Human trial testing gene silencing injection therapy for MASH kicks off
Safety, tolerability of TGM-312 being assessed in patients and healthy volunteers
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The first participant has been dosed in a large clinical trial testing TGM-312, a novel gene-silencing therapy designed to slow the progression of metabolic dysfunction-associated steatohepatitis (MASH), a severe type of steatotic liver disease.
Dubbed RESTORE-MASH (NCT07427680), the Phase 1/2 study will evaluate the safety, tolerability, and pharmacological properties of the Tangram Therapeutics injection therapy in an estimated 99 participants, ages 18-70. The trial will involve both healthy volunteers and people with MASH.
“Initiating RESTORE-MASH dosing is a defining moment for Tangram and an important step [toward] bringing our GalOmic medicines to patients,” Ali Mortazavi, CEO of Tangram, said in a company press release announcing that the trial is now underway. GalOmic is the company’s proprietary platform, which aims to selectively silence disease-driving genes in liver cells.
“Having generated outstanding preclinical data, we’re excited to now evaluate TGM-312 in clinical trials,” Mortazavi said.
Initial safety data from the trial are expected in the second half of this year, according to the developer.
MASH is a severe form of liver disease typically linked to metabolic conditions such as obesity, type 2 diabetes, and high cholesterol. The condition develops when excess fat accumulates in the liver, triggering inflammation and liver cell damage.
Over time, this inflammation can lead to tissue scarring, or fibrosis. As liver fibrosis worsens, patients may develop cirrhosis, marked by irreversible scarring that can interfere with normal liver function. Advanced disease can result in liver failure, liver cancer, or the need for a liver transplant.
TGM-312 aims to silence particular gene in liver cells
TGM-312 belongs to a new class of medicines known as GalOmics. This treatment combines small interfering RNA (siRNA) technology, which allows for the targeting of individual genes, with GalNAc, a delivery system that directs the therapy specifically to liver cells.
Using siRNA, TGM-312 is designed to selectively silence a particular gene inside liver cells, which is expected to address several key drivers of MASH, among them fat buildup, inflammation, and fibrosis.
Its mechanism is complementary to those of approved and experimental MASH therapies, suggesting it could also be used in combination with other medications. With the potential to be administered as a subcutaneous, or under-the-skin, injection once every three months, the therapy may offer patients a more convenient dosing schedule.
TGM-312 was first tested in preclinical studies using the GAN-DIO mouse model, which closely mimics the metabolic and liver changes observed in human MASH. Treatment markedly reduced the NAFLD Activity Score, a measure of steatotic liver disease, and also lessened liver inflammation, as well as slowing progression of fibrosis.
These benefits were seen “both as [a] monotherapy and in combination with approved and emerging MASH therapies,” the release stated.
TGM-312 has the potential to offer a patient-friendly treatment option to support liver health.
RESTORE-MASH is testing TGM-312 against a placebo in both healthy adults and people living with MASH. The researchers will evaluate single ascending doses of the therapy in healthy participants, and multiple ascending doses in adults with MASH, with an optional expansion phase.
The trial’s goals include assessing the therapy’s safety and tolerability, as well as its pharmacokinetics — its movement into, through, and out of the body — and pharmacodynamics, or its effects on the body. To understand the effects of treatment on liver health, participants with MASH will also undergo liver biopsies, along with imaging scans and blood-based biomarker tests.
“We believe TGM-312 could serve as a differentiated backbone therapy across MASH segments, both as monotherapy [single therapy] and in combination with approved and emerging treatments,” Mortazavi said. “TGM-312 has the potential to offer a patient-friendly treatment option to support liver health in a rapidly evolving landscape.”
