Clinical Development
The Impres Trial of Imatinib as a Treatment of PAH
WHO Group 1 : Pulmonary Arterial Hypertension (PAH)
Based on the compelling data of imatinib on animal and human PAH, Novartis conducted a Phase 3 clinical trial known as IMPRES, to evaluate imatinib compared with placebo for the treatment of PAH patients. The IMPRES trial was a randomized, double-blind, placebo-controlled 24-week trial in PAH patients on ≥2 PAH therapies. The primary outcome was change in 6-minute walk distance. The improvement in the six-minute walk distance seen imatinib treated patients in the IMRES trial was highly significant. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 meters (95% confidence interval, 12–52; P=0.002)
The magnitude of hemodynamic improvement is notable given that all patients had severe PAH despite already being on multiple PAH treatments. The changes in 6-minute walk distance were almost entirely due to improvements in patients randomized to imatinib rather than to deterioration in the placebo group. Thus, the IMPRES trial provided strong evidence that imatinib, as the first of a new class of drugs for the treatment of PAH, improves exercise capacity and hemodynamics in patients with advanced PAH who remain symptomatic on at least 2 drugs of the currently available 4 drug classes.
The problem that was encountered in the IMPRES trial was an overall dropout rate of 33% in the imatinib group and 18% in the placebo group, giving an excess dropout rate of 15% in the imatinib group. The majority of patients who discontinued were from adverse reactions due to gastric intolerance in the imatinib group. Because of the high dropout rate, the FDA requested a second Phase 3 trial to confirm the efficacy results. Novartis chose to decline and withdrew the NDA.
Future Phase 3 Study
The IMPRES trial has established that Imatinib is effective as a treatment of PAH. Learning from the problems encountered in the conduct of the IMPRES study, Tenax has developed a unique clinical trial design and has agreement from the FDA to conduct a Phase 3 trial of TNX-201 (oral enteric coated imatinib mesylate) in patients with PAH for regulatory approval. The trial design incorporates a novel oral formulation designed to mitigate gastric intolerance, an enrichment enrollment strategy designed to maximize the treatment effects and minimize risks, and thus increase the overall likelihood of a successful study.
We believe that TNX-201 (oral enteric coated imatinib) holds great promise as a novel disease modifying therapy for PAH. A review of the published literature, and a responder analysis from the phase 3 IMPRES trial of imatinib for PAH show that imatinib produces a markedly greater treatment effect, and a much longer durability of treatment effect than any other available treatment, alone or in combination.
