Breast cancers driven by a particular genetic signature can already be treated by a particular class of targeted therapies, but the race is on to develop next-generation medicines that improve the safety and efficacy of this approach. Novartis sees an early clinical program of Synnovation Therapeutics as potentially best in this drug class, and it’s paying $2 billion to add the clinical-stage asset to its pipeline.
The cancer drug comes from Pikavation Therapeutics, a subsidiary of precision medicine startup Synnovation. By acquiring Pikavation, Novartis gets that subsidiary’s entire portfolio of PI3Kα inhibitors, according to deal terms announced Friday. That includes SNV4818, which is currently in Phase 1/2 testing for patients with HR-positive/HER2-negative metastatic breast cancer and other solid tumors driven by PI3Kα.
Phosphoinositide 3-kinase, or PI3K, is an enzyme that regulates a variety of cellular processes. Mutated versions of this enzyme can contribute to cancer, both liquid and solid tumors. Gilead Sciences developed the first PI3K inhibitor, Zydelig, which was approved for certain blood cancers in 2014. Novartis commercialized the first PI3K inhibitor for solid tumors following the 2019 approval of alpelisib, brand name Piqray, for breast cancer.
In 2022, alpelisib expanded its label to include PIK3CA-related overgrowth spectrum (PROS), a rare tissue overgrowth disorder, where the pill is marketed under the brand name Vijoice. Across both cancer and PROS, aleplisib’s $382 million in 2025 revenue was a 15% decline from the prior year, which Novartis attributed to competition facing Piqray in all markets. It was the second straight year that sales for the product have dropped. Meanwhile, Roche competes with inavolisib, brand name Itovebi. This PI3Kα-targeting drug for breast cancer received FDA approval in 2024 and European Commission approval last year.
The Novartis and Roche PI3Kα inhibitors hit both mutated and non-mutated versions of the enzyme. In addition to insufficiently blocking mutant PI3Kα, lack of selectivity to the mutated versions of the protein causes dose-limiting toxic effects that lead patients to reduce or discontinue treatment with these drugs. In Novartis’s announcement of the Pikavation acquisition, Shreeram Aradhye, president of development, acknowledged challenges for effectively blocking the target pathway while also offering acceptable tolerability. The pharma company sees Pikavation’s drug as part of potential drug combinations with already approved breast cancer therapies, such as CDK inhibitors and hormonal therapies.
“SNV4818 applies new mutant selective chemistry to more precisely target tumor biology while sparing normal cells,” Aradhye said. “This approach has the potential to translate proven biology into improved tolerability and more durable benefit for patients through precision medicine.”
The Pikavation acquisition brings Novartis into a group of companies aiming to bring better selectivity to PI3Kα inhibition. Relay Therapeutics might be at the front of the pack with zovegalisib, currently in Phase 3 testing in patients with advanced cases of HR-positive, HER2-negative breast cancers. In results from Phase 1/2 testing, Relay has reported median progression-free survival of 10.3 months for all 52 patients. For the 31 patients with measurable disease, the objective response rate was 39%. For patients who received the Relay drug as a second-line treatment, median progression-free survival was 11.4 months and the objective response rate was 47%.
Other companies developing selective PI3Kα inhibitors include OnKure Therapeutics, which is in Phase 1 testing with OKI-219, a drug designed to target PI3Kα mutations with a first focus on breast cancer. BridgeBio Oncology Therapeutics is also in Phase 1 testing with BBO-10203, a small molecule designed to target the RAS-binding domain of PI3Kα. In January, the biotech reported preliminary Phase 1 data showing no hyperglycemia observed, which it said differentiates it from other drugs in the class. More data are expected in the second half of the year.
Big pharmas have also demonstrated interest in better PI3Kα-targeting drugs. Last year, Eli Lilly acquired Scorpion Therapeutics and its selective PI3Kα inhibitor, STX-479, for a purchase price later disclosed to be $1.4 billion. The drug, now renamed tersolisib, is in Phase 1 testing for breast cancer and other types of solid tumors.
Synnovation launched in 2024 backed by $102 million in financing led by Third Rock Ventures. Other investors in the syndicate included Nextech, Lilly Asia Ventures, Sirona Capital, and Cormorant Asset Management. The Wilmington, Delaware-based startup is led by an executive team comprised of veterans of Incyte and focuses on developing medicines for validated cancer targets that still have room for improvement on the potency or selectivity in the drugging of such targets. Besides the PI3Kα program, the Synnovation pipeline includes a next-generation PARP1 inhibitor in early clinical development.
Beyond the $2 billion upfront payment, Novartis could pay Synnovation up to $1 billion in milestone payments. The transaction is expected to close by the end of June. When that happens, Synnovation will retain ownership of its other R&D assets and will continue operating independently; Novartis will be solely responsible for development and potential commercialization of the acquired PI3Kα assets.
Public domain image by Stuart S. Martin via the National Cancer Institute
