Date: 2015-03-26
Type of information: Granting of a Market Authorisation in Japan
Product name: Opsumit®
Compound: macitentan
Therapeutic area: Rare diseases
Action mechanism: endothelin receptor antagonist. Macitentan is an oral dual endothelin receptor antagonist. This means that it is expected to block the receptors (type A and B) which endothelin-1 normally attaches to and activates. Endothelin is a naturally occurring substance that is released from lining of the blood vessels. It is present at raised levels in patients with pulmonary arterial hypertension, causing the blood vessels to constrict and the blood vessel walls to thicken. By blocking endothelin receptors , macitentan is expected to stop endothelin from constricting the blood vessels, thereby leading to a decrease in the blood pressure and a reduction of the symptoms of pulmonary arterial hypertension.
Company: Actelion (Switzerland)
Disease: pulmonary arterial hypertension (PAH)
Latest news: * On March 26, 2015, Actelion announced that Japan's Ministry of Health, Labor and Welfare granted marketing approval for Opsumit® (macitentan) for the treatment of pulmonary arterial hypertension (PAH). The approval was based on data from a local study conducted in Japan and the landmark global Phase III SERAPHIN study. In both studies, improvements in pulmonary vascular resistance, 6MWD, and WHO function class were observed. In the SERAPHIN study, treatment with macitentan 10 mg per day resulted in a 45% risk reduction (p <0.0001) of the composite morbidity-mortality endpoint when compared to placebo. Actelion Pharmaceuticals Japan will co-promote Opsumit with Nippon Shinyaku in Japan and the companies will jointly ensure that Opsumit is made available to patients as soon as possible. * On February 14, 2014, Actelion has announced that SwissMedic has approved Opsumit® (macitentan) for PAH patients within Switzerland. The SwissMedic approval was based on data from the landmark Phase III SERAPHIN study. In the SERAPHIN study, treatment with macitentan 10 mg resulted in a 45% risk reduction (hazard ratio 0.55; 97.5% CI: 0.39 to 0.76; logrank p < 0.0001) of the composite morbidity-mortality endpoint when compared to placebo. Full data from this study will be made available through scientific disclosure at upcoming congresses and publications.
* On February 7, 2014, Actelion has announced the approval of Opsumit® (macitentan) 10 mg for the treatment of pulmonary arterial hypertension (PAH) by the Therapeutic Goods Administration (TGA) of Australia. Opsumit®, as monotherapy or in combination with approved PAH treatments (phosphodiesterase-5 inhibitors or inhaled prostanoids), is indicated for the treatment of idiopathic and heritable PAH as well as PAH associated with connective tissue disease and PAH associated with congenital heart disease with repaired shunts in patients with WHO Functional class II,III or IV symptoms.
The TGA's approval was based on data from the landmark Phase III SERAPHIN study. In the SERAPHIN study, treatment with macitentan 10 mg resulted in a 45% risk reduction (hazard ratio [HR] 0.55; 97.5% CI: 0.39 to 0.76; logrank p < 0.0001) of the composite morbidity-mortality endpoint when compared to placebo. The most common adverse events that were reported at a frequency at least 3% greater on macitentan than on placebo were nasopharyngitis (14.0% macitentan vs 10.4% placebo), headache (13.6% vs 8.8%) and anaemia (13.2% vs 3.2%) Opsumit® was approved by the FDA in October 2013, Health Canada in November 2013 and by the EU Commission in December 2013. It is also undergoing regulatory assessment in other countries including Switzerland.
* On January 31, 2014, Actelion has announced that following approval by the EU Commission, Opsumit® is available for prescribers in Germany from 1 February 2014. Opsumit® (macitentan) was granted marketing authorisation by the European Commission for the long term treatment of pulmonary arterial hypertension (PAH) in the EU on 20th December 2013. Opsumit is indicated as monotherapy or in combination, for the long term treatment of PAH in adult patients of WHO Functional Class (FC) II to III.
* On December 20, 2013, Actelion has announced that Opsumit® (macitentan) has been granted marketing authorisation for the long-term treatment of PAH in the EU by the European Commission. Opsumit®, as monotherapy or in combination, is indicated for the longterm treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III. Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders, and PAH associated with corrected simple congenital heart disease. Macitentan 10mg is also described as reducing the risk of PAH related death or hospitalization for PAH up to end of treatment (EOT) by 50% (HR 0.50; 97.5% CI: 0.34 to 0.75; logrank p < 0.0001). Macitentan 10mg improved quality of life assessed by the SF-36 questionnaire.
The EU label was based in part on data from the landmark Phase III SERAPHIN study which was published in the New England Journal of Medicine in August 2013, the SERAPHIN study demonstrated that treatment with macitentan 10 mg resulted in a 45% risk reduction (hazard ratio [HR] 0.55; 97.5% CI: 0.39 to 0.76; p < 0.0001) of the composite morbidity-mortality endpoint up to (EOT) when compared to placebo.
The most commonly reported adverse drug reactions are nasopharyngitis (14.0%), headache (13.6%) and anaemia (13.2%). The majority of adverse reactions are mild to moderate in intensity.
Opsumit® was approved by the FDA on 18 October 2013 and by Health Canada in November 2013. It is also undergoing regulatory assessment in other countries including Switzerland.
* On November 12, 2013, Actelion has announced that Health Canada has granted a Notice of Compliance (NOC) approving the orally available endothelin receptor antagonist Opsumit® (macitentan) 10 mg once daily for the treatment of pulmonary arterial hypertension.* On November 4, 2013, Actelion has announced the commercial availability of Opsumit® (macitentan) 10mg, for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression.
Opsumit® carries a Boxed Warning alerting patients and health care professionals that the drug should not be used in pregnant women because it can harm the developing fetus. Female patients can receive the drug only through the Opsumit REMS Program. All female patients must be enrolled in the program, comply with pregnancy testing requirements and be counseled regarding the need for contraception.
* On October 24, 2013, the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending the granting of a marketing authorisation for Opsumit® 10mg film coated tablet intended for the treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III. Opsumit® was designated as an orphan medicinal product on 29 September 2011.
* On October 18, 2013, Actelion has announced that the FDA has approved the use of the orally available endothelin receptor antagonist Opsumit® (macitentan) 10 mg once daily for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression. Opsumit® is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). Opsumit® also reduced hospitalization for PAH. Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients were treated with Opsumit® monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).
The US label for Opsumit® carries a Boxed Warning alerting patients and health care professionals that the drug should not be used in pregnant women because it can harm the developing fetus. Female patients can receive the drug only through the Opsumit REMS Program. All female patients must be enrolled in the program, comply with pregnancy testing requirements and be counselled regarding the need for contraception.
The most common adverse reactions (more frequent than placebo by 3% or more) observed in patients treated with Opsumit® were anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, and urinary tract infection. Physicians are advised to measure hemoglobin and liver enzymes prior to initiation of Opsumit® and repeat during treatment as clinically indicated.
In the United States, Actelion expects Opsumit® to become available to patients in November. Outside of the United States, Actelion continues to work with health authorities to obtain regulatory approval for Opsumit® .
The FDA approval was based in part on data from the landmark phase III SERAPHIN study. Published in the New England Journal of Medicine in August 2013, the SERAPHIN study showed the risk of the first occurrence of a morbidity or mortality event, the primary endpoint of the study, was reduced by 45% (p<0.0001) with macitentan 10 mg compared to placebo. This effect was observed irrespective of whether or not patients were already treated with other therapies for PAH. SERAPHIN also showed a risk reduction in PAH related hospitalization and death of 50% (p<0.0001) compared to placebo.
* On December 14, 2012, Actelion has announced that the FDA has officially accepted the New Drug Application (NDA) for macitentan (Opsumit®). On the 19th October Actelion submitted the NDA dossier for macitentan (Opsumit®) for the treatment of patients with pulmonary arterial hypertension to the FDA.
* On November 22, 2012, Actelion has announced that the submission of the Marketing Authorisation Application (MAA) for macitentan (Opsumit®) for the treatment of patients with pulmonary arterial hypertension to the EMA has been accepted. The EMA will now start the formal review process.
* On 22 October 2012, Actelion announced that it has submitted a New Drug Application (NDA) to the FDA seeking approval for macitentan (Opsumit®) for the treatment of patients with pulmonary arterial hypertension. Macitentan was studied in the pivotal, long-term, event-driven Phase III outcome study, SERAPHIN, in which 742 patients suffering from pulmonary arterial hypertension were randomized to receive either placebo or macitentan at 3 mg or 10 mg once daily. Treatment with macitentan has demonstrated a reduction in the risk of morbidity and mortality event over the treatment period versus placebo. This risk was reduced by 45 percent for patients in the 10 mg dose group (p<0.0001). The observed risk reduction was 30 percent (p=0.0108) for patients receiving the 3 mg dose. Patients in SERAPHIN were treated for up to three and a half years, providing safety data which showed that macitentan was well tolerated. The most common adverse events associated with the use of macitentan were nasopharyngitis, headache and anemia.
Patents:
Submission of marketing authorization application USA : 2012-10-19
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2013-10-18
UE authorization: 2013-12-20
Favourable opinion UE: 2013-10-24
Favourable opinion USA:
Orphan status USA: 2009-03-09
Orphan status UE: 2011-09-27
Pediatric exclusivit _USA:
Pediatric exclusivity UE: OTC status: Other news:
