riding on aducanumab, as its pipeline has suffered recent setbacks including the failure of multiple sclerosis candidate opicinumab and a gene therapy for spinal muscular atrophy (SMA) at a time when big selling SMA drug Spinraza (nusinersen) is facing increased competition.

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Shots:

• The advisory committee voted 1-8, with 2 members voting uncertain that EMERGE study (without regard for ENGAGE study) provides strong evidence, supporting the effectiveness of aducanumab as a treatment for AD. The committee also voted 0-7 with 4 members voting uncertain that PRIME study provides supporting evidence for aducanumab
• The committee voted 5-0 and 6 uncertain on showing PD effect of aducanumab on AD pathophysiology. Finally, the committee voted 0-10 & 1 for exploratory analyses of Study 301 & 302, along with study 103 and evidence of a PD effect on AD pathophysiology
• Following the committee’s opinion, the US FDA is expected to make a decision on approval of aducanumab’s BLA by Mar 7, 2021

Click here ­to­ read full press release/ article | Ref: Biogen | Image: The Conversation

The post The US FDA’s Advisory Panel Slams Biogen’s Aducanumab for Alzheimer’s Disease first appeared on PharmaShots.

The nonbinding panel recommendation to reject the drug goes against what FDA scientists presented but they throw up another obstacle for the drug, which is trying to succeed on a front where others have failed.

Regulatory reviews of Biogen’s Alzheimer’s drug aducanumab are now ongoing on both sides of the Atlantic, but debate is still ongoing about whether the data behind the drug is strong enough to support approval.

The EMA has just kicked off its review of the anti-amyloid therapy, following in the footsteps of the FDA in the US which has been looking at the drug since August, but a new analysis of the mixed phase 3 data for aducanumab argues that an additional trial should be carried out.

The paper in the journal Alzheimer’s & Dementia, led by Mayo Clinic neurologist David Knopman, says that efficacy of aducanumab “as a treatment for the cognitive dysfunction in Alzheimer’s disease cannot be proven by clinical trials with divergent outcomes.”

Meanwhile, the paper also notes that Knopman has been excluded from an FDA advisory committee meeting due to discuss the data on Friday, ahead of a decision on the marketing application due in March.

The expert – who was an investigator in the phase 3 trials of Biogen’s drug – told Reuters he was recused from the panel because of his involvement in conducting clinical trials of aducanumab.

Aducanumab – which Biogen is developing with Japanese drugmaker Eisai – was all but abandoned in 2019 after the partners decided that two phase 3 trials of the drug were unlikely to show an effect on cognitive decline in Alzheimer’s.

Shares in Biogen were hit hard, as investors lost hope that aducanumab might be rescue the almost defunct amyloid hypothesis of Alzheimer’s disease, which holds that blocking the formation of amyloid plaques in the brain could delay the onset of dementia.

Just a few months later however they said a fresh look at the results of the EMERGE and ENGAGE studies had revealed that the initial futility analysis was “incorrect.” In fact, the drug reduced clinical decline in patients with early, a chance was put down to more exposure to a higher dose in additional patient follow-up.

Some patients showed statistically significant improvements on symptoms like memory, orientation, and language, as well as being able to carry out day-to-day tasks more easily.

There’s a lot riding on the FDA and EMA reviews. If approved, aducanumab will become the first therapy to reduce the clinical decline of Alzheimer’s and to change the course of the disease, says Biogen. It would also be the first amyloid-targeting drug to reach the market, after dozens of others have failed in clinical development.

Meanwhile, aducanumab is the big hope in Biogen’s late-stage pipeline, which otherwise is looking fairly thin, at a time when the biotech is facing the loss of patent protection for its blockbuster multiple sclerosis therapy Tecfidera (dimethyl fumarate).

Knopman and fellow authors argue in the Alzheimer’s & Dementia paper that Biogen’s interpretation of data in the two trials might not be correct.

They write that they have found alternative explanations for the apparent drug benefits unrelated to the treatment, and say that while there is evidence that aducanumab was working on amyloid and other biomarkers like tau protein as expected, “no evidence was presented to correlate biomarker changes to cognitive benefits.”

They also say there were differences in the placebo responses between the two studies, which could have contributed to the divergent results.

“Our analysis supports the conduct of a third, definitive phase 3 trial with high‐dose aducanumab [that is] optimally designed and adequately powered to prove efficacy,” they conclude.

The FDA has not commented on the reasons for Knopman’s exclusion from the advisory committee meeting publicly, but in these cases there is usually a conflict of interest.

Along with his involvement in EMERGE and ENGAGE, Knopman also serves on a data safety monitoring board for a tau drug for Alzheimer’s developed by Biogen, and is an investigator in a trial sponsored by Eli Lilly and the University of Southern California.

He also performs unpaid consultancy work for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences, according to the paper’s conflict of interest statement.

The post Trials and tribulations in Biogen’s Alzheimer’s drug reviews appeared first on .

Biogen’s Alzheimer’s drug aducanumab could be on the market in the next few months after the FDA accepted a clinical trial dossier and granted a fast Priority Review.

The FDA reserves these quick reviews for drugs that have the potential to improve care standards for serious diseases.

There have been no new drugs approved for Alzheimer’s since 2003 and those that are on the market are only able to treat the symptoms.

Biogen aims to change this with aducanumab, after clinical trial data showed the drug helped to slow onset at a higher dose in two clinical trials that had initially been written off as failures earlier last year.

The FDA has set a decision date for March 27 next year, and Biogen said that the regulator could make a ruling before then.

Biogen said that the FDA is planning to hold an advisory board meeting, which will make a non-binding vote about whether to approve the drug.

The meeting will discuss data from Biogen’s re-analysis of the EMERGE and ENGAGE trials, which last October concluded the drug reduced clinical decline in patients with early AD.

At the time the announcement was a complete shock as the trials had been deemed failures following an analysis last spring.

The renaissance was due to greater exposure to a higher dose of the anti-amyloid antibody in a larger data set, which was not available to the independent committee that initially concluded the trials were unlikely to slow cognitive decline.

Biogen’s share price, which fluctuated wildly to reflect its fortunes with aducanumab, was up more than 10% after the news broke on Friday.

This builds on gains last month when Biogen completed its filing based on the reanalysed study data.

An approval could also be seen as vindication for the hypothesis that tackling the amyloid plaques that are seen in the brains of people with the disease helps to slow the onset of symptoms.

Many people had given up on the hypothesis after a string of trial failures over the last decade or so.

The other main method of action being investigated is targeting the tau protein tangles that are seen in brain cells of people with Alzheimer’s.

At the end of last month Roche signed a deal worth up to $2 billion with Belgium’s UCB to develop its anti-tau antibody UCB0107.

 

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Biogen and Eisai said the FDA had accepted and given priority review to their application for aducanumab. The drug will undergo an advisory committee meeting at an undisclosed date. Biogen’s stock rose 10%, but analysts had mixed opinions.

The FDA has 60 days to decide whether or not to accept the application. An analyst wrote that the agency accepting it with a priority or standard review may signal whether the agency is seriously considering approval or has continued reservations about the amyloid beta-targeting drug’s clinical benefit.