Tangram Therapeutics advances TGM-312 into MASH patient cohorts
Tangram Therapeutics has moved its lead candidate TGM-312 into Part B of the Phase 1/2 RESTORE-MASH trial, following a favourable review by the independent Data Monitoring Committee. The transition takes the GalNAc-conjugated siRNA from single ascending dose testing in healthy volunteers into multiple ascending dose cohorts in patients with metabolic dysfunction-associated steatohepatitis, commonly known as MASH. Interim patient data are expected during 2027.
Four cohorts of healthy volunteers have now been dosed with TGM-312 without any serious or severe adverse events, a result the London-based company says both validates its novel SLC25A5 target and de-risks the proprietary GalOmic chemistry platform more broadly. TGM-312 is designed for infrequent subcutaneous administration, potentially quarterly, which Tangram positions as a patient-friendly attribute relative to daily oral regimens.
The science and the appointment
TGM-312 silences SLC25A5, a mitochondrial transporter, in hepatocytes. Tangram says the target was identified internally using a network biology approach combined with population genetic data from MASH and MASLD patient cohorts. The company claims a dual mode of action addressing both hepatic inflammation and steatosis, the two principal pathological drivers of disease progression. In preclinical work conducted in the GAN-DIO mouse model, TGM-312 reduced the NAFLD Activity Score, decreased liver inflammation and slowed fibrosis, both alone and alongside approved agents.
Tangram also announced the appointment of Dr Sonya Montgomery as Chief Development Officer. Montgomery brings more than 25 years of drug development experience across genetic medicines and other modalities, having held senior roles at Pfizer, ProQR Therapeutics, Gyroscope Therapeutics and Evox Therapeutics, and most recently as Chief Development Officer at OSE Immunotherapeutics. In a statement accompanying the announcement, Montgomery noted her intention to progress not only TGM-312 but also TGM-148, an earlier programme targeting bleeding disorders.
Interim Chief Executive Officer Dr Laura Roca-Alonso said the Phase 1/2 transition "reflects the strength of our GalOmic platform and the dedication of our team," and described Montgomery's hire as timely given the company's clinical momentum.
Market context
MASH is one of the most crowded therapeutic areas in hepatology. Madrigal Pharmaceuticals' resmetirom (Rezdiffra) received FDA approval in March 2024 as the first drug specifically indicated for MASH with liver fibrosis, establishing a commercial reference point for the category. Several other programmes are in late-stage development, including candidates from Novo Nordisk, Eli Lilly and a number of smaller biotechs pursuing GLP-1 combinations or novel liver-directed mechanisms.
Tangram's RNAi approach places it alongside a cluster of companies exploiting GalNAc-siRNA chemistry for hepatic targets, a modality now well validated by Alnylam's marketed products and the broader Silence Therapeutics and Arrowhead Research pipelines. Differentiation in this setting will ultimately hinge on efficacy in fibrosis regression, a regulatory endpoint the FDA has signalled as critical for full approval, and on tolerability relative to combination regimens. The 2027 interim readout will be the first meaningful test of whether TGM-312's preclinical promise translates in a patient population.
With a named CDO now in post and the trial progressing on schedule, Tangram appears well-positioned to maintain investor confidence ahead of that data window, though the company has not disclosed its current cash position or anticipated funding requirements.