By David Bautz, PhD
READ THE FULL MNOV RESEARCH REPORT
Positive FDA Feedback Regarding Phase 3 ALS Development Plan
On September 25, 2018, MediciNova, Inc. (MNOV) announced that the FDA provided positive feedback in regards to the company’s development plan for MN-166 (ibudilast) in amyotrophic lateral sclerosis (ALS). The FDA did not raise any concerns with the safety of MN-166, only a single trial may be necessary if there is a statistically significant result when comparing MN-166 to placebo in a functional outcome (such as ALSFRS-R), and the agency would like to see a broad range of ALS patients with randomization stratified by baseline disease severity. The company will now finalize the design of a Phase 3 trial based on these suggestions and we anticipate learning additional details in the first half of 2019.
SPRINT-MS Data Published in the New England Journal of Medicine
In August 2018, MediciNova announced the publication of the results of the Phase 2 SPRINT-MS trial of MN-166 in patients with progressive multiple sclerosis (MS) in the New England Journal of Medicine (Fox et al., 2018). The company had previously announced positive topline results from the study that showed a statistically significant 48% reduction in the rate of progression of whole brain atrophy compared to placebo (P=0.04). The following graph shows the estimated rate of change in the brain parenchymal fraction, which was -0.0010 per year for those on MN-166 compared to -0.0019 per year for those on placebo. This represented approximately 2.5 mL less brain-tissue loss with MN-166 compared to placebo over the 96 weeks of the study.
View Exhibit I
While not powered to show statistical significance, a key secondary endpoint of the trial was confirmed disability progression. The following graph shows a Kaplan-Meier plot of confirmed disability progression as measured by EDSS (Expanded Disability Status Scale). The hazard ratio for progression in the MN-166 group compared to placebo was 0.74, representing a 26% reduction in confirmed disability progression in the MN-166 group.
View Exhibit II
To help put these data into context we believe a comparison to the Phase 3 data for Ocrevus® (ocrelizumab) is warranted since that study involved patients (n=732) with primary progressive MS and a primary endpoint of confirmed disability progression (Montalban et al., 2017). The following table shows confirmed disability progression at 12 weeks (primary endpoint) and 24 weeks (secondary endpoint) with a hazard ratio for those two endpoints of 0.76 (P=0.03) and 0.75 (P=0.04), respectively. Thus, a hazard ratio of 0.74 for MN-166 is right in line with data that resulted in the approval of Ocrevus® for the treatment of progressive MS.
View Exhibit III
MN-166 was generally well tolerated during the study. Patients taking MN-166 experienced a higher rate of gastrointestinal side effects compared to those on placebo, however there were no increased serious adverse events (SAEs), no increased risk of infections, no cancer signal, no cardiovascular events, and no deaths related to MN-166 treatment. In addition, there was no statistically significant difference in the number of discontinuations between the two groups. In comparison, the first page of the Ocrevus® (ocrelizumab) label contains a number of warnings about potentially serious safety issues including malignancies, infusion reactions, and infections. We believe this is an important distinction as safety is a major driver of market share in MS. For example, Copaxone achieved the highest market share in the relapsing MS market, with annual sales in excess of $4.0 billion, due to its superior safety profile and despite the fact that it did not have the best efficacy. The data available so far indicates that MN-166 would likely have the best safety profile in the progressive MS market.
MediciNova is currently preparing for an “end-of-Phase 2” meeting with the FDA after which a Phase 3 program can begin.
Potential New Indication for MN-166
In August 2018, MediciNova announced plans to conduct a Phase 2/3 trial of MN-166 in degenerative cervical myelopathy (DCM) through an agreement with the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust. The Principal Investigator is Dr. Mark Kotter and the trial is being funded by a grant from the National Institute for Health Research (NIHR) in the United Kingdom. MediciNova is not funding the trial but will provide the study drug supply, regulatory support, and safety monitoring support.
DCM is the leading cause of spinal cord dysfunction (Fehlings et al., 2013). It is typically caused by degeneration of the vertebral column, which can include changes to the vertebrae or the ligamentum flavum and/or posterior longitudinal ligament, as shown in the following figure.
View Exhibit IV
Symptoms of DCM include pain and numbness in the limbs, poor coordination, vertigo, and bladder/bowel problems. The most commonly reported symptoms in a 2004 study of 79 DCM patients were numb arms or hands, numb legs or feet, clumsy hands, and neck pain (King et al., 2004). Additional symptoms include muscle weakness, stiff muscles, and overactive reflexes. There are over 200,000 procedures performed each year in the U.S. to relieve compression on the spinal cord or nerve roots. The condition is uncommon in those younger than 40 and incidence increases with age. Treatment for DCM includes both surgery and non-surgical options such as physical therapy, muscle relaxants, and neck collars. There are no approved medications for DCM.
The Phase 2/3 clinical trial is titled “Regeneration in Cervical Degenerative Myelopathy – a multi-centre, double-blind, randomized, placebo-controlled trial assessing the efficacy of ibudilast as an adjuvant treatment to decompressive surgery for degenerative cervical myelopathy”. This is a two-part trial; the plan is to enroll 25-80 subjects in part 1 and 220-325 subjects in part 2 with a total of 300-350 subjects enrolled in the study. Patients will be administered MN-166 (up to 100 mg/day) for two to three months prior to decompression surgery and then MN-166 treatment will continue for six months following surgery. The primary endpoint is the modified Japanese Orthopaedic Association (mJOA) Score, which assesses neurological function through evaluating motor function in upper and lower extremities, sensation, and micturition.
MediciNova’s lead programs are in progressive MS and ALS, and both of those programs have received a positive boost in the past month between the publication of the SPRINT-MS results in the NEJM and the positive feedback from the FDA regarding the Phase 3 program for ALS. We look forward to hearing additional details about each of these programs in the coming months. While the focus is on those two programs, the study of MN-166 in DCM represents additional upside as the company is not funding that trial and the approximately 200,000 patients affected by the disorder each year represents a sizeable potential market. Our current valuation is $19 per share.
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By David Bautz, PhD