Parkinson's Treatments Advance With Phase 3 Win, FDA Clearance, Biomarker Data

AbbVie's once-daily oral therapy tavapadon eased motor symptoms and daily-function problems in people with early Parkinson's disease in a Phase 3 clinical trial, with a U.S. Food and Drug Administration (FDA) decision expected later this year. The same period brought an FDA clearance for Gain Therapeutics' GT-02287, a Phase 2 biomarker study for Abli Therapeutics' risvodetinib, and the dosing of the first patient in GEN Pharmaceuticals' Phase II trial of SUL-238.

Tavapadon is an experimental oral small molecule that selectively and partially activates dopamine receptor proteins D1 and D5. Data from the TEMPO-2 trial (NCT04223193), which tested tavapadon against a placebo once daily for 27 weeks in 304 adults with early Parkinson's, showed the combined MDS-UPDRS Parts II and III score decreased by an average of 10.3 points with tavapadon, compared with 1.2 points with the placebo. Improvements versus placebo were seen by week 5 and continued through the end of treatment. On the Patient Global Impression of Change, 46% of tavapadon-treated participants rated their condition as "much improved" or "very much improved" versus 19% of placebo-treated patients. Side effects were mostly mild to moderate and more common with tavapadon (76% vs. 55%); the most frequent were nausea, headache, and dizziness, with side effects occurring most often during dose titration. The data were published in The Lancet Neurology and the study was funded by AbbVie. AbbVie has submitted an application to the FDA seeking approval, with a decision expected later this year.

Abli Therapeutics reported that risvodetinib, an oral experimental therapy being developed for Parkinson's disease, reduced multiple disease-related biomarkers in an expanded analysis of the Phase 2 201 study (NCT05424276). The 12-week trial enrolled patients with bradykinesia and tested once-daily risvodetinib against a placebo for three months in people with early, untreated Parkinson's. The new analysis involved 7,300 individual measures from as many as 80 participants and found that 11 disease-related biomarkers responded to treatment, reflecting nerve cell degeneration, mitochondrial health, and neuroinflammation. All three tested doses (50 mg, 100 mg, and 200 mg) inhibited c-Abl kinase activity; the 100 and 200 mg doses substantially reduced alpha-synuclein biomarkers in cerebrospinal fluid, and all three doses reduced phosphorylated alpha-synuclein levels in blood. All doses suppressed markers of neuroinflammation, including the NLRP3 protein and the cytokines interleukin-1 and interleukin-18. Abli said it will discuss the findings with the FDA this month.

The FDA gave Gain Therapeutics a green light to launch a clinical trial testing GT-02287, an oral therapy designed to prevent the formation of toxic protein clumps in Parkinson's disease. The Phase 2 trial is planned to start between July and September at sites in the U.S., Australia, and Europe. In a Phase 1 trial enrolling 73 healthy volunteers, GT-02287 was generally safe and well tolerated, and at a daily dose of 7.7 mg/kg and higher reached therapeutic blood levels and was detected in the cerebrospinal fluid. Additional results from an open-label Phase 1b trial (NCT06732180) showed that GT-02287 improved motor function and daily living activities over three months in people with Parkinson's, with or without GBA1 mutations. Use of the therapy also reduced levels of glucosylsphingosine (GluSph), with drops of 81% on average in patients with elevated levels at the start of the study.

GEN Pharmaceuticals announced that the first patient has been dosed in its Phase II Proof of Concept Trial for SUL-238, a first-in-class, hibernation-inspired small molecule designed to target mitochondria. The randomized, double-blind, placebo-controlled, single-center SHEPHERD study (NCT07322887) will assess the effects of SUL-238 on high energy phosphates with magnetic resonance spectroscopy in patients with early, untreated Parkinson's disease. SUL-238 supports mitochondrial bioenergetics via complex I/IV activation and has undergone extensive safety evaluation in preclinical and clinical Phase I studies. GEN licenses SUL-238 from Sulfateq B.V. for neurodegenerative disease applications.

The Michael J. Fox Foundation for Parkinson's Research has granted $2.74 million to X-tosis to support the preclinical development of XTS001, an oral, brain-penetrant small molecule designed to selectively inhibit the clumping of voltage-dependent anion channel 1 (VDAC1). The funding, from the Therapeutics Pipeline Program, will support laboratory research to gather initial safety and efficacy data for investigational new drug (IND) studies. Preclinical studies in animal models of Parkinson's showed that VDAC1 oligomerization inhibitors reduced the loss of dopaminergic neurons, restored dopamine levels, and protected against other disease-associated events by preserving mitochondrial function. X-tosis is also developing XTS001 for Alzheimer's disease.

The recent milestones come as a research note from Jefferies argues that neuroinflammation has become one of the field's most important storylines, with the addressable early Parkinson's population across the U.S. and EU expected to exceed two million patients by 2035 and a potential disease-modifying therapy market approaching $8 billion. The note noted that no therapy has convincingly demonstrated an ability to slow neurodegeneration, and pointed to Roche and Prothena's prasinezumab, which missed its primary endpoint twice but was pushed into Phase III after both trials hinted at slower motor decline, and Denali's LRRK2 drug BIIB122, which failed outright in broad Parkinson's patients and is now being tested only in a genetically defined subgroup. Several companies are targeting inflammation directly, including Ventyx Biosciences with oral inhibitors of NLRP3, Olatec Therapeutics with dapansutrile, BioVie with bezisterim, and Tiziana Life Sciences with intranasal foralumab in Multiple System Atrophy.