Medicare coverage refused for Aduhelm and amyloid-based therapies: what’s next?

The 7 April 2022 CMS decision denying Aduhelm medicare coverage

On 7 April 2022, the Centers for Medicare and Medicaid Services (CMS) have finally accepted a new policy on aducanumab coverage, which they entitle themselves as ‘Medicare Coverage Policy for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease’.

CMS have made an extremely unusual move here; whereas normally FDA drug approval leads to a decision on coverage, in this case the decision only allows coverage for the few patients in trial. The other patients will have to wait until the FDA grants final approval to Aduhelm, and there would need to be proof of clinical benefit. As a reminder, Aduhelm was granted accelerated approval. The CMS decision clearly indicates that this accelerated pathway is insufficient for coverage.

The title of the CMS decision as quoted above already shows its expansion to amyloid-based therapies. The content of this decision therefore implicates Eli Lilly’s donanemab and Roche’s gantenerumab, and other drug candidates less in view of possible accelerated approval pathways.

The timeline for Biogen is long. Biogen is screening patients for its Phase 4 confirmatory trial, which still hasn’t started, and expects its readout to occur only four years after start of the trial. That’s in 2026 if all goes well. Meanwhile, patients can procure the drug, if prescribed by their doctors, outside of the trial, but then they will not receive coverage.

I expect the AD landscape to be totally different four years from now, and expect Aduhelm to die a slow death.

Big pharma’s visions on market control and multibillion profits wiped out for some years

I believe the CMS decision was a worst-case scenario for Biogen and others, which had invested massively in lobbying, awareness-creation and commercialization, both with the FDA, practitioners as patients and families. Biogen clearly commented on the CMS decision in that vein:

These coverage restrictions, including the distinction between accelerated approval and traditional approval, have never been applied to FDA-approved medicines for other disease areas.

This was not a scenario they were expecting.

Big pharma’s lobbying efforts could have been called success if patients, families, doctors and scientists would have accepted that, because there isn’t anything better anyways for the time being, all of the serious side effects accompanying Aduhelm and other therapies removing amyloid plaques (ARIA – amyloid-related imaging abnormalities) would have still been better than nothing. Patients and families clearly had their hopes up; that was obvious at times when drug approval and CMS coverage were discussed. The disease and its outlook are terrible, so getting any therapy probably seems better than doing nothing. Doctors and scientists seemed less convinced. And the CMS added a financial balance question to the equation, which finally led to its decision.

What will have been the overwhelming feeling over the past weeks in the offices of big pharma majors? Surely a sense of clarity, as the path forward is now more clear. For those that did not have a direct competitor for Aduhelm in the pipeline: perhaps relief and a bit of a smile. For those that did have such a competitor in play, probably some question marks as to how to deal with these drug candidates now, and a sense of a probable loss if they were to move ahead.

The amyloid approach had to make it to market to officially be ruled out as a potential therapy.

As Biogen quarterly results and employee lay-offs are showing, Aduhelm will never lead to blockbuster returns, if already Biogen is not losing big right now because of it. There will be no market dominance based on the amyloid approach, even if further drugs would make it to market.

Clarity is what the world needs, and in that sense, one can at last put an end to all speculations on how promising this therapy could be. We have Biogen to thank for having taking that risk.

For sake of completeness: in Europe, coverage of Aduhelm was simply refused. That’s a harder setback at first sight, but at least it avoids any losses on commercialization efforts, and so it may have been the least losing one at second sight.

Hopes on alternative approaches

Meanwhile, the huge patient population keeps on growing bigger, the need is dire, and the future is bright. But hopes on market dominance and blockbuster returns should not be sought with amyloid. They should be sought elsewhere. Where then?

Voices have been stating that, after this CMS decision, the accelerated approval pathway is of no use in Alzheimer’s disease. I see things slightly different. The CMS decision does not extend to any approaches than the amyloid-based approach. That means that, if drugs that aren’t based on the amyloid-based approach would be approved under the accelerated approval pathway, with possibly more clinical benefit, then CMS has freedom to change its stance. And that actually makes sense.

Tau-based approaches?

The first alternative one could think of could be an approach based on reduction of tau neurofibrillary tangles. Neurofibrillary tangles are the second classic hallmark of Alzheimer’s disease, and the link between cognition and reduction of tau is more clear than that between amyloid plaques and tau. Many big pharma companies have drug candidates in their pipeline based on tau-related therapies. However, after so many failures of these drug candidates in the past, what’s to say we are not heading to the same scenario as the one that has currently been played out? Also, a tau-based approach, although probably more sensible in light of recent science, has less weight of tradition, and I assume those in favor to push the fast-forward button in favor of such an approach would more easily be able to be set aside.

I would consider that big pharma may not risk making the same mistake again twice. In other words, in my opinion, any tau-based approaches are not likely to receive massive attention from big pharma in the near future.

Whether that’s necessarily a good thing is another question? I had more hopes on tau than on amyloid removal to improve cognition, and perhaps the best tau-based therapy, in combination with one based on another pathway, could in the end yield good results.

Inflammation-based approaches

That leaves me with the idea that approaches alternative to amyloid and tau could receive light from the momentum that the AD field still has.

Neuroinflammation is the last and most recent hallmark of Alzheimer’s disease, and I would expect the focus to shift to this approach.

The first results are there, and come from Alector and INmune Bio; both target neuroinflammation and microglia, and yield results. Denali plays in the same field.

Alector has partnered with GSK in a $ 2,2 b with a $ 700 m upfront payment, and is about to have its Phase 3 readout in frontotemporal dementia in a subset of patients with a granulin mutation. Of note as well, Alector has reported that their biomarker Neurofilament Light (NfL), a biomarker of axonal damage, diminishes over the course of treatment. Their drug candidate shows a 54% slowing of decline of FTD in treated patients over 12 months, but also quite some treatment-related adverse events. There is a further partnership with AbbVie for another drug candidate.

INmune Bio has not partnered yet.

Denali is at an earlier stage of its progress and has yet to produce significant results but has already partnered with Biogen in a $1 billion deal, with a $ 560 m upfront payment.

That leaves one further partnership candidate on the table: INmune Bio.

I would add Cassava Sciences here too, insofar as simufilam shows reduction of neuroinflammation in (disputed) scientific articles. Recently, when answering an investor request as to whether simufilam could extend to other neurodegenerative diseases, Cassava Sciences’ CEO answered that, insofar as simufilam reduces neuroinflammation, this may be possible but there may be intellectual property issues.

Other approaches

And there are the other approaches too, which may garner some interest from big pharma. As these are a bit all over the place, and in my eyes find less coverage in recent overall scientific research, covering all of these would lead this too far.

What’s next: faster innovation and further partnerships

The unusual CMS decision is clearly a setback for big pharma. The setback will be all the harder to swallow for those mostly involved. In order of importance, these are Biogen, Eli Lilly and Roche. There is little news on Roche in this field lately, although historically, I believe Roche has suffered most setbacks in earlier trials, and has always kept on confirming its focus on Alzheimer’s and neurodegenerative diseases in general. I would say, don’t rule them out.

All of big pharma will be looking at how to read this decision and how to work with it, both for internal research and for external partnerships. I think the CMS has pushed innovation forward even faster; big pharma cannot sit back, relax, conquer the market and take some profits with Aduhelm, donanemab or gantenerumab in the years to come, while waiting for further innovation to start shining.

I expect additions in big pharma pipelines focused on novel approaches. As to external partnerships, Biotech valuations are historically low, acquisitions are still low, and big pharma is flush with cash. With 4 years of missed blockbuster gains, I expect them to make additional partnering moves in months and years to come.

Future will tell if I’m right.

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