CREATE Medicines Doses First Patient in Frontline HCC Trial Evaluating MT-303, an In Vivo CAR Therapy, in Combination with Standard-of-Care Immunotherapy

• Frontline setting accelerates potential for deep, durable responses in the treatment of liver cancers
• Study builds on clinical validation from one of the largest datasets in the in vivo CAR field

CAMBRIDGE, Mass., Dec. 9, 2025 /PRNewswire/ -- CREATE Medicines Inc., a clinical-stage biotechnology company pioneering in vivo multi-immune programming, today announced that the first patient has been dosed in the frontline cohort of its metastatic hepatocellular carcinoma (HCC) clinical trial evaluating MT-303. The study is assessing MT-303, an investigational in vivo GPC3-targeted CAR therapy delivered by the company's proprietary mRNA-LNP platform, in combination with atezolizumab and bevacizumab, the current global standard-of-care regimen for frontline HCC.

This milestone marks the first time MT-303 is being evaluated in systemic treatment-naïve patients, where immune fitness is better preserved and there is greater potential for deep, durable responses to immunotherapy. Clinical correlative data from CREATE's ongoing monotherapy programs, including MT-302 and MT-303, have demonstrated in vivo CAR expression, immune activation, and tumor infiltration across more than 40 treated patients. These findings provide strong biological rationale for combination therapy and support the potential for additive or synergistic benefit when MT-303 is paired with atezolizumab and bevacizumab in the frontline setting.

In addition, MT-303 has shown a manageable and differentiated safety profile as a monotherapy, reinforcing the suitability of CREATE's mRNA-LNP in vivo CAR approach for use alongside established immunotherapies. The platform's flexibility, redosability, and absence of lymphodepletion requirements position MT-303 well for combination regimens in earlier-line settings where coordinated immune activation is essential.

"Advancing MT-303 into a frontline combination study represents an important evolution for the in vivo CAR field," said Matthew Maurer, M.D., Chief Medical Officer of CREATE Medicines. "Our monotherapy experience across MT-302 and MT-303 has generated compelling correlative evidence of immune activation, myeloid engagement, and tumor infiltration. These data, combined with MT-303's favorable safety and tolerability profile, support our confidence in evaluating the therapy alongside atezolizumab and bevacizumab. We believe MT-303 is well-positioned to drive deeper and more durable responses for patients with HCC."

"New modalities capable of expanding the benefit of the current treatment options for hepatocellular carcinoma are urgently needed," said Vladimir Andelkovic, M.D., FRACP, Principal Investigator, ICON Cancer Centre, Brisbane, Australia. "Adding the immune engagement potential of MT-303 to atezolizumab and bevacizumab in frontline systemic therapy, where immune fitness is more preserved, is both scientifically compelling and potentially clinically meaningful."

About MT-303

MT-303 is an experimental, in vivo GPC3-targeted CAR therapy that selectively programs myeloid cells using CREATE's redosable mRNA-LNP system. MT-303 is designed to produce:

• CAR expression in circulating and tumor-infiltrating myeloid cells
• Direct cytotoxicity against GPC3-positive tumor cells
• Immune-modulating effects that recruit adaptive immunity
• Repeat-dose capability with improved durability, requiring no lymphodepletion or ex vivo manufacturing

GPC3 is highly expressed across a majority of HCC cases and absent in normal adult tissue, making it an ideal target for directed immunotherapy. In the monotherapy dose escalation cohort of the MT-303 Phase 1/2 trial, the therapy demonstrated human proof-of-mechanism for in vivo CAR expression, myeloid-cell activation, tumor infiltration, evidence of clinical activity and the feasibility of repeat-dose regimens. These results provide the foundation for advancing MT-303 into combination and earlier-line settings.

About the Frontline HCC Study Evaluating MT-303

The frontline HCC study evaluating MT-303 (NCT06478693) is a multi-center, open-label, dose-escalation and expansion trial designed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of MT-303 in combination with atezolizumab and bevacizumab. The trial will evaluate MT-303 in adults with unresectable or metastatic HCC who have not received prior systemic therapy.

The study will also characterize markers of immune activation, including CAR expression kinetics, cytokine/chemokine profiles, tumor infiltration by innate and adaptive immune cells, and early signs of antitumor activity. Data generated from this trial will inform recommended Phase 2 dose selection, further combination strategies, and potential expansion into additional earlier-line or biomarker-defined patient populations.

About Hepatocellular Carcinoma

Liver cancer is among the fastest-growing causes of cancer-related mortality globally, with more than 850,000 new cases diagnosed each year. Hepatocellular carcinoma accounts for most liver cancer cases and often arises in the context of chronic liver disease, viral hepatitis, metabolic syndrome, or cirrhosis. Although recent advances in targeted agents and immunotherapies have improved patient outcomes, durable, long-term benefit remains limited for most patients. Once frontline therapies fail, treatment options become scarce, and prognosis worsens sharply. Novel therapeutic approaches capable of generating coordinated and sustained immune responses represent an urgent and unmet need for the global HCC patient community.

About CREATE Medicines
CREATE Medicines (formerly Myeloid Therapeutics) is a clinical-stage biotech pioneering in vivo multi-immune programming. Its proprietary mRNA-LNP platform directly programs immune cells inside the body to deliver scalable, repeat-dose, off-the-shelf immunotherapies. With proven human validation and next-generation RNA technology, CREATE is advancing a pipeline of in vivo CAR therapies to transform outcomes in cancer, autoimmunity, and fibrosis.

For more, visit createmedicines.com. Follow us on LinkedIn and X (Twitter).

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SOURCE CREATE Medicines, Inc.