A late-stage amyotrophic lateral sclerosis (ALS) patient has shown disease stabilization after treatment with TRE-515, an investigational drug developed by Trethera Corporation. The treatment was administered under the FDA's Expanded Access program, marking the first clinical use of the drug beyond its current trials for solid tumors.
The patient, diagnosed with ALS in May 2022, had previously undergone more than 10 different treatments without success, including Riluzole, the only FDA-approved drug for ALS. Prior to beginning treatment with TRE-515, the patient's forced vital capacity—a critical measure of lung function—had declined dramatically from 60% to 37% over just four months, despite receiving multiple drugs and experimental stem cell therapies.
During the three-month dosing period with TRE-515, objective measures demonstrated disease stabilization, including improvements in forced vital capacity and scores on the Revised ALS Functional Rating Scale (ALSFRS-R). The patient also reported subjective improvements, including weight gain, improved neck tone, and increased arm strength.
"Our laboratory research has revealed potential to treat a range of autoimmune and inflammatory diseases, including MS, Crohn's, and lupus. This trial marks a significant milestone as the first clinical use of TRE-515 beyond cancer," said Dr. Ken Schultz, CEO of Trethera. "Our approach has the potential to extend survival and improve quality of life for patients facing this devastating neurodegenerative disease."
Novel Mechanism of Action
TRE-515 works by targeting deoxycytidine kinase (dCK), the rate-limiting enzyme in the nucleoside salvage pathway—one of two biosynthetic pathways that generate DNA precursors. This unique mechanism of action differentiates it from existing ALS therapies.
The drug is currently in dose escalation trials for solid tumors, but Trethera's research suggests it may have applications in autoimmune and inflammatory conditions due to its ability to selectively modulate inflammation.
Notably, no adverse events occurred during the treatment period, and the multicenter medical review group unanimously voted to increase the TRE-515 dose and extend the trial.
Expanding Treatment Options for ALS
"FDA approved options to treat ALS are severely limited. Exploring alternatives with first-in-class drugs for patients lacking available therapies represents the continued advancement of science," said Dr. Frank Diaz, Assistant Professor of Neurology at Cedars-Sinai and treating neurologist. "We are pleased to work closely with Trethera in advancing this novel therapy."
ALS, also known as Lou Gehrig's disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord, leading to loss of muscle function and control. The disease can be traced to mutations in more than 20 different genes and is often caused by a combination of multiple subtypes. Patients with ALS have an average life expectancy of just two to three years after diagnosis, and there is currently no cure.
Dr. Dan Kelly, President of the Pacific Neuroscience Institute Foundation at Saint John's Health Center, expressed optimism about TRE-515's potential: "We are particularly excited about the potential for TRE-515 as an ALS treatment given its ability to selectively modulate inflammation and its favorable safety profile. We look forward to continued development of this promising therapeutic candidate for patients in need of therapies that improve the course of disease."
FDA Expanded Access Program
The patient was enrolled in the trial through collaboration between Trethera, Cedars-Sinai, and Providence Saint John's Health Center under the FDA's Expanded Access (EA) program. This program allows patients with life-threatening conditions to access investigational therapies when no satisfactory alternatives exist.
EA trials enable physicians and their patients to explore promising treatments under carefully designed protocols that align with ongoing clinical development. These trials can provide valuable data to inform and refine clinical research, though larger randomized clinical trials will ultimately be necessary to prove clinical benefit.
About TRE-515
TRE-515 is a first-in-class clinical stage drug administered as an oral capsule. It has twice been designated by the FDA as an Orphan Drug. The drug inhibits deoxycytidine kinase (dCK), which plays a key role in the nucleoside salvage pathway.
Researchers believe that some forms of cancer may be preferentially dependent on the salvage pathway to support tumor growth, and certain autoimmune diseases might also respond to TRE-515 treatment. Trethera is developing the drug for use as both a monotherapy and in combination with other treatments.
Future Directions
While these initial results are promising, the company acknowledges that future randomized clinical trials with larger patient populations will be necessary to definitively prove clinical benefit in ALS patients.
Trethera, a clinical-stage biopharmaceutical company founded by prominent UCLA scientists, continues to explore the potential applications of TRE-515 across multiple disease areas, including cancer and autoimmune conditions.
