DUBLIN – Tempest Therapeutics Inc. raised $70 million in a series B round to progress four small-molecule drug development programs addressing different aspects of immunometabolism in the tumor microenvironment.

The company is yet another graduate of the Versant Ventures-backed Inception Sciences Inc. stable. It was spun out as an independent entity in late 2017 under the leadership of CEO Tom Dubensky, formerly chief scientific officer of Aduro Biotech Inc., of Berkeley, Calif., and of Immune Design Corp., of Seattle, and co-founder of Cerus Corp. spin-out Anza Therapeutics Inc.

Tempest – named for an Italian renaissance painting rather than the Shakespeare play – aims to develop molecules that are either first in class or best in class and that target metabolic pathways with a direct bearing on the immunological milieu within a tumor. Its lead molecule, TPST-8844, is an inhibitor of indoleamine-2,3 dioxygenase (IDO), the inducible enzyme that catalyzes the breakdown of tryptophan to kynurenine, leading eventually to the production of nicotinamide adenine dinucleotide.

It is increasingly recognized as a key component of a tumor's immune evasion mechanisms. Turning on the kynurenine pathway has several effects – it leads to tryptophan starvation of cytotoxic T cells, while also promoting the maturation of CD4 T cells into regulatory T cells. "I think it's pretty clear that kynurenine is strongly immunosuppressive," Dubensky told BioWorld.

Expectations that IDO could become a key immuno-oncology target are high, following a phase I/II readout from Incyte Corp. indicating that its IDO inhibitor, epacadostat, combined with a PD-1 inhibitor exhibited strong efficacy in patients. "The overall response rate, particularly in advanced melanoma, is at the level of PD-1 and CTLA-4 blockade, without the side effects observed with that combination," said Dubensky.

Progression-free survival data from Incyte's Echo-301 pivotal trial of epacadostat plus the PD-1 inhibitor Keytruda (pembrolizumab, Merck & Co. Inc.) in melanoma are imminent. "People are watching very intently the data Incyte is about to publish later this year," Versant's managing partner, Tom Woiwode, told BioWorld.

"That is going to more or less set the stage for IDO in terms of the immunotherapy backbone," Dubensky said.

Incyte, of Wilmington, Del., has eight more pivotal trials of the same combination or of epacadostat plus Opdivo (nivolumab, Bristol-Myers Squibb Co.) underway in a range of other cancer indications.

Although Tempest has company in that area, it is less than might be expected given its potential importance. There are more than 30 PD-1 blockers in clinical trials. "There's not the same number of companies with good IDO inhibitors," Dubensky said. In fact, there are fewer than a handful. "There's a huge opportunity, in our opinion, for a good IDO inhibitor."

The other big contender in the area is Bristol-Myers Squibb Co., of New York, which is currently running a phase III trial of BMS-986205 (F001287) plus Opdivo in melanoma. It gained the asset – through its acquisition of Flexus Biosciences Inc., of San Carlos, Calif., for $800 million plus up to $400 million in milestones. (See BioWorld Today, Feb. 24, 2015.)

Although chemically distinct from the BMS compound, TPST-8844 is closer to it in terms of its mechanism than it is to epacadostat. The latter acts on the holoenzyme, whereas the other two compounds target the apo-form of IDO and prevent or displace the binding of a heme co-factor required for activity. That mechanism sustains inactivation longer than epacadostat, he said.

TPST-8844 looks to have a clean profile and exhibits low binding to plasma proteins, which could offer advantages in terms of dosing. It will take a little more time to confirm that hypothesis. Tempest aims to file an IND later this year and to commence clinical trials early in 2019.

Funding to mid-2020

Its second program is focused on the development of antagonists of peroxisome proliferator-activated receptor alpha (PPAR-alpha). "This is a target that actively regulates lipid metabolism," Dubensky said.

During periods of energy deprivation PPAR-alpha, a transcription factor, promotes the expression of genes that encode proteins involved in fatty acid oxidation. It has particular significance in the metabolism of the tumor microenvironment.

"It turns out that some of the bad players – myeloid suppressor cells, Tregs and M2 macrophages – all use fatty acid oxidation," Dubensky said. Hitting PPAR-alpha antagonism, the theory goes, flips the energy switch. "It forces the tumor to use glycolysis to generate its own energy to sustain metabolism." As well as down-regulating immunosuppressive cells, the switch boosts the viability of T effector cells, which also favor glycolysis.

"It's an emerging field," Dubensky said. "This notion is not clinically validated." Tempest's drug candidate is currently undergoing IND-enabling studies. "We anticipate filing an IND for that molecule – it's called TPST-120 – sometime in 2019," he said.

The company's third disclosed program is focused on the development of E-prostanoid (EP) receptor antagonists, in order to damp down levels of another immunosuppressive species, prostaglandin. That is expected to yield a clinical candidate in 2019. The company's fourth program is undisclosed at this point.

The $70 million B round comes on top of about $20 million prior investment from Versant during the incubation stage of the company at its San Diego Inception Sciences facility. It will take the company to around mid-2020, when it aims to have early clinical proof-of-concept data on TPST-8844, as well as initial clinical data on two other programs.

"Where we go from there remains to be seen," Woiwode. Although a trade sale or a licensing deal represent obvious targets, he is not shutting down the possibility of an IPO or even the development of a fully fledged commercial entity, given niche scale associated with many cancer indications.

Versant has long pursued a blended business model, mixing classical VC investing with incubation. About half of its portfolio was created in-house, either through its Inception discovery engine, which is headed by renowned drug hunter Peppi Prasit, or as a de novo startup, such as Crispr Therapeutics AG.

On the present round, Versant was joined as lead investor by F-Prime Capital and Quan Capital. Lilly Asia Ventures, Foresite Capital and Eight Roads Ventures also participated.