Nimbus hopes to best Bristol’s Sotyktu

When Bristol Myers Squibb’s Sotyktu got approved in September with a relatively clean label, it was seen as a good thing for groups with next-generation Tyk2 inhibitors designed to be even more selective.

The hope is that greater selectively could lead to improved efficacy. Nimbus Therapeutics is the most advanced player here and will soon be putting this theory to the test, with phase 2 data on NDI-034858 in psoriasis due this quarter. But others are not far behind, and some analysts reckon that one rival, Ventyx, could have an even better compound.

The thesis behind all the next-gen Tyk2 inhibitors is that Sotyktu, an oral drug, has “left efficacy on the table”, as Nimbus’s chief executive, Jeb Keiper, puts it. In phase 3, Bristol’s agent outperformed Amgen’s oral PDE4 inhibitor Otezla, but fell short of existing injectable therapies like Novartis’s Cosentyx and Abbvie’s Skyrizi.

Privately-held Nimbus hopes to go one better with NDI-034858, which Mr Keiper tells Evaluate Vantage is “just as potent as Sotyktu, but biochemically 1.4 million times more selective”.

The trick, as ever, will be striking a balance between efficacy and safety. The chief exec notes that Sotyktu showed Cosentyx-like efficacy with a 12mg daily dose in phase 2, but that Bristol ultimately plumped for 6mg once daily. “We don't know exactly what safety issues [Bristol] was looking to avoid, but now that we have the label for Sotyktu, they did a good job.”

Ultimately, Nimbus hopes to set the bar for what Tyk2 inhibition can do, and answer the question of whether it can achieve “even more profound efficacy than Cosentyx”. Mr Keiper flags Skyrizi as the psoriasis market leader in terms of efficacy – 75% of patients on Abbvie’s IL-23 inhibitor achieved Pasi90 in phase 3.

Dose ranging

Nimbus’s phase 2 trial is testing NDI-034858 at 2-30mg once daily and its primary purpose will be selecting a dose to take into phase 3. Mr Keiper says the group is looking for “improved efficacy, with a similar safety profile, to the approved 6mg Sotyktu dose”.

Specifically, Sotyktu led to Pasi75 rates of 53-58%, but the drug was less convincing on Pasi90, which was only achieved by 27-36% of patients. Differentiation on this more stringent measure would represent a win for the next-gen Tyk2s, Stifel analysts have noted.

It is far from clear whether Nimbus can achieve this aim, however. An admittedly small phase 1 trial found that a middle dose of NDI-034858, 10mg, spurred an encouraging 47% reduction in Pasi score, but no Pasi75 responses.

As for adverse events, Mr Keiper flags a couple of things that have been seen with Sotyktu and could be worth watching: increases in triglycerides and creatine kinase, a sign of muscle damage.

All being well, a phase 3 trial of NDI-034858 should start next year. Nimbus is also testing the project in psoriatic arthritis, with a phase 2 study set to read out in 2023. The risk/benefit equation could be different here, given that psoriatic arthritis's “defining characteristic is pain”, the chief exec says.

While there are still many unknowns about NDI-034858, at least one thing has already been cleared up. Bristol previously had an option on the project, through a deal between Nimbus and Celgene. That is no longer the case after the companies settled a legal dispute in January.

As for plans to go public, Mr Keiper says he would “never say never” but adds that at present Nimbus is well funded, having raised $125m days after Sotyktu was approved.

Tyk2 too

Nimbus’s most advanced rival at present appears to be another private group, Alumis – formerly known as Esker. But other companies have plans to go into phase 2 soon, including Ventyx.

Like Sotyktu and NDI-034858, Alumis's ESK-001 and Ventyx's VTX958 target the allosteric domain of Tyk2, which is thought to make them more selective than projects that hit the active domain. It is notable that Priovant’s Tyk2 inhibitor, ropsacitinib, a Pfizer cast-off that recently disappointed in hidradenitis suppurativa, inhibits the active domain. It no longer appears in Priovant's pipeline.

As for which of the remaining candidates could be the ultimate winner, Stifel has noted that “VTX958 appears to be able to achieve higher exposure versus Nimbus, and may therefore be a better test of the next-gen Tyk2 hypothesis”.

There is much still to prove, for all of the agents listed below. It could soon become clear whether Nimbus, for one, will be able to challenge Bristol.