Developing drug treatments for traumatic brain injury (TBI) has been notoriously difficult. While most of the severe neural damage that accompanies acute TBI results from the initial impact, considerable additional damage occurs over the following hours and days by biochemical cascades triggering inflammation, cell death and disruption of neural pathways. It would be ideal to have a treatment that prevents this degeneration, but decades of clinical research have so far been unsuccessful. In addition, there are non-acute symptoms such as prolonged disorders of consciousness, long-term cognitive and physical impairments, for which treatments have not been developed.
The ability to treat patients with disorders of consciousness is assumed to be dependent on neuro-rehabilitation and the process of neural plasticity, wherein brain function improves by altering neural networks or neuronal cell activity. Typically, the faster the patient emerges from a decreased consciousness state, the better the chances for recovery of functionality. Traditionally, the scientific and medical community has been skeptical about the possibility of restoring lost neural connections to damaged nerve cells. However, with a better understanding of the mechanisms ruling neural plasticity, it has been possible to begin addressing post-acute and chronic TBI rehabilitation from a drug therapy perspective.
The aim of this article is to outline the drug development process, highlight some specific hurdles for developing drugs for treating TBI patients and provide an example of a drug treatment in development, all in order to spur thinking by IBIA members about drug development for TBI patients.
General therapeutic drug development process
The development of all therapeutic drug products is subject to extensive regulations by national health authorities. In the U.S., the Food and Drug Administration (FDA) whose primary interest is to assure the safety and efficacy of new products for the public, regulates pharmaceutical and biological therapeutic drugs, whether totally novel or generic. The pre-clinical, manufacturing, and clinical testing of a drug candidate in a manner compliant with FDA and comparable national health regulations represents a great challenge to drug development. The drug approval process required by the FDA is similar to the processes required by most other major regulatory agencies and international harmonization guidelines exist (ICH: see www.ich.org).
Drug development usually begins with extensive laboratory and pre-clinical research focused on a biological drug target. This can either be a specific protein or binding sites on a specific protein. Some of these mechanisms may have been validated through already approved products; others may have been validated through various levels of biological proof. In small molecule drug discovery, libraries of chemical compounds are screened against this target to identify a new chemical entity (NCE). Despite improvements in identification of target proteins, crystallization models do not exist for many targets and despite major advances in computational chemistry, often many rounds of medicinal chemistry synthesis are required to optimize the pharmacological properties of a drug candidate, including route of administration and method of delivery. The drug candidate is then extensively tested in vitro and in vivo for desirable drug qualities, and studied in animal models of the human disease or condition.
Once there is reasonable evidence to believe that the drug might be effective, considerable preclinical work is conducted to ascertain its safety, especially around the projected therapeutic dose to establish a projected safety margin. Drugs for non-life threatening situations generally require a larger margin of safety than treatments for immediately life-threatening situations. Since all drugs have side effects at some doses, it is important to identify the potential side effects and the dose limiting toxicity in animals, so the premonitory signs in humans are known ahead of first clinical exposure.
In order to conduct trials in humans, it is necessary to submit an Investigational New Drug (IND) to the FDA. The IND requires evidence that the potential new treatment has a reasonable chance of working and that at the anticipated exposure levels the benefit/risk ratio is sufficient to justify testing it in people. An IND contains a summary of all known research data to date by the investigator or others; in vitro and in vivo data to suggest safety and efficacy in relevant systems designed to model human physiology and drug pharmacokinetic ADME (absorption, distribution, metabolism, excretion) properties; extensive details about the chemical characterization, manufacturing methods; and stability of the entity and the design of the first human clinical study.
The clinical development path depends on the nature of the disease and its severity. In most cases, it goes through three phases. The initial Phase I study employs limited drug exposure that is focused on safety and tolerability in small numbers of normal, healthy, volunteers. (There are exceptions in which patients can be used in Phase I, but these are relatively rare.) Phase II studies are conducted in a subset of the target patient population and tend to be larger in sample size and often of longer duration than Phase I. As in Phase I, safety is a major concern, but the drug developer is looking for evidence that the drug will in fact be useful in these patients and also is trying to find the minimally effective dose. Phase III studies are large studies in the target population using the treatment regimens that will ultimately be used if the drug is approved (the criteria used will determine the official FDA drug label) and are described as “pivotal”. They have to demonstrate clinically statistically significant effects on pre-specified outcome measures, usually in comparison to a placebo treatment group.
As the development of a drug progresses through the various phases of clinical development, there are ever more stringent requirements of chemical and manufacturing information and preclinical safety data, including animal toxicology necessary before the next level of trials can start.
If these studies are successful, the drug developer submits all the data as a New Drug Application (NDA) to the FDA for approval to register and market the drug in the U.S. The FDA may request additional studies, audit manufacturing facilities, or stop a study at any point along the way. Even after approval, the FDA may require the sponsor to perform additional post-marketing studies (Phase IV). See www.fda.gov/drugs for useful resources and more details about the US approval process.
Drug development for TBI and some hurdles
For a discussion of drug development for patients with a TBI, it is important to underscore the differences in the pathobiology, medical needs and treatment of acute from post-acute/chronic TBI.
There are a number of processes that occur at the time of a TBI and during a period of hours to days thereafter often causing irreversible brain damage. Therefore to treat the sequelae of an acute TBI injury, it is essential to intervene early to minimize or prevent further damage. Numerous pathological processes have been targeted, with an emphasis in drug development on secondary mechanisms of brain injury including antioxidants, free radical scavengers, ion channel blockers, NMDA antagonists, GABA agonists and other neuro-protectants to protect neurons from the sequelae of ischemia and hypoxia immediately post injury.
Unfortunately despite considerable efforts to develop treatments for acute TBI (nearly 50 compounds have been tested in patients) none of the compounds advanced to phase III clinical trials have demonstrated evidence of efficacy.
There are also many differences between developing therapies for acute TBI and post-acute/chronic neuro-rehabilitation treatments. In the acute situation, the location of damage within the brain and the mechanisms of injury are very diverse, and there are ongoing biological challenges to many organ systems other than the brain. In contrast, in the chronic situation one can wait until the general health of the patient has stabilized and the major focus is on recovery of consciousness neuro-rehabilitation. This dramatically eases the implementation of the clinical trial as well as removing concerns about drug/drug interactions.
There are no approved pharmaceutical therapies for either acute or post-acute TBI, so this is an area of considerable medical need. Some of the current challenging in drug development for TBI include:
- Biology/Targets: The brain is the least molecularly defined and understood organ of the body. The known neurotransmitters and receptors probably represent only the needle in the haystack of “drugable” targets. Better validated targets are needed.
- Animal models
While there are limitations of any animal model to fully replicate the spectrum of a human disease or condition, the animal models of TBI cannot possibly capture the diversity of the human physical injury after TBI. Given the uniquely human nature of consciousness, it is hardly surprising that there are no animal models in which to study the human VS and MCS state.
- Drug delivery
Beyond the normal biophysical properties that drugs must have to be active in humans, any drug targeting the CNS needs to cross the blood-brain barrier. Toxic side effects can often be ameliorated by strategies using new formulations, routes of administration or site specific drug delivery. For TBI drugs, these strategies are less available given the isolated nature of the skull encased brain.
- Resources and risks
Drug development is expensive, lengthy and fraught with safety and efficacy challenges. Means to attenuate these risks are eagerly sought. One successful approach to overcoming these hurdles to developing needed drugs is re-positioning, or seeking “new uses for old drugs.” In this approach, one uses scientific insight into a medical need to identify a compound that has already been through clinical testing for another indication. Often such drugs can also be reformulated to further improve efficacy, reduced side effects or to address patient/doctor compliance issues. By discovering a new use of such a known compound, R&D timelines can be drastically reduced.
- Lack of pharmaceutical industry attention to TBI
The number of patients with a moderate to severe TBI in the US is staggering. Given this market opportunity, one would expect much discovery research and drug development in this area by pharmaceutical companies. But drug development for acute TBI and stroke has suffered so many clinical failures that it will likely take significant new insights to motivate further industry investment in this area.
However, the post acute/chronic neurorehabilitation market should be of interest to the pharma industry. The neuroscience drug discovery groups in large pharma are currently focused on a limited number of CNS indications including Alzheimer’s, multiple sclerosis, schizophrenia and pain. How can interest in developing drugs for TBI be bolstered? a) pharma is often driven by the current research interests and findings in academia and clinical settings, b) new understandings into the clinical pathobiology in severe TBI, c) predictive animal models and d) the success of an approved treatment.
NeuroHealing is a private company developing a drug treatment to help patients regain consciousness, accelerate recovery and improve the functional outcome of patients who remain in a vegetative (VS) or minimally conscious state (MCS) after a TBI. The premise is that a biologically active drug can augment or catalyze the natural healing process.
The scientific rationale of the approach is based on dopaminergic (DA) stimulation and isolated reports of weak DA agents (l-dopa, amantadine, bromocriptine) helping patients emerge from a VS or MCS. In patients remaining in a VS or MCS after a TBI, areas of the brain remain viable, but the connections between distant areas in the brain areas are impaired due to the diffuse axonal injury. Stimulating the dopaminergic pathways is expected to promote integration between distant functional regions of the brain resulting in the regaining of consciousness and allowing patients to initiate active rehabilitation and thus improve functional outcome.
Thus a first task in developing an effective drug was to find a stronger dopamine stimulant that could be safety administered to patients with a TBI. The approach could have been either an extensive R&D program to screen for a NCE with strong DA activity or to identify and reposition an existing compound. A strong dopaminergic agent that has been used safely for many years to treat patients with Parkinson disease (PD) was identified: apomorphine is a broad dopamine agonist active at both D1 and D2 class of dopamine receptors. It is used as a “drug of last resort” for the treatment of hypomobility in advanced PD as a rescue treatment once other less potent DA drugs lose efficacy. A practical limitation of apomorphine is that it is not orally bioavailable and must be administered by injection. While a disadvantage for ambulatory PD patients, this route has pharmacological advantages for treating unconscious patients. Apomorphine is a small molecule drug, rapidly absorbed after sc injection, quickly crosses the blood brain barrier due to its high solubility in lipids and reaches brain concentrations six times higher than in plasma. These are all excellent drug properties.
NeuroHealing compiled the safety data on sc apomorphine, designed a clinical trial to test this treatment and arranged for a pre-IND meeting with the FDA Division of Neurology Drug Products to discuss the adequacy of the safety data and the design of a clinical trial protocol. While a pre-IND meeting is not required, this drug had previously been designated an Orphan Drug product, was submitted under IND subpart E of the regulations (which because of the population being treated, requires the FDA to participate in discussions with the developer) and, at the time, the drug was available for use for another indication outside the US. An IND was submitted and accepted by the FDA for a Phase II double-blind placebo-controlled multicenter trial to study the safety and efficacy of NH001 (reformulated continuous infusion sc apomorphine) in accelerating recovery and improving the functional outcome of patients post TBI in a vegetative state and minimally conscious state. Improvements in functional outcome, measured by the CRS-R and DRS, well established clinical outcome and disability scales are the primary outcome measures for the trial.
The study’s principal investigator (PI) and first clinical site is Dr. Ross Zafonte, Chair of the Dept of Physical Medicine & Rehabilitation at Harvard and VP of Medical Affairs for Spaulding Rehabilitation Hospital.
To gather preliminary clinical data, a small open-label clinical trial was conducted in parallel at two sites, at the Fleni Hospital in Buenos Aires, Argentina and at the Lowenstein Hospital Rehabilitation Center in Israel. Similar to US regulations, submission of the protocol and safety information was submitted to the respective national regulatory agencies for approval and to the local hospital Helsinki (IRB) Committees. A case report of the first patient treated was recently reported (Fridman, EA et al., “Fast awakening from minimally conscious state with apomorphine,” Brain Injury 23(2):172-7, 2009).
Most clinical trials for TBI have been driven by pharmaceutical and biotech companies using the above drug testing approach of demonstrating preclinical safety, animal model testing, phase I safety testing and then studies in a double-blinded fashion against a placebo control. There is an active role for physicians, researchers and the pharmaceutical industry to bolster efforts to help develop much needed and effective drug therapies for treating patients with traumatic brain injuries. A few successes will create the tipping point.