Gene Therapy for Knee Osteoarthritis Advances; India Plans Regulatory Framework

Five investigative intra-articular gene therapy platforms for knee osteoarthritis are currently in human trials at sites in the US, according to ClinicalTrials.gov. The therapies deliver gene-altering vectors or cells directly into the affected joint in a single injection, eliminating the need for ongoing treatments.

The knee has drawn much attention from gene therapy researchers because clinicians treating osteoarthritis have extensive experience injecting corticosteroids directly into the joint. The approach involves injecting a virus that carries a therapeutic gene or a gene that will promote and direct the synthesis of a therapeutic protein. Once that protein gets into the joint, it delivers its DNA to the cell nuclei so that the cells can start making the therapeutic protein in large amounts for months or years.

PCRX-201 (enekinragene inzadenovec) has been described in a clinical trial for low back pain as a high-capacity, helper virus-dependent adenovirus serotype 5 vector that expresses interleukin (IL)-1 receptor antagonist (IL-1Ra). A phase 2 clinical trial evaluating the treatment in knee osteoarthritis is currently recruiting 135 patients.

Results of a phase 1 trial of 72 patients with knee osteoarthritis showed that those who received an intra-articular corticosteroid injection before getting the PCRX-201 injection had greater improvement in pain scores than those who did not, so pretreatment corticosteroid injections are mandated in the phase 2 trial. In the phase 1 trial, a single intra-articular injection of PCRX-201 with corticosteroid pretreatment demonstrated an acceptable safety profile and sustained pain relief for up to 156 weeks.

GNSC-001 delivers IL-1Ra via a serotype 2.5 recombinant adeno-associated virus (rAAV). Results of a phase 1 trial of 67 patients demonstrated an acceptable safety profile and sustained expression of IL-1Ra in the synovial fluid of the knee. Like the PCRX-201 trial, patients who had pretreatment with a corticosteroid injection had increased IL-1Ra expression.

The multifaceted nature of osteoarthritis means that more than one pathway is likely causing the condition, suggesting that a gene therapy targeting one pathway may need to be combined with others. All the osteoarthritis gene therapies in the pipeline align with the pathophysiologic properties of the disease. The issue is that with the introduction of these molecules — some with a virus, others with molecules in which there could be an immunologic reaction — there is a requirement for some of them to give steroids/glucocorticoids with the medication to reduce the potential for an immune response.

The current wave of gene therapy development follows a resurgence over the past two decades, since the FDA in 2003 suspended human gene therapy trials. That decision came after two children in a gene therapy trial in France developed a leukemia-like disease, and a teen volunteer in a gene therapy study at the University of Pennsylvania in Philadelphia died. Those mishaps were attributed to the use of adenoviral vectors, which promoted inflammation. Since then, safer recombinant adeno-associated virus (rAAV) vectors have ushered in a resurgence in gene therapy.

Meanwhile, India is preparing to overhaul its drug regulatory system to accelerate research and innovation in emerging technologies. An expert committee formed to recommend regulatory changes has submitted its final report, and the Centre has issued an office order assigning specific reforms to concerned divisions of the Central Drugs Standard Control Organisation (CDSCO) for implementation.

The order, dated February 24 and signed by drug controller general of India Rajeev Singh Raghuvanshi, directs officials to develop guidelines for mRNA therapeutics, Advanced Therapy Medicinal Products (ATMP), Cell and Gene Therapies and advanced biotherapeutics aligned with international standards. Among the key recommendations is extending priority or expedited pathways for novel biologics, rare disease, and breakthrough therapies. The committee has also recommended allowing innovative clinical trial designs including basket, umbrella, and adaptive trials.

The drug regulator will prepare detailed guidelines and standard operating procedures to define how these reforms will work in practice. This will include setting criteria, reviewing timelines and processes for priority pathways, laying down evaluation frameworks for innovative trial designs, and specifying timelines and fees for mandatory pre-submission meetings.