The markets stress over Nuvectis

The first significant clinical data for Nuvectis have turned into a nightmare. The US biotech's lead project, NXP800, has managed to yield just one response among 11 patients, and that hasn't been confirmed; meanwhile, the threat of thrombocytopenia hangs over the results, though Nuvectis claims to have solved the problem through intermittent dosing.

Though on Thursday the company called the results "encouraging", and said this study, in pretreated, Arid1a-mutated ovarian cancer, was proceeding as expected, its stock crashed 46%. The data could raise questions for other companies developing early-stage projects that also aim ultimately to inhibit the heat shock transcription factor HSF1.

Working on such stress response pathways is a key aim of Nuvectis, a company founded in 2020 and listed on Nasdaq two years later. That flotation raised just $16m, and though the shares peaked last year at over three times their $5 listing price, they are now at $5.73, with Nuvectis capitalised at $110m.

The company licensed NXP800 from the UK's Institute for Cancer Research, and the molecule yielded its first signs of activity in March, when Nuvectis reported one unconfirmed partial response among four Arid1a-mutated ovarian cancer patients. However, three of the four patients suffered grade 4 thrombocytopenia, and the company increased monitoring to enable dose interruption.

On Thursday Nuvectis said a further eight patients had now been treated, with an intermittent dosing schedule of 50mg/day for five days then two days off, and among these the highest rate of thrombocytopenia observed was grade 2. That's encouraging, but with seven of these eight patients evaluable for efficacy there were no responses either.

Moreover, the one previous PR hadn't been confirmed, so formally the response rate stands at 0%. Nuvectis admitted that it was clear dosing had to be increased to drive more efficacy, and it now plans intermittent dosing at 75mg/day; whether this yields any confirmed responses – without an increase in thrombocytopenia – is now the big question.

Stress response

At the time of its IPO Nuvectis was calling NXP800 an HSF1 pathway inhibitor, but it is now more precise, saying the molecule activates GCN2 kinase, a process that subsequently causes inhibition of HSF1 activation. The pathway mediates cellular stress response.

Projects also claiming to act on GCN2 include APL-4098 and HC-7366, at the private companies Apollo Therapeutics and HiberCell respectively; both are in early clinical trials for AML or myelodysplastic syndromes. APL-4098 had a preclinical poster at this year's ASCO, while HC-7366 is separately being studied in combination with Merck & Co's Welireg in renal cancer.

HiberCell is also working on a molecule coded HC-5404, which inhibits another stress response protein kinase, called PERK. That's relevant because a dual inhibitor of PERK and GCN2, NMS-03597812, is in development at Nerviano in a phase 1 AML trial; Ono has rights, through its takeover of Deciphera, to the similarly acting preclinical molecule DP-9024.

And a related mechanism is inhibition of FACT, a process said to prevent the transcription of genes involved in cancer-associated signalling pathways, including that of HSF1. A phase 1/2 study of CBL0137, a FACT inhibitor originated by the micro-cap Stratera BioPharma, is in an investigator-sponsored trial, but the precise status of Stratera is unclear.

Selected projects with activity on HSF1

Source: OncologyPipeline.