EMA Issues Positive Recommendations for Two Rare Disease Therapies

The European Medicines Agency separately issued positive recommendations for Rhythm Pharmaceuticals and GW Pharmaceuticals their experimental rare disease therapies.

The EMA’s Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending Rhythm Pharmaceuticals’ setmelanotide for designation as an orphan medicinal product for the treatment of patients with Bardet-Biedl Syndrome (BBS). People living with BBS may experience an insatiable hunger and severe obesity beginning early in life. Rhythm is currently evaluating setmelanotide in an ongoing pivotal phase 3 trial in patients with BBS and Alström syndrome.

The orphan medicinal product designation by the EMA s granted to medicines being developed for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition that affects fewer than five in 10,000 people in the European Union. This designation could allow for a number of incentives, including protocol assistance, access to the centralized authorization procedure, reduced regulatory fees, and a ten-year period of market exclusivity in the EU after product approval.

“We believe setmelanotide has the potential to transform the treatment of BBS and other rare genetic disorders of obesity by addressing underlying defects in the melanocortin-4 receptor (MC4R) pathway,” said Murray Stewart, chief medical officer of Rhythm. “This designation reflects the significant need for new therapies for BBS and we look forward to working with the EMA to potentially deliver setmelanotide to patients in Europe.”

BBS is an ultra-rare, genetic disorder that affects multiple organ systems.  Clinical features may include and are not limited to severe obesity, insatiable hunger, retinal degeneration, polydactyly, kidney abnormalities, and developmental delays. There is great variability in presentation and severity of these features across individuals with BBS.  Currently there are no approved therapies for regulating hunger in BBS.

Setmelanotide is a potent MC4R agonist in development for the treatment of rare genetic disorders of obesity. It activates MC4R, part of the key biological pathway that independently regulates energy expenditure and appetite. Variants in genes within the MC4R pathway are associated with unrelenting hunger and severe, early-onset obesity. Rhythm is currently developing setmelanotide as a replacement therapy for patients with monogenic defects upstream of MC4R.

The FDA has granted Breakthrough Therapy designation to setmelanotide for the treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway. The European Medicines Agency has also granted Priority Medicines (PRIME) designation for setmelanotide for the treatment of obesity and the control of hunger associated with deficiency disorders of the MC4R pathway.

GW Pharmaceuticals said the EMA’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending marketing authorization of its cannabidiol oral solution Epidyolex for use as adjunctive therapy of seizures associated with Lennox‑Gastaut syndrome (LGS) or  Dravet syndrome, in conjunction with clobazam, for patients 2 years of age and older. The European Commission is expected to make a final decision on the marketing authorization application in approximately two months. If approved, cannabidiol oral solution will be the first plant-derived cannabis-based medicine to be approved in Europe for the treatment of any form of epilepsy.

“This is a significant milestone for patients with LGS and Dravet syndrome as there remains a severe unmet medical need for these rare, lifelong forms of epilepsy,” said Martin Brodie, president of the International Bureau for Epilepsy. “Today’s positive opinion brings hope to both patients and their families of a treatment option that has the potential to better control seizures and notably improve quality of life.”

The COMP’s positive opinion is based on results from four randomized, controlled late-stage trials, results of which were reported in May. These studies incorporate data from more than 714 patients with either LGS or Dravet syndrome, two forms of epilepsy with high morbidity and mortality rates, which place a significant burden on families and caregivers. Many patients with LGS or Dravet syndrome have multiple seizures per day, which puts them at ongoing risk of falls and injury. Despite current anti-epileptic drug treatment, both of these severe forms of epilepsy remain highly treatment-resistant.

GW received US FDA marketing approval in June 2018 for Epidiolex for the treatment of seizures associated with LGS or Dravet syndrome in patients two years of age or older. Epidyolex has received Orphan Drug designation by the EMA.

Dravet syndrome is a severe infantile-onset and highly treatment-resistant epileptic encephalopathy frequently associated with genetic mutations in the sodium channel gene SCN1A. Onset typically occurs during the first year of life in previously healthy and developmentally normal infants. Initial seizures are often body temperature related, severe, and long-lasting. Over time, patients with Dravet syndrome often develop multiple types of seizures, including ones that can be life threatening. Most Dravet sufferers also develop moderate to severe intellectual and development disabilities that require lifelong supervision and care.

The onset of Lennox‑Gastaut syndrome typically occurs between ages of three to five years and can be caused by a number of conditions, including brain malformations, severe head injuries, central nervous system infections and genetic neuro-degenerative or metabolic conditions. In up to 30 percent of patients, no cause can be found.

Patients with LGS commonly have multiple seizure types including drop and convulsive seizures, which frequently lead to falls and injuries, and non-convulsive seizures. Resistance to anti-epileptic drugs is common in patients with LGS. Most patients with LGS experience some degree of intellectual impairment, as well as developmental delays and aberrant behaviors.

Photo: Martin Brodie, president of the International Bureau for Epilepsy