Lilly and Roche learn from Biogen’s mistakes

As Biogen continues to provide a case study in how not to launch a drug, Lilly and Roche insist the focus must remain on pivotal readouts.

When pharma companies have to remind investors to wait for confirmatory phase 3 results you can be sure that expectations had departed from reality. But this plea for patience was heard on two earnings calls yesterday – those of Roche and Lilly, both of which are nearing crucial readouts with their respective Alzheimer’s projects.

It was Biogen that had raised hopes of shortcuts to the Alzheimer’s market, of course; the beleaguered biotech also reported yesterday, laying bare the dismal repercussions of its pursuit of an approval without first generating real evidence of efficacy. No wonder Roche and Lilly are now backing away from such a strategy.

True, Roche had never sounded convinced about pursing accelerated approval for gantenerumab, but then the Swiss group has been struggling to generate strong signals from the project for years. It firmly walked away from this pathway yesterday, with the company’s head of pharma, Bill Anderson, insisting that the MAb had "to deliver two large, robust studies that are run to the end”.

“Physicians, patients, payers, want compelling evidence; in [Aduhelm’s] case they seem to be voting with their feet that they don’t have that yet,” he said in a clear swipe at Biogen.

Lilly had previously signalled a more aggressive approach to donanemab’s filing, emboldened by a well-received readout from Trailblazer-Alz last year. But in the wake of the CMS’s national coverage determination for Aduhelm, which applies to all amyloid-beta MAbs, it has decided to delay its accelerated approval submission, from this quarter to later in the year.

“The CMS draft NCD proposal … clearly reduces some of the ability to help patients faster than we were hoping for with the accelerated approval,” said Dan Skovronsky, Lilly’s chief science officer.

“What hasn't changed for us is the importance of the Trailblazer-Alz 2 readout,” he said, referring to the phase 3 trial due to yield topline results in mid-2023. If that study “provides positive confirmatory data we can't see a scenario where there's not global reimbursement, patient access and broad use of donanemab”.

On the horizon for the amyloid-beta space   
Date Project Event 
April Aduhelm (and others) Final NCD from CMS on US reimbursement
H2 2022 Donanemab; Lilly Topline data from Trailblazer-Alz 4, H2H vs Aduhelm
Q3 2022 Lecanemab (BAN2401); Eisai and Biogen Topline readout from phase 3 Clarity-AD
Q4 2022 Gantenerumab; Roche Topline results from the ph3 Graduate programme
By YE 2022 N3pG 4; Lilly Pivotal trials to start; amyloid-clearing project said to work similarly to donanemab but with potential for better dosing and administration
Mid-2023 Donanemab Lilly to report topline data from ph3 Trailblazer-Alz 2
Source: company statements.  

Lilly also seemed to level some criticism towards the CMS, saying it was “disappointed” with the position, because it negates any benefits patients can gain from the FDA’s accelerated approval pathway. Mr Skovronksy also warned that the NCD’s position could mean a slow launch for donanemab even if Trailblazer-Alz 2 was positive because it would take some months for the CMS to reconsider its position.

Lilly does not expect the final coverage decision, due in April, to change much, said Anne White, head of Lilly’s neuroscience division. The company is seeking confirmation from the CMS that should Trailblazer-Alz 2 succeed donanemab would be fully covered and a coverage decision “not be needed or appropriate”.

“We want that path for this coverage to be clearly laid out. We have been and will continue to meet with CMS to make our points known and to work through what that process is,” she said.

The CMS’s refusal to accept Biogen’s claims for Aduhelm’s efficacy have effectively scuppered the drug’s launch. The company reported a mere $1m of sales in the fourth quarter of 2021, up from $300,000 in the third quarter but still half of what the sellside was expecting. 

Biogen's chief executive, Michel Vounatsos, yesterday repeated his warning of having to take “aggressive steps” should the NCD remain in its current form. This means cuts and, probably, job losses. Realistically, however, until a planned phase 4 study called Envision yields data towards the end of this decade it is hard to see what Biogen can provide to change the CMS’s mind.

Wait for the data

As such, it falls to other amyloid-beta MAbs to support the class, and it could be another Biogen project that reports next. Phase 3 data on the Eisai-partnered lecanamab are due in the third quarter. Roche’s Graduate-1 and 2 studies will follow, the readout from which has shifted from the second half of this year to the fourth quarter, though the company denied that this was a delay.

An accelerated review submission has also been commenced for lecanemab, but with the CMS’s stance not expected to change it does raise the question why Eisai and Lilly are still pursuing this. 

Perhaps the slim chance that the CMS will loosen the purse strings makes it worthwhile. But it is becoming increasingly clear that the Alzheimer’s disease market – at least where it concerns amyloid-beta MAbs – will take years to grow into anything substantial, if indeed there is a future here at all.

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