Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please could you give a brief introduction to sleep disorders and who they affect?
Sleep disorders are a large area. We are focused on one particular type of sleep disturbance called “non-restorative” sleep. People with this problem do sleep, but they don’t wake up feeling refreshed or feeling that their sleep has had the restorative effects of healthy sleep.
To put this into context with all of the different sleep disorders, it is important to note that most sleep disorders are classified as insomnia. Most insomnia is a problem with the quantity of sleep. Non restorative sleep is a problem with the quality of sleep. Sleep quantity and sleep quality are different. We are focused on improving the quality of sleep for people with non-restorative sleep.
People suffer from non-restorative sleep for a number of reasons. We are particularly focused on patients with fibromyalgia syndrome. Fibromyalgia is a chronic pain syndrome. Patients with fibromyalgia hurt all over their bodies. They also can’t get restorative sleep. There is a vicious cycle of chronic pain and non-restorative sleep. Pain disturbs sleep and people with non-restorative pain have a greater sensitivity to pain and more trouble extinguishing pain.
While sleep quality and sleep quantity are different, no one can get good quality sleep if they don’t get enough sleep. One reason that non-restorative sleep is so prevalent in our modern society is that people did not evolve to function on so little sleep. Less than a hundred years ago, the vast majority of humans were awake when it was light outside, and slept when it was dark. In areas away from the equator, in winter people slept more than 12 hours a night.
It is challenging for people to adapt to sleeping less and less. A good night’s sleep for most people is around 8 hours; but many people have to get by on 6 hours or less. One of the reasons that people sleep so little is because there is so much artificial light and so much nighttime stimulation keeping them awake, like television and the Internet. For people with non-restorative sleep, the first thing I like to advise them is, ‘Give sleep a chance’. Many people in the field refer to this as “sleep hygiene”. In the same way that people should wash their hands to remove germs, they should pay attention to get enough good quality sleep to avoid the consequences of poor sleep.
Another modern problem with sleep quality, that is just about 30 or 40 years old, is the jet lag people suffer as a consequence of the widespread use of airplanes and the challenges that people face in trying to adjust to time-zone changes. Most people can recover from jet lag if they take care to give sleep a chance. However, some people can’t easily recover from jet leg and in these people jet lag can trigger a series of events that can become a downward spiral into worse and worse sleep problems. These people are not able to recover from jet lag, because they can’t get restorative sleep even if they spend time in bed staring at the ceiling. When someone can get sleep and recover from jet lag, then I call it compensation. When someone is unable to back on track, I think of their problem as decompensation. Once someone has decompsenated, their inability to get restorative sleep can lead to other problems.
One of the most important challenges to getting good quality sleep is the fact that the body changes over time and people can’t always adjust their sleep hygiene to the changes in their bodies as they grow older. Young people can get away with much less sleep than older people. Women find menopause challenging, because sweating and hot flashes lead to sleepless nights.
When people begin to experience chronic problems sleeping, the body is able initially to compensate and maintain health despite poor sleep. However, if the sleep problem continues for a long time, at some point the body becomes unable to compensate. This progression leads to a vicious cycle where non-restorative sleep leads to pain and pain leads to further difficulty sleeping.
Why is a good night’s sleep so important?
Sleep is an active process. It is not a time when the brain is inactive. It is a time when the brain is actively processing information from the day - storing certain experiences into memory, but also editing other experiences, so that they will be excluded from the repertoire of frequently recalled memories.
It is during restorative sleep that painful memories are edited. For healthy people with restorative sleep, this means that they won’t get fixated on reliving painful memories. For people with non-restorative sleep, these painful memories can be recalled and they can become psychological fixations that become nightmares during sleep and resurface during awake hours and can be troubling for days, weeks, months or years.
Another very important aspect of restorative sleep is that it refreshes the body’s system for perceiving and processing pain. Healthy people who experience an athletic injury, or some other sort of painful event, can wake up from a night of restorative sleep, with the pain significantly diminished. Healthy people also find that a good night’s sleep restores the body’s ability to perceive and process pain. Even before the injury is repaired, their bodies have a mechanism that operates during restorative sleep to adapt to pain and to work around it.
However, people who are unable to get restorative sleep, frequently cannot reset the body’s processes that perceive and process pain. Their pain can accumulate from day to day. Over time, their pain swamps the system. They become unable to adapt to pain or to work around it.
The mechanism by which the body can turn off or extinguish pain is called, “central inhibition”. Extreme examples of central inhibition’s capabilities have been described when a rock has pinned the arm of a mountain climber or a when soldier’s limb is severely damaged by a blast or shell. Central inhibition is the process that allows the brain to turn off perception of pain from such injured limbs. Central inhibition in such extreme cases kicks in when there’s no hope for the body to avoid further pain and when continuing to perceive pain is counter-productive.
Fibromyalgia seems to be connected with a problem in central pain, because fibromyalgia patients experience pain all over their bodies despite the fact that it’s counter-productive. In healthy people, central inhibition can extinguish local pain perception connected with severe, local injuries. In fibromyalgia, central inhibition seems to fail at a higher level, because their pain is widespread.
Almost the opposite of central inhibition is called “phantom limb” syndrome, when people experience pain from limbs that have been amputated. Some cases of phantom limb or physical pain result in a spreading of the pain to other parts of the body that were not part of the original injury. These cases seem to illustrate the processes that cause fibromyalgia. In fact, some fibromyalgia cases begin with a physical injury. For example, Rheumatologists believe that the artist Frida Kahlo suffered from fibromyalgia and that her problems began with a back injury.
One of the our company’s important long term goals is to provide a medicine that helps people get back the ability to get a restful night’s sleep on their own. We don’t know if our existing medicine TNX-102 SL will have this capability or if it will require better understanding of sleep and the development of second or even third generation sleep quality products. It might be helpful to regard such a medicine using the metaphor of a crutch. If someone can’t walk because of a temporary injury, a crutch can help until they can walk again on their own. We hope that our efforts will lead to a bedtime medicine can help improve the quality of sleep in patients who can’t get restorative sleep, until the time when these patients can sleep normally again on their own.
Whatever processes are going on in the brains and bodies of fibromyalgia patients, all we can hope to do with TNX-102 SL is get them back to the point of being able to get restorative sleep and allowing sleep’s natural restorative processes to work on reducing pain. We hope that it will refresh their ability to process pain.
What do patients currently use to try to get to sleep?
People who have trouble getting restorative sleep often learn from their life experiences that, they feel better all over, if they are able to get a night of restful sleep. Since people who have trouble getting restorative sleep frequently suffer with chronic pain from fibromyalgia or PTSD, they often learn that their pain improves if they are able to get a night of restful sleep.
For people who experience this kind of relief, getting a night of restorative sleep can become an all-consuming quest. It may even take over their lives. They may risk other consequences in order to achieve it. For this reason many chronic pain patients turn to prescription sleep drugs in the hopes of getting restorative sleep. These medicines may work once, twice or for a short period. But unfortunately, prescription sleep drugs increase only the quantity of sleep. They do not increase the quality of sleep.
People who turn to prescription sleep drugs may become dependent upon them, and not get the benefit that they are really seeking in a reliable way. In fact, dependence on prescription sleep drugs is one of the reasons why people cannot get restorative sleep.
Our program is heading in a completely different direction, as we’re trying to help people get increased sleep quality, not necessarily increasing sleep quantity.
Alcohol is probably the most common non-prescription chemical that people use to help them sleep. Men typically use alcohol more frequently than women and men seem to have a higher predisposition for self-medicating using alcohol.
Alcohol has some ability to work as a sedative. Unfortunately, alcohol fragments sleep and does not help to improve sleep quality. Another feature of alcohol is that it exerts an effect that is fairly short-acting and not long-lasting. If someone uses alcohol to help them go to sleep at 10pm at night, it is not uncommon for them to wake up at 2am or 3am more activated than if they had not taken alcohol.
From a drug-designer’s perspective, alcohol does not have the right pharmacokinetic profile to be an effective sleep medicine since people wake up activated in the middle of the night. Obviously, alcohol also has other issues. For example, only small amounts of alcohol have any beneficial effects. If someone drinks too much alcohol then there are other consequences. Drinking more alcohol to try to extend the time that it acts as a sedative is a dangerous and unhealthy proposition.
Tonix Pharmaceuticals have recently announced that they have a promising new drug under development for treating fibromyalgia and the sleep problems that come with this condition. Please could you tell us a little bit about this drug and what are its benefits over traditional sleep drugs?
We’re working on a new type of sleep quality medicine that is a sublingual tablet, which patients will take at bedtime under their tongue. It is designed to improve the quality of sleep. We are focusing on two indications: fibromyalgia and PTSD.
Our lead indication is for patients with fibromyalgia. Fibromyalgia is a pain syndrome that affects mostly women. Approximately, 90% of fibromyalgia patients are women and only approximately 10% are men. Our second indication is for people with PTSD. PTSD affects a significant number of the soldiers returning from deployments in Afghanistan and before that, from Iraq.
In the United States, fibromyalgia affects approximately 5 million people. It is a chronic pain syndrome that is characterized by chronic widespread pain and it can frequently take over the life of the patient. The patient may have:
- trouble working
- trouble with normal daily activities
- trouble maintaining social relationships
This is because the pain caused by fibromyalgia becomes so pervasive.
We have evidence from our Phase IIa study, which is a study on 36 patients with fibromyalgia, that bedtime treatment with a primitive version of our product resulted in improved sleep quality and decreased pain from fibromyalgia.
We’re excited to move forward with the development of our product and we will be starting a Phase III efficacy study in the first quarter of 2013.
Our PTSD program is not as advanced as our fibromyalgia program, so we anticipate that we will start enrolling into a proof-of-concept study early in 2013. In PTSD, we are testing a similar hypothesis to FM. People with PTSD have difficulty sleeping and many of them experience chronic widespread pain. We believe that by improving the quality of sleep they will experience less pain.
Please could you tell us how this drug has been developed?
The discovery of the effects of our drug all began with Dr Iredell Iglehart, who is a rheumatologist in Baltimore in private practice. Dr Iglehart started experimenting with patients in his practice, using low doses of a prescription drug that is already available called Flexeril®, which is the Merck brand name for cyclobenzaprine.
Dr Iglehart realized that low doses of cyclobenzaprine, given 2-3 hours before bedtime, resulted in an improvement in patients with fibromyalgia. Patients noticed the benefit initially after several days of dosing but the benefit could be sustained for long periods of time.
Dr. Iglehart’s results and his treatment paradigm were radically different from what people had seen before. Some other clinical scientists had experimented on fibromyalgia patients with cyclobenzaprine, but they used larger doses of cyclobenzaprine and they dosed it during the day. We suspect that the higher doses and the daytime dosing are why the effects that were seen by other investigators were fairly short-term and were lost with chronic treatment. In contrast Dr Iglehart, used lower doses, 2-3 hours before bedtime, and his patients got benefits that seemed more frequent and had more durable clinical responses.
After Dr Iglehart’s discovery, we applied medical and pharmaceutical science to the program to make an improved product, because it is very difficult for any patient to be disciplined enough to take a medicine 2 or 3 hours before they are planning to go to sleep.
We recognized that if we could have a fast-acting product, it would be a significant advantage for patients. Also, we hoped to design a product with faster clearance of the drug from the bloodstream, so the patient would not be hung-over the next morning – which is a side-effect of using the currently available cyclobenzaprine products off-label at bedtime.
We started with Dr Iglehart’s discovery but we have taken it a long way through pharmaceutical development. We are now at the point where we have an elegant sublingual tablet that has characteristics that are not available by taking the currently available cyclobenzaprine products.
At what stage of drug development are you currently at?
The short answer is that we are phase III ready. We are on track to begin the first of two phase III studies in the first quarter of 2013.
The first phase III study will involve 76 subjects in each of two groups. 38 patients will get our new medicine, which is called TNX-102 SL (where SL stands for sublingual). 38 patients will get a placebo. It will be a double-blind, randomized, placebo controlled study and we should have the patients enrolled, studied and finished with the protocol, and the data analyzed, before the end of 2013.
When do you think that the drug will be available for patients?
Our current plan projects that we will have the FDA approved product in the first quarter of 2017. It’s a conservative plan and we hope to beat our own projected timelines by perhaps a quarter. However, getting a prescription drug approved in the US is not a simple process and we are going to apply the most rigorous scientific testing to meet the hurdles set by the FDA and to address the natural skepticism of the doctors and patients. We believe that scientific evidence is the best way to advance the field and to convince doctors and patients to try our product and to adopt our product if they find it beneficial.
Is this drug only for patients with fibromyalgia, or will it be available for patients with other conditions that cause sleeping difficulties?
Our first product will be exclusively tested in fibromyalgia patients. But we believe that the technology behind the product can be used to create other products that would be tested separately in different conditions. These include distinct prescription products for PTSD, and possibly some other related conditions such as traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE) and also alcoholism.
Each one of those products would have a completely distinct development path associated with it. Also, each of these products would probably have a different dose that would be selected by a dose ranging study, which would help us find the dose that is most effective for each of those conditions. In some cases it might be a higher dose and other cases it might be lower than the dose we have selected for fibromyalgia based on our Phase IIa study.
In addition, when we get to the point where we understand more about these conditions and learn whether our technology results in a treatment effect, we may have to make other modifications to the products so we can tailor them precisely to the condition we are treating.
What are Tonix Pharmaceutical’s plans for the future?
We believe that we are the leading company in addressing sleep quality and improving restorative sleep. We also believe we are the leading company making the connection between sleep quality and chronic pain.
So, in addition to the challenge of developing drugs for marketing approval in the United States and other countries, we also have an ambitious program to unravel the causes and mechanisms of disturbed sleep and to learn how it relates to chronic pain. We want to be the leader in unravelling these connections and advancing the science of disturbed sleep and chronic pain.
We believe that developing effective drugs is an extremely important part of advancing medical science. We are primarily a patient-focused company, and all the people in the company are motivated by a shared passion to help patients with chronic pain and disturbed sleep. We also know that this is not easy problem to solve. One of the first things we need to show is that we have an effective treatment. By an effective treatment, I mean a drug that will be FDA approved for fibromyalgia and win substantial use by satisfied patients and by doctors who rely on evidence-based medicine. If we have an effective treatment, we hope to be able to take that advance and tinker with it, improve on it, and use it as a springboard to make better medicines in the future.
One of the challenges of working on the medical conditions that originate in the brain and particularly conditions that are unique to human brains is that we cannot rely exclusively on any particular animal model or group of animal models. We don’t know of any animal models that are relevant for all of the complexity of the conditions that we are trying to treat. I don’t mean to disparage the potential impact of the large, talented and productive group of people who are working on animal models. I just mean to express humility at the daunting challenge of unravelling problems that are uniquely human. It is important to note that there are intriguing animal models for one or another aspect of fibromyalgia. Similarly, there are animal models for one or another aspect of PTSD. However, in terms of finding out how the human brain winds up with experiencing the symptoms of chronic pain and disturbed sleep, in my opinion, there is no substitute to human investigation.
This is why we are focused on human investigation and why we believe we have the expertise, and, with our new products, the tools to start unravelling these complex problems.
How do you think the future of sleep disorder treatments will develop?
We think that the most important advance on the horizon, and one that we are part of, is to move the area of treating sleep problems beyond insomnia. I think that too much emphasis has been put on the prescription insomnia drugs and their ability to increase the time that people are asleep. I believe we need to move past insomnia and understand the processes of sleep. We need to understand what active processes during sleep process good memories and edit out bad memories. We need to understand what processes in sleep restore the ability of the body to reset its pain sensory process.
I think that with time we should be able to develop more and more specific drugs to help people get a good night’s sleep that has the full restorative function people need and deserve. Sleep in a healthy person should occupy about 1/3 of their life. If we can give back to people that 1/3 of their life and make it a healthy, beneficial experience, I think that we can make a significant impact on the health and well-being of large populations.
Would you like to make any further comments?
Many people have made a distinction between life-saving and lifestyle drugs. That may be a useful distinction in other conditions, but we feel that what we are doing is as important as making life-saving drugs.
I started my career trying to develop treatments and vaccines for AIDS. I also spent several years working in oncology. I founded a company, that was later sold, whose drug for colon cancer was approved last year. So, I have spent most of my career working on life-saving medicines. But I have seen the suffering and disability of fibromyalgia patients. I have been able to appreciate that fibromyalgia has stolen their lives from them. I believe that what we’re doing at TONIX, in trying to give fibromyalgia patients and PTSD patients back their lives, is arguably just as important as saving a life.
We are really committed to advancing the area and making better medicines.
Where can readers find more information?
For more information on Tonix Pharmaceuticals please visit: http://www.tonixpharma.com/
About Dr. Seth Lederman
Seth Lederman is a physician, scientist, and a founder and builder of specialty pharmaceuticals companies. Prior to founding TONIX, from 2007-2008 Dr. Lederman co-founded and was a managing partner of Konanda Pharma Partners, LLC and Konanda Pharma Fund I, LP.
He co-founded and served as director and chairman of its wholly-owned operating companies Validus and Fontus Pharmaceuticals Inc., which market Equetro® (carbamazepine – Extended Release), Marplan® (isocarboxazid) and Rocaltrol® (calcitriol).
In 2000 Dr. 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.
In 1998 Dr. Lederman co-founded Vela Pharmaceuticals, which developed several drugs for central nervous system disorders, including VLD-cyclobenzaprine.
A member of the faculty of Columbia University’s College of Physicians and Surgeons since 1985, Dr. Lederman maintains an appointment as Associate Professor. At Columbia, he was an NIH Physician-Scientist from 1985-1990. Dr. Lederman became an Associate Professor with tenure in 1996 and Director of the Laboratory of Molecular Immunology in 1997.
From 1988 to 2002, he directed basic science research at Columbia in molecular immunology, infectious diseases and the development of therapeutics for autoimmune diseases. Dr. Lederman has authored numerous scientific articles, and has been issued several patents for drug development technologies.
Dr. Lederman’s fundamental research on the CD40-Ligand (CD154) elucidated the molecular basis of T cell helper function and led to the development of therapeutic candidates for autoimmune diseases and organ transplant rejection in collaboration with Biogen-IDEC and CellTech/UCB. The successful defense of his CD154 patents established important precedents defining the relationship between therapeutics and molecular targets.
In collaboration with Prof. David Baltimore (then at Rockefeller University and later MIT), Dr. Lederman identified and functionally characterized the CD40 signaling molecule, TRAF-3. Dr. Lederman’s earlier research efforts in HIV contributed to understanding how the V3 loop of HIV gp120 affected fusion with CD4 cell membranes, an early and essential event in viral entry and infection.
Dr. Lederman earned an AB from Princeton in Chemistry cum laude in 1979 and an MD from Columbia University’s College of Physicians and Surgeons in 1983. He trained in internal medicine and rheumatology at Columbia’s Presbyterian Hospital, serving as an attending physician in its Edward Daniels Arthritis and Autoimmunity Clinic from 1988-1996.