In our February issue, we ran the first part of this Q&A, titled “Looking to past medications for the future” and, in so doing, we examined some of the issues related to the rising costs of research and development for pharma and biotech firms and how this could be eased to some degree by repurposing existing, approved therapeutics for new indications. Here is the rest of DDNews’ discussion on the topic of repurposing and reformulation with Dr. Seth Lederman, co-founder, CEO and chairman of Tonix Pharmaceuticals.
DDNews: What molecular clues do you look for before you embark upon the process of identifying a drug candidate for a specific reformulating application?
Seth Lederman, M.D.: Our process starts by identifying unmet medical needs. Some of the biggest and most challenging medical needs lack known animal models or validated molecular targets. So, next we have to identify some prospective active ingredients that could be not only therapeutics, but probes to understand the condition. Then, we have to develop a treatment regimen because the timing of drug administration might be critical to the therapeutic effect. It’s only after we have identified the medical need, after we have identified some prospective therapeutic ingredients and after we have developed a regimen concept, that we focus on the specific reformulation technology.
We start our process with some evidence for clinical efficacy in affected people, so mechanism and molecular clues typically come late in the process. It’s essential to understand the molecular targets of any drug so that one can understand the mechanism as well as potential side effects and drug interactions. We have done significant work on the molecular targets of cyclobenzaprine (the active ingredient of TNX-102 SL) and found that it inhibits serotonin receptor type 2a (5HT2a), adrenergic receptor alpha-1 receptor (alpha-1) and the presynaptic transporters for serotonin and norepinephrine. We describe the interactions of the multifunctional drug cyclobenzaprine by calling it a “serotonin and norepinephrine receptor antagonist and reuptake inhibitor,” or SNARI. We believe the 5HT2a and alpha-1 activities may account for its effect on nonrestorative sleep, but that the overall effect is unique and includes contributions from these activities and possibly other target interactions (including histamine receptor type 1 [H-1] antagonism).
DDNews: What is the process Tonix (and, of course, others) must go through to add a new indication to a drug’s label?
Lederman: TNX-102 SL is an investigational new medicine being developed under an Investigational New Drug application (IND). We are seeking the indication of “management of fibromyalgia syndrome.” We will need to complete two pivotal studies that demonstrate safety and efficacy of TNX-102 SL in fibromyalgia. In addition we will need to expose sufficient fibromyalgia subjects to TNX-102 SL therapy for a year to satisfy the FDA safety requirement for chronic dosing of a drug approved for short-term use.
Please note that we are not “adding” a new indication to the label of Flexeril (cyclobenzaprine immediate release). We plan to submit the TNX-102 SL product as a distinct New Drug Application (NDA). The only connection between TNX-102 SL and Flexeril is that they both contain cyclobenzaprine as an active ingredient and that we have been able to reference some safety data from Flexeril’s dossier and marketing experience to support our application under the 505(B)(2) approval pathway.
DDNews: In your estimation, how many approved therapeutics might have the potential for repurposing? What therapeutic areas are likely to be most fruitful?
Lederman: To use the metaphor of an artist, our palette is the universe of approved drugs. I think the potential for repurposing is better defined by the therapeutic areas to which it can be fruitfully applied. First, consider the number of unmet medical needs. Second, consider the number of unmet needs for which we lack relevant animal models or validated molecular targets. This group includes some of the biggest and most challenging medical needs. I would prefer not to cite specific examples of the most fruitful areas because we may have programs in these areas that are too early for us to disclose. For competitive reasons, we need time for early programs to develop to the point where patents are filed before we alert the respective fields of our research.
DDNews: Tonix developed TNX-102 SL, a sublingual formulation of cyclobenzaprine for the treatment of fibromyalgia. Do most reformulation applications involve similar closely related extensions of labeling?
Lederman: In the case of TNX-102 SL, we are both repurposing and reformulating. Repurposing means that we are developing the active ingredient (cyclobenzaprine) for an entirely new indication (fibromyalgia) and not the indication for which cyclobenzaprine is currently used (muscle spasm). Reformulating means that we are formulating cyclobenzaprine in a sublingual tablet to optimize the pharmacokinetic profile for the new indication and not using the oral, swallowed tablet in which cyclobenzaprine is currently available.
From our perspective, the indications of fibromyalgia and muscle spasm are not closely related. Fibromyalgia patients typically do not experience muscle spasm and muscle spasm patients typically do not suffer from fibromyalgia. Also, fibromyalgia is a chronic condition and muscle spasm is an acute condition. Further, fibromyalgia results from abnormal signal processing in the brain, while muscle spasm results from peripheral injury. From our perspective, the formulations of TNX-102 SL and Flexeril are not closely related. TNX-102 SL is a very low dose of cyclobenzaprine (2.8 mg) once nightly, while Flexeril is dosed at 5 mg or 10 mg three times a day. TNX-102 SL is a tablet that dissolves under the tongue, while Flexeril is ingested by swallowing.
For these reasons, we don’t envision TNX-102 SL as an extension, but rather as a transformation. We believe TNX-102 SL, if approved, will be a first-in-class medication for the treatment of fibromyalgia targeting non-restorative sleep, which would be an entirely new therapeutic class.
DDNews: What has been your experience thus far with TNX-102 SL for the treatment of post-traumatic stress disorder (PTSD)?
Lederman: Personally, I have less experience with PTSD than fibromyalgia. I have direct experience caring for fibromyalgia patients, because I practiced in the rheumatology clinic at Columbia University for about 10 years, while I was an instructor, assistant professor and associate professor in the Division of Rheumatology. Frankly, I was not knowledgeable about PTSD until we backed into this as a new indication for TNX-102 SL. Also, like many other New Yorkers and Americans, I learned a lot about PTSD after the terror attacks against the United States on 9/11/2001 and the subsequent wars in Iraq and Afghanistan.
What I’ve learned is that fibromyalgia and PTSD have significant clinical overlap. A number of patients with fibromyalgia meet the criteria of PTSD and vice-versa. Key symptoms are common to fibromyalgia and PTSD, including widespread pain, disturbed sleep and hypervigilance. One way to understand the connection is that fibromyalgia patients “hurt all over and can’t sleep.” PTSD patients “can’t sleep and hurt all over.”
We believe our Phase 2a study in fibromyalgia patients provides a hint of evidence that TNX-102 SL in a bedtime treatment regimen may improve symptoms of PTSD patients. We have not studied PTSD patients prospectively in a clinical trial to confirm the effect. We met with the FDA in October 2012 to discuss our clinical development program and based on the feedback from that meeting, we currently plan to file an IND for PTSD in the second quarter of this year and to start dosing a proof-of-concept study in the third quarter of this year.
DDNews: What other reformulation successes do you foresee in the near future for Tonix?
Lederman: We are developing a pure isomer of isometheptene as TNX-201 for the treatment of tension-type headache. Developing a pure isomer drug is a type of reformulation because it means that the new product will contain only one isomer and not contain another isomer, which was present in predicate products that were widely used to treat headache. Isometheptene is one of the active ingredients present in several combination drug products for tension headaches and migraine, which is being sanctioned by the FDA to withdraw from marketing. Because of the decreasing availability of the products in the standard prescription channels, many patients and doctors are compelled to resort to compounding pharmacies to obtain isometheptene-containing products. We have announced that we will be meeting with the FDA to discuss our plans in the first quarter this year. After that meeting, we should be able to provide more specific guidance about what will be involved in bringing TNX-201 through the regulatory process toward approval. We believe this will be an important addition to the therapeutic options for tension headache patients. Currently, the only approved prescription medications for tension headache in the U.S. contain butalbital, which is a barbiturate and is associated with medication overuse headache (MOH). We hope that pure isomer isometheptene might help tension headache patients, reduce the use of butalbital and reduce the incidence of MOH.
Seth Lederman is a physician, scientist and specialty pharmaceuticals entrepreneur, as well as an associate professor at Columbia University. Prior to founding Tonix Pharmaceuticals, Lederman co-founded and was a managing partner of Konanda Pharma Partners LLC and Konanda Pharma Fund I LP from 2007 to 2008. He co-founded and served as director and chairman of its wholly owned operating companies Validus Pharmaceuticals and Fontus Pharmaceuticals Inc., which market Equetro, Marplan and Rocaltrol. In 2000, Lederman founded Targent Pharmaceuticals to develop late-stage oncology drugs, including pure-isomer levofolinic acid, which was sold to Spectrum Pharmaceuticals and is now FDA-approved and marketed as Fusilev for colorectal cancer.