An innovation challenge: Using pharma R&D as a tool for social change

By definition, innovation is intended to be revolutionary and transformative, and when the lives of millions and millions of patients are involved, successful innovation has the power to change the standard of care. Dr. Seth Lederman, CEO of New York City-based Tonix Pharmaceuticals, is pursuing this type of innovation through three clinical development programs associated with central nervous system (CNS) therapeutics—fibromyalgia, post-traumatic stress disorder (PTSD) and episodic tension-type headache (ETTH). 

According to Dr. Lederman, who is trained in internal medicine and has years of experience running a research lab at Columbia University, these disorders are characterized by chronic disability, inadequate treatment options, high utilization of healthcare services and significant economic burden. "The patients we focus on have been denigrated, ignored and left out of the system," he told BioPharma Dive in an interview. "They have fallen through the cracks."

For the Tonix research team the focus is on not only addressing the unmet pharmacologic needs associated with these disorders, but on using innovation to shift the entire biopsychosocial paradigm of how these disorders are addressed and how patients are viewed.

Leveraging the connection between pain and sleep quality

Tonix is developing two molecules for three indications. The lead candidate,TNX-102 SL (cyclobenzaprine HCl sublingual tablet), is being developed to address sleep quality and pain in patients with both fibromyalgia and PTSD. The second candidate TNX-201(dexisometheptene mucate) is in development for episodic tension-type headache, the most common form of headache.

Cyclobenzaprine was first approved in 1977 as Flexeril as a muscle relaxant. However, phase 2b clinical trial data confirms Dr. Lederman’s central thesis that if you can improve sleep quality in fibromyalgia patients, then their other symptoms will also improve.  For Tonix researchers, understanding this connection is the key to providing a completely different way of approaching fibromyalgia, which affects more than five million Americans.

Quantifying the sleep quality-pain connection

In a phase 2b, 12-week, randomized, placebo-controlled study involving 205 fibromyalgia patients, TNX-102-treated patients experienced improvements in all of the measures of sleep quality and pain, and four weeks in, the results were statistically significant compared with placebo. Most strikingly, however, is that fact that improvement in sleep measures as measured by a validated sleep measure was strongly correlated with improved pain. In short, patients who slept better, had less pain.

From a development perspective, the major changes to cyclobenzaprine are the dose, which is basically cut in half (from a 5mg/10mg option to 2.8 mg), and TNX-102 SL’s sublingual delivery system.  One thing that has not changed is the dosing schedule, which calls for every-night, nocturnal dosing. But does changing the delivery mechanism and dose really make what Tonix is doing innovative?

How’d you sleep last night?

According to Dr. Lederman the answer is yes. “TNX-102 SL is first-in-class. We are focusing on improving sleep quality as a mechanism for addressing fibromyalgia. When you think about the most common approach to addressing sleep disorders, you think about sedatives or hypnotics, but this is not a sedative. Also because Flexeril does not have a dependency label, we don’t have to be concerned about addiction—which is important since this is intended to be a long-term, every-night therapy,” he says.

As for PTSD, which affects roughly 8.5 million Americans, poor sleep quality is a major problem. Patients often experience distressing dreams in which they relive nightmarish combat situations. They are also often in a state of hyper-arousal while sleeping. Also, PTSD is correlated with depression, substance abuse and suicide. Dr. Lederman explains,“PTSD is widely recognized as a serious psychotic illness. Although we are going after a broad PTSD indication, we are focusing on veterans with combat-related PTSD in our clinical studies. These patients have been left behind, and it’s important that we serve them.”

Currently, PTSD is treated with antidepressants, but Tonix is focused on targeting the mechanism associated with disturbed sleep in PTSD patients. Tonix’s clinical study evaluating TNX-102 SL in PTSD patients is currently recruiting, with the goal of completing a 220-person study and reporting results in the first half of 2016. Once again, Dr. Lederman’s goal is to not only shift the treatment paradigm for PTSD, but change the way it’s viewed. “PTSD is another example of a stigmatized illness. Even the most well-intentioned people are often dismissive. The problem with PTSD is that the wounds are hidden. There is no deformity, scar or missing limb.”

ETTH: Old diagnosis, new term

Tonix’s development program in episodic tension type headache (ETTH), which affects roughly 75 million Americans, is based on using dexisometheptene, which dates back to the 1950’s but has not been used in many years. Currently, all of the approved medications for addressing ETTH contain barbiturates, but Tonix is using dexisometheptene to target a completely different receptor—the imidazoline-1 receptor. 

“This drug is not addictive,” Dr. Lederman explains. “It’s an entirely new offering. Some patients do not find relief with OTC medications and don’t want to rely on barbiturates. We are trying to provide another option for a disease that affects a lot of people. There are more E.R. visits for tension headaches than migraines, but most people don’t know that.” So far, phase 1 results have been positive, suggesting that TNX-201 has a good side-effect profile. Phase 2, which is underway, has enrolled 150 patients, with a primary endpoint of patients being “pain free” two hours after taking the drug.

Making the pain go away

In many ways, Tonix’s development program is part of a growing patients’ rights movement for people who suffer with chronic pain that is often not diagnosed and frequently dismissed. “Despite the National Pain plan, pain is overlooked and generally left out of the conversation. There continues to be an unmet medical need around pain, and our goal is to develop non-barbiturate treatment options that address the pain inherent in fibromyalgia and ETTH,” says Dr. Lederman.

A new twist on an old model?

At first blush, Tonix may just seem like another company bringing old, off-patent drugs back to market and contemporizing the positioning and marketing.  However, according to Dr. Lederman, this is not the case. He says, “We are different from companies that resurrect old drugs. We are pursuing fundamentally novel uses of existing drugs, with novel treatment paradigms.”

Tonix, which was formed in 2007 and went public in October 2011, was uplisted to Nasdaq in 2013. Based on the trajectory of market response to Tonix, the company is already being rewarded for its innovative approach to fibromyalgia, PTSD and ETTH. But for Dr. Lederman and close to 100 million patients, the real reward---product approval, could be as close as 2017 for at least one of the indications.

Dr. Lederman sees this as a good time to be involved in innovative endeavors in biopharma. “There is a great deal of innovation out there. Obvious examples are the breakthroughs in curing hepatitis C and the incredible advances in oncology. Our goal is to have a similar impact in CNS disorders.”

Filed Under: Drug Discovery Marketing Corporate News