Pharming Group N.V. has announced positive results from a Phase 2 clinical study of Ruconest (recombinant C1 esterase inhibitor, 50 IU/kg) for prophylaxis in patients with HAE. In the study, Ruconest showed a clinically relevant and statistically significant reduction in attack frequency for both the twice-weekly and once-weekly treatment regimens as compared with placebo.
32 HAE patients deficient in C1 esterase inhibitor and with a history of at least four attacks per month were enrolled in the randomized, double-blind, placebo-controlled study. The patients received Ruconest once and twice weekly and placebo in each of three four-week treatment periods in a cross-over design. The primary efficacy endpoint was the number of HAE attacks per 28 day treatment period and the secondary endpoint was clinical response, defined as a ≥ 50% reduction in the number of attacks from treatment with placebo to treatment with Ruconest.
In the intent-to-treat analysis (ITT), the study found a statistically significant difference in the mean number of HAE attacks that patients experienced during treatment with both the twice-weekly (p-value <0.0001) and once-weekly (p-value =0.0004) Ruconest regimen as compared with placebo.
Patients on placebo had a mean of 7.2 attacks (95% confidence interval[CI]: 5.8-8.6) per four week treatment period which was reduced to a mean of 2.7 attacks on Ruconest twice weekly (95% CI: 1.8-3.7) and a mean of 4.4 attacks on Ruconest once-weekly (95% CI: 3.1-5.6).
For the analysis of the secondary endpoint in the ITT population, 74% of patients (95% CI: 57-86) on the twice-weekly Ruconest regimen had at least a 50% reduction in their attack frequency.
This was confirmed in the per-protocol population of patients, which included patients who completed the study without any major deviations (n=23), where 96% of patients (95% CI: 79-99) on the twice-weekly Ruconest regimen and 57% (95%CI: 37-74) on the once weekly Ruconest regimen had at least a 50% reduction in their attack frequency. Furthermore, in this group, twice weekly Ruconest treatment reduced the attack frequency by 72% (95% CI: 63-81) and once weekly Ruconest treatment reduced attack frequency by 44% (95% CI: 27-62) as compared with placebo.
Ruconest was generally well-tolerated in the study. No patients withdrew from the study due to adverse events. There were no related serious adverse events. There were no thrombotic or thromboembolic events observed. There were no hypersensitivity or anaphylactic reactions. There were also no neutralizing antibodies detected.
Marc Riedl, Professor of Medicine and Clinical Director of the US HAEA Angioedema Center at UCSD and co-prinicipal investigator for the study, commented: “The results of this well-controlled prophylactic study demonstrate a clinically relevant reduction of HAE attack frequency and a high responder rate with the recombinant C1INH treatment. Combined with the excellent safety profile, this data supports further development of recombinant C1INH as a useful preventive therapy for HAE.”
Marco Cicardi, Professor of Internal Medicine University of Milan, Hospital L. Sacco Milan and co-prinicipal investigator for the study, remarked: “The clinical efficacy and responder rate in this well-controlled study clearly indicate that, despite its short half life, recombinant C1-inhibitor has the potential to become a prophylactic treatment for HAE. The results also mark an important step forward to further understanding the underlying mode of action of C1-inhibitor therapy in the treatment of HAE.”
Prof. Dr. Bruno Giannetti, Pharming’s COO, added: “We are very encouraged by these results and now look forward to reviewing the results with the FDA and EMA to be able to determine how to bring Ruconest, as the first and only recombinant C1- inhibitor, to patients who need prophylactic treatment for their HAE.”
Under the terms of the North American licensing agreement with Valeant Pharmaceuticals International, Valeant and Pharming share 50/50 the development costs for Ruconest for prophylaxis of HAE. Pharming will receive an undisclosed milestone payment from Valeant as and when FDA approval for this additional indication is given. Ruconest has been granted Orphan Drug designation by FDA for the prophylactic treatment of angioedema caused by hereditary or acquired C1 esterase inhibitor deficiency, with data exclusivity until 2026 under the Biologics Price Competition and Innovation Act.