FDA red and green lights: November 2024

With December looking like a busy month for approvals, the FDA took a bit of a breather in November. Nevertheless, the four approvals that did come were a big deal for the companies involved, particularly Autolus, which got its first ever nod, and Syndax, which has much riding on its menin inhibitor revumenib.

The month was rounded out by Jazz, which gained an accelerated go-ahead for its HER2 x HER2 bispecific MAb zanidatamab, which now needs to show that it’s more than Enhertu also ran, and Shorla, which got the thumbs up for its liquid formulation of Gleevec.

Solo blues

Autolus now faces the daunting prospect of a solo launch. While on a cross-trial basis Aucatzyl has been shown to cause less toxicity than the first wave of anti-CD19 Car-T therapies, it’s still subject to manufacturing failures and lengthy waits for infusion, during which patients risk having their disease progress, and during which bridging chemo is often used.

A recent NEJM paper on Auctazyl’s registrational Felix trial spelled out the problem: 217 patients were assessed for eligibility, but 64 discontinued before enrolment, and of the 153 formally enrolled only 127 received an Aucatzyl infusion (15 died, and there were seven manufacturing failures, for instance). Autolus makes no secret of this, and Aucatzyl's label says 112 were leukapharesed for the phase 2 part, and just 65 of these were evaluable.

Menin questions

Syndax got the all clear for its revumenib, now branded Revuforj, in the niche of KMT2A-rearranged acute leukaemia, ahead of its December PDUFA date. However, its label includes warnings about differentiation syndrome and QTc prolongation. While the former looks likely to be a class effect, Kura’s rival project ziftomenib has so far avoided QTc prolongation.

Fears that Revuforj might lose out to its rival might explain the fact that Syndax shares have been at a 2024 low since the approval. The group has also failed to attract a buyer, while Kura recently bagged Kyowa Kirin as a partner; still, that deal was seen by many as disappointing.

Enhertu challenger

Jazz’s accelerated approval for Ziihera – the brand name for zanidatamab – came in previously treated, HER2-positive biliary tract cancer. The drug’s label carries warnings of left ventricular dysfunction, infusion-related reactions and severe diarrhoea, and serious adverse reactions were seen in 53% of Ziihera-treated patients in the supporting Herizon-BTC-01 trial.

AstraZeneca and Daiichi’s HER2-targeting ADC Enhertu isn’t formally approved for BTC, but it can be given to relapsed HER2-positive BTC patients with no other treatment options, under a solid tumour-agnostic accelerated approval backed by the Destiny-Pantumor02 trial. Enhertu is also in the first-line phase 3 Destiny-Biliary Tract Cancer-01 study, with or without rilvegostomig, Astra’s TIGIT x PD-1 bispecific.

Jazz’s own first-line confirmatory trial, Herizon-BTC-302, is evaluating Ziihera as monotherapy or alongside PD-1 inhibitors. BTC is a niche use, with around 12,000 cases per year in the US, Europe and Japan, according to Jazz. But the group has its eye on bigger indications, including breast cancer, where it’s initially aiming for a post-Enhertu population, and gastroesophageal adenocarcinoma, where phase 3 data are due next year.

Jazz licensed zani’s western development and commercialisation rights from Zymeworks in October 2022 for $50m up front, four years after Asia rights were picked up by BeiGene for $40m.

BeiGene itself is separately overdue a decision on its anti-PD-1 MAb Tevimbra in first-line oesophageal squamous cell carcinoma. The PDUFA date was in July 2024, but a decision was delayed by an FDA adcom; approval could come in December here and in gastric/gastroesophageal junction cancers, with the main outstanding question being to what extent the FDA might limit the drug to PD-L1 expressers.

Selected November 2024 US regulatory decisions in oncology

Note: BTC=biliary tract cancer; CML=chronic myelogenous leukaemia; GIST=gastrointestinal stromal tumours; MDS=myelodysplastic syndromes; MPD=myeloproliferative disorders. Source: OncologyPipeline.