FDA has approved a new drug Ozanimod for the treatment of multiple sclerosis

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he U.S. Food and Drug Administration has approved ozanimod, an immune-modulating therapy invented at Scripps Research, for the treatment of adults with relapsing forms of multiple sclerosis.

The drug is also in advanced clinical development for adults and children with moderate-to-severe ulcerative colitis and Crohn’s disease.

In patient studies supporting ozanimod’s New Drug Application, those who took the once-daily oral medicine experienced significantly less disease progression – including fewer relapses and preservation of the brain from atrophy – than those who received standard care, with very few side effects.

The drug, licensed to Bristol Myers Squibb, will be sold under the trademarked name Zeposia.

“Today’s FDA approval of ozanimod is a celebratory milestone for the multiple sclerosis community, which is in need of new, intelligent drug interventions to help patients control the progression of their disease,” says Hugh Rosen, MD, PhD, who invented ozanimod along with fellow Scripps Research professor Edward Roberts, PhD, and their laboratory colleagues.

Nearly 1 million people in the United States are living with multiple sclerosis, according to the National MS Society, and approximately 85 percent of those patients are diagnosed with the relapsing forms of the disease that ozanimod is designed to treat.

In multiple sclerosis, the immune system mistakenly attacks myelin sheath, the protective layer that surrounds nerves in the brain.

This disrupts the flow of information within the brain and between the brain and body, bringing about symptoms that can range from numbness and bladder issues to vision problems and muscle paralysis.

Ozanimod works by acting on certain types of immune cells called lymphocytes that are centrally involved in the autoimmune attack on myelin sheath.

It binds to receptors on the cells’ surface, keeping them from reaching the brain.

As a result, the number of activated lymphocytes is decreased, diminishing the immune attack.

The fundamental discoveries that led to ozanimod were reported by Rosen, Roberts and their Scripps Research colleagues in a series of papers from 2002 to 2008. In 2009, Scripps Research licensed ozanimod to biotechnology startup Receptos, which Celgene purchased in 2015 for $7.3 billion. Celgene was acquired by Bristol Myers Squibb in 2019.

Ozanimod is also being studied as a treatment for forms of inflammatory bowel disease, with late-stage clinical trials underway for ulcerative colitis and Crohn’s disease, for which it is a first-in-class treatment.

Nearly 1 million people in the United States are living with multiple sclerosis, according to the National MS Society, and approximately 85 percent of those patients are diagnosed with the relapsing forms of the disease that ozanimod is designed to treat.

The ozanimod approval for multiple sclerosis is the latest in a string of FDA-approved drugs to originate from Scripps Research’s laboratories, following on most recent approval of tafamidis for the rare but often fatal heart disease known ATTR-CM.

Scripps Research also invented drugs that have been brought to market to treat more than a dozen other conditions with major unmet medical needs, including arthritis, lupus, respiratory distress syndrome, gastric cancer, metastatic non-small cell lung cancer, hemophilia, anthrax inhalation and neuroblastoma.

Additional drugs are in development for more than 10 other conditions, ranging from osteoarthritis to Parkinson’s disease, with several in clinical trials.

“There are hardly any other academic institutions in the world that have the multidisciplinary expertise to discover a new disease-modifying compound and generate clinical data in support of its development,” Rosen says.

Additional molecules developed by Rosen and Roberts at Scripps Research are currently in phase 2 clinical trials for major depressive disease and anxiety, and in phase 1 studies for treatment of autism.


Ozanimod is a sphingosine 1-phosphate receptor modulator, which selectively binds to sphingosine 1-phosphate receptor subtypes 1 and 5 with high affinity. In the RADIANCE phase 2 study in participants with relapsing multiple sclerosis, ozanimod was associated with better efficacy than placebo on MRI measures and was well tolerated.

The RADIANCE phase 3 study aimed to confirm the safety and efficacy of ozanimod versus interferon beta-1a in individuals with relapsing multiple sclerosis.

Methods

We did a 24-month, multicentre, double-blind, double-dummy phase 3 trial in participants with relapsing multiple sclerosis at 147 medical centres and clinical practices in 21 countries. Participants were aged 18–55 years, had multiple sclerosis according to 2010 McDonald criteria, a relapsing clinical course, brain MRI lesions consistent with multiple sclerosis, an expanded disability status scale score of 0·0–5·0, and either at least one relapse within 12 months before screening or at least one relapse within 24 months before screening plus at least one gadolinium-enhancing lesion within the 12 months before randomisation.

Participants were randomly assigned (1:1:1) via an interactive voice response system to daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular interferon beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment allocation. The primary endpoint was annualised relapse rate (ARR) over 24 months.

The primary analysis was done in the intention-to-treat population of all participants who received study drug and safety was assessed in all randomly assigned participants who received study drug, grouped by highest dose of ozanimod received. This trial is registered at ClinicalTrials.govNCT02047734, and EudraCT, 2012-002714-40.

Findings

Between Dec 27, 2013, and March 31, 2015, we screened 1695 participants, of which 375 did not meet inclusion criteria. 1320 participants were enrolled and randomly assigned to a group, of whom 1313 received study drug (433 assigned to ozanimod 1·0 mg, 439 assigned to ozanimod 0·5 mg, and 441 assigned to interferon beta-1a) and 1138 (86·7%) completed 24 months of treatment.

Adjusted ARRs were 0·17 (95% CI 0·14–0·21) with ozanimod 1·0 mg, 0·22 (0·18–0·26) with ozanimod 0·5 mg, and 0·28 (0·23–0·32) with interferon beta-1a, with rate ratios versus interferon beta-1a of 0·62 (95% CI 0·51–0·77; p<0·0001) for ozanimod 1·0 mg and 0·79 (0·65 to 0·96; p=0·0167) for ozanimod 0·5 mg.

The incidence of treatment-emergent adverse events was higher in the interferon beta-1a group (365 [83·0%] of 440 participants) than in the ozanimod 1·0 mg group (324 [74·7%] of 434) or the ozanimod 0·5 mg group (326 [74·3%] of 439). More participants in the interferon beta-1a group had treatment-emergent adverse events leading to treatment discontinuation than in the ozanimod groups.

Incidences of infections and serious treatment-emergent adverse events were similar across treatment groups. No cases of ozanimod-related symptomatic reduction in heart rate and no second-degree or third-degree cases of atrioventricular block were reported.

Interpretation

In this 24-month phase 3 study in participants with relapsing multiple sclerosis, ozanimod was well tolerated and associated with a significantly lower rate of clinical relapses than intramuscular interferon beta-1a. These findings show the potential of ozanimod as an effective oral therapy for individuals with relapsing multiple sclerosis.


Source:
Scripps Research Institute

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