By David Bautz, PhD
NASDAQ:MNOV
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Business Update
Phase 3 ALS Trial Ongoing
MediciNova, Inc. (NASDAQ:MNOV) is currently evaluating MN-166 (ibudilast) in a Phase 3 clinical trial for amyotrophic lateral sclerosis (ALS). The trial initiated in 2019 and, if successful, results from this trial are expected to support a New Drug Application (NDA) for MN-166 in ALS. A data readout is anticipated in 2025.
The Phase 2b/3 clinical trial is a multi-center, two-arm, randomized, double blind, placebo controlled trial that is comparing MN-166 to placebo in approximately 230 patients with ALS (NCT04057898). Participants in the trial will be randomized 1:1 between placebo and 100 mg/day of MN-166 for 12 months of treatment. The primary endpoint of the trial is the mean change in ALS functional rating scale-revised (ALSFRS-R) (Cedarbaum et al., 1999). The ALSFRS-R consists of a series of 12 questions on basic tasks (speech, salivation, swallowing, handwriting, cutting food, dressing and hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency) that are rated on a five-point scale where 0 = can’t do and 4 = normal ability. The individual items are summed to produce a score of between 0 = death and 48 = best. The ALSFRS-R score is utilized to keep track of the health of all ALS patients, and is a common outcome measure in ALS clinical trials as well as an established FDA-approvable endpoint. Secondary endpoints in the trial include the mean change from baseline in muscle strength and quality of life, time to survival, and safety and tolerability.
Important inclusion criteria include onset of ALS no more than 18 months prior to screening, the use of riluzole for at least 30 days prior to initiation of the study drug, slow vital capacity at least 70% of predicted, and an ALSFRS-R score of at least 35 at screening.
Positive Results from Phase 2 Trial of MN-166 in ALS
MediciNova previously studied MN-166 in a Phase 2 trial in ALS. This was a single center, double blind, placebo controlled six-month study with patients randomized 2:1 to receive riluzole (100 mg/day) plus either MN-166 (60 mg/day) or placebo. The six-month double blind portion was followed by a six-month open label extension phase during which all patients received MN-166. The intent-to-treat (ITT) population consisted of 51 patients who were randomized to placebo (n=17) or MN-166 (n=34) for the double-blind portion of the study. The per protocol (PP) population consisted of 44 patients that completed the double-blind portion of the study (n=15 for placebo; n=29 for MN-166) and 35 patients that completed the open label extension (n=12 for placebo; n= 23 for MN-166).
Since this was the first time MN-166 was tested in ALS patients the primary outcome of the study was safety and tolerability of the drug when administered along with riluzole (100 mg/day), the standard of care for ALS patients. The study achieved the primary outcome with no serious or life-threatening treatment-related adverse events (TRAEs). There were six subjects that had a total of seven serious adverse events (five for MN-166 group and one for placebo group), however none of them were related to treatment.
In addition to the primary endpoint of safety and tolerability, the study also evaluated secondary efficacy endpoints. These secondary endpoints, which included an analysis of ALSFRS-R, were not powered for statistical significance but were evaluated to look for positive trends that would help guide the design of future clinical trials. For this study, a responder was defined as someone who had a ≤1-point decline in the ALSFRS-R during the six-month double blind period while a non-responder was defined as someone who had >1-point decline in ASLFRS-R. For the ITT population, the results showed that 29.4% (10/34) of MN-166-treated patients were responders, compared to 17.6% (3/17) of placebo-treated patients. In the open-label six-month extension phase, 35.3% (6/17) of the patients who had received placebo during the double blind portion of the study were responders when taking MN-166. This compares quite favorably with the 29.4% of patients who were responders with MN-166 during the double blind portion of the study.
Phase 2 Trial of MN-001 in MASLD, Type 2 Diabetes, and Hypertriglyceridemia Ongoing
MediciNova is currently conducting a Phase 2 clinical trial of MN-001 (tipelukast) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD), Type 2 diabetes mellitus (T2DM), and hypertriglyceridemia. It is a multi-center, two-arm, double-blind, placebo-controlled trial in approximately 40 patients in the U.S. Patients will be randomized 1:1 to receive 500 mg/day of MN-001 or placebo for a total of 24 weeks. The co-primary endpoints will be 1) change from baseline in liver fat content as measured by MRI-PDFF; and 2) change from baseline in fasting serum triglycerides (TGs) at Week 24. Secondary endpoints will include changes in liver profiles, safety, and tolerability. Earlier this year, the company reported that 33 patients have been enrolled in the study, with 19 patients currently randomized and 14 patients having completed the study. Thus far, three subjects have reported serious adverse events, however they were all considered “unlikely related” or “unrelated” to study drug.
The Phase 2 trial builds upon multiple previous studies examining the effect of MN-001 on TGs in MASH/MASLD (formerly NASH/NAFLD) patients, preclinical studies in mice, and in vitro studies examining the mechanism of action of MN-001 in lowering TGs.
• MediciNova previously reported positive results from a Phase 2 clinical trial of MN-001 in patients with NASH and NAFLD with hypertriglyceridemia. A total of 15 patients completed eight weeks of treatment with MN-001 (four weeks at 250 mg/day and four weeks at 500 mg/day), with MN-001 reducing serum TG levels in 14/15 subjects. The average pre-treatment serum TG level was 328.6 mg/dL, which was reduced to an average 192.9 mg/dL following eight weeks of treatment (-41.3%, P=0.02). The company also analyzed the data excluding an outlier subject that had an extremely high serum TG level of 1288 mg/dL prior to treatment that was reduced to 300 mg/dL after treatment. That analysis showed that 13 out of 14 subjects had a reduction in serum TGs, from an average 260.1 mg/dL prior to treatment to an average 185.2 mg/dL following treatment (-28.8%, P=0.00006). Importantly, there were no clinically significant safety or tolerability issues during the study.
• In November 2021, MediciNova announced the presentation of results from a study investigating the mechanism by which MN-001 (tipelukast) alters TG metabolism in hepatocytes at The Liver Meeting 2021. The study involved the treatment of HepG2 cells with arachidonic acid (AA), LXR agonist T0901317, and MN-001 either alone or in various combinations. Compared to vehicle, T0901317 increased TG synthesis by 3.8-fold, AA alone increased TG synthesis by 15.3-fold, and the combination of T0901317 + AA increased TG synthesis by 24.3-fold. The addition of MN-001 decreased TG synthesis when added in combination with T0901317 or AA. Compared to MN-001 alone, MN-001 + T0901317 increased TG synthesis by 1.7-fold, AA + MN-001 increased TG synthesis by 3.7-fold, and the combination of T0901317 + AA + MN-001 increased TG synthesis by 3.7-fold. The mechanism by which MN-001 decreases TG synthesis appears to be due to a decrease in CD36 expression. CD36 is one of the receptors responsible for fatty acid uptake into hepatocytes, thus the inhibition of CD36 expression may explain its ability to lower TG levels.
• Two separate studies in mouse models of NASH have shown MN-001 to have both anti-NASH and anti-fibrotic activity:
o Study #1: MN-001 was administered orally once daily (10, 30, or 100 mg/kg) for three weeks in the STAM™ (NASH-HCC) mouse model of NASH. The model is created by a combination of chemical and dietary interventions in a standard laboratory mouse strain. Treatment with MN-001 resulted in a dose-dependent reduction in liver fibrosis as demonstrated by a reduction in liver hydroxyproline content (P<0.01). In addition, there was a significant improvement (P<0.01) in the NAFLD activity score (NAS), which is a summation of the separate scores for steatosis (0–3), hepatocellular ballooning (0–2) and lobular inflammation (0–3). Concurrently, MN-001 was shown to significantly down-regulate (P<0.01) the expression of MCP-1, CCR2, collagen type-1, and TIMP-1; all of which are genes associated with the formation of fibrosis.
o Study #2: In a second study, the same STAM™ (NASH-HCC) mouse model of NASH was utilized, however the mice were at a more advanced stage of NASH. MN-001 was administered orally once daily (10, 30, or 100 mg/kg) for four weeks. Once again, treatment with MN-001 resulted in a statistically significant decrease in NAS score (P<0.001), owing mostly to a decrease in hepatocyte ballooning score and lobular inflammation score. Fibrosis area was also significantly reduced in the MN-001 treated group (P<0.01). MN-001 was once again shown to decrease expression levels of the previously tested genes along with LOXL2, a gene shown to be upregulated in fibrotic livers (Barry-Hamilton et al., 2010). Importantly, treatment with MN-001 had no effect on body weight or general condition of the mice compared to placebo.
New Patent for MN-166 in Long Covid
On August 29, 2024, MediciNova announced it received a Notice of Allowance from the U.S. Patent and Trademark Office for a pending patent application that covers MN-166 for post-COVID conditions. The patent covers administering ibudilast to alleviate a range of post-COVID conditions including anxiety, fatigue, depression, shortness of breath, post-traumatic stress disorder, chest tightness, palpitations, smell or taste dysfunction, sleep difficulties, hair loss, and rash. Once issued, the patent is expected to expire no earlier than November 2042.
Financial Update
On August 8, 2024, MediciNova filed Form 10-Q with financial results for the second quarter of 2024. As expected, the company did not report any revenues in the second quarter of 2024. R&D expenses in the second quarter of 2024 were $1.6 million compared to $1.7 million in the second quarter of 2023. The decrease was primarily due to a decrease in performance-based stock option expense and product liability insurance. G&A expenses in the second quarter of 2024 were $1.4 million compared to $1.6 million in the second quarter of 2023. The decrease was primarily due to a decrease in performance-based stock option expense and payroll costs.
MediciNova exited the second quarter of 2024 with approximately $44.3 million in cash and cash equivalents. We estimate the company has sufficient capital to fund operations at least through the end of 2025. As of August 5, 2024, the company had approximately 49.0 million shares outstanding and when factoring in stock options a fully diluted share count of approximately 57.5 million.
Conclusion
We look forward to data readouts from the Phase 3 ALS trial and the Phase 2 trial of MN-001. After having discussions with management, it has become apparent that the company will not be able to move MN-166 forward in development in progressive multiple sclerosis (MS) but will instead require a partner to help fund the Phase 3 trial and commercialization, if successful. Due to this we have drastically reduced the contribution of the MS indication in our model, which has decreased our valuation to $10 per share.
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