After receiving a Special Protocol Assessment (SPA) from the FDA at the end of September, Athersys (NASDAQ:ATHX) hopes to launch a pivotal trial next summer administering its intravenous MultiStem cell therapy in patients following an ischemic stroke.
“This SPA represents a major de-risking event by specifying the precise criteria for approval from a successful pivotal trial,” chairman and CEO, Gil Van Bokkelen, says in an interview with BioTuesdays.
“It provides a clear, efficient path to success, by establishing the acceptability of the study to the FDA,” he adds.
The company intends to conduct the 300-patient study at approximately 50 leading stroke centers in the U.S., Europe and Canada. “Since each site would enroll about six patients on average, we think this is a study that could be conducted pretty efficiently,” Dr. Van Bokkelen says.
“Current treatment for stroke is limited to the first several hours after a stroke has occurred, and many patients don’t get to the hospital right away,” he adds. “This trial will assess treatment with MultiStem within 18-to-36 hours after a stroke has occurred, which we believe would represent a major step forward for stroke victims by enabling treatment within a clinically practical time frame.”
Athersys’ Japanese partner, Healios K.K., an emerging leader in regenerative medicine, also plans to begin a confirmatory pivotal trial in Japan in early 2017, treating patients with MultiStem following an ischemic stroke. The trial will be conducted in accordance with a new, accelerated regulatory framework for cell therapies in Japan. According to a recent filing on Clinicaltrials.Gov, Healios expects to release trial data from the study in the first half of 2018.
Dr. Van Bokkelen explains that MultiStem is a novel cell therapy formulated for “off-the-shelf” use, moving from the hospital pharmacy freezer to an IV bag to a patient in less than an hour. In addition, MultiStem does not require tissue matching or any immune suppression drugs, he adds, making it a very simple and easy to administer.
MultiStem works by regulating multiple factors and pathways that are important to brain recovery following a stroke. Based on published research and presentations at leading scientific conferences by Athersys and independent research teams, these effects include the simultaneous down regulation of an inflammatory cascade, emanating from the spleen that amplifies damage in the brain, and stimulation, or upregulation, of reparative immune responses and other repair mechanisms.
For stroke, MultiStem is administered using a simple intravenous procedure. However, Dr. Van Bokkelen points out that MultiStem can be administered systemically or locally, depending on the indication. Studies have shown that the cells travel to sites of tissue damage or injury, as well as other relevant organs that play an important role after an injury has occurred.
Once the product is made, it is kept in frozen form until needed. “We have more than seven years of stability data and have shown that millions of doses can be produced from a clinical grade cell bank established from each donor.” And production is highly scalable, which is essential to successful commercialization. The company’s patent estate covers more than 130 patents.
While there are six clinical programs underway with MultiStem in neurological, cardiovascular, and inflammatory and immune disorders, ischemic stroke is Athersys’ lead program.
Ischemic strokes occur as a result of an obstruction within a blood vessel supplying blood to the brain. Annually, there are some 800,000-stroke victims in the U.S. annually, and more than 2.2 million first time ischemic stroke victims in the U.S., Europe and Japan each year. Given that the world’s elderly population is rapidly growing in size due to the aging baby boomer generation, that number is expected to increase in the years ahead, since the risk of stroke increases with age.
Ischemic stroke clearly represents a major unmet medical need. The current standard of care, tPA, must be administered within three to 4.5 hours of a stroke and thrombectomy, the surgical removal of a blood clot, must be performed within six hours. Combined, the two procedures are currently used on less than 10% of ischemic stroke patients, since many don’t get to the hospital right away, and due to other limitations that may impact treatment.
“Based on our recently completed Phase 2 trial, MASTERS-1, which was a double blind, randomized, placebo controlled study conducted at 33 leading stroke centers in the U.S. and the UK, we believe we have compelling evidence that MultiStem could extend the treatment window out to 36 hours. That’s a time frame that is relevant to potentially 90% to 95% of stroke patients,” Dr. Van Bokkelen contends.
In addition to extending the treatment window, the MASTERS-1 trial demonstrated a statistically significant benefit at one year for “Excellent Outcomes” in MultiStem treated patients, compared with a placebo.
Among all subjects enrolled in the trial, nearly three times as many patients achieved an Excellent Outcome in each of the three clinical evaluations used to assess each patient following treatment with MultiStem (p=0.02). Furthermore, when patients were treated within 36 hours, the benefits appeared to be even more pronounced.
According to Dr. Van Bokkelen, improvements were seen in key parameters of clinical scales that assess the patient’s ability to independently engage in activities of daily living, and the rates of improvement were higher among patients receiving MultiStem treatment within 36 hours of a stroke. And a biomarker analysis provided direct evidence of an impact on circulating immune cells and inflammatory cytokines.
Jason Kolbert, an analyst with Maxim Group, says Athersys’ transformative therapy could represent the first new treatment for stroke in 30 years. He rates the stock at “buy” with a $10 price target. Shares of Athersys closed at $1.61 on Friday.
“We view the FDA’s decision of a SPA as consistent with the message we are hearing from regulators in the U.S., EU and Japan: cell therapy is safe,” he adds.
If approved for ischemic stroke, MultiStem could be a blockbuster product. While it’s too early to suggest a cost for the therapy, Dr. Van Bokkelen figures that treating even one million patients in the U.S., Canada, Europe and Japan would represent a major step forward for stroke clinical care, and a multibillion market opportunity.
Under the partnership with Healios of Japan, Athersys received a $15-million license fee up front, and can receive $30-million in development and approval milestones and $185-million on achieving substantial sales milestones. Athersys also is eligible for double-digit royalties that escalate with sales levels.
In Athersys’ upcoming Phase 3 trial, MultiStem will be administered within 18-to-36 hours to patients after a moderate to moderate-severe ischemic stroke, with a treatment arm of 150 patients and a placebo arm of 150 patients, who will receive standard of care.
Dr. Van Bokkelen says the primary endpoint will evaluate disability using the modified Rankin Scale (mRS) scores at three months, comparing the distribution, or the "shift," between the MultiStem treatment and placebo groups. The mRS shift analysis considers disability across the full spectrum, enabling recognition of large and small improvements in disability and differences in mortality and other serious outcomes among strokes of different severities.
The Phase 3 study also will assess Excellent Outcome at three months and one year as key secondary endpoints, as well as other measures of functional recovery, biomarker data and clinical outcomes, including hospitalization, mortality and life-threatening adverse events, and post-stroke complications, such as infection.
Dr. Van Bokkelen says Athersys is in discussions with potential partners to conduct its Phase 3 trial. “Now that we have achieved some important clarity on the regulatory path, we feel we are in a good position, and are exploring our options.”
In addition to ischemic stroke, Athersys is developing MultiStem to treat acute myocardial infarction, which is commonly known as a heart attack, and for acute respiratory distress syndrome, which causes a high rate of mortality and a high level of morbidity, and typically requires extended intensive care hospitalization.
An earlier open label Phase 1 study in heart attack demonstrated that delivery of MultiStem directly into the area of blood flow blockage, after angioplasty, was safe and resulted in meaningful improvements in left ventricular ejection fraction, which is a measure of how well the heart pumps with each beat, as well as stroke volume and wall motion.
Athersys is currently recruiting heart attack patients in a Phase 2 study, with results from the study expected next year. The trial has $2.8-million of funding from the NIH. The primary endpoint is myocardial perfusion as determined by MRI at four months.
“This is an opportunity to improve outcomes and reduce risk of progression to congestive heart failure,” which gradually leaves the heart too weak or stiff to fill and pump efficiently, Dr. Van Bokkelen suggests.
In acute respiratory distress syndrome, Athersys’ preclinical data demonstrated that MultiStem was able to correct lung damage, reverse inflammation and return lung function to normal.
“MultiStem conveys multiple mechanisms relevant to acute pulmonary inflammatory damage,” he adds, noting that the product naturally distributes to the pulmonary system, downregulates acute inflammatory pathways and upregulates reparative cells and pathways.
An exploratory clinical trial has been initiated in the U.S., with additional NIH funding, and with collaborators in the UK, with data anticipated next year. The study is evaluating MultiStem for functional lung improvements as well as the impact on morbidity and mortality, and the quality of life.