The Secrets to Survival in the Emerging Biopharma Industry

What is the secret to running a small and successful biopharmaceutical company? In this interview, Seth Lederman shares his clinical trial insights as CEO of Tonix Pharmaceuticals. Lederman discusses Tonix’s diverse research and development pipeline-including potential therapies for post-traumatic stress disorder (PTSD), fibromyalgia, and cocaine intoxication.

Moe Alsumidaie: Tonix has completed two clinical trials for the treatment of PTSD, and currently has another ongoing. Could you tell me what challenges your initial PTSD study faced, and how have you overcome those challenges to move ahead with the current trial?

Seth Lederman

Seth Lederman: We conducted two extensive studies in PTSD of our experimental drug, TNX-102 SL, which is a sublingual formulation of cyclobenzaprine. In the first, we enrolled approximately 250 patients. In the second, we had planned to enroll 550 patients, but we stopped enrolling at the interim analysis when 275 were evaluated. We recognized that the patients who had experienced trauma within nine years of being screened responded to our new drug as expected; however, patients who were more than nine years from trauma did not respond as we expected. From this interim analysis we learned an essential feature about PTSD: that PTSD has distinct stages. The early phase is approximately the first nine years after exposure, and during this time, individuals are more responsive to treatment than at a later stage. In the later stage of the disease, the brain seems to be more scarred, and there is less plasticity, which means there is a diminished capacity to heal.

Addressing how we overcame these challenges, we used an adaptive design in the Phase III study.  The adaptive design included an interim analysis, so we could stop the study early if it did not make sense to continue it. Indeed, we did end up stopping the first study early because the results were not headed in the anticipated direction. After we stopped the study and unblinded the data, we performed a retrospective analysis. The results of the retrospective analysis convinced us of two things – the first learning was that the drug has great promise, and the second learning was that the adaptive design with an interim analysis was strategic and allowed us to save more than six months on the study and over $15 million.

MA: From an operational standpoint, what issues surfaced from the sites with regards to this study's design, and how did you use those from a procedural standpoint to improve the study's design?

SL: We've always taken the view that although we engage clinical research organizations (CROs), we should also be very involved at the sites to get feedback and to improve the operations throughout the trials. In the first two studies, we exclusively enrolled people with military-related PTSD, and as such, we learned a considerable amount about military culture. Through education, we also learned how to make participation in the study as appealing as possible for people with PTSD. In the current Phase III study, we are enrolling both civilian-related trauma and military-related trauma, and now are beginning to understand the nuances between the populations. For example, civilians suffering from PTSD generally appear to be more open to discussing their symptoms and seeking a diagnosis.

MA: Tonix has previously studied TNX-102 SL for the treatment of fibromyalgia. What are you planning to do differently when you launch your next study for fibromyalgia from a design standpoint?

SL: I have a long-standing interest in fibromyalgia, and it is really the condition that brought me to study the brain. When I was a professor at Columbia University in the Department of Medicine, and for a time in the division of Rheumatology, I took care of fibromyalgia patients and taught about fibromyalgia. At Tonix, we performed two extensive clinical studies in fibromyalgia – one was about 200 patients, and the other was 520 patients. In both studies, we narrowly missed the primary endpoints which was particularly disappointing because the second was a Phase III study. Although we failed on the primary endpoint, we barely missed the statistical hurdle for a positive study, and all the secondary endpoints were very encouraging. By the time we got the data from the Phase III fibromyalgia study, we had already gotten the data from a Phase II PTSD study.  From the Phase II PTSD study, we learned that a higher dose of our TNX-102 SL medicine, 5.6 milligrams, was more active than the original, 2.8 milligrams. 

MA: The treatment for cocaine intoxication addresses a different problem than a chronic disease, such as PTSD or fibromyalgia. How do you envision your clinical trial for cocaine intoxication? How can executives mitigate clinical trial risk in a new therapeutic area?

SL: Cocaine intoxication is a huge problem in both the United States and abroad. Tonix’s cocaine neutralizer, which is officially called “cocaine esterase,” is a potentially remarkable antidote. Technologically, the product began from an enzyme isolated from bacteria that live near the root of cocaine plants. Because these bacteria survive by eating cocaine, which is their sole source of carbon and nitrogen, the enzyme evolved to digest cocaine exceptionally efficiently. In a Phase II study on cocaine-abusing volunteers, the volunteers were injected with 50 milligrams of cocaine, then either injected with the control or with the enzyme that we now call TNX-1300. For those injected with TNX-1300 following the cocaine, more than 90% of the cocaine in their bloodstream was disintegrated within two minutes.

In experiments with rats who were given a fatal dose of cocaine and were already experiencing seizures, the symptoms from cocaine intoxication were interrupted abruptly by treatment with TNX-1300. This is exciting because this means that the TNX-1300 enzyme creates a phenomenon where the very low level of cocaine in the blood relative brain, results in the bloodstream sucking the cocaine out of the brain. It's a remarkable effect because the TNX-1300 enzyme itself doesn't enter the brain.  Our next step in development is to go into a study in hospital emergency rooms (ERs) where we will take people who meet specific criteria of a cocaine overdose and administer the TNX-1300 drug and attempt to reverse the effects of intoxication. 

In an emergency room setting, we expect to experience all sorts of study challenges. The first being study prioritization, as we would be competing with many studies in the ER, and we will have to find an ER that has research coordinators available around the clock. Secondly, recruitment; we will have to be very selective and conduct our research to find the right study site with high cocaine intoxication patient volumes, and we have to figure out how to capture as many patients as we can around the clock. Lastly, processes and workflows are going to be a challenge, as every single procedure has to be documented appropriately, and dose administration needs to happen within concrete timeframes to minimize data variability; hence, we are going to develop detailed workflows and robust training programs for sites.

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.