Overcoming the Complexities of Neurodegenerative Clinical Trials

Neurodegenerative diseases are complex, and many, such as amyotrophic lateral sclerosis (ALS), Parkinson’s and Alzheimer’s, to name a few, are incurable. Developing therapies for those indications are extremely challenging and risky, especially when introducing novel mechanisms of action, such as regenerative medicine. Brainstorm Cell Therapeutics, however, is implementing advanced methodologies to mitigate study complexity and therapeutic area risk. In this interview, Ralph Kern, COO and CMO of BrainStorm, will discuss how they are overcoming these challenges and advancing science in neurodegenerative disease.

Alexander Neumeister:  Why did BrainStorm focus first on the area of ALS?

Ralph Kern

Ralph Kern: Currently, there is an enormous unmet medical need in ALS. It is estimated that at least 30,000 
individuals in the U.S. currently have ALS, and an additional 6,000 new patients are diagnosed each year. At the same time, there are only two approved treatments, both of which have limited effect on the natural history of this relentlessly progressive and fatal disease.  Brainstorm initiated early Phase I/II, IIa and Phase II trials of our innovative cell therapy in ALS and continued to evaluate NurOwn through the current Phase III pivotal trial after the initial studies showed great promise.

AN: How are the protocol and operational design of BrainStorm’s Phase III study uniquely adapted for ALS?

RK: From a protocol standpoint, our ALS clinical trial includes a three-month run-in period, which is the time between initial screening and patient’s first treatment from their own cells. This time is also used to harvest the patient’s bone marrow cells and manufacture the final, autologous cell product. During that time, we also evaluate the patient’s rate of functional decline, which is one of our inclusion criteria. We know that the rate of decline in ALS can vary widely from patient to patient, and we learned from our Phase II trial that individuals who progress more rapidly might experience a better result from this treatment. These rapid progressors, who compose about half of the total ALS patient population, may have higher levels of brain and spinal cord inflammation compared to other patients.

From an operations standpoint, we’ve simplified the healthcare system workload dramatically compared to what is common in many stem cell studies. In our study, once the bone marrow is harvested, it is sent directly to the manufacturing site. All the steps necessary to manufacture the treatment occur at our manufacturing site before being sent back in a pre-labeled, ready-to-use syringe for injection. Typically, stem cell studies are highly complex and require extensive, hours-long, on-site preparation in the cell and biology labs.  As you can see, we have simplified this greatly.

AN: Can you explain the process in more detail?

RK: Once a patient’s bone marrow is harvested, it is shipped to the manufacturing site in a temperature-controlled shipping container, where all the steps needed to manufacture the finished product occur. The treatment is then packaged into a pre-labeled ready-to-use syringe containing 4MLs of fluid hosting 125 million patient autologous differentiated mesenchymal stem cells that secrete high levels of neurotrophic factors and dampen inflammation. That syringe is shipped to the study site, and treatment is administered to the patient with a simple lumbar puncture once the manufacturing site has informed the Investigator that the product has passed all release tests.

To decrease the patient burden, we have introduced cryopreservation into our technology platform, which allows us to take a single bone marrow aspirate. By freezing the expanded mesenchymal stem cells prior to differentiation, we can produce repeated dosing from a single bone marrow aspiration. The patient experience, therefore, involves a one-time 30-minute bone marrow aspiration (BMA) procedure and pre-scheduled 30-minute treatments when the cells are re-introduced back as the therapeutic agent into the cerebrospinal fluid by lumbar puncture, every two months.  This means the patients do not need to undergo repeated bone marrow aspirations for every dose.

Over the past 10 years that our technology has been in development, we’ve built a strong track record of quality control and have consistently met the highest cell therapy product manufacturing standards. Each step of our process is fully validated, from manufacturing to cryopreservation, to the shipping parameters we have put in place so that the cells are viable for up to 72 hours. We are confident we have laid the groundwork for highly successful commercialization of this innovative cell therapy technology.

Moe Alsumidaie: What are the inclusion criteria, and how is enrollment progressing?

RK: We are recruiting 200 patients at six sites and currently are 85% enrolled. Inclusion criteria include:

• Early ALS patients, whose disease duration is less than two years;

• A score of 25 or more on the ALS Functional Rating Scale;

• Breathing capacity of 65 percent or higher on the predicted slow vital capacity.

Additionally, during the run-in period, we select for rapid progressors, or patients with a minimum level of functional decline, so that we have a higher probability to demonstrate a treatment effect. Enrolled patients typically are mobile and able to travel.

Our clinical trial sites are Mayo Clinic in Rochester, MN; University of Massachusetts in Worchester; Mass General in Boston; CPMC in San Francisco; UCI in Irvine, CA; and Cedars Sinai in Los Angeles, CA.

MA: How does your treatment approach compare to that of your competitors and to currently available treatments?

RK: BrainStorm’s approach is clearly different for several reasons. First, we have the potential for disease modification rather than symptomatic treatment. Second, our treatment is delivered directly to the central nervous system through the cerebrospinal fluid and is not dependent on crossing the blood-brain barrier, which enables free access to the spinal cord and brain through the spinal fluid transport system. Third, our treatment works by supplementing or replacing a deficiency of neurotrophic factors thought to play a critical role in ALS progression. This provides a significant stimulus to help with survival and functioning of the surviving motor neurons and other brain tissue.

MA: How is BrainStorm using biomarkers to differentiate its approach to treatment?

RK: Our Phase III study assesses three types of cerebrospinal fluid biomarkers in evaluating patient response to treatment. First are the cell-secreted neurotrophic factors, which serve to confirm that the biological molecules have been delivered to the target. Second are neuroinflammatory factors, which imply target engagement and the direct effects of treatment. Third are measures of neuronal damage, which can include neurofilaments, measures of cell death, and support the action of our therapy on the survival and viability of motor neurons and other brain cells. We feel very confident in these three types of biomarkers based upon our experience in our Phase II study.  We are also open to exploring the potential of new evolving ALS biomarkers, and we will incorporate these new advances in our Phase III study analyses as the science evolves.

MA: What outcomes do you anticipate from this Phase III trial?

RK: The best outcome we can hope for is drug approval so that ALS patients have an innovative and effective treatment option. Our primary study endpoint is to demonstrate the proportion of treated patients who achieve meaningful change in the rate of decline in the ALS Functional Rating Scale. The study design is quite rigorous and has a 90% power to demonstrate efficacy in our primary outcome measure. Once enrollment is completed in Q4 2019, the study will be completed approximately one year later, in the fall of 2020.

MA: Have you experienced any operational challenges that are particularly unique for this study? How did you overcome those challenges?

RK: Our study includes many assessments and patient visits. Our sites did experience some challenges related to the complexities of bringing in new patients, administering the second and third intrathecal transplants. Additionally, there is tremendous co-ordination needed among different hospital departments, from the hematologist who performs the initial bone marrow aspirate, to the unblinded injection teams who aren't involved in the clinical care, to the clinical care teams who manage patients and perform the blinded assessments. As you can imagine, clinical trials have complexities that are much greater than routine clinical care. 

From the manufacturing side, we needed to expand our manufacturing capabilities to accelerate enrollment early in the trial. Doing so required a technology transfer, which is a complicated procedure involving many people and has been a challenge for other cell therapy developers. Our manufacturing team did an excellent job, and we had outstanding support and guidance from the FDA. As we transition to a commercial treatment after our study, our success with technology transfers and our ability to successfully scale up manufacturing capabilities is very encouraging.

Other challenges we anticipated did not come to pass. For example, we were concerned that our three naïve sites which had not participated in Phase II would take longer to learn the trial procedures. That turned out not to be the case, and one of our newer clinical trial sites is a top-performer for enrollment. We also were uncertain about patient demand. However, the sites were so well connected to the ALS community through advocacy organizations that the challenge became having to efficiently manage robust patient demand.

MA: How might the BrainStorm platform be applied to other unrelated indications?

RK: Our approach is based upon our hypothesis that in conditions such as ALS, Alzheimer's, Parkinson's and progressive MS, neurons and other brain tissue go through a period of injury prior to cell death and may be salvageable in that period by reducing the inflammatory environment and improving their viability via neurotrophic and other repair factors. We have solid pre-clinical data in Parkinson's, Huntington's Disease, autism, and other brain diseases, and we recently initiated a Phase II trial in progressive MS. We're optimistic that this technology platform can play widely across many neurodegenerative diseases.

Alex Neumeister is Head of Medical Affairs at CliniBiz and specializes in protocol design, drug safety and clinical trial management. Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials