This story has been updated to correctly show that MOMA Therapeutics has not yet filed an investigational new drug application with the FDA, but expects to by Q1 2025.
NEW YORK – MOMA Therapeutics recently celebrated treating the first patient in a Phase I trial of the polymerase theta (pol theta) helicase inhibitor MOMA-313, a significant milestone in the company's mission to develop therapeutics targeting the molecular machinery of the cell.
MOMA, which stands for Molecular Machines, launched in 2020, attracting $86 million from Third Rock Ventures and other investors betting that deep investigations into the structure and function of proteins involved in cellular housekeeping could unlock new therapeutic targets. The large, multi-domain proteins that MOMA focuses on convert chemical energy into large-scale conformational changes and help carry out tasks like protein transport and degradation, DNA unwinding, and programmed cell death. When these molecular machines malfunction, however, they play a key role in a range of diseases including autoimmune, nervous system, and cardiovascular conditions as well as cancer. MOMA is initially focusing on developing cancer drugs.
Unlike many biotech companies, which are founded based on technologies licensed from an academic institution, MOMA was built on the collective expertise of its founders Dorothee Kern, Eva Nogales, Johannes Walter, and Timur Yusufzai. Kern, a professor of biochemistry at Brandeis University, has studied protein folding using nuclear magnetic resonance techniques and cofounded the Cambridge, Massachusetts-based biotech Relay Therapeutics in 2016. Nogales, a professor of biochemistry and molecular biology at the University of California, Berkeley, has published extensively on how electron microscopy can be harnessed to characterize protein structure and functions. Walter is a professor of biological chemistry and molecular pharmacology at Harvard University and is an expert in DNA replication and repair.
Kern, Nogales, and Walter are also investigators and collaborators at the Howard Hughes Medical Institute. In 2020, they linked up with Yusufzai, at the time an entrepreneur-in-residence at Third Rock Ventures and a former assistant professor of biochemistry at Harvard Medical School, and built MOMA around their work on molecular machines.
Since its founding, MOMA has had a good track record raising the funds it needs. After raising that initial $86 million Series A financing, the firm, also based in Cambridge, Massachusetts, went on to raise $150 million in Series B financing in May 2022, which CEO Asit Parikh describes as "one of the worst times in the biotech market." He views the company's ability to raise funds in a difficult economic climate as a reflection of MOMA's ability to execute on its objectives.
In January, the firm also inked a discovery collaboration deal with Roche, in which it received $66 million upfront and is eligible to receive up to $2 billion in milestone payments as well as tiered royalties. Under that agreement, MOMA is responsible for identifying targets and selecting development candidates, and Roche is in charge of investigational new drug-enabling activities, clinical development, and commercialization. If multiple programs reach pivotal clinical trials, MOMA has the right to co-fund late-stage development of one product in exchange for increased US royalties.
Following this deal with Roche, MOMA has sufficient cash to carry it through the end of 2025, Parikh said. That agreement does not include the pol theta helicase inhibitor MOMA-313 or the company's Werner helicase candidate, MOMA-341, which are both wholly owned by MOMA.
The clinical trial of MOMA-313 that MOMA just started marks its transition from a platform research organization to a clinical-stage company. "It's pretty magical when that happens," Parikh said. "Some of my employees had been in the industry for a while, and never had an IND go through and a drug be dosed in a patient. I was thrilled for them to have that feeling."
The company is optimistic that the pol theta inhibitor, if it reaches the market, may make a real difference in patients' lives. Pol theta repairs double-stranded DNA breaks in the cell nucleus. It comprises two functional domains, a DNA polymerase domain and a helicase domain. It is part of a family of DNA damage response factors that also includes poly ADP polymerase 1 (PARP1). Inhibitors of PARP1 form a synthetic lethal combination with homologous repair deficiency mutations such as BRCA1 and BRCA2 in cancer. However, not all patients respond to PARP inhibitors and many patients develop resistance.
Homologous repair-deficient cancer cells tend to be reliant on pol theta to carry out DNA repair activities, making the enzyme an alternative synthetic lethality target. Academic and industry researchers have established pol theta as a druggable target with promising in vitro and in vivo activity, and several pol theta inhibitors are in clinical trials.
Based on its studies of pol theta using an X-ray crystal structure, MOMA researchers identified a different way to block the enzyme via the helicase domain. Most of the earlier pol theta candidates have been designed to target the polymerase domain, while MOMA and some other research organizations have shifted focus to the helicase domain. "MOMA and others have demonstrated … considerably more cell killing in culture with a helicase inhibitor than with a polymerase inhibitor," Parikh said. "The mechanistic basis for this observed difference remains to be elucidated."
In its newly launched Phase I trial, MOMA researchers are evaluating MOMA-313 alone and with AstraZeneca's PARP inhibitor Lynparza (olaparib) as a treatment for patients with homologous repair-deficient advanced or metastatic solid tumors. They'll be tracking MOMA-313's safety and tolerability as the primary endpoint in the study and identify a recommended Phase II dose. Secondary endpoints include objective response rate, progression-free survival, and overall survival.
In the dose-escalation portion of the study, investigators will enroll patients with advanced or metastatic homologous repair-deficient solid tumors who are not eligible for curative therapy but are eligible for PARP inhibitors. In the subsequent dose-optimization portion of the study, researchers will focus on patients with homologous repair-deficient advanced prostate, breast, and pancreatic cancer. To be eligible for the trial, patients must have alterations in certain genes, including BRCA1, BRCA2, RAD51 B/C, PALB2, and others, involved in homologous repair.
Parikh said MOMA is expecting a readout from the trial in the middle of 2026, but researchers may be able to share preliminary data sooner.
Even though there are several other clinical-stage pol theta inhibitors in development — including Artios' polymerase domain inhibitor ART6043, Ideaya Biosciences and GlaxoSmithKline's pol theta helicase inhibitor GSK101, and Repare Therapeutics' pol theta polymerase inhibitor RP-3467 — Parikh views the competition as healthy and ultimately beneficial for patients. "Some people are doing good work," Parikh said. "When there's competition in a field like this, it's better for patients, because that makes it more likely something will actually address the need that they have."
In addition to MOMA-313, the firm anticipates filing an IND with the US Food and Drug Administration for its Werner helicase-targeted drug candidate MOMA-341 by the Q1 2025. Werner helicase is another DNA damage response enzyme that plays a role in microsatellite unstable tumors. The company plans to study the drug alone and in combination with chemo and immunotherapy in cancers such as colorectal, gastric, and endometrial that are characterized by microsatellite instability.
"Werner is a notoriously hard target to drug because it undergoes such complex, dynamic motion as it's doing its work within the cell," Parikh said. "To block this from interacting with DNA in a way that is toxic to cancer cells and fine for normal cells — that's a challenge."
To address that difficulty, MOMA-341 binds covalently to its target, irreversibly inhibiting it.
Looking ahead, Parikh said MOMA is in a "great position" to ramp up its clinical programs and expects to have multiple cohorts of patients in dose escalation with MOMA-313 and Lynparza plus the expected IND filing for MOMA-341 and potential dose escalation for that program in 2025.