MNOV: Expecting Data for MN-166 in GBM and Chlorine Gas-Induced Lung Injury…
NASDAQ:MNOV
READ THE FULL MNOV RESEARCH REPORT
Business Update
Data Expected for MN-166 in GBM
In January 2023, MediciNova, Inc. (NASDAQ:MNOV) announced that the Phase 2 trial of MN-166 (ibudilast) in combination with temozolomide (TMZ) for the treatment of glioblastoma (GBM) was fully enrolled (NCT03782415). This is a two-part trial taking place at Dana-Farber Cancer Institute; Part 1 of the trial evaluated the safety and tolerability of MN-166 in combination with TMZ and determined the optimal dose of MN-166 to use in Part 2 of the study. In August 2021, MediciNova announced completion of a safety review of Part 1 of the trial, which enrolled 15 subjects. There were no concerning safety signals observed in Part 1 and there were no serious adverse events related to MN-166. Five out of 15 subjects completed cycle 6 without disease progression, i.e. 33% of subjects were progression-free at 6 months. Part 2 will evaluate the efficacy of MN-166 and TMZ as measured by the proportion of subjects who are progression-free at 6 months. Additional outcome measures will include overall survival, response rate, and median six-month progression-free survival.
In February 2023, MediciNova announced the presentation of new data regarding tumor tissue analysis and clinical outcome from Part 1 of the study (the dose ranging portion of the trial). The tumor tissues were analyzed to determine potential predictors of tumor response to MN-166 and TMZ combination therapy. Study participants were divided into two groups: non-responders (disease progression within five months of receiving MN-166/TMZ) and responders (no disease progression for five months after receiving MN-166/TMZ). The data showed that responders had a lower percentage of CD3+ T cells than non-responders (P<0.05). In addition, CD74 expression was also lower in the responders compared to the non-responders (P=0.06). The best predictor for tumor progression for five months in recurrent GBM patients was CD3 expression.
The use of MN-166 in GBM is based on a proteomic profiling study of GBM samples from 30 GBM patients which was presented at the 2017 American Society of Clinical Oncology (ASCO) annual meeting (McDonald et al). The results showed that macrophage migration inhibitory factor (MIF) was expressed in “poor responders” (e.g., those that lived < 1 year). MIF is an inflammatory-related cytokine that is secreted by cancer stem cells. The researchers then examined an additional 168 GBM samples and found co-expression of MIF and its receptor CD74 in 57% of the samples. In addition, co-expression of MIF and CD74 was significantly associated with poor survival. These results point to MIF being a suitable target for GBM treatment. MN-166 is an inhibitor of MIF (Cho et al., 2010).
An in vivo study was previously performed using RN1 GBM cells, which were intracranially injected into the brains of mice followed by no treatment or a combination of TMZ and MN-166 at two different concentrations. Results showed that mice treated with the combination of TMZ and MN-166 had significantly enhanced survival (median overall survival 114 days vs. 100.5 days, P=0.005) with suppression of MIF and CD74 expression also noted.
On August 17, 2023, MediciNova announced that an abstract regarding tumor tissue analysis data from a clinical trial of MN-166 has been selected for a poster presentation at the 28th Annual Meeting of the Society for Neuro-Oncology (SNO), which is being held November 15-19, 2023. The title of the presentation is: “Immunohistochemistry evaluation on pre-treatment tumor tissue predicts treatment response to MN-166 (ibudilast) and Temozolomide combination therapy in glioblastoma patients”.
Glioblastoma (GBM) is a primary malignant brain tumor that is complex and difficult to treat. The five-year survival rate for glioblastoma patients is only 6.9%, and the average length of survival is estimated to be only 8 months (National Brain Tumor Society). Despite available treatments including surgery, radiation, and chemotherapy, survival rates and mortality statistics for GBM have been virtually unchanged for decades. There have only been a few drugs ever approved by the FDA specifically for the treatment of glioblastoma, and none of these treatments have succeeded in significantly extending survival beyond a few extra months. As such, there is a great unmet medical need for better treatments for GBM.
Update on MN-166 as a Medical Countermeasure
In March 2021, MediciNova, Inc. (NASDAQ:MNOV) announced a partnership with the Biomedical Advanced Research and Development Authority (BARDA) to test the potential for MN-166 (ibudilast) as a medical countermeasure (MCM) for the treatment of chlorine gas-induced acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). MN-166 is being evaluated in preclinical efficacy models of chlorine gas-induced ALI, and these experiments could help support the use of MN-166 in ARDS/ALI caused by other ailments, including the flu, infections, severe burns, and pancreatitis. Under the FDA animal rule (FDA), development of MCMs do not require human clinical trials to establish efficacy as these would not be ethical or feasible. The FDA can grant approval of a drug for an MCM indication based on well-controlled animal studies, when the results of these studies establish that the drug is reasonably likely to produce clinical benefit in humans.
ARDS is a serious lung disorder that results from the small blood vessels of the lung leaking fluid that fills up the alveoli, thus preventing proper oxygen exchange (Stevens et al., 2018). There are many causes of ARDS, including infections (e.g., pneumonia), severe burns, pancreatitis, inhalation of smoke or chemicals, or other serious illnesses. An excessive inflammatory response appears to be involved in the pathogenesis of ARDS (Li et al., 2019). Current treatment options involve supportive care while the lungs heal, which involves oxygen therapy supplied through a ventilator. There are no pharmacological treatments specifically for ARDS and approximately 40% of hospitalized patients die from it (Siegel et al., 2020).
According to the NIH, infections are the most common risk factors for ARDS (NIH). The most common infections are due to influenza (and other respiratory viruses), pneumonia, and sepsis. There are approximately one million adults hospitalized in the U.S. each year for pneumonia (ATS), approximately 400,000 hospitalizations due to influenza each year in the U.S. (CDC), and approximately 1 million hospitalizations due to sepsis (UMich). While not all of these patients will go on to develop ARDS, it is this pool of patients that are at a high-risk of developing ARDS that will be the target market for MediciNova.
The release of toxic chemicals, either deliberately through chemical weapons or accidentally through an industrial accident, can also result in ALI or ARDS. Chlorine is a widely used industrial chemical (e.g., water purification) that has been previously implicated in both intentional and accidental releases:
• During World War I, Germany launched the first known chemical weapon attack by releasing chlorine gas from 6,000 cylinders against French troops, which caused >1,000 casualties.
• Multiple times in the past decade, the Syrian government of Bashar al-Assad used chlorine as a chemical weapon against its enemies, and a report by the U.S. government in 2020 claimed the regime continues to pursue chemical weapons development.
• In June 2005, a train derailment in South Carolina resulted in the accidental release of 40-60 tons of chlorine gas (Van Sickle et al., 2009). Nine individuals died and >250 were treated for toxic chlorine exposure.
• A mixture of sodium hypochlorite and hydrochloric acid is sometimes used as a cleaning solution. The chlorine gas that is produced can cause airway damage and reactive airways dysfunction syndrome (RADS) (Gorguner et al., 2004).
Chlorine inhalation results in the formation of hydrochloric acid (HCl) and hypochlorous acid (HOCl) as it dissolves into the airway surface liquid. Both of those compounds can result in oxidative injury following the formation of reactive oxygen species, which can result in edema, inflammation, and immediate airway constriction. In addition, chlorine exposure results in the recruitment of inflammatory neutrophils and macrophages (Balakrishna et al., 2014). The inflammatory response is accompanied by increases in various inflammatory markers such as CXCL1, GM-CSF, IL-6, and VEGF.
Current treatment for chlorine inhalation is mostly supportive care. For patients who show airway obstruction, inhaled β-2-adrenergic agonists are used (Wang et al., 2004) with early administration of corticosteroids shown to prevent ALI in mouse models (Jonasson et al., 2013). Humidified oxygen is typically administered to all victims, however supplemental oxygen could worsen cardiopulmonary function (Okponyia et al., 2018).
The Department of Homeland Security estimates that a deliberate release of highly concentrated chlorine gas upwind of an urban area with 700,000 individuals would lead to approximately 5% being exposed to a lethal dose of chlorine with approximately 17,500 fatalities and 100,000 hospitalizations (Department of Homeland Security). Chlorine gas is fairly easy to produce, thus the U.S. government is interested in finding MCMs to treat lung injuries caused by chlorine exposure.
The potential market opportunity for MN-166 in chlorine gas-induced ALI is significant as the U.S. government would likely decide to purchase large quantities of the drug for public health emergencies in the homeland (Strategic National Stockpile) and to protect U.S. military personnel abroad.
In addition, drugs approved as MCMs are eligible for a priority review voucher (PRV). A PRV allows the holder of the voucher to receive an expedited six-month review from the FDA for a new drug application (NDA) or biologics license application (BLA) instead of the usual ten-month review. PRVs are fully transferrable and in the past couple of years a number of them have sold for approximately $100 million each.
MN-166 was previously tested in a lipopolysaccharide (LPS) ARDS mouse model (Yang et al., 2020). While this model induces ARDS through a different mechanism than chlorine gas exposure, a number of the resulting phenotypes are similar between the two models. MN-166 was shown to reduce the overexpression of PDE4, reduce the overexpression of different inflammatory cytokines (e.g., TNF-⍺, IL-1b, IL-6, MCP-1), reduce pulmonary edema, and reduce lung cell apoptosis. Since ARDS can be induced by a number of different pathologic insults, success in one model system (e.g., LPS-induced ARDS) is likely to translate to success in other models (e.g., chlorine gas-induced ARDS).
In June 2022, MediciNova announced positive results from a Phase 2 clinical trial of MN-166 (ibudilast) in hospitalized COVID-19 patients at risk for developing ARDS. The trial achieved statistical significance for one of the co-primary endpoints (the proportion of subjects free of respiratory failure), and achieved statistical significance for the proportion of subjects discharged from the hospital. A total of 34 subjects were randomized 1:1 to receive MN-166 or placebo for seven days, and on Day 7, 71% of subjects in the MN-166 group and 35% of the placebo group were free of respiratory failure (P=0.02).
Phase 2 Trial of MN-166 in AUD Not Successful
In June 2023, MediciNova announced that results of the Phase 2b trial of MN-166 in alcohol use disorder (AUD) were presented at the 46th Annual Research Society on Alcoholism Scientific Meeting. The study was a randomized, double blind, placebo controlled trial in treatment-seeking men and women with moderate or severe AUD. Participants were administered MN-166 50 mg or placebo twice a day for 12 weeks. A total of 102 subjects were enrolled in the study. The primary objective was to evaluate the effects of MN-166 compared to placebo on percent heavy drinking days (≥5 drinks for men and ≥4 drinks for women over the course of a 12-week treatment period.
The results of the study showed that MN-166 was not superior to placebo for reducing percent heavy drinking days. Nor was MN-166 superior to placebo for multiple secondary endpoints. This was due to the fact that both MN-166 and the placebo decreased heavy drinking days by equal magnitudes. It’s notable that all of the patients in this study, including the placebo-treated patients, were “treatment-seeking” individuals who were highly motivated to reduce their drinking and this made it more difficult to show a difference using MN-166.
Financial Update
On August 9, 2023, MediciNova filed Form 10-Q with financial results for the second quarter of 2023. As expected, the company did not report any revenues in the second quarter of 2023. R&D expenses in the second quarter of 2023 were $1.7 million compared to $2.6 million in the second quarter of 2022. The decrease was primarily due to a decrease in manufacturing expenses. G&A expenses in the second quarter of 2023 were $1.6 million compared to $1.5 million in the second quarter of 2022. The increase was primarily due to increased non-cash stock-based compensation.
Net cash used in operating activities was $2.4 million for the second quarter of 2023. MediciNova exited the second quarter of 2023 with approximately $52.9 million in cash and cash equivalents. We estimate the company has sufficient capital to fund operations for at least the next few years. As of August 9, 2023, the company had approximately 49.0 million shares outstanding and when factoring in stock options a fully diluted share count of approximately 57.3 million.
Conclusion
We look forward to results from Part 2 of the Phase 2 trial of MN-166 in GBM as well as results from the studies of MN-166 as a MCM against chlorine gas-induced lung injury in the near future. We have removed MN-166 as a treatment for AUD, which has caused a very slight decrease in our valuation by $1 to $26 per share.
SUBSCRIBE TO ZACKS SMALL CAP RESEARCH to receive our articles and reports emailed directly to you each morning. Please visit our website for additional information on Zacks SCR.
DISCLOSURE: Zacks SCR has received compensation from the issuer directly, from an investment manager, or from an investor relations consulting firm, engaged by the issuer, for providing research coverage for a period of no less than one year. Research articles, as seen here, are part of the service Zacks SCR provides and Zacks SCR receives quarterly payments totaling a maximum fee of up to $40,000 annually for these services provided to or regarding the issuer. Full Disclaimer HERE.
