By M.E. Garza
Dr. Yuichi Iwaki, President and CEO of Nasdaq listed small-capMediciNova, Inc. (NASDAQ:MNOV - News)took the time to answer BioMedReports' questions about his firm's pipeline, upcoming milestones and recent clinical trial results.
BioMedReports: Your company is focused on a treatment for "acute exacerbations of asthma." What are the symptoms of this condition?
MediciNova President and CEO, Dr. Yuichi Iwaki:AEA episodes involve progressively worsening shortness of breath, cough, wheezing and chest tightness, or some combination of these symptoms that are characterized by a decrease in expiratory airflow. Exacerbations can vary in severity from mild to life-threatening and can occur in patients with any level of asthma (i.e., intermittent, mild, moderate or severe persistent asthma). In severe episodes, AEA can involve bronchial spasm, airway inflammation and mucous plugging, leading to progressive increases in airflow resistance, carbon dioxide retention, hypoxemia, respiratory muscle fatigue and respiratory failure.
Question: What are some of the major drawbacks of current treatments for acute asthma?
MediciNova President and CEO, Dr. Yuichi Iwaki:AEA requires aggressive treatment with inhaled or nebulized beta-agonists, anticholinergics, and corticosteroids. Beta-agonists are generally most effective in the early asthma reaction phase. Albuterol or salbutamol, terbutaline and levalbuterol are the mainstays of beta-agonist agents in status asthmaticus. They act via stimulation of cyclic adenosine monophosphate (AMP)-mediated bronchodilation. The airway is rich in beta receptors; the stimulation of these receptors relaxes airway smooth muscles, increases mucociliary clearance and decreases mucous production. However, a large number of patients, upwards of 50 percent that present to the emergency room each year, do not respond to initial nebulized treatment. The inhaled route is generally more effective; however, in these severe cases, there is so little airflow that inhalation does not work as the beta-agonist is not properly absorbed. These refractory AEA patients are then treated with repeat doses of standard-of-care and may be hospitalized if their condition does not improve. In addition, the amount of inhaled treatments a patient can tolerate is limited due to the potential for cardiovascular side effects (i.e., increased heart rate).
Question: How has MediciNova managed to gain access to potentially high-value clinical-stage compounds primarily developed by mid-sized pharma companies in Japan?
MediciNova President and CEO, Dr. Yuichi Iwaki:MediciNova was founded in September 2000 with seed funding from Tanabe Seiyaku Co., Ltd. of Osaka, Japan. MediciNova was established in San Diego as a biopharmaceutical company focused on acquiring and accelerating the global development and commercialization of innovative pharmaceutical products. The Company's strategy is to build a strong product portfolio through alliances with Japanese (as well as North American and European) biotechnology and pharmaceutical companies. MediciNova's relationships with mid-sized Japanese pharmaceutical companies have enabled it to license its first development candidates in 2002. MN-001 was licensed from Kyorin Pharmaceutical Co., Ltd. of Tokyo and MN-029 from Angiogene Pharmaceuticals Ltd. of Oxford, UK. In 2004, the company licensed four more development candidates: MN-221 from Kissei Pharmaceutical Co., Ltd. of Matsumoto City, Japan; MN-305 and MN-246 from Mitsubishi Pharma Corp. of Osaka; and MN-166 from Kyorin Pharmaceutical Co., Ltd. of Tokyo. In February 2005, MediciNova became the first U.S. company to have its initial public offering in Japan.
Question: Your company believes that intravenous treatment of acute asthma may prove more promising than the kind of treatment that is possible with inhalers. Can you tell us why?
MediciNova President and CEO, Dr. Yuichi Iwaki:A compound-such as bedoradrine sulfate-administered intravenously has been studied as an adjunctive treatment to standard-of-care medications in both AEA as well as COPD, with results indicating increased effects on forced expiratory volume in one second (FEV1) with minimal effects on heart rate and blood pressure. These studies have been motivated by the fact that no new options for AEA have been introduced in the emergency setting during the past two decades. During a severe asthma attack, the patient may experience tight bronchoconstriction and mucus plug formation, which makes it difficult for inhaled medications to reach the target beta receptors deep within the patient's lungs. Due to the high selectivity of our compound for the beta2 receptor as opposed to the beta1 receptor, which is associated with cardiovascular stimulation, we are able to administer MN-221 in an intravenous formulation and add it in addition to the inhaled medications when they are not effective. Some 25-30 percent of patients who present at the ER with AEA are not responsive to the inhaled medications and end up being admitted to the hospital. It is the goal of MediciNova to add MN-221 when these inhaled therapies are not effective in hopes that the patient will respond sooner, breathe easier, and be discharged from the hospital.
Question: Can you briefly summarize the mechanism of action for MN-221, and why this makes the treatment a viable alternative to existing treatments?
MediciNova President and CEO, Dr. Yuichi Iwaki:Preclinical studies conducted in vitro and in vivo showed MN-221 to be highly selective for the beta2-adrenergic receptor. In these studies, the beta1-adrenergic receptor stimulating activity of MN-221 was less than that of other beta2-adrenergic receptor agonists in isolated rat atrium and in vivo cardiac function tests in rats, dogs and sheep, thereby suggesting that the stimulating action of older, less selective beta2-adrenergic receptor agonists on the heart via beta1-adrenergic receptors may be reduced with MN-221 due to its greater beta2-adrenergic receptor selectivity. In addition, in vitro studies also suggested that MN-221 might act as only a partial beta1-adrenergic receptor agonist in cardiac tissue, while acting as a full beta2-adrenergic receptor in lung tissue. MN-221 has been shown to exhibit a ≥4-fold greater beta2 vs. beta1 selectivity when compared alongside terbutaline, albuterol and levalbuterol. Investigators believe that this improved receptor binding and functional selectivity may result in fewer cardiovascular side effects than are commonly observed with other beta2-adrenergic receptor agonists used to treat these conditions.
Question: How does a small biotech like yours distinguish itself from potential competitors? Is showcasing your drug's economic value for both patients and prescribers a key goal?
MediciNova President and CEO, Dr. Yuichi Iwaki:AEA episodes now account for more than 1.5 million annual emergency room visits in the U.S. alone. Meanwhile, COPD has grown to become the third leading cause of death in the U.S.; in 2007, its economic burden in this country was $42.6 billion in healthcare costs and lost productivity. We believe any company that can demonstrate its product's ability to lower these costs will have a leg up on potential competitors. A large driver of costs for asthma and COPD patients is hospital admissions and length of stay in the hospital or ED. It is the goal of MN-221 to reduce the time a patient must spend in this costly healthcare environment. In our recent Phase 2b trial, MN-221 also showed a trend supporting that patients who take MN-221 have a less likely chance of relapsing and returning to the ED within a seven-day period.
Question: If approved by the FDA, do you anticipate that your treatment will change the standard of care for asthma?
MediciNova President and CEO, Dr. Yuichi Iwaki:It would be much too bold for us to claim that MN-221 alone could change the standard of care in this area. It might, however, alter the sequence of treatment for a patient admitted to the ER. For these patients, every second counts; if MN-221 can be shown to alleviate the symptoms of AEA more quickly than the currently accepted first line of treatments (i.e. inhaled beta-agonist agents), it could become the new first line of treatment. We do believe that as medical researchers and clinicians come to understand more widely the potential of intravenous administration of compounds such as bedoradrine sulfate, the stage will be set for an evolution in care.
Question: What specific factors does a small biotech like MediciNova need to consider when planning clinical trials in the emergency department setting?
MediciNova President and CEO, Dr. Yuichi Iwaki:Prior to initiating a trial with ED sites, three factors must be thoroughly considered in order to achieve success: investigators' unique needs, study timing and enrollment patterns. When a patient's life is on the line, the luxury of time is not available for an elaborate evaluation. ED physicians want to be especially comfortable with the safety and efficacy of a therapy since there are limited follow-up visits compared to a trial in the typical clinical setting. Therefore it is vital to conduct early-stage studies to accumulate as much data as possible. In addition to safety and efficacy data, it is also beneficial to show other pharmacoeconomic endpoints, such as reduction in hospital stays, which help make a compelling case for encouraging patient enrollment in the trial. In addition to ensuring that ED physicians are comfortable with the investigational therapy, the time frame for treatment should closely resemble a "real world" scenario. For example, if an endpoint is reduction in hospitalizations after five hours, but ED physicians typically decide to admit after three hours, then it might inhibit the recruitment process. To maximize success, design the trial to ensure that the trial endpoints match the "real world" decision points. Following this "match rule" will not only help get to the next stage of clinical development, but also, if everything else falls into place, commercialization. Finally, when gauging enrollment patterns, it is important to understand the underlying patient population and other factors, such as seasonality. If a condition, such as AEA, is more prevalent during the winter, for example, then sites need to be prepared to be busier during the cold months-and have patience if enrollment is not as high as expected during the warmer months.
Question: If the treatment you are working on is successful, will it reduce the length and cost of hospital stays, and can you estimate by how much? What do you see as its stronger potential selling point: the prospect of fewer hospital admissions or the reduction in cost of care for patients?
MediciNova President and CEO, Dr. Yuichi Iwaki:We anticipate that MN-221, if and when adopted widely by health providers, holds the potential of reducing both the length and the cost of hospital stays for those with AEA. However it would be very difficult to try to offer quantitative estimates of these reductions at this time. But we believe there will be equal appeal in the treatment's potential to reduce hospital admissions and its potential to reduce cost of care. Our goal for our pivotal trials will be to show the pharmacoeconomic benefit of using MN-221 in three main areas: (1) Reduction of time in the ED (2) Reduction in the number of patients who are admitted to the hospital and (3) reduction in the number of patients who return to the ER within a seven-day period following their initial visit. We also plan to show a reduced number of ICU admissions, similar to what we saw in our Phase 2 program.
Question: You recently completed a Phase 2b clinical trial of MN-221 in patients with acute asthma. Could you summarize the results?
MediciNova President and CEO, Dr. Yuichi Iwaki:MN-221 showed a benefit over placebo for forced expiratory volume in one second (FEV1) from baseline at all time points as measured by Area Under the Curve in change in FEV1 hours 0-1, 0-2 and 0-3. The trial also demonstrated a reduction in hospital admissions with MN-221 added to standard drug treatments in our performing sites and a reduction in return visits to the ER and fewer number of ICU admissions. Moreover, there was a significant improvement in clinical symptoms such as dyspnea score (patients' score of difficulty breathing) with MN-221-treated patients and benefit over placebo in regards to respiratory rate and other clinical symptoms. The safety profile of MN-221 continues to be positive as no safety/tolerability issues of clinical significance were observed. Overall FEV1 improvement was better in the MN-221 treatment group than the placebo and standard-of-care (SOC) alone group. In the performing sites analysis, MN-221 showed a significant benefit over SOC alone for FEV1 Area Under the Curve (AUC Hr 0-1, 0-2, 0-3) of median change from baseline (p=0.043, p=0.050, p=0.066 respectively). Furthermore, MN-221 showed a significant improvement in clinical respiratory parameters including dyspnea score (shortness of breath). MN-221 also improved AUC (Hr 0-3) of change in dyspnea score by 34 percent more than SOC alone (p=0.055). Fewer patients were hospitalized in the MN-221 treatment group than the (SOC) alone group. Additionally, MN-221 reduced the overall hospitalization rate by 17 percent vs. SOC alone. Finally, there were no significant clinical safety concerns when adding MN-221 to standard treatments. A more detailed discussion of trial results is available at:
Question: Given the results of this Phase 2b trial, what are your plans going forward with regard to evaluating MN-221?
MediciNova President and CEO, Dr. Yuichi Iwaki:MediciNova believes it has the efficacy data, safety data and trial design necessary for a successful end-of-phase 2 meeting with the FDA. The Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) of the FDA reviewed MediciNova's meeting request submission and granted an End-of-Phase 2 meeting scheduled for October 22, 2012. In advance of the meeting, MediciNova will provide DPARP with a MN-221 briefing package including the recent Phase 2 trial outcomes and the company's proposed pivotal trial(s) and additional development plans. In addition to representatives from MediciNova, several individuals with clinical expertise in asthma exacerbations, regulatory affairs, manufacturing or biostatistical fields will participate as part of the MediciNova team. MediciNova anticipates moving our program into pivotal development in the first half of 2013.
Question: What are the biggest challenges that face MediciNova right now?
MediciNova President and CEO, Dr. Yuichi Iwaki:Our biggest challenge is to ensure we have a positive outcome from the End-of-Phase 2 meeting with the FDA in October, while securing the financing available, either through strategic partnerships or investment in equity, to launch and complete a pivotal program.
Question: What are some of the upcoming milestones for 2012?
- Top-line Results from Phase 1b Multi-Dose Trial in COPD 3Q, 2012
- Plan to Announce Phase 2 Clinical Program for Ibudilast (Addiction) 3Q, 2012
- Plan to Announce Phase 2 Clinical Program for Ibudilast (Progressive MS) 4Q, 2012
- End of Phase 2 Meeting with FDA for MN-221 Development 4Q, 2012
The full report on MNOV is available at:
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