Non-genetic amyloidosis lives again, thanks to Darzalex and Astra

Astrazeneca’s exercise of a legacy takeover option over Caelum Biosciences will remind investors that interest in AL amyloidosis has quietly been growing. Caelum’s CAEL-101 had two years ago been mired in an obscure investigator-sponsored trial, but is today the subject of two registrational studies in the disease.

Interest might have been piqued by this year’s approval of Johnson & Johnson/Genmab’s blockbuster Darzalex. Despite the obvious scientific rationale behind using multiple myeloma drugs like Darzalex in AL amyloidosis, though, clinical successes have been scarce, and the pipeline of industry-sponsored trials remains fairly modest.

Symptoms vs cause

Apart from CAEL-101 the only other phase 3 asset appears to be Prothena’s birtamimab, an antibody that aims not to target the disease’s underlying cause – malfunctioning plasma cells – but instead to clear the resulting damaging amyloid deposits.

This in itself is remarkable: birtamimab had in 2018 failed the phase 2 Pronto trial in AL amyloidosis, prompting discontinuation of its phase 3 study, Vital. However, this year Prothena claimed to have seen a survival benefit in Vital patients at high risk of early mortality, and started a new pivotal trial, Affirm-AL, in this population.

Meanwhile, Darzalex’s January approval was based on haematologic complete response rates in the Andromeda study. As Darzalex targets plasma cells – the antibody-producing cells that cause multiple myeloma – it can be said to hit the underlying cause of AL amyloidosis. The disease is also called light-chain amyloidosis, and is quite distinct from familial amyloidosis.

Other multiple myeloma drugs have fared less well in AL amyloidosis. Kyprolis completed phase 1 years ago with no further work by Amgen, while Takeda’s Ninlaro failed the Tourmaline-AL1 study in 2019. Numerous studies with Revlimid, Pomalyst and others continue in academic hands, but pharma’s involvement with multiple myeloma drugs in AL amyloidosis is limited to Oncopeptides’ Pepaxto, Sanofi’s Sarclisa and Karyopharm’s Xpovio.

For its part CAEL-101 also targets AL amyloidosis symptoms rather than its cause, being a fibril-reactive MAb that binds to misfolded kappa and lambda light chain proteins and amyloid.

In June Caelum, a Fortress Bio subsidiary, reported data at the European Hematology Association Congress that it said supported CAEL-101’s phase 3 studies. Phase 2 had yielded 1,000mg/m² as the phase 3 dose of the MAb, and combination with cyclophosphamide, Velcade, dexamethasone and Darzalex was said to raise no new toxicity signals or alter pharmacokinetics.

Today’s takeover of Caelum by Astra dates back to early 2019, when Alexion, now owned by the UK company, paid $30m in stock for a 19.9% stake with an option to buy the remainder on the basis of phase 2 data. This has now been exercised, with Astra paying $150m to Caelum, some $64m of which will accrue to Fortress.

Other industry work in AL amyloidosis includes Sorrento’s STI-6129, like Darzalex and Sarclisa an anti-CD39 MAb, and Ascentage’s Bcl-2 inhibitor APG-2575. An academic trial of Abbvie/Roche’s marketed Bcl-2 inhibitor, Vencexta, was terminated after being put on FDA hold.

After Darzalex CAEL-101 looks like the most-advanced industry project: its two phase 3 studies are slated to complete next August.