Novel Science, Familiar Regulatory Pathways: Inside Tonix's Clinical Development Strategy
A conversation between Tonix Pharmaceuticals President and CEO Seth Lederman, MD, and Clinical Leader Executive Editor Abby Proch
In August 2025, TONMYA became the first fibromyalgia treatment approved for adults in more than 15 years. For Tonix Pharmaceuticals President and CEO Seth Lederman, MD, the approval reflects a development philosophy the company now applies well beyond fibromyalgia: Pursue scientific novelty but avoid regulatory novelty.
In this Q&A, Lederman explains how Tonix decides which underserved areas are worth pursuing and why it looks for first-in-class opportunities, either a novel target or a novel approach to a validated one. He describes how targeting disturbed sleep shaped TNX-102 SL in fibromyalgia and now in major depressive disorder, and how stricter FDA expectations for missing data and updated diagnostic criteria have raised the bar for trials related to pain. He also discusses TNX-4800, a long-acting monoclonal antibody against outer surface protein A (OspA) for Lyme disease prevention, and the elements of an adaptive Phase 2 field study that depends on tick exposure, geography, and seasonality. Finally, he shares how Tonix carries lessons across all three programs in fibromyalgia, major depressive disorder, and infectious disease.
Clinical Leader: Both fibromyalgia and Lyme disease prevention represent areas where patient need may not always align with industry investment. How do you decide when an underserved treatment area is not only scientifically compelling, but commercially and operationally viable?
Seth Lederman, MD: Fibromyalgia remained underserved for many years because scientific understanding had not advanced enough to create a clear path for the development of new drugs. It took years of study before the field understood the range of symptoms that extend beyond chronic pain and how those symptoms fit together. What catalyzed our interest was the recognition that nonrestorative sleep was a novel target in fibromyalgia, which motivated us to pursue the development of a first-in-class medicine.
When we evaluate a potential program at Tonix, we ask four questions. First, does the disease place a substantial burden on patients? Second, how large is the gap between what patients need and what current treatments provide? Third, is there potential for a first-in-class medicine, which means either a novel target or a novel approach to a validated target? Finally, does the combination of biology and an established regulatory pathway offer a reasonable chance of success?
In fibromyalgia, the patient burden and treatment gap were very clear. Opioids are not recommended for fibromyalgia, and there is growing backlash against the gabapentinoids, which are widely prescribed for chronic pain but carry side effects such as dizziness, sleepiness, and weight gain, along with concerns about misuse. Patients and physicians want effective nonopioid options that people can tolerate over the long term with sustained benefit.
In major depressive disorder, which we are currently studying, the patient burden and treatment gap are also very clear, despite multiple FDA-approved treatment options. Even with incumbents such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and newer options such as dextromethorphan-bupropion and esketamine, the burden of depression remains high. There are still unmet needs for improving sleep quality and for treating patients with mild-to-moderate depression. Patients and physicians want effective treatment options that work in new ways and can address multiple symptoms.
A similar combination of burden and unmet need is evident in Lyme disease prevention. Millions of people live in or visit areas where Lyme disease is endemic, and there is currently no FDA-approved vaccine or other product indicated to prevent it. Vaccine approaches require multiple immunizations over six months or more to generate high antibody levels, and because those levels wane, they are expected to need annual boosters.
Once we have identified a substantial unmet need, a novel target or approach, and a strong scientific rationale that provides a high probability of success, the final question is execution: whether we can design a study that will give a clear answer, ideally along a regulatory path that earlier approvals have already established. We look for scientific novelty, but we try to avoid regulatory novelty. When all those line up, we have an opportunity worth pursuing.
Where have you seen the most meaningful overlap in trial planning among your programs for fibromyalgia, major depressive disorder, and Lyme disease?
These are very different conditions, but our programs share a common philosophy. In fibromyalgia, the field tended for years to think narrowly about pain. What became increasingly clear was that widespread pain, disturbed sleep, fatigue, brain fog, and mood are connected, and disturbed sleep may be closer to the origin of fibromyalgia in the brain than these other symptoms. To develop a novel and effective treatment, we had to recognize that disturbed sleep is the Achilles’ heel of the fibromyalgia problem, and we needed a drug that could potentially target it near the root of the problem in the brain. In two Phase 3 studies, we found that TONMYA, the commercial name for TNX-102 SL, a sublingual, transmucosal, nonopioid medicine, taken once daily at bedtime, decreased pain in fibromyalgia. These findings support our continued investigation of the relationship between sleep and chronic conditions.
That insight carries directly into our program to develop TNX-102 SL for the treatment of depression. Sleep disturbance, classically early-morning awakening, is a core part of the experience of depression, and our currently enrolling potentially pivotal Phase 2 study has the potential to show that disturbed sleep is also a novel target in depression. The question is the same one we asked in fibromyalgia: If you target disturbed sleep in depression, will the core symptom of depressed mood also improve?
TNX-4800 reflects the other half of that philosophy. Rather than a new target, it could be a new way to address a validated one. OspA has been validated as a target by the LYMErix vaccine and seems to be the Achilles’ heel of Borrelia burgdorferi. Natural immunity to OspA is very rare, which is probably why people can get Lyme disease over and over again without developing protective immunity. What makes TNX-4800 potentially a first-in-class medicine is the novel approach of using a long-acting monoclonal antibody instead of a vaccine. Because it provides passive immunity, TNX-4800 does not depend on the recipient’s own immune system to protect against Lyme transmission and disease.
What the fibromyalgia, depression, and Lyme disease programs have in common in trial planning is precision about the biology: what the target is, how the intervention engages it, and what a study has to show to support FDA approval. In the case of TNX-4800, we designed a study that is closely modeled on vaccine trials, which have the benefit of precedent in FDA review.
Chronic pain trials can be difficult because symptoms are subjective, heterogeneous, and influenced by multiple factors. How do you address and overcome those challenges?
Chronic pain is difficult to study. Pain endpoints are subjective, and a significant placebo response is typical. Beyond that, the goalposts have moved on how trials account for patients who drop out. Many older pain trials used methods such as last observation carried forward, which credits a patient who improved and then quit because of side effects as if the improvement had lasted. The FDA’s analgesic division was already pressing sponsors on how they imputed missing data when the first fibromyalgia drugs were approved, and expectations have become much more rigorous since. Today, a patient who discontinues because of an adverse event is generally analyzed as having lost any benefit from the drug.
That changes the calculus of pain drug development. A drug’s side effects now count directly against its efficacy result, because every patient who drops out for tolerability reasons effectively becomes a treatment failure. In effect, tolerability has become part of efficacy. TONMYA is the only fibromyalgia medicine evaluated and approved under this more rigorous standard. Going forward, it will be very hard to develop fibromyalgia medicines whose side effects lead patients to discontinue, however active those medicines are. To win in the modern environment, it’s essential to have a medicine that is active and generally well tolerated. That was central to our thinking about TNX-102 SL: a sublingual, nonopioid medicine taken once daily at bedtime.
The diagnostic criteria have also changed, which raises the bar in another way. The drugs the FDA approved from 2007 to 2009 were studied in patients diagnosed under the 1990 American College of Rheumatology criteria, which required a tender-point exam. Newer criteria, introduced in 2010 and revised in 2016, eliminated that requirement. Generally, patients who meet the tender-point criteria have more severe disease, so studying patients diagnosed under the 2016 criteria means a drug must be effective in a broader population that includes less severe patients. Drug developers generally prefer to study more severe patients because there is more room to show improvement. TNX-102 SL is the only fibromyalgia medicine that was tested and approved in patients diagnosed under the 2016 criteria.
I often compare scientific progress on complex problems to constructing a brick building. You don't build one side three stories high while leaving the rest at knee height. You keep working around the whole structure, so it rises evenly. The same is true in chronic pain research. We continue to learn about disease biology and apply those learnings to improve clinical trial methods and treatment approaches. For us, that meant identifying a novel target. In our Phase 3 program, the primary endpoint was daily pain, but our development strategy was to address the central pain problem by targeting disturbed sleep. Because sleep, pain, fatigue, and mood are connected, and disturbed sleep may be closer to the origin of the problem, a sleep-focused approach offered a way to work on the whole structure rather than one symptom at a time.
What did Tonix learn from earlier FDA interactions on TONMYA that is helping it approach regulatory alignment for TNX-4800 and TNX-102 SL?
The understanding and treatment of fibromyalgia did not advance to where it is today overnight. Before the FDA approved the first fibromyalgia treatments between 2007 and 2009, there were years of work to develop and validate the endpoint of daily pain reduction and establish a way for regulators to evaluate new treatments. Those approvals reflected a great deal of effort by researchers, companies, patient advocates, and the FDA, and they showed the pathway to approval. We followed that pathway rather than inventing a new one, even as the standards for missing data and the diagnostic criteria evolved. That groundwork, along with our own productive discussions with the FDA, helped lead to the August 2025 approval of TONMYA, the first fibromyalgia treatment for adults in more than 15 years.
For us, one takeaway is the value of staying engaged with the FDA throughout development. Another is that we try to avoid regulatory novelty. A first-in-class medicine does not need a first-of-its-kind regulatory path, and where there is a precedent, we use it. It is important to be clear early about what question a study is asking and what evidence will be needed. We are taking the same approach in investigating TNX-102 SL in depression, where decades of antidepressant approvals have established the endpoints and trial designs the FDA expects, and with TNX-4800. For Lyme disease, the precedent is LYMErix, an alum-adjuvanted OspA vaccine the FDA approved in 1998 based on a field efficacy trial. Its manufacturer withdrew it in 2002, citing insufficient demand, but the approval showed the pathway for a Lyme disease preventive. We have already aligned with the FDA on a TNX-4800 Phase 2 design modeled on that kind of vaccine trial.
What has Tonix learned about using adaptive elements responsibly, not simply to accelerate development, but to make trials more informative, feasible, and responsive to real-world conditions?
Lyme disease prevention presents a different challenge than fibromyalgia because we depend on natural exposure. In a field study, you don’t know in advance exactly what the infection rate will be. One region may have more Lyme disease activity than another, and the spread of deer ticks into new areas, with Lyme disease following them, is a rapidly evolving story.
Our goal is to obtain data that the FDA and the scientific community can interpret clearly. The Phase 2 study needs to accommodate the reality of how Lyme disease occurs in the field. Adaptive elements help with that, but they have to be prespecified in the protocol and discussed with the FDA in advance, so they make the study more informative without compromising its integrity. For example, the proposed TNX-4800 study design allows enrollment to extend into an additional tick season if the Lyme disease attack rate is lower than expected, so the study can still accrue enough cases to give a clear answer.
When you design a study in a field setting, such as Lyme disease prevention, what lessons from chronic pain development still translate, and what has required a completely different operational mindset?
One of the important developments in fibromyalgia was recognizing that altered pain processing represented a distinct biological phenomenon. It wasn't simply a matter of unexplained symptoms. In Lyme disease prevention, you also begin with biology. Borrelia burgdorferi expresses OspA while it lives in the tick’s gut. When an infected tick feeds on a person who has received TNX-4800, it takes in the antibody with its blood meal, and the antibody can kill the bacteria inside the tick before they are transmitted. That is the same biology that made OspA a vaccine target; we simply deliver the antibody directly. The lesson is that biology matters.
The practical differences are considerable: Fibromyalgia studies focus on symptom improvement in people who already have the condition, whereas Lyme disease prevention depends on factors such as exposure, geography, timing, and seasonality. Those factors drive where we place study sites, when we enroll participants, and how large the study needs to be, which requires a very different operational mindset from a chronic pain trial. The antibody approach also shapes the operations. Because TNX-4800 is expected to provide protection within two days and does not depend on the participant’s own immune response, participants can be dosed at the start of tick season rather than the six months or more ahead that vaccine approaches require.
Finally, as CEO, how do you create continuity across programs so that lessons from one development or commercialization effort are captured, shared, and applied?
When you have a team that has gone through the full life cycle of drug development and commercialization, including clinical studies, FDA approval, physician education, patient engagement, and market launch, you can draw on that experience when a new program reaches a similar stage.
The science is different across fibromyalgia, Lyme disease prevention, and major depressive disorder, but the lessons about clinical development, regulatory interactions, and execution carry over from one program to the next and help us improve as a drug developer. The common thread is the search for first-in-class opportunities: a novel target, as with disturbed sleep in fibromyalgia and depression, or a novel approach to a validated target, as with a long-acting antibody against OspA. In both cases, we pursue scientific novelty along regulatory paths that earlier approvals have already established.
About The Expert:
Seth Lederman, MD, is the president and CEO of Tonix Pharmaceuticals, a fully integrated, commercial-stage biopharmaceutical company focused on central nervous system (CNS) disorders, infectious diseases, and immunology conditions with high unmet medical need. Dr. Lederman founded Tonix Pharmaceuticals in 2007 and has acted as its chairman of the board of directors since its inception and as president since 2010. Prior to becoming a biopharma executive, Dr. Lederman served as an associate professor at Columbia University, where he directed basic science research in molecular immunology, infectious diseases, and the development of therapeutics for autoimmune diseases. In addition to his research, Dr. Lederman served as attending physician in the Edward Daniels Arthritis and Autoimmunity Clinic on the Medical Service at Columbia Presbyterian Hospital. Dr. Lederman earned his B.A. in chemistry from Princeton University and his MD from Columbia University.