Biopharma developments over the Christmas period
Investors nursing a fall in biotech indices now have to digest the failure of Bridgebio's acoramidis in 2021’s last important catalyst.
Going into the 2021 festive period one key biotech catalyst remained: readout of Bridgebio’s phase 3 Attribute-CM study of acoramidis. Though Bridgebio’s stock had ticked up in previous days the trial’s result, unveiled on December 27, was a resounding failure, though it remains a mystery why placebo performed just as well as acoramidis.
Elsewhere, regulatory agencies and the business development divisions of biopharma groups did not shut down completely, though in the event the somewhat bizarre rumour that Samsung was mulling a $40bn takeover of Biogen appears to have been scotched. Key biopharma developments between Christmas Eve and New Year’s Eve included the following.
Madrigal delayed the readout from resmetirom’s phase 3 Maestro-Nafld-1 study to January. The trial tests subjects with non-alcoholic fatty liver disease that is “presumed” to be Nash, and there had been hopes that it might yield data at November’s AASLD meeting. Madrigal blamed the delay on unexpected staffing issues at a third party contracted to perform statistical analyses.
The Korea Economic Daily reported that South Korea’s Samsung Group was in talks to buy Biogen for over $40bn. Analysts were sceptical as to whether Biogen would agree to be taken out at a point where its stock is trading at lows not seen for over two years, and while shares climbed 10% on the news they were off 7% the following day when Samsung denied the rumours.
Some say a likelier scenario is Biogen buying out the remainder of Samsung Bioepis, a biosimilars joint venture of which it currently owns 49.9%. An added element is that Biogen and Samsung are in arbitration, initiated by the latter, and perhaps relating in part to the former’s separate biosimilars deal with Bio-Thera, signed in April.
Separately, Johnson & Johnson filed teclistamab, its bispecific T-cell engager targeting BCMA, in the US for multiple myeloma. If this is greenlit J&J would likely boast two novel approved anti-BCMA products, given that the Car-T therapy cilta-cel is likely a shoo-in, notwithstanding the FDA extending its regulatory action date by three months to February 28.
Daiichi Sankyo filed its EZH1/2 inhibitor valemetostat for adult T-cell leukaemia/lymphoma, based on a phase 2 study of 25 Japanese patients that at Ash showed a 48% overall response rate. This represents the project’s first ever filing; a global trial, Valentine-PTCL01, started in June.
The first day back after Christmas started badly, with Bridgebio Pharma reporting long-awaited 12-month results of its phase 3 Attribute-CM study of the transthyretin stabiliser acoramidis in wild-type and hereditary ATTR cardiomyopathy. The result was a clear failure, and Bridgebio stock crashed 72%.
The question now is whether acoramidis or trial design is to blame. Attribute-CM’s primary endpoint measured the six-minute walk test (6MWT), and Bridgebio had set 20m of decline from baseline as the bar acoramidis had to beat.
Acoramidis met this by a wide margin, treated patients showing a 12-month decline of 9m. But placebo recipients did even better, showing a 6MWT decline of 7m, versus 40m or more seen previously in untreated patients; both cohorts behaved similarly to what would be expected from healthy elderly adults, a fact neither the company nor analysts were able to explain.
Bridgebio said possible reasons included context bias, training bias, and an evolution in diagnosis and standard of care. A 30-month readout will measure all-cause mortality and cardiovascular hospitalisations, but whatever optimism remains a mid-2022 US filing, backed by 12-month data and a priority review voucher, is off the table now.
A related faller was Alnylam, off 17% on concerns that the high placebo response in Attribute-CM might increase the risk to Alnylam’s Apollo-B trial of Onpattro. This also primarily evaluates 6MWT, and represents Alnylam’s attempt to move into cardiomyopathy.
Onpattro is already approved for hereditary ATTR polyneuropathy, a separate use in which Bridgebio is evaluating acoramidis, and for which Alnylam’s subcutaneous follow-up, vutrisiran, is awaiting US approval. The concerns have arisen even though acoramidis’s failure removes a potential competitor to Onpattro and vutrisiran.
Elsewhere, Sutro got $40m up front from Tasly Biopharmaceutical for China rights to its folate receptor α antibody-drug conjugate STRO-002. Targeting FRα got a new lease of life when STRO-002 and Immunogen’s mirvetuximab recently scored in separate ovarian cancer trials.
And the Japan regulator approved Merck & Co’s Keytruda in combination with Eisai’s Lenvima for second-line endometrial carcinoma, backed by the Keynote-775 study. This trial also supports the combo’s US approval, which interestingly is restricted to non-MSI-high/mismatch repair deficient disease; a separate US filing for Keytruda monotherapy in second-line MSI-high/dMMR endometrial carcinoma has a March 28 Pdufa date.
Eisai/Biogen’s lecanemab was granted US fast-track designation, adding to the breakthrough therapy designation it had secured in June. A rolling US filing for the Alzheimer’s disease amyloid-beta MAb was initiated in September, based on a phase 2b trial, but approval before lecanemab's phase 3 Clarity AD study yields data towards the end of 2022 is seen as unlikely.
Clarity AD data are a huge 2022 catalyst, especially considering that lecanemab is the encore to Biogen’s Aduhelm, which has sold dismally since its mid-2021 approval. Biogen might not be getting taken out just yet, but controversy around Alzheimer’s disease treatments will continue well into the new year.