Synta Pharmaceuticals was a biopharmaceutical company focused on developing novel treatments for serious medical conditions. It primarily focused on addressing unmet needs in oncology. Its mission was to create innovative small-molecule drugs.
The Scientific Focus of Synta
Synta’s scientific strategy centered on Heat Shock Protein 90 (Hsp90) inhibitors. Hsp90 is a “chaperone protein” that assists in the proper folding and stabilization of many other proteins, including those promoting cancer cell growth, survival, and spread. In cancer cells, Hsp90 is often overexpressed, maintaining the stability and function of proteins that drive tumor development.
Targeting Hsp90 was a promising approach because inhibiting it could disrupt multiple cancer-promoting pathways. Hsp90 inhibitors aim to inactivate and destabilize these “client proteins,” causing their degradation and hindering tumor growth and survival. This broad impact offered a potential advantage over therapies targeting a single protein, potentially reducing drug resistance.
Developing Treatments for Cancer
Synta’s primary drug candidate was Ganetespib (STA-9090), a novel Hsp90 inhibitor. Ganetespib was designed to bind to Hsp90, disrupting its ability to fold and stabilize client proteins. This action aimed to degrade cancer-promoting proteins, inhibiting tumor development and progression.
Ganetespib was evaluated in various cancers, including non-small cell lung cancer (NSCLC), breast cancer, gastric cancer, and acute myeloid leukemia. It progressed through Phase 1, Phase 2, and pivotal Phase 3 clinical trials. For instance, it was studied in combination with docetaxel for second-line treatment of advanced non-small cell lung adenocarcinoma in the GALAXY-2 Phase 3 trial.
Challenges and Outcomes in Drug Trials
Ganetespib’s clinical trials showed varied results. In a Phase 2 study of Ganetespib as a single agent in advanced NSCLC, the drug was well tolerated, with mild to moderate diarrhea as the most common side effect. While some patients with specific genetic abnormalities, such as EML4-ALK rearrangements, showed promising responses, overall efficacy in broader NSCLC populations was less consistent.
Despite some encouraging early results, the pivotal Phase 3 GALAXY-2 trial, evaluating ganetespib combined with docetaxel for advanced non-small cell lung adenocarcinoma, did not meet its primary endpoint of improving overall survival. An interim analysis concluded that adding ganetespib was unlikely to show a statistically significant benefit compared to docetaxel alone, leading to the trial’s termination. This outcome highlighted the challenges in treating advanced lung cancer and identifying the patient population most likely to benefit from Hsp90 inhibition.
The Company’s Legacy
Following the GALAXY-2 trial’s disappointing results and a strategic review, Synta Pharmaceuticals underwent organizational changes. In 2016, Synta merged with Madrigal Pharmaceuticals. This merger shifted the combined company’s focus from oncology to developing small-molecule drugs for cardiovascular-metabolic diseases and non-alcoholic steatohepatitis (NASH).
After the merger, Synta Pharmaceuticals became Madrigal Pharmaceuticals, Inc. The future of their oncology drug candidates, including Ganetespib, became uncertain. While Ganetespib was not commercialized, Synta’s work contributed to understanding Hsp90 inhibition in cancer biology and the complexities of translating preclinical promise into clinical success, especially in challenging diseases like lung cancer.