SNV-4818

Armed with medical chemistry expertise, the biotech has worked to create better molecules against validated targets. A group of familiar faces to Incyte watchers has broken off to start their own biotech, pulling in $102 million to develop competitors to approved cancer drugs from AstraZeneca, GSK, Novartis and Pfizer. The biotech, Synnovation Therapeutics, was founded by Wenqing Yao, Ph.D., and Liangxing Wu, Ph.D. Yao spent 19 years at Incyte, rising to the post of head of discovery chemistry, before leaving and setting up Synnovation in 2021. Wu worked alongside Yao at Incyte, where he spent almost a decade to end up with the title executive director, medicinal chemistry. Armed with medical chemistry expertise that contributed to Incyte products such as Olumiant, Pemazyre and Tabrecta, the pair have worked to create better molecules against validated targets, namely PARP and PI3K. It is now almost 10 years since the first drugs against the targets were approved, with AstraZeneca and Merck & Co.’s PARP inhibitor Lynparza and Gilead’s PI3K inhibitor Zydelig both winning authorizations in 2014. Other companies have since secured approval for competitors to those first-in-class products but work to address the limitations of Lynparza and Zydelig is yet to yield a flawless therapy. Synnovation, which officially launched today, has identified hematologic toxicity as a weakness of first-generation PARP inhibitors. Like other companies, the biotech has fingered inhibition of PARP2 as the cause of the toxicity and bet that it can expand the therapeutic index by selectively targeting PARP1.  That isn’t a new idea. AstraZeneca has taken one selective PARP1 inhibitor, AZD5305, into phase 3 and moved its brain-penetrating sibling AZD9574 into the clinic. Gilead joined the race last year by acquiring XinThera and Merck KGaA has placed two PARP1 bets, one on Nerviano Medical Sciences and another on Jiangsu Hengrui Pharmaceuticals. Synnovation plans to start dosing patients in a phase 1 clinical trial of its brain-penetrating challenger, SNV1521, in the coming weeks. In preclinical tests, the biotech showed the molecule has greater than 500-fold selectivity against PARP2 and is more effective at inhibiting tumor growth than Lynparza. The biotech’s second candidate, SNV4818, is aimed at a target that has proven particularly troublesome. Zydelig and three other Gilead drugs that are too small to warrant their own line in the earnings collectively brought in $171 million over the first nine months of the year. Potential rivals have fled the space amid concerns PI3K inhibitors may shorten life expectancy and a resulting regulatory pushback.  Synnovation’s attempt to crack the PI3K puzzle has resulted in a molecule that targets the alpha form of the kinase and, according to the biotech, “is differentiated from competitor molecules by virtue of its excellent selectivity for H1047X and moderate selectivity over relevant E545/542X mutants.” The design reflects the belief that a lack of selectivity against wild type PI3K-alpha has held the class back to date.    Wu and Yao respectively work as CEO and senior vice president, drug discovery at Synnovation. The pair have been joined at the new biotech by two other leaders with lengthy stays at Incyte on their résumés. Phillip Liu, Ph.D., came on board as SVP, head of biology, while Kevin O’Hayer, M.D., Ph.D., took up the SVP, head of clinical development position last year.

Synnovation isn't breaking any new ground with the targets it is developing small molecules against; but instead, the cancer company aims to make a name for itself by being a best-in-class drug developer – and Third Rock partner Reid Huber is confident that CEO Wenqing Yao and his team can make that happen. Huber's firm led the biotech's $102-million series A, which closed Wednesday with participation from Nextech, Lilly Asia Ventures, Sirona Capital and Cormorant Asset Management. While the amount may seem eye-popping for such an early round, the funds will advance three experimental cancer treatments – a PARP1 inhibitor, a small molecule targeting mutant PI3Kα, and a third undisclosed programme – to the clinic by early 2025."It's rare that you get to have a multi-asset, multi-indication oncology company that's nearly clinical-stage across three programmes at the time of launch," Huber told FirstWord. But more so than the pipeline, it was the team behind Synnovation that enticed Third Rock to become a seed investor in 2023. Up until mid-2021, Yao was head of discovery chemistry at Incyte, where Huber served as chief scientific officer from 2011-2018. Together, they brought over 30 molecules into the clinic, while Yao’s tenure eventually produced five approved drugs: Jakafi (ruxolitinib), Olumiant (baricitinib), Pemazyre (pemigatinib), Tabrecta (capmatinib) and Opzelura (ruxolitinib)."Wenqing and his team are one of the strongest –  if not, arguably, over the last few decades, the strongest – highest output chemistry team there is in industry," Huber said. "It's rare to get one drug approved if you’re a fortunate scientist in industry; it's extremely rare to get five." Making drugs – not just clinical candidatesAt Synnovation, the team is approaching known targets with a best-in-class mentality. It's not enough for a compound to be selective and potent, Huber said. A best-in-class drug means a low-milligram dose, long half-life, and an improved safety profile, especially if the compound inhibits PARP, like Synnovation's lead candidate SNV1521."I think Wenqing's team knows the difference between a drug and a clinical candidate, and they're focused on making drugs," Huber added. All approved PARP inhibitors non-selectively hit both PARP1 and PARP2. The first protein most likely drives the therapies' efficacy to treat cancer, while scientists believe the second triggers the haematological toxicities that have limited the drug class' approved indications, as well as their use in combination with chemotherapy and other next-gen treatments like antibody-drug conjugates and radiotherapeutics. Synnovation's molecule selectively inhibits PARP1, which could open up a world of combinations. SNV1521 also penetrates the central nervous system, making it potentially viable to treat metastatic disease or even primary brain tumours. The compound is slated to start a clinical trial in mere weeks, Huber said. Following closely behind is SNV4818, which inhibits PI3Kα – another target that has been saddled with safety concerns. Synnovation's candidate zeros in on the enzyme's mutant form, as blocking the wild type can cause dose-limiting side effects, Huber said. The candidate is expected to enter the clinic in the fourth quarter.Synnovation has a third precision medicine programme as well against an undisclosed oncology target, with clinical testing also scheduled to start by year-end. Given Yao's impressive Incyte track record and the team's approach to best-in-class drug development, Huber believes Third Rock has placed a good bet on Synnovation. "There's an old adage that when you find a good jockey, you bet on the jockey," Huber said. "Wenqing and his team absolutely represent that great jockey."