Genascence Corporation has launched the Phase 1B DONATELLO clinical trial (NCT05835895) to evaluate GNSC-001, an adeno-associated virus (AAV) vector gene therapy for knee osteoarthritis (OA), potentially offering the first disease-modifying treatment for this debilitating condition.
The dose-ranging, randomized, double-blind, placebo-controlled trial is currently recruiting approximately 50 participants across 10 clinical centers throughout the United States. Researchers will assess the safety, tolerability, and pharmacodynamics of a single intra-articular injection of GNSC-001 in patients with knee OA.
"Osteoarthritis is incapacitating, causing years of pain and disability for people living with the disease, and there are no currently available treatments to slow down disease progression," said Thomas Chalberg, PhD, founder and CEO of Genascence. "This is a critical next step toward the development of the first gene therapy for prevalent musculoskeletal diseases like OA."
Mechanism of Action and Treatment Approach
GNSC-001 represents a novel therapeutic approach that utilizes a recombinant AAV vector to deliver an optimized form of IL-1Ra, a protein designed to block interleukin-1 (IL-1) signaling. IL-1 is a key inflammatory mediator that contributes to joint inflammation, pain, and cartilage destruction in knee OA.
Unlike conventional treatments that provide only temporary symptom relief, this gene therapy aims to deliver sustained IL-1 suppression with a single injection directly into the affected joint. The approach could potentially modify disease progression rather than merely addressing symptoms.
Lachy McLean, MD, PhD, chief medical officer at Genascence, emphasized the transformative potential: "Our GNSC-001 gene therapy has the potential to transform the treatment landscape for individuals suffering from OA. We look forward to sharing initial 6-month data from the DONATELLO clinical trial in the fourth quarter of 2024."
Promising Phase 1 Results
The advancement to Phase 1B follows encouraging results from an investigator-initiated Phase 1 trial (NCT02790723) conducted at Mayo Clinic. Data presented at the European American Society of Gene & Cell Therapy's 30th Annual Congress in October 2023 demonstrated that GNSC-001 was well-tolerated across all dose cohorts.
The Phase 1 study evaluated three dose levels: 1×10¹¹ vector genomes (vg)/knee (low dose), 1×10¹² vg/knee (mid dose), and 1×10¹³ vg/knee (high dose). Key findings included:
- No dose-limiting toxicities up to the highest dose level
- Only two participants experienced vector-related adverse events (mild/moderate knee effusions), which resolved with conservative management
- Elevated IL-1Ra expression in synovial fluid sustained throughout the 12-month study duration
- Positive trends in pain scores via Visual Analogue Scale (VAS) and in pain and function via WOMAC scores
- Evidence of limited disease progression
"These study results provide encouraging preliminary evidence that GNSC-001 may have a role to play in helping OA patients in a safe and effective manner," noted Annahita Keravala, PhD, founder and chief scientific officer at Genascence.
Trial Timeline and Significance
Genascence plans to complete enrollment in the DONATELLO trial by the first quarter of 2024, with topline 6-month data expected in the fourth quarter of 2024. The study represents a significant milestone in addressing the substantial unmet need in osteoarthritis treatment.
Osteoarthritis affects millions worldwide, causing chronic pain, reduced mobility, and diminished quality of life. Current treatment options primarily focus on symptom management through pain medications, physical therapy, and eventually joint replacement surgery for advanced cases. A disease-modifying therapy could fundamentally change the treatment paradigm.
Immunological Considerations
The Phase 1 data revealed that all participants developed various degrees of anti-AAV neutralizing antibodies after injection, though no capsid-targeted T-cell response was detected. Small amounts of viral genomes were found in peripheral blood starting one day after injection but cleared within four weeks in most participants.
These immunological findings will likely be monitored closely in the current Phase 1B trial, as they have implications for the therapy's safety profile and potential for redosing if necessary.
As the DONATELLO trial progresses, Genascence's innovative approach could potentially pioneer a new era in osteoarthritis treatment, offering hope to millions of patients currently lacking disease-modifying therapeutic options.
