As the costs of research and development continue to rise for pharma and biotech firms—and as the era of blockbuster drugs seems to be on the wane, at least for now—so too does interest rise in the realm of repurposing existing, approved therapeutics for new indications. To find out a bit more about the philosophy and practice of retooling “old” drugs for new purposes, DDNews spoke with Dr. Seth Lederman, co-founder, CEO and chairman of Tonix Pharmaceuticals.
DDNews: When and how did the process of “repurposing” come into its current vogue (if that’s a good term)?
Seth Lederman, M.D.: Repurposing has been an essential part of drug discovery and development since before the modern era. Colchicine and quinine are perhaps the first drugs discovered and used by humans that are still actively prescribed and considered effective today. Colchicine and quinine were used for a number of different conditions before they were found to be particularly useful for treating and preventing gout and malaria, respectively. Aspirin (acetylsalicylic acid) is the first semi-synthetic drug to be developed, and it has been repurposed repeatedly during the period it has been marketed from pain to fever, headache, migraine, and preventing angina and heart attack (among others). It is often the case that drugs need to be on the market and in active use for doctors and patients to appreciate important new uses. Divalproate and carbamazepine were widely used for epilepsy before they were appreciated to be active in treating bipolar disorder.
Repurposing is most useful when the human condition that is being treated has an obscure pathology and when there is no known animal model or validated molecular target. Thalidomid (thalidomide) was repurposed into a treatment for multiple myeloma, which transformed both the treatment of multiple myeloma and also focused efforts of scientists on learning more about the targets of thalidomide, which led to the development of new drugs like Revlimid (lenalidomide).
I was a co-founder of Vela Pharmaceuticals in 1998, which was among the first companies (that I know of) which was focused on harnessing repurposing in a systematic way. Dr. Donald Landry and I founded the pre-cursor to Vela (L&L Technologies, which sold its portfolio of products to Vela) with a simple mission: to address the most important problems in medicine. We identified repurposing simply as a tool that could facilitate our bold, ambitious vision. Vela began some of the development programs that are now in the portfolio of Tonix Pharmaceuticals, including TNX-102 SL that is in clinical development for treating fibromyalgia syndrome and TNX-301 that will be developed for treating alcohol abuse and addiction. Neither product is approved by the FDA for any indication. These programs were considered too risky for a venture-capital backed company, so it took the passion and commitment (some would say stubbornness) of Landry and me to bring these innovations to fruition as experimental therapies to benefit patients.
DDNews: How does your team at Tonix Pharmaceuticals go about the process of reformulating rather than inventing?
Lederman: That we innovate and reformulation is just one of the tools we use. The kind of reformulations that interest us are only those that involve invention. In order to be effective, a drug product needs to be taken by the patient, which is called compliance or adherence. After the patient takes the medicine, the active ingredient needs to be at the right place in the body at the right time. We formulate our products to optimize compliance and to optimize the probability that the active ingredient will be in the right place in the body at the right time.
Compliance is the sine qua non of any effective pharmaceutical product: without the drug entering the patient’s body, it will not work. That’s why we focus on formulation technologies that we believe will improve compliance. For our lead product, TNX-102 SL, we have designed a sublingual tablet for bedtime dosing. Our previous work indicated that an oral tablet would have to be taken approximately an hour before bedtime to provide patients with the desired treatment effect. It seemed to us that taking a medicine one hour before someone intends to go to sleep is a very difficult regimen for even the most motivated patient. This is especially problematic considering that TNX-102 SL is a therapy for a chronic condition and requires nightly dosing.
Once in the body, the active ingredient needs to be at the right place in the body at the right time. For most of our products, the right place in the body is the brain because we focus on central pain disorders, like fibromyalgia, PTSD and headache. In our efforts to get the active ingredient to the right place, we try to minimize how much of the drug winds up in the wrong place, where it might cause side effects or just get delayed in transit. For our lead product, TNX-102 SL, the right time for the drug to be in the brain is during the sleeping hours. While trying to deliver the active ingredient into the brain during sleep, we also try to minimize how much of the drug winds up in the body at the wrong time, where it might cause side effects. For example, if the active ingredient of TNX-102 SL stays too long in the body after a bedtime dose, it can cause next morning drowsiness that some patients describe as a hangover.
It’s important to state that TNX-102 SL is an experimental drug being developed under an Investigational New Drug Application (IND) and it is not approved for any condition. While it’s designed to reduced side effects, in clinical trials TNX-102 SL has an adverse event profile similar to other drug products that contain cyclobenzaprine.
There are several examples where truly inventive reformulations have transformed therapy. One example is Concerta (methylphenidate extended release), which reduced the need for school-age children with attention-deficit disorder (ADHD) to get medicated during lunch. This kind of improvement has been rewarded by widespread adoption and improved health of large numbers of patients.
DDNews: As an example, perhaps, how was TNX-102 SL identified as a candidate sleep aid?
Lederman: TNX-102 SL is being developed as a treatment for fibromyalgia syndrome and not as a sleep aid. The invention of TNX-102 SL began with the work of Dr. Iredell Iglehart, who is a physician and rheumatologist. Dr. Iglehart took notice of the groundbreaking work of Dr. Harvey Moldofsky, who recognized that fibromyalgia patients had a kind of disturbed sleep, called non-restorative sleep. Iglehart took special notice of Moldofsky’s work, because Iglehart believed it was good practice to ask all his patients about their sleep and he quickly corroborated Moldofsky’s publications with his own experience treating fibromyalgia patients.
Iglehart took this line of inquiry further in two steps. First, he started asking fibromyalgia patients if they ever felt better. Iglehart noticed that a number of fibromyalgia patients volunteered that they felt better on the rare occasions when they were able to get a good night’s sleep. When he prompted fibromyalgia patients by asking if they felt better after they got a good night’s sleep, then many more recognized the connection between rare nights of good sleep and improvement in their condition. At this point, Iglehart recognized the therapeutic potential of restorative sleep. I consider this his “Jenner Moment,” in an analogy to Dr. Edward Jenner’s recognition that cowpox could be a vaccine for smallpox. In Jenner’s case, that “Ah-ha” or “Eureka” moment began when a milkmaid told him that she believed she was protected from smallpox by having experienced cowpox.
For Iglehart, like Jenner before him, eureka was only the beginning. Second, Iglehart embarked on a quest for medications that would increase the chances that fibromyalgia patients could get nights of restorative sleep. As a rheumatologist, he was familiar with cyclobenzaprine from its use as a muscle relaxant and he knew that somnolence was a common side effect. Therefore he tried harnessing the side effect of somnolence as a treatment effect for fibromyalgia patients. He experimented with different doses and dosing regimens of cyclobenzaprine before recognizing that very low-dose cyclobenzaprine was an effective treatment for fibromyalgia if prescribed between dinner and bedtime.
Dr. Iglehart’s work was confirmed by the double-blind placebo-controlled Phase 2a trial which showed that TNX-102 (cyclobenzaprine) capsules decreased pain in fibromyalgia patients, compared to placebo, if administered between dinner and bedtime. We were delighted that Harvey Moldofsky, who first recognized the issue of non-restorative sleep in fibromyalgia, was principal investigator of the Phase 2a trial. Today, both Moldofsky and Iglehart serve on our scientific advisory board and they have become colleagues and friends.
(Part 2 of this Q&A from the March issue of DDNews is here)
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.