Computational Discoveries for Clinical Development of Novel Cancer Therapies

Initially founded as a computational discovery company, today Compugen maximizes the commercial value of novel targets identified using its proprietary algorithms by advancing them through the clinic. Its lead candidates are novel immune checkpoint inhibitors that comprise a broad and promising early-stage target pipeline for immuno-oncology.

Pharma’s Almanac Editor in Chief David Alvaro discussed Compugen’s technology and pipeline with President and Chief Executive Officer Anat Cohen-Dayag, Ph.D.

Computational Discovery Expertise

Compugen discovers novel drug targets through a unique, predictive, computational process that combines human biology derived from genome analysis with disease information derived from analysis of vast amounts of proprietary and publicly available data. This process enables the identification of first-in-class drug target candidates that are difficult to identify using traditional screening approaches.

The applicability of Compugen’s technology has been demonstrated internally in multiple therapeutic and diagnostic areas. It is designed to identify first-in-class drug target candidates, which are generally difficult to identify using traditional experimental approaches.

Immune Checkpoints

In recent years, the blockade of the immune checkpoints CTLA4 and PD-1/PD-L1 emerged as “game changers” in cancer therapy, forming the foundation for a new era of cancer immunotherapy. However, many patients and many tumor types do not respond to these treatments, indicating that there may be additional immune-suppressive mechanisms mediated by unknown checkpoint inhibitors.

Compugen’s discovery platform has predicted multiple novel proteins as possible additional immune checkpoints. These findings included PVRIG and TIGIT, which are two parallel and complementary pathways in the DNAM axis. Potential molecular interactions between PVRIG, TIGIT, and the PD-1 pathways underscore the potential of a combination treatment approach. 

Compugen therefore hypothesizes that, to increase antitumor immune responses, treatments will need to inhibit various combinations of PVRIG, TIGIT, and/or PD-1 PD-L1 simultaneously. In different cancers and different patient populations, different pathways may be dominant, and inhibition of two or all three of these pathways may be necessary to improve outcomes. The need to block the appropriate pathway(s) may address a portion of the approximately two-thirds of cancer patients who do not respond to checkpoint inhibitors.

Targeting PVRIG

To support this hypothesis, Compugen is studying whether PVRIG alone or in combination with TIGIT and PD-1 inhibitors will provide effective treatments for a variety of cancers.

In vitro and in vivo studies have been performed in collaboration with researchers at Johns Hopkins University to confirm that the PVRIG pathway affects antitumor immune responses. In vitro studies have also evaluated the performance of Compugen’s first-in-class humanized antibody PVRIG inhibitor candidate, COM701. These were supported by in vivo studies demonstrating tumor growth inhibition through PVRIG pathway inhibition. In addition, Compugen’s computational capabilities were used to analyze patient tumor samples, determining that the indications for which the PVRIG pathway may be dominant include ovarian, breast, and endometrial cancers, as well as non–small cell lung cancer. All of this information has been used to design several human clinical trials with COM701, Compugen's most advanced program.

COM701 is currently being evaluated in a phase I study in patients with advanced solid tumors who have exhausted all available standard therapies. The study, performed in collaboration with Bristol-Myers Squibb (BMS), is designed to evaluate the safety and tolerability of COM701 as monotherapy and in combination with BMS's PD-1 immune checkpoint inhibitor Opdivo® (nivolumab).

Preliminary results from the monotherapy dose-escalation studies have been encouraging. Stabilization of disease was observed in nine of 13 patients treated with COM701. In addition, one patient with a type of ovarian cancer exhibited a confirmed partial response. Furthermore, five of six patients with microsatellite-stable colorectal cancer (MSS-CRC) showed stable disease and some level of initial dose/response relationship. In the combination arm, an MSS-CRC patient also exhibited a confirmed partial response. CRC was not initially selected by Compugen as having a high likelihood of response to COM701, as it is a medium expressor of the PVRIG pathway. These results are particularly encouraging.

Currently, Compugen is completing the monotherapy dose-escalation studies and continues to conduct the combination dose-escalation studies, with data presented at AACR in April 2020. Compugen anticipates initiating enrollment in the monotherapy expansion cohort, which has been amended to include CRC based on the clinical results seen to date, with initial results released in the first half of 2021.

Recently, the company announced the expansion of its collaboration with BMS to include a phase I/II triple-combination study to evaluate COM701 in combination with Opdivo and BMS's TIGIT inhibitor candidate BMS-986207 in patients with endometrial and ovarian cancers. The study will also test Compugen’s biomarker hypothesis for patient selection in a third arm enrolling various cancer types and is expected to begin in the second half of 2020.

TIGIT-Targeted Candidate

Given its discovery of TIGIT in 2009 and preclinical data suggesting that the simultaneous blockade of TIGIT and PVRIG may be essential for inducing robust antitumor immune responses, Compugen is pursuing the development of its own TIGIT inhibitor. As a result, Compugen is the only company advancing inhibitors in clinical programs targeting both TIGIT and PVRIG, uniquely positioning the company to synergistically target these two immune checkpoints.

COM902 is a therapeutic, high-affinity, fully human, immuno-oncology antibody. It has been shown to block the interaction of TIGIT with PVR, its ligand, and consequently to enhance T cell function.

Compugen recently dosed the first patient in a COM902 phase I trial. The open-label clinical trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of escalating doses of COM902 monotherapy in patients with advanced malignancies who have exhausted all available standard therapies.

Early-Stage Myeloid Drug Targets

Compugen has a number of other discovery-stage programs focused mainly on myeloid targets.

Myeloid immune checkpoint inhibition offers potential for efficacy in patients with cancers possessing a strong immune-suppressive environment or that are refractory to available immune checkpoint inhibitors. As such, blocking myeloid targets may offer a complementary strategy to immune checkpoint inhibition, providing new treatment solutions for nonresponsive or relapsing patients and expanding the patient population responsive to immunotherapies.

Translational Medicine Powered by Computational Discovery

“Compugen is highly differentiated from other biotech companies because we uniquely combine computational discovery expertise with advanced drug development capabilities,” explained CEO Anat Cohen-Dayag. “Developing algorithms for target identification requires a completely different skill set than developing those targets and translating them into actual drug products. In addition, when we discover new drug targets computationally, we incorporate our understanding of drug development to ensure better target selection. As a result, we are able to discover completely new targets that have a high potential to be both developable and commercializable.”

The approximately $75 million raised in Compugen’s recent underwritten public offering will fund its various clinical studies. As Compugen turned to be a predictive discovery company and a developer of effective, novel medicines, it also plans to continue to leverage collaborations with big pharma companies like those it has already established with BMS, Bayer, and AstraZeneca.

David Alvaro, Ph.D.

David is Scientific Editor in Chief of the Pharma’s Almanac content enterprise, responsible for directing and generating industry, scientific and research-based content, including client-owned strategic content, in addition to serving as Scientific Research Director for That's Nice. Before joining That’s Nice, David served as a scientific editor for the multidisciplinary scientific journal Annals of the New York Academy of Sciences. He received a B.A. in Biology from New York University in 1999 and a Ph.D. in Genetics and Development from Columbia University in 2008.