Date: 2017-12-04
Type of information: Collaboration agreement
Compound: aprocitentan (ACT-132577)
Company: Idorsia (Switzerland) Janssen Biotech, a J&J company (USA - NJ)
Therapeutic area:
Type agreement: development - commercialisation
Action mechanism:
- dual endothelin receptor antagonist. Aprocitentan is an orally active dual endothelin receptor antagonist. Aprocitentan counteracts these deleterious effects in animal models of hypertension, including in salt-sensitive models. In such models, aprocitentan also provide significant blood pressure lowering effects on top of existing therapies (e.g. renin angiotensin system blockers).
- In a dose-finding study to explore the efficacy, safety and tolerability of aprocitentan in 490 patients with essential hypertension, aprocitentan significantly lowered blood pressure in a dose-dependent manner.
Disease:
Details:
- • On December 4, 2017, Idorsia announced that Janssen Biotech has exercised its option to enter into a collaboration agreement with Idorsia to jointly develop and commercialize aprocitentan and any of its derivative compounds or products. Headline results from the phase 2 study were released on 22 May 2017.
- Both parties have joint development rights over aprocitentan. Idorsia will oversee the Phase 3 development and regulatory submission for the treatment of patients with hypertension that is not controlled by at least three therapies (called resistant hypertension in the medical community). The costs will be shared equally between both partners. Janssen will oversee the Phase 3 development and submission for any additional indications.
- A Phase 2 study that evaluated the efficacy, safety and tolerability of aprocitentan in patients with essential hypertension to identify the optimal dose for further studies was completed in May 2017. The study evaluated the efficacy, safety and tolerability of a once-a-day oral regimen of 4 dose levels of aprocitentan (5, 10, 25, and 50mg) to identify the optimal doses for further studies. In this study 490 patients were randomized to receive either aprocitentan 5, 10, 25, 50 mg, placebo, or lisinopril 20 mg once daily. After 8 weeks of treatment the mean reduction from baseline in diastolic blood pressure - as measured at trough with a novel automated office blood pressure device - ranged between 6.3 and 12.0 mmHg in a statistically significant dose-dependent manner for the aprocitentan groups versus a decrease of 4.9 mmHg in the placebo group and a decrease of 8.4 mmHg in the lisinopril group (in the per-protocol population comprised of 410 patients).
- Systolic blood pressure reductions ranged from 10.3 to 18.5 mmHg in a statistically significant dose-dependent manner in the aprocitentan groups and were 7.7 and 12.8 mmHg in the placebo and lisinopril groups, respectively.
- These findings were confirmed in all randomized patients (Intent-to-Treat principle) and by 24 hours Ambulatory Blood Pressure Monitoring.
- The safety population included 327 patients in the aprocitentan groups, 82 patients in the placebo group and 81 in the lisinopril group. Aprocitentan was well tolerated across all four doses in this patient population. Discontinuation from study treatment due to an adverse event ranged between 1.2% and 3.7% for the aprocitentan groups versus 6.1% in the placebo group and 3.7% in the lisinopril group. The overall frequency of adverse events was similar to those observed in the placebo group. In this study, there were two cases of increased liver enzymes above three times the upper limit of the normal range, one in the placebo and one in the aprocitentan 5 mg group. Four cases of peripheral edema were observed, two in the aprocitentan 25 mg group and two in the aprocitentan 50 mg group. Mean body weight remained unchanged from baseline in the aprocitentan 5, and 10 mg groups, increased by 0.4 kg in the aprocitentan 25 and 50 mg groups, and by 0.3 kg in the placebo group and decreased by 0.3 kg on lisinopril. There was an expected dose related decrease from baseline in the hemoglobin concentration in the aprocitentan groups (ranging from 1.3 to 6.7 g/L) versus increases of 2.2 and 0.1 g/L in the placebo and lisinopril groups, respectively.
- Based on the positive dose-finding results and the feedback from health authorities, Idorsia is currently finalizing the design of a Phase 3 study. It will consist of a specifically designed study evaluating the initial and long-term effect of aprocitentan on systolic and diastolic blood pressure in patients requiring resistant hypertension management (RHM). The study is expected to start in 2018. If successful, the study will provide the basis for registration of the product.
Financial terms:
- Following Janssen's opt-in decision, Idorsia will receive a one-time milestone payment of $ 230 million that will be reflected in its fourth quarter 2017 financial results.
- Janssen will have the sole worldwide commercialization rights. Idorsia is entitled to royalty payments on any future net sales generated. Royalty payments will amount to 20% of annual net sales up to $ 500 million, 30% of annual net sales between $500 million and $2 billion, 35% of annual net sales above $ 2 billion.
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