Mr. Brook Riggins reports

THIOGENESIS THERAPEUTICS EXPANDS ON PLANS FOR PHASE 3 PIVOTAL TRIAL OF TTI-0102 IN NEPHROPATHIC CYSTINOSIS

Thiogenesis Therapeutics Corp. plans to initiate a phase 3 pivotal clinical trial of its lead compound TTI-0102 for the treatment of nephropathic cystinosis, an inherited lysosomal storage disorder requiring lifelong cystine-depleting therapy. The company plans to submit an investigational new drug (IND) application in early 2026.

About nephropathic cystinosis

Nephropathic cystinosis is a rare, autosomal recessive lysosomal storage disorder caused by mutations in CTNS, leading to toxic intracellular cystine accumulation and progressive multiorgan damage. Without disease-modifying therapy, patients develop renal Fanconi syndrome, growth failure and progression to end-stage renal disease. Lifelong cysteamine treatment slows but does not eliminate disease progression and tolerability challenges frequently lead to suboptimal adherence. There are two currently approved drugs for cystinosis: immediate release cysteamine (Cystagon); and delayed-release cysteamine (Procysbi). Both require multiple daily dosings and have significant side effects. The global cystinosis population exceeds 2,000 patients worldwide, representing a market opportunity of over $300-million.

A next-generation approach to cystine depletion

TTI-0102 is a next-generation cysteamine-based prodrug engineered to address long-standing limitations of current standard-of-care therapies, including their short half-life, side effects and dosing frequency.

TTI-0102 is designed to potentially offer:

• Once-daily oral dosing, enabled by controlled prodrug metabolism and extended exposure;
• Reduced peak-related GI intolerance, a major limitation of current cysteamine products;
• Improved tolerability across weight ranges, supported by results from the company's MELAS phase 2 program;
• Dual mechanistic activity: cystine depletion and enhancement of intracellular antioxidant pathways (glutathione and taurine), consistent with cysteamine biology.

Phase 3 cystinosis trial utilizing well-established end points and trial design, informed by biomarker and tolerability data from the MELAS clinical study

Despite being a new chemical entity (NCE), TTI-0102 is reduced and metabolized in the GI tract releasing cysteamine, the active ingredient in Cystagon and Procysbi, and therefore the phase 3 trial will be conducted under the U.S. Food and Drug Administration's (FDA) 505(b)(2) regulatory pathway.

A key design advantage of the planned pivotal study is the incorporation of dosing insights from Thiogenesis's continuing phase 2 MELAS trial, which demonstrated:

• Clear biomarker responses supporting thiol-mediated mitochondrial antioxidant activity;
• Dose-dependent tolerability patterns, particularly in lighter-weight patients;
• A fully characterized exposure-response profile, now informing cystinosis trial dosing strategies.

These data enable Thiogenesis to initiate a cystinosis phase 3 program with refined dosing regimens and enhanced biological rationale, reducing typical development risk.

Further, the end points and trial design are well understood; members of the Thiogenesis leadership and clinical team previously played pivotal roles in successfully advancing delayed-release cysteamine through clinical development and commercialization, giving the company unique insight into optimal trial design and cysteamine pharmacology.

Delayed-release cysteamine remains the current standard of care but is associated with:

• Twice-a-day dosing requirements;
• Nausea, vomiting, diarrhea, abdominal pain, halitosis and dysgeusia (common adverse events);
• Fibrosing colonopathy, a rare but serious adverse event identified in multiple postmarketing case reports, prompting FDA labelling changes in 2022.

"We understand the underlying mechanism of cystinosis at a deep biochemical level, cystine accumulation, oxidative stress and the burden of lifelong thiol therapy," said Dr. Patrice Rioux, chief executive officer, Thiogenesis Therapeutics. "TTI-0102 was engineered specifically to overcome the limitations of existing cysteamine formulations. By enabling the potential for once-daily or reduced dosing with a far better tolerability profile, we believe TTI-0102 represents the next-generation therapy that patients and families that would significantly increase their quality of life."

About TTI-0102

TTI-0102 is a sulphur-based disulphide prodrug consisting of two cysteamine molecules and one molecule of pantothenic acid (vitamin B5). Following oral administration, metabolic activation delivers sustained cysteamine exposure with reduced peak-related toxicity, enabling once-daily dosing. TTI-0102 is currently in clinical development for MELAS, Leigh syndrome, pediatric MASH and nephropathic cystinosis.

About Thiogenesis Therapeutics Corp.

Thiogenesis Therapeutics is a clinical-stage biopharmaceutical company with operations based in San Diego, Calif. The company is publicly traded on the TSX Venture Exchange and in the United States on the OTCQX. Thiogenesis is developing sulphur-containing prodrugs that act as precursors to previously approved thiol-active compounds, with the potential to treat serious pediatric diseases with unmet medical needs. Thiogenesis's lead product candidate, TTI-0102, has an active phase 2 clinical trial in mitochondrial encephalopathy lactic acidosis and stroke (MELAS), an IND-cleared phase 2a clinical trial planned in Leigh syndrome spectrum, a phase 2 clinical trial planned in pediatric metabolic dysfunction-associated steatohepatitis (MASH) and a phase 3 clinical trial planned in nephropathic cystinosis.

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