The potential of small molecules and biologics for new therapeutics 

Dr Seth Lederman is a physician-scientist, entrepreneur, and CEO of Tonix Pharmaceuticals. He talks to Lu Rahman about Tonix Pharmaceuticals’ mission to research and manufacture small molecules and biologics for the treatment of CNS and immunological conditions. 

Since its formation in 2011, Tonix Pharmaceuticals has harnessed the power of clinical research and strategic collaborations to develop novel in-house and in-licensed compounds for the treatment of CNS and immunology disorders. Its initial research efforts focused on developing small molecules and biologics to address neurological diseases such as fibromyalgia, psychiatric disorders, migraine headaches, and substance abuse. Its leading candidate for the bedtime treatment of fibromyalgia, TNX 102-SL, is currently in mid- Phase III development.  

Tonix’s commitment to innovating solutions for the complications of psychological indications stems from a tremendous unmet need of patients diagnosed with these conditions. Dr. Seth Lederman, CEO of Tonix Pharmaceuticals, considers the medical and scientific research backgrounds of Tonix team members a driving force for the company’s work in central nervous system, or CNS, indications. Many of his team have scientific or clinical backgrounds and have experienced first-hand the demand for viable solutions to chronic neuropsychiatric, pain and addiction conditions – often overlooked by larger pharmaceutical companies. 

Tonix has also recognised the potential of developing its small molecules and biologics in the immunology space. The company expanded its therapeutic scope to immunology when engineering its proprietary horsepox vaccine platform. This platform is being used to develop its Covid-19, smallpox, and monkeypox vaccine candidates. Independent vaccine genome researchers concluded that the vaccine used to eradicate smallpox prior to and during the US Civil War era had 99.7% colinear identity to the horsepox virus, and Tonix cites this as support for the use of horsepox as a vector in the prevention of viral infections1.   

Lederman’s previous clinical research discovered the CD40-ligand and established its role in T cell helper function, a significant scientific advancement used to develop multiple immunological and oncological treatments. As an immunologist, Lederman has noticed a lack of emphasis on the role of T cells in developing immunological treatments because T cells are harder to measure than antibodies. Whereas other companies’ vaccines and immunologic therapies focus on the activity of antibodies alone, Tonix’s immunology candidates aim to activate both T cells and antibodies to elicit an immune response. Tonix has also developed a monoclonal antibody directed against the CD40-ligand to prevent organ transplant rejection and to treat autoimmune disorders.  

LR: The company has expertise in small molecules and biologics development. Where does it see opportunity and potential for these? 

SL: Small molecules and biologics each have distinct potential for new therapeutics. Small molecules provide significant benefits over biologics for some conditions. First, small molecules are literally smaller than peptides or biologics, and their small size allows some of them to be absorbed after oral dosing, or some to cross the blood brain barrier and enter the brain, or some to target intracellular targets. Some small molecules have all three properties: work after being swallowed as pills, act on the brain and target proteins inside cells. 

Oral drugs can be administered outside of a clinical care setting and in the comfort of patients’ homes.  

Small molecules can be manufactured by chemical synthesis, so they have an advantage in scalability of manufacturing which can translate into more efficient and cost-effective production.  

On the other hand, biologics, and particularly monoclonal antibodies are larger in size, but make up a rapidly growing class of pharmaceuticals. Generally, they can have high specificity for individual targets with a low number of off-target effects that leads to applicability across many disease states. Biologics, by nature, are derived from a living organism and require a high amount of sophisticated equipment to manufacture and purify. A challenge with biologics is the difficulty of administering them to patients. 

In either case – small molecules and biologics – there has been relatively little interest in developing treatments for pain, psychiatric and addiction conditions. Bucking this trend, Tonix is studying small molecules such as cyclobenzaprine and tianeptine oxalate for use in chronic pain, psychiatric, neurological and addictive conditions; the small peptide oxytocin for neurological indication of chronic migraine; the biologic cocaine esterase as an antidote for cocaine intoxication and the biologic anti-CD40-ligand for preventing transplant rejection and treating autoimmune conditions. In addition, the company is also developing live virus vaccines based on synthesized horsepox for the prevention of smallpox, monkeypox, and Covid-19; and the antibiotic and antiviral sangivamycin for the treatment of Covid-19.  

LR: Tonix is currently mid Phase III trials for TNX-102 SL. What led to the development process? What challenges were encountered and how were they overcome? What are potential adaptations for its therapeutic use in a variety of indications and how likely are these programs to progress?  

SL: Tonix is investigating the therapeutic properties of our sublingual cyclobenzaprine candidate, TNX 102-SL, across indications of fibromyalgia, post-traumatic stress disorder, agitation in Alzheimer’s disease, alcohol use disorder, and Long Covid syndrome. A common characteristic of all these conditions is disturbed sleep.  Fibromyalgia and Long Covid both also commonly include the symptoms of chronic widespread pain, fatigue and cognitive issues.  

Some oral pill formulations of cyclobenzaprine are designed for swallowing and are approved by the Food and Drug Administration (FDA) as a skeletal muscle relaxant for the indication of muscle spasm.  

We believe TNX-102 SL, our rapidly disintegrating sublingual cyclobenzaprine tablet, may be able to address symptoms of patients suffering from a variety of chronic pain, neurologic, psychiatric and addiction conditions. Its formulation is designed to optimise delivery and absorption of cyclobenzaprine to improve sleep quality while minimising the potential side effects sometimes associated with oral swallowed formulations of cyclobenzaprine. The FDA approved oral cyclobenzaprine products are only approved for treating muscle spasm for two to three weeks of daily use in the United States. Our aim is to develop TNX-102 SL for long term use in fibromyalgia, Long COVID, PTSD, agitation in Alzheimer’s disease, alcohol use disorder and some other indications in which sleep disturbance plays a role in the exacerbation of symptoms.   

TNX-102 SL is currently in mid- Phase III trial for the management of fibromyalgia. Fibromyalgia is a chronic pain disorder afflicting 6 to 12 million adults in the United States, approximately 90% of whom are women. Fibromyalgia patients often experience disturbed and non-restorative sleep, along with persistent widespread pain, fatigue, and brain fog.  

TNX-102 SL targets mechanisms which are associated with disturbed sleep patterns in fibromyalgia patients, and our belief is that improving the quality of sleep may trigger the body’s adaptive ability to modulate pain perception in fibromyalgia. Participants in clinical trials self-administer two sublingual tablets totalling 5.6 milligrams of cyclobenzaprine nightly.  

TNX-102 SL is believed to utilise a trimodal mechanism of action2, potentially serving as a functional antagonist to improve sleep quality and reduce pain in fibromyalgia patients. Antagonism of the Serotonin-2A receptor is thought to increase restorative slow wave sleep and to decrease the frequency of waking-after-sleep onset3. Antagonism of the Alpha-1-adrenergic receptor is found to reduce trauma-related nightmares and other forms of sleep disturbances4.  Antagonism of the Histamine-1 receptor promotes a decrease in wakefulness and increase in restorative slow wave sleep in preclinical studies5. Inhibitions of these receptors are believed to increase the quality of sleep and decrease chronic widespread pain in patients with fibromyalgia, even during the day.  

We are pleased by the safety and efficacy data obtained from the positive Phase III RELIEF study of TNX-102 SL in management of fibromyalgia. The trial enrolled 503 participants across approximately 40 U.S. sites. TNX-102 SL reduced mean pain in the treated group, which was the primary endpoint. A subsequent Phase III study, called RALLY had disappointing results at the pre-planned and blinded interim analysis, but we look forward to the release of topline data in RALLY so that we can see what went wrong and hopefully design future studies based on what we learn. 

LR: You mentioned developing TNX-102 SL for Long Covid. How much opportunity do you see here? 

SL: We have mobilised our efforts to address the Covid-19 pandemic and its consequences. As a company seeking treatments for chronic illnesses like fibromyalgia, we have jump-started efforts to develop drugs and vaccines for Covid-19. So far, the patient population diagnosed with Long Covid has not been addressed. Long Covid, officially known as Post-Acute Sequelae of Covid-19 (PASC), occurs in more than 30% of patients following SARS-CoV-2 infection6.   

Long Covid Syndrome has often been compared to fibromyalgia because of similar symptoms of sleep disturbance, chronic pain, fatigue, and brain fog. Long Covid Syndrome also predominantly occurs in a female-predominant population, which is similar to fibromyalgia. With these commonalities in mind, along with the overwhelming urgency to develop a treatment for this disease, we are eager to initiate the next steps to testing TNX-102 SL in Long Covid.   

We are in a dialogue with FDA and look forward to agreement with FDA on the design of a Phase II clinical trial of TNX 102-SL for the treatment of symptoms of Long Covid Syndrome in the subset of patients who have symptoms that overlap with fibromyalgia. Because of ongoing research of TNX 102-SL’s therapeutic properties in pain relief in fibromyalgia, we hypothesise that TNX-102 SL can address fibromyalgia-like symptoms in a subset of patients with Long Covid. 

LR: What do you see as the long-term opportunities for biopharmaceutical development?  

SL: To augment our internal research and development efforts, we have identified, negotiated and executed collaborative research and licensing agreements on new programs.   

Tonix has entered into a number of collaborative research programs and licensing agreements to advance or expand therapeutic and vaccine candidates. With a national and international approach, we have entered into research collaborations with the University of Geneva, Kansas State University, Southern Research, University of Alberta, Massachusetts General Hospital, and the French National Institute of Health and Medicine (Inserm).  

Collaboration is essential to scientific innovation. However, the complexity of intellectual property agreements can deter companies and academic parties from collaborating. However, diversity of thought is one of the strongest reasons for scientists to develop product candidates together. If we, in the biopharmaceutical industry, continue to collaborate with academia and non-profits, then we expect the community will continue to innovate. We will be able to bring product candidates through the clinical trial and regulatory approval process and to patients who need them most. 

Volume 22, Issue 4 – Fall 2021 

About the author 

Dr Seth Lederman is a physician-scientist, entrepreneur, and CEO of Tonix Pharmaceuticals. A rheumatologist by training, Dr. Lederman’s research on the CD40-Ligand (CD154) helped identify the molecular basis of T cell helper function. At Tonix, Dr. Lederman leads his team of science-minded individuals in innovating novel therapeutics targeting central nervous system (CNS) and immunology indications. 

References 

  1. Brinkmann A et al, Genome Biology (2020) 21:286 https://doi.org/10.1186/s13059-020-02202-0 
  2. Krystal AD, Richelson E, Roth T. Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications. Sleep Med Rev. 2013;17(4):263-272. 
  3. Monti JM. Serotonin control of sleep-wake behavior. Sleep Med Rev. 2011;15(4):269-281. 
  4. Hendrickson RC, Raskind MA. Noradrenergic dysregulation in the pathophysiology of PTSD. Exp Neurol. 2016;284(Pt B):181-195. 
  5. Krystal AD, Richelson E, Roth T. Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications. Sleep Med Rev. 2013;17(4):263-272. 
  6. Nalbandian, Ani, et al. “Post-acute COVID-19 syndrome.” Nature Medicine (2021): 1-15. 

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