Synthetic lethality is becoming an emerging approach for drug discovery and development recently. Genomic instability is one of the hallmarks of cancer cells, and the resultant mutations render cancer cells more dependent on alternative pathways for survival and proliferation, so these cancer cells are more vulnerable to targeted perturbations on those alternative pathways – a phenomenon known as synthetic lethality. Synthetic lethality can be exploited as next-generation targeted drug development approaches selectively target cancer cells with certain mutations, for example, deficiencies in DNA damage response (DDR).

 

Utilizing the synthetic lethality approach enables indirect targeting of many tumor mutations, including non-druggable ones, which greatly expands the potential repertoire of drug targets for cancer treatment. Combination therapy approaches have been widely recognized as a major trend in the development of synthetic lethality-based therapeutics and targeted anticancer therapeutics to expand indications as well as to enhance anti-tumor activity.

 

 IMPACT Therapeutics has assembled one of the most comprehensive DNA damage response (DDR) global pipelines of novel drug candidates generated by in-house discovery efforts and is expanding to other novel synthetic lethality targets to broaden its pipeline.

 

With three synthetic lethality compounds in clinical stage including the PARP inhibitor in pivotal studies, Impact possesses a highly differentiated and de-risked pipeline with the most synthetic lethality clinical assets among biotech companies. Unlike many me-too or me-better drugs which are usually modified from existing compounds, IMPACT’s compounds are uniquely designed with novel chemical scaffolds to obtain high potency and selectivity, which potentially leads to wider therapeutic windows in clinical. It enables the company to target broader cancer indications and provide more opportunities for its in-house combination therapies.

 

IMPACT pipeline products include PARP inhibitor (Senaparib/ IMP4297), Wee1 inhibitor (IMP7068), and other novel DDR pathway inhibitors. The lead clinical program, PARP inhibitor (Senaparib/ IMP4297), is in Phase II/III studies for ovarian cancer, prostate cancer, small cell lung cancer and other indications worldwide, including in China. Senaparib’s preliminary clinical data demonstrated superior tolerability and a wider therapeutic window compared with other PARPis.  The Phase I study of the Wee1 inhibitor (IMP7068) is being conducted globally. The ATR Inhibitor IMP9064 has received IND clearance by the US FDA to start its first-in-human Phase I/II study not only as a single agent but also in combination with Senaparib in advanced solid tumors.

 

Taking the ATR program as an example, ATR is a synthetic lethality target of ATM mutations, which are commonly found in hematologic malignancies as well as a variety of solid tumors. ATR inhibitors have demonstrated proof-of-concept (POC) efficacy data in tumors harboring ATM mutations in previous clinical studies, and the combination of the ATR inhibitor with the PARP inhibitor might overcome PARP resistance.  Based on public information, IMPACT is the only emerging biotech company who owns a clinical-staged PARP inhibitor and an ATR inhibitor at the same time. IMP9064 is an ATR inhibitor discovered and developed in-house with worldwide intellectual property rights. Preclinical studies of IM9064 showed high potency in vitro and in vivo, high selectivity and better PK profile. The first-in-human study is designed as a Phase I/II, dose escalation and expansion study, including individual arms to evaluate the safety, pharmacokinetics, and anti-tumor activities of IMP9064 as monotherapy and in combination with PARP inhibitor Senaparib in patients with advanced solid tumors. It represents a major leap of IMPACT’s global development strategy for its synthetic lethality pipeline. 

 

Looking to the future, synthetic lethality is a comprehensive field full of imagination. More and more targets in this field will be further validated or appear in the future, and the approach will likely usher in a new paradigm for anti-cancer targeted therapy. From an industrial perspective, multinational companies began to increase their strategic focus on synthetic lethality and the capital market is also seeing the growth of several but not many key players.