Macitentan Patents

By: Divya Goyal from GreyB Service (guest author)

Macitentan (trade name Opsumit) is a drug by Actelion for the treatment of Pulmonary Arterial Hypertension (PAH). Macitentan delays progression of PAH.  Macitentan received approval from the FDA in December 2013. Since then 35 other countries have given an affirmation for its usage.

After its approval, in the first quarter of 2015, Opsumit sales were $99.5 million, which further rose to $390.2 million in the first half of 2016.

We at GreyB service studied patents relating to Macitentan.  Actelion currently owns 55% of the total patents for Macitentan. 

What is Macitentan and how it’s exclusive?

Before approval of Macitentan, Tracleer and Letairis were the only two FDA approved endothelin receptor antagonist ETRAs for oral PAH treatment. The problem with these two drugs was their adverse effect on a liver. Also, the phase-III clinical trials of the two drugs were primarily based on 6 minutes walking distance test. Macitentan’s phase-III clinical trial, on the other hand, was based on delaying disease progression.

The structure of Macitentan is derived from Tracleer which has a dual ET_A/ET_B activity. ET_A and ET_B are endothelin receptors whose activation results in raising or lowering blood pressure. It has more affinity to bind to ET_A which increases blood pressure when endothelin binds to it. Also, ET_A is responsible for curing PAH more as compared to ET_B.

Unlike Tracleer that requires two dosages per day, Macitentan requires only one. It also has enhanced oral efficacy and has less severe effects on the live and bile salt transport system. Also, Macitentan is designated as an orphan drug. An orphan drug is that which is used for the treatment of a rare disease.

Key Patents of Macitentan

The patent US7094781 titled Sulfamides And Their Use As Endothelin Receptor Antagonists by Actelion Pharmaceuticals is the key patent of Macitentan which claims its chemical structure. 

• Twenty-one unique patent families are published based on Macitentan.
• Out of these twenty-one unique patent families, only one is the API (active pharmaceutical ingredient) patent i.e. it claims the only the structure of Macitentan.

Macitentan has 21 unique patent families out of which one is the API (active pharmaceutical ingredient) patent. Actelion has protected Macitentan in 23 different countries details of which is in the table below:

Publication Number	Expiry
DK1345920T3	December 18, 2020
ES2260318T3	December 18, 2020
LU92381I2	December 18, 2005
PT1345920E	December 18, 2020
AT323079T	December 18, 2020
EP1345920B1	December 4, 2021
DE60118782D1	December 4, 2021
NO2014014I2	August 31, 2015
HU229403B1	December 04, 2026
KR819668B1	December 18, 2020
CN100432070C	December 18, 2020
IL155805A	December 04, 2021
MY129150A	December 18, 2020
AU2002227984B8	December 04, 2026
NZ525614A	December 04, 2021
ZA200303695A	December 18, 2020
AR35610A1	December 18, 2020
BR200116237A	December 04, 2021
MX2003004780A	December 04, 2021
US7094781B2	October 12, 2022
CA2431675C	December 4, 2021
JP04245130B2	December 04, 2021

In Australia, US and Hungary, Macitentan patents have the expiry date of Dec 2026, Oct 2022, and Dec 2026 respectively. However, in Luxembourg and Norway, Actelion’s patents on Macitentan have expired thus opening the market for generic versions.

Patents by Other Assignees on Macitentan

Other than Actelion, there are patents filed by other assignees on Macitentan that are going to be in effect even after expiration of the key patent. The classification of these patents based on the features they are protecting is provided below.

Distribution of Patents on the Basis of Features

At least 20 patents have been filed by assignees other than Actelion on Macitentan. Out of these 20, 1 patent is on formulation filed by INSERM of France.

Three patents are filed on methods of use. These patents disclose development of Endothelin receptor antagonist in treating other diseases.

There are four patents related to structures in which companies have made attempts to circumvent and develop technologies for different crystalline or amorphous structure of Macitentan.

Sandoz, for example, has a patent application, US20160074398A1 , that discloses a polymorph of Macitentan.

In the rest 12 patents, 5 are on combinations, 5 are on process and 2 are on intermediates.

What are the features Companies Should Avoid when Launching a Generic version of Macitentan

The table below provides the list of feature that different patents protect in different jurisdictions which a company that is trying to launch a generic drug of Macitentan should avoid.

Category		Patent		Assignee		Patent Scope/Protected features	Market Coverage
Formulation		US9265762B2		Actelion Pharmaceuticals		Formulation comprising Macitentan and a filler (lactose monohydrate with microcrystalline cellulose), disintegrant (sodium starch glycolate and polyvinylpyrrolidone), 0.1 to 3% in weight of surfactant (polysorbate) and lubricant (magnesium stearate).	AU, BR, CA, CN, DK, EP, ES, HK, HR, IL, JP, KR, MY, NO, NZ, PT, RU, SI, TW, ZA
Combination		US8999934B2		Board Of Regents, The University Of Texas System		Use of Macitentan with cytotoxic agents for inhibiting an astrocyte mediated protection of a brain metastasis cell.	AU, CA, CN, DK, EA, EP, ES, HR, IL, IN, JP, KR, MA, MX, NZ, PT, SG, SI, TW, US, WO
		US8541433B2		Actelion Pharmaceuticals		Use of Macitentan with paciltaxil for the treatment of ovarian Cancer	AR, AU, CA, CN, DK, EP, ES, HR, JP, KR, MX, PT, RU, SI, TW, US, WO
		EP2670405B1				Use of Macitentan with cytotoxic agents such as temozolomide and paciltaxil for the treatmnet of malignant glioma.	EP, AR, AU, CA, CN, CO, EA, EP, IL, JP, KR, MA, MX, NZ, SG, TN, TW, US, WO
		US8268847B2				Use of Macitentan with PDE5-inhibitory agents to treat disorders involve vasoconstriction.	AR, AU, BR, CA, CL, CN, DK, EP, ES, HK, HR, IL, JP, KR, MA, MX, MY, NO, NZ, PT, RU, SI, TW, WO, ZA
		US8809334B2				Use of Macitentan along with agents having prostacyclin receptor (IP) agonist properties.	AR, AU, BR, CA, CN, EP, IL, JP, KR, MA, MX, NZ, RU, TW, WO
Process		WO2015121397A1		Actelion Pharmaceuticals		Production method for synthesis of Macitentan	EP
		EP2978746A1					CA, CN, KR, TW, US, WO
		KR2016030972A (hyperlink not available)
		CA2915736A1				Production method for synthesis of Macitentan and reaction solvent such as ethylene glycol.	TW, WO
		CN104447572A		Nanjing Nmg-Adds		Production method for synthesis of Macitentan by reacting N- propyl sulfonamide and 5- (4- bromophenyl) -4, 6- dichloropyrimidine.
Intermediates	CN104311492A		Chengdu Climb Pharmaceutical		Disclosure of preparation of intermediates for the production of Macitentan
	CN104897833A				Disclosure of detection of intermediate (N- propylamino sulfonamide), which can be employed for the prodcution of Macitentan.
Structure	WO2014198178A1		Hangzhou Pushai Pharmaceutical Technology		Disclosure of a polymorph of Macitentan and its XRD configurations.
	WO2016009322A1		Sifavitor		Disclosure of amorphous form of Macitentan.
	US20110082151A1		Auspex Pharmaceuticals		Disclosure of deuterium incorporation in the structure of Macitentan.
	US20160074398A1		Sandoz AG		Disclosure of a polymorph of Macitentan and its XRD configurations.			AU, CA, EP, WO
Method of Use	CA2641952C		Actelion Pharmaceuticals		Use of an endothelin receptor antagonist for the treatment of early stage idiopathic pulmonary fibrosis			AU, BR, CN, EP, IL, JP, KR, MX, NO, RU, SG, US, ZA
	EP2509594A1		French Institute of Health and Medical Research (INSERM)		Use of endothelin inhibitor for the treatment of rapidly progressive glomerulonephritis.			US
	WO2015110593A1		Unassigned		Use of ETBR-inhibitor for use in the prevention or treatment of a HCMV infection.

Actelion, no doubt, is the most dominant player of the Macitentan drug segment. It owns 55% of the total patents filed on Macitentan while the rest 45% are filed by different players.  There is one patent by Auspex, a company acquired by Teva, that protects Macitentan molecule.