European radiopharmaceuticals head for the clinic

A pair of lutetium-based radiopharmaceuticals being developed by European biotechs feature among the latest biopharma entrants into phase 1. These are the Swedish biotech Akiram’s 177Lu-AKIR001, and 177Lu-OncoFAP-23, originated by the Swiss/Italian company Philogen, the latest listings on the clinicaltrials.gov registry reveal.

Also of note are the initiations of first-in-human trials of Menarini’s KAT6 inhibitor MEN2312 and C4 Therapeutics’ EGFR L858R degrader CFT8919. Both molecules are the subjects of recent licensing activity, respectively with InSilico Medicine in January and with Betta Pharmaceuticals last year, and use approaches that have significant industry interest.

Target degradation, for instance, is seen as a possible way of hitting a mutated protein harder than with a straight inhibitor. However, the recent ESMO conference heard underwhelming updates on several degraders, including C4’s own BRAF V600X-targeting CFT1946.

In May 2023 C4 received $10m up front from China’s Betta, plus a $25m equity investment, for China rights to the degrader CFT8919, which will shortly start phase 1 in patients with EGFR-L858R-mutated non-small cell lung cancer. A possibly relevant comparator is BeiGene’s EGFR degrader BG-60366, though that molecule is still preclinical.

Radiopharma

Radiopharmaceuticals continue to generate licensing interest, most recently from Sanofi, so the latest clinical entrants are noteworthy.

Akiram, a private biotech, is a radioligand specialist, and 177Lu-AKIR001 is its lead asset. The molecule targets CD44v6; this antigen is the subject of just two other clinical-stage projects, namely Shenzhen Geno-Immune’s Car-T therapy 4SCAR-CD44v6 and Amcure/Hinova’s small-molecule inhibitor AMC303/HP558.

An anti-CD44v6 Car-T therapy from AGC Biologics failed in phase 2, while Boehringer Ingelheim’s anti-CD44v6 ADC bivatuzumab mertansine was discontinued in phase 1. No other CD44v6-targeting radiopharmaceuticals are in development, according to OncologyPipeline.

177Lu-AKIR001 uses the beta-emitter lutetium-177 as the radioisotope, as does Philogen’s phase 1 entrant 177Lu-OncoFAP-23. The latter appears to be Philogen’s first foray into radiopharma, and is to be studied in FAP-positive tumours; it joins clinical-stage anti-FAP radioconjugates including Lilly’s Point-derived PNT2004, and Novartis’s ex-Clovis FAP-2286.

Olema left behind again

Meanwhile, the relatively novel area of KAT6 inhibition has so far been a one-horse race featuring Pfizer’s PF-07248144, whose ASCO data helped drive up the share price of Olema, which has rights to the competing project OP-3136, courtesy of Dr Reddy’s.

However, OP-3136 is still preclinical, and now faces a second clinical threat: Menarini’s MEN2312, whose phase 1 study is now under way. Menarini licensed MEN2312 from InSilico Medicine for $12m up front in January, and clinical entry makes this the second time Menarini has beaten Olema to the punch; Menarini’s SERD Orserdu is approved, while Olema’s rival palazestrant is still in phase 3.

Finally, biotech investors will take note of Daiichi Sankyo’s DS-2243a, whose mechanism is undisclosed. Its phase 1 trial is in HLA-A2/NY-ESO-positive cancers, strongly suggesting that it is an engineered T-cell receptor – potentially a new departure for the Japanese company, which is more famous for its ADCs.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 15 and 16 Oct 2024.