LONDON – Indian generics manufacturer Lupin Ltd. has secured market exclusivity for an off-patent drug, receiving the EMA's seal of approval for Namuscla (mexiletine) in the orphan indication of non-dystrophic myotonia (NDM) in adults.

The product is set to become a cornerstone of Lupin Neurosciences, a specialty division the company is building in Europe to move up the value chain and reduce its dependence on low-margin generic drugs.

"The positive opinion represents an important milestone for Lupin Neurosciences as we build a leading specialty pharma company focused on the development, registration and commercialization of science-based therapies for neurological disorders," said Thierry Volle, president EMEA, Lupin.

Mexiletine is widely used off-label in NDM, but neither it, nor any other product, previously has had EMA approval for treating those rare, inherited disorders, in which muscles are slow to relax following contraction. Nor is there any FDA-approved treatment.

The sole exception is France, where mexiletine was approved for treating NDM in 2010.

The EMA's Committee for Medical Products for Human Use (CHMP) recommended approval based on a 25-patient phase III trial carried out at Pitié-Salpêtrière Hospital in Paris, and on three phase II studies and case reports from the literature. In the phase III study, mexiletine, now branded Namuscla, was shown to block sodium ion channels, significantly improving the ability of muscles to relax after contraction.

Mexiletine originally was developed by Boehringer Ingelheim GmbH as a treatment for arrhythmia, and approved in 1975 under the brand name Mexitil.

Lupin's interest dates from its July 2015 acquisition of a portfolio of specialty pharma products from Temmler Pharma GmbH, of Marburg, Germany. Temmler was not at that time marketing mexiletine, but just before the sale of the portfolio, in November 2014, had been granted EMA orphan drug status in the treatment of myotonia.

"Mexiletine was in the portfolio, but it was not active," Volle said. "However, it had been studied and used off-label by neurologists, and the most advanced data was the French [phase III trial]," he told BioWorld Asia.

Much of the earlier research was carried out by specialists involved in the Consortium for Clinical Investigations of Neurological Channelopathies, a body established by U.S. NIH to conduct robust trials in those rare conditions.

The consortium involves eight centers in North America and two European centers, in London and Milan. Seven of the centers took part in a 59-patient phase II trial published in 2012, which laid the groundwork for phase III development.

NDM is caused by a range of mutations in two skeletal muscle ion channels – voltage sensitive sodium channels that carry action potential, and chloride channels that maintain resting membrane potential.

There are estimated to be 7,500 adult NDM patients in Europe. However, the onset of symptoms is between 4 and 12 years of age. Volle said a pediatric clinical development plan agreed with the EMA will increase the size of the market. "The sooner [NDM] is diagnosed the better," he said. "We would expect more diagnoses as a result of increased awareness."

Approval of Namuscla will significantly expand the geographical scope of Zug, Switzerland-based Lupin's neurosciences business, which currently is focused on selling acquired products in the German market.

Building on approval of Namuscla, it is intended to bring in other products and develop treatments for other neuromuscular diseases. "We will both in-license and develop new chemical entities, but will focus first on in-licensing," Volle said. "Repurposing is not our mantra, but the opportunity was there [with mexiletine], and it was also interesting to see it can be done."

Other positive recommendations

At its monthly meeting, CHMP also recommended approval of Takhzyro (lanadelumab), Shire plc's monoclonal antibody for preventing recurrent attacks of hereditary angioedema (HAE).

Takhzyro, the first MAb for treating HAE, binds to kallikrein, blocking the kallikrein-kinin system that drives edema. The product is administered subcutaneously every two to four weeks, an improvement on current therapies which are administered intravenously, or that require more frequent subcutaneous dosing. Takhzyro received FDA approval in August. (See BioWorld, Aug. 27, 2018.)

CHMP gave the nod to Sanofi SA's Dengvaxia, the first vaccine to be approved in Europe for the prevention of dengue. However, the indication excludes its use in Europe, since dengue is not endemic, but covers a number of EU territories in tropical regions where it is.

The indication also excludes use of Dengvaxia in people who have never contacted dengue, because there is a risk of developing a more severe form of the disease if subsequently infected with the virus.

Dengue is unique in that a second infection tends to be worse than the first. CHMP said the vaccine has positive effects in preventing symptomatic and severe disease in people who have had previous dengue infection and who live in endemic areas.

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