Nimbus hopes to strike thrice

Deals with Gilead and Takeda have established Nimbus Therapeutics as a successful negotiator. The former picked up Nimbus's Nash contender NDI-010976, now known as firsocostat, for $400m up front in 2016, and last year the Japanese company bagged the Tyk2 inhibitor NDI-034858 for a chunky $4bn.

This is the sort of track record that could justify an early retirement, but Nimbus’s chief executive, Jeb Keiper, reckons the group can pull off the trick again. Its most advanced project now is an HPK1 inhibitor, and Mr Keiper hopes that this will become the next big class in immuno-oncology. In a space full of recent disappointments, however, this could be a tough task.

Monotherapy activity

Mr Keiper admits: “The bar with HPK1 needs to be high: we need to see monotherapy activity.” He claims Nimbus has already begun to see this, in the dose-escalation portion of a phase 1/2 trial in solid tumour patients refractory to checkpoint inhibitors.

These data will be presented this year, and the dose-expansion part of the study will also begin in 2023. In addition, the trial will evaluate a combination of the HPK1 inhibitor, NDI-101150, and Merck & Co’s Keytruda, but “that’s not something we’re doing right now; we’re focused on monotherapy activity first”, Mr Keiper tells Evaluate Vantage.

While PD-(L)1 inhibitors stimulate T-cell activity, HPK1 inhibition has been shown to activate B cells and dendritic cells, as well as T cells. Nimbus is not the only one with an interest in this target: Pfizer and Beigene are also developing HPK1 inhibitors.

Mr Keiper sees these two groups as Nimbus’s biggest rivals, but says: “We believe we have the most selective molecule.” However, he admits that he cannot be sure, given the limited disclosures from Pfizer and Beigene so far.

Selectivity was a key part of Nimbus’s claim to fame in Tyk2 inhibition, and Mr Keiper says it will be just as important for HPK1 blockade. HPK1 belongs to the MAP4K family, which has seven members. “Those seven have good amounts of homology amongst them. It’s important you just hit HPK1 and not some of the other members – not just for safety, but also for efficacy.”

On the topic of selectivity, he adds that an asset belonging to another rival, Treadwell Therapeutics, hits other targets including Flt3, as well as HPK1. Treadwell did not respond to questions from Vantage about this.

With all the HPK1-targeting projects at a similarly early stage, it might be some time before any signs of differentiation emerge.

Preclinical shots

Nimbus has several other shots; all are in the preclinical phase, but the group hopes to start human testing with two more candidates in 2024. This does not include its AMPK activator, which Lilly licensed last year, taking on responsibility for clinical development.  

Selectivity is a common theme at Nimbus, but just as important is picking “great targets”, Mr Keiper says. “We've never in-licensed anything. Everything is developed in house. We've certainly had attrition, but so far we’ve taken it all preclinically.”

Another unusual thing about Nimbus is that it has stayed private. The chief exec describes a capital cycling model that allows the group to return money to shareholders, and this has seen it used as a case study by Harvard Business School.

“Do we need to go public? No. Will we? Maybe.” He adds that even if Nimbus did float it would keep its current structure, which involves a subsidiary being created around each asset.

The most important factor for the company is the science, he says. “If the programmes aren't there, the business structure doesn't mean a thing.” Given the disappointments seen with many once-hot immuno-oncology targets, Nimbus’s scientific prowess could be facing its toughest test yet.