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23andMe Details Genetically Informed Cancer Immunotherapy Development Plans

genetics drug development

NEW YORK – 23andMe's nascent drug development programs will integrate exploratory biomarker research, including the use of polygenic risk scores, to identify cancer patients most likely to benefit from the therapies it is advancing.

"23andMe is incorporating clinical genotyping into our clinical trials because this could enable more efficient clinical [drug] development and improve the probability of success for all of our programs," Jennifer Low, 23andMe's head of therapeutics development, said during an R&D day presentation on Monday. "Developing drugs in genetically defined populations may differentiate future medicines based on better outcomes and improved benefit-risk profiles."

During the webcast event, Low and other executives at the company, which went public last year via a merger deal with special purpose acquisition company VG Acquisition Corp., updated investors on two immune-oncology compounds in the clinic: GSK6097608, the CD96-targeting antibody it is developing with GlaxoSmithKline under a 2018 pact, and 23ME-00610, a CD200R1-targeting drug 23andMe is developing on its own.

Ahead of the R&D presentations, 23andMe announced that GSK has decided to extend their four-year drug target-discovery alliance, slated to expire this year, until July 2023, triggering a $50 million payment.

Sunnyvale, California-based 23andMe started out more than 15 years ago as an online seller of direct-to-consumer genetic tests for ancestry, traits, disease risk, and drug response. The company launched a therapeutic division in 2015 hoping to use its rapidly growing database of consented customers' genotype and phenotype data to expedite drug discovery and development.

Its deal with GSK in 2018 provided 23andMe an opportunity to demonstrate the potential of its genomically driven drug discovery engine to a large pharma. During its R&D day, 23andMe executives boasted that using the genotype-phenotype associations on nearly 12 million of its customers, the firm has identified 40 therapeutic programs within its alliance with GSK.

"Evidence shows that genetically validated drug targets have at least double the probability of success in becoming medicines," John Lepore, senior VP and head of research at GSK, said in a statement. "Today more than 70 percent of our targets in research have genetic validation."

Kenneth Hillan, 23andMe's head of therapeutics, estimated that it still takes on average seven years for therapies to go from discovery phase to first-in-human trials. Even though drugmakers are applying deeper genetic insights to decide which agents to advance in the clinic, only 10 percent of their candidates make it to the market, keeping the average cost of developing a drug high at $2.6 billion.

During its R&D day, 23andMe executives highlighted GSK6097608 (GSK'608) as an example of how the firm's genomically driven approach can improve on these metrics. The company's genotype-phenotype database allows the company to start the drug development process with a "playbook of the potential drivers of disease," Hillan said, highlighting that the anti-CD96 therapy program went from a research concept to the clinic in four years, which is significantly shorter than the industry average.

Based on 23andMe's insights on CD96 as a target and biologically rational combination approaches, GSK advanced GSK'608 into the clinic in July 2020. CD96 is a part of the CD226 pathway but can block the ability of CD226 to activate cancer-killing NK and T cells. Drawing on data from its genetically based drug-development platform, 23andMe proposed that it may be possible to improve cancer patients' response to immunotherapy via combination treatment strategies that simultaneously inhibit CD96, alongside other checkpoint proteins like PD-1 and TIGIT.

Low pointed out that GSK has acquired access to all the agents that 23andMe's research suggests would work synergistically with GSK'608, including the PD-1 inhibitor dostarlimab (Jemperli), the PVRIG inhibitor SRF813, and the anti-TIGIT therapy GSK4428859.

In July 2020, based on 23andMe's insights, GSK started a Phase I first-in-human trial of GSK'608 in patients with locally advanced, recurrent, or metastatic solid tumors who aren't responding to or can't receive standard treatments. In the first part of the study, GSK is studying escalating doses of single-agent GSK'608, and in the second part of the trial, patients receive escalating doses of GSK'608 in combination with a fixed dose of dostarlimab.

Researchers are interested in establishing the safety profile of the drug but will also track patients' responses to GSK'608 monotherapy and the combination. Low noted that GSK will report data from this study sometime this year. "Combining the inhibitors of CD96, TIGIT, and PD-1 to activate the CD226 pathway may be more efficacious than inhibiting single components," Low said. "However, in order to demonstrate the contribution of components, this will require more complex clinical trials."

Even though GSK'608 is still in early stages of development, 23andMe said it is exercising an option to receive worldwide royalties of up to the low double digits if the drug comes to market. This absolves 23andMe from having to continue to split development costs for the agent in later-stage trials or contribute to marketing and commercialization costs, and frees up the firm to invest that money in other therapies in its pipeline.

Toward that end, 23andMe said it has dosed the first patient in a Phase I trial of 23ME-00610 (23ME'610), an investigational drug that targets CD200R1, a protein expressed largely on T cells and myeloid cells. When CD200R1 binds to its ligand CD200 on tumors, it allows cancer cells to hide from attacking T cells. 23ME'610 is designed to block this mechanism so cancer cells can be recognized and attacked by the immune system.

23andMe believes it is unique among drugmakers in targeting CD200R1. Adrian Jubb, head of the firm's clinical oncology and neurology drug portfolios, said during R&D day that the company decided to go after the CD200R1 receptor as the target because it is expressed primarily on immune cells offering the best chance of fully inhibiting the pathway. Jubb pointed out that Alexion Pharmaceuticals has tried to target CD200R1's ligand CD200 with a drug called samalizumab, and cited data from a published Phase I study showing that the drug at the doses tested couldn't inhibit CD200 receptors on the surface of chronic lymphocytic leukemia cells.

"They weren't fully able to shutdown signaling through CD200R1, owing largely to the abundance of CD200 ligands expressed throughout many different cell types in the body, including tumor cells," Jubb said. "By contrast, CD200R1 expression is much more restricted just to immune cells." He added that preclinical studies comparing the activity of 23ME'610 against other CD200-targeting drugs gives 23andMe confidence that it is going after the right target in CD200R1.

The firm has launched a Phase I trial for 23ME'610 involving cancer patients with locally advanced or unresectable tumors who have stopped responding to or can't receive standard treatments. The first part of the trial will test escalating doses of the drug in up to 26 patients, while the second part will further evaluate the activity of the drug in 75 patients stratified into tumor-specific cohorts.

Researchers will assess the safety of the drug as well as patients' objective response rates on therapy. They will also explore secondary endpoints in the trial, such as progression-free survival and overall survival, as well as pharmacokinetics and pharmacodynamic biomarkers.

"We anticipate using a variety of approaches to try and identify which patients are most likely to benefit from these therapies," Jubb said.

Across this and other clinical trials, 23andMe is also broadly genotyping patients to gain insights into whether they are likely to respond to the therapies or if they'll experience adverse events and then using this data to improve these drugs' chances of reaching the market, Low said.

"In our 23andMe clinical trials, we're having our patients spit in a tube just as they do for our consumer product," Low said. "Then, they are genotyped."

The company will use genetic classifiers to conduct exploratory research on how biomarkers may be influencing patients' outcomes on investigational treatments, she said. Additionally, 23andMe will also offer clinical trial participants the option to use its direct-to-consumer genetic testing products, which in turn, allows the company to extract even more genotype-phenotype learnings from patients beyond the clinical trial.

As an example of the types of biomarker research 23andMe plans to conduct, Low cited the example of two failed trials of the PD-L1 inhibitor atezolizumab (Genentech's Tecentriq): IMpassion131 in first-line triple-negative breast cancer and IMvigor211 in advanced, platinum-treated bladder cancer. She noted that subsequent research on polygenic risk scores (see here and here) have demonstrated the ability to predict which patients were susceptible in immunotherapy trials to treatment-related adverse events like hypothyroidism and psoriasis, but also identify which patients were more likely to experience progression-free or overall survival benefits.

"Because of the size of our database," Low said, 23andMe "may be able to generate more accurate and impactful polygenic risk scores, and this could improve our clinical trial outcomes." This plan on the therapeutic development side aligns with the company's future goals within its consumer-facing genotyping business to roll out more PRS tests for predicting disease risk and encouraging healthier lifestyles. Specifically, the company said it plans to bolster PRS with data on customers' lifestyle to improve the accuracy of disease risk predictions.

When asked for more details on its biomarker-guided strategy within the 23ME'610 clinical trial, however, Low said 23andMe will provide more details on the program at a future medical meeting. Currently, the trial is a solid tumor, allcomer trial, she said, but noted 23andMe is particularly interested in tumor types that tend to have high CD200 expression, such as ovarian cancer, as well as tumor types where currently marketed checkpoint inhibitors lack efficacy.