CREATE Medicines Doses First Patient in Frontline HCC Trial of In Vivo CAR Therapy MT-303

CAMBRIDGE, MA — December 9, 2025

CREATE Medicines Inc., a clinical-stage biotechnology company focused on in vivo multi-immune programming, announced today that the first patient has been dosed in the frontline cohort of its metastatic hepatocellular carcinoma (HCC) clinical trial. The study is evaluating MT-303, an investigational in vivo GPC3-targeted CAR therapy, in combination with the current global standard-of-care regimen for frontline HCC: atezolizumab and bevacizumab.

Pioneering In Vivo CAR Therapy in the Frontline Setting

MT-303 is delivered by the company’s proprietary mRNA-LNP platform and is designed to selectively program myeloid cells to express a GPC3-targeted CAR. This milestone marks the first time MT-303 is being evaluated in systemic treatment-naïve patients, where immune fitness is generally better preserved, offering a greater potential for deep and durable responses to immunotherapy.

Clinical correlative data from CREATE’s ongoing monotherapy programs have already demonstrated:

• In vivo CAR expression

• Immune activation

• Tumor infiltration

These findings establish a strong biological rationale for combining MT-303 with the existing standard-of-care, suggesting potential additive or synergistic clinical benefit.

“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. “The data from our monotherapy experience, combined with MT-303’s favorable safety and tolerability profile, support our confidence in evaluating the therapy alongside atezolizumab and bevacizumab.”

MT-303’s Differentiated Profile

MT-303 is an experimental, redosable therapy that does not require the lymphodepletion or ex vivo manufacturing typical of traditional CAR T-cell therapies. It is designed to produce direct cytotoxicity against GPC3-positive tumor cells and to induce immune-modulating effects that recruit adaptive immunity. GPC3 is an ideal target as it is highly expressed in the majority of HCC cases but absent in normal adult tissue.

Vladimir Andelkovic, M.D., FRACP, Principal Investigator, noted that adding the immune engagement potential of MT-303 to the established frontline systemic therapy regimen is “both scientifically compelling and potentially clinically meaningful.”

The frontline HCC study (NCT06478693) is an open-label, dose-escalation and expansion trial investigating safety, pharmacodynamics, and preliminary anti-tumor activity in adults with unresectable or metastatic HCC who have not received prior systemic therapy.