Major depressive Disorder (MDD) is characterized by a chronic depressed mood, markedly diminished interest in normally pleasurable activities, unintentional weight changes, insomnia, fatigue, and feelings of worthlessness. The first widely used pharmacological treatment for depression was imipramine, which was discovered by accident during a research program seeking novel sedatives for treating patients with psychosis. Over the next decade a plethora of analogs of imipramine, tricylic antidepressants (TCAs), were synthesized and tested. Although some of these demonstrated a modest reduction in side effects such as sedation and anticholinergic effects, no significant improvement in the modest efficacy of imipramine was achieved (Goodman and Gilman, The Pharmacological Basis of Therapeutics, 10th ed.).
The availability of more sophisticated pharmacological methods in the 1970s led to multiple theories of how the TCAs exert their activity, in turn leading to a dizzying sequence of novel agents categorized as selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (NRIs), and selective serotonin and norepinephrine reuptake inhibitors (SRNIs). These oral medications work by increasing the levels of monoamines available for post-synaptic receptors. Examples of classes of agents working under this mechanism include TCAs like Tofranil and Elavil, SSRIs like Prozac, Celexa, Lexapro, Luvox, Paxil, and Zoloft, and SNRIs like Effexor, Pristiq, Cymbalta, and Savella.
Prozac (fluoxetine), perhaps the most widely used of these agents, was first discovered by scientists at Eli Lilly (LLY) in 1974 and approved by the U.S. FDA in 1987. Prozac sales peaked at $2.8 billion in 1998 prior to the patent expiration in 2001. Despite being off patient for over a decade, physicians are still prescribing over 25 million prescriptions per year for fluoxetine. Perhaps this is because peer-reviewed literature suggests that fluoxetine is no worse than its SSRI successors or the next-generation SNRI molecules that large pharmaceutical companies continue to actively promote today (1, 2). In fact, the drug offers only modestly superior results to imipramine (3).
In spite of substantial effort and billions of dollars in R&D, the pharmaceutical therapy as a treatment for depression has improved only marginally over the last 50 years. Pharmaceutical companies have largely exhausted the theory that neurotransmitter imbalances will lead to a dramatic improvement in the standard of care. Thus, treatment failure rates remain high. We suspect this is because patient response to antidepressants is often greater in randomized controlled trials than in real-world settings (4). It could also be because antidepressants offer only modest benefits over placebo for patients with mild-to-moderate disease. In fact, a U.S. FDA meta-analysis published in February 2008 found that, "The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication" (5). The graph below is from the FDA meta-analysis and shows mean standardized improvement as a function of initial disease severity:
A patient level meta-analysis published in JAMA in 2010 agrees with the FDA's own meta-analysis. The authors of this study noted, "The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial." (6)
Or perhaps failure rates with SSRI / SNRI antidepressants are so high because these molecules carry significant side effects and subject patients to potentially nasty adverse events. Reading the Prozac label alone induces depression! It includes known increased risks of nausea, insomnia, somnolence, anorexia, anxiety, nervousness, asthenia, and tremor. SSRI drugs may also confer sexual side effects, including decreased libido, anorgasmia, erectile dysfunction, and anhedonia. Finally, all SSRI and SNRI molecules carry a U.S. FDA "Black Box" for risk of suicidality.
The Neurogenesis Theory of Depression
In the search for new treatment paradigms, many researchers have been attracted to data suggesting that depression and many other CNS disorders represent a failure of neurogenesis, and that this failure must be addressed directly in efforts to discover better therapeutics. Although speculative, the neurogenesis theory of depression potentially offers the possibility to provide breakthrough therapies in a disorder thought to affect as much as 5% of the U.S. population.
For many years a central dogma of neurobiology was that new neurons do not develop in the adult brain. Based in part on studies that use labeled DNA precursors to stain dividing cells, it is now well-established that the proliferation and differentiation of neuronal precursor cells (NPCs) into neurons is maintained throughout adulthood in the dentate gyrus of the hippocampus (7). The hippocampus, which plays a key role in memory, cognitive function, and mood regulation, is particularly vulnerable to chronic stress; multiple studies have demonstrated that major depression is accompanied by hippocampal atrophy, and that the extent of atrophy is related to the duration of depressive episodes.
For example, the concept of hippocampal atrophy and recurrent major depression has been gaining steam since first introduced two decades ago (8, 9). Assaults on neurons in the human hippocampus are suspected to be linked to many devastating diseases of the mind and brain, such as Alzheimer's disease (AD) and major depressive disorder . Scientists are now starting to believe that the onset of neurogenesis may be a major contributor to normalizing or ameliorating a disease state once established (10). Thus, drugs that stimulate the generation of new neurons - an aspect of the healthy brain that seems to be negatively impacted by many neurodegenerative conditions such as AD and MDD - could address these conditions at their root cause.
Neurogenesis takes place in three stages: proliferation of endogenous stem cells, differentiation into neurons, and neuron maturation/synapse formation (plasticity). While any of these stages could in principle be a point of intervention, evidence has accumulated that various classes of approved antidepressants may impact these stages differently, with imipramine primarily enhancing plasticity, and fluoxetine affecting proliferation. Thus compounds acting on different stages of the neurogenesis process could provide diverse therapeutic effects and perhaps act synergistically.
A major impediment to identifying neurogenesis-promoting drugs and testing their efficacy in the clinic has been the absence of suitable platforms for in vivo testing
Neuralstem's Novel Platform
Most investors know Neuralstem, Inc. (CUR) as a leader in cell therapy and regenerative medicine. The company's human spinal cord stem cells (HSSCs) product, NSI-566, has demonstrated impressive safety and proof-of-concept data in patients with Amyotrophic lateral sclerosis (ALS), and is the company's leading pipeline candidate. Results from the company's Phase I study with NSI-566 in ALS have been both presented and published, as well as covered extensively by the media. We first wrote on the topic in June 2012, calling the company's pioneering efforts a potential breakthrough for the treatment of ALS.
Recently, we examined the potential for NSI-566 in the treatment of patients with spinal cord injury (SCI). The preclinical data here is very encouraging and the U.S. FDA gave clearance to move forward into human testing for this indication earlier in the year. But what is far less known about Neuralstem is how the company's efforts to create stable neural stem cell lines has led to innovative new novel small molecule candidates for the treatment of central nervous system (CNS) disorders potentially arising from problems in the hippocampus.
When Neuralstem was founded in 1996, the company's goal was to develop human neural cell lines to treat neurological disorders like ALS or SCI. This work led to the creation of a large library of mature human hippocampal cell lines. Company scientists then connected the dots, realizing that these cell lines could also be used as a screening tool for discovering chemical compounds with neuroprotective properties. They represent, in essence, disease models in a dish.
In 2000, the U.S. Department of Defense Advanced Research Projects Agency (DARPA) awarded Neuralstem a contract to use these cells lines to screen for orally available small molecules with activity in the hippocampus. The objective was to identify compounds that could trigger hippocampal neurogenesis to counteract the stress-induced hippocampal atrophy that is believed to cause impaired cognition and memory in soldiers (11). Although a major terrorist attack and two wars dried up funding from the Department of Defense, the initial grant was enough to generate encouraging data and expand upon the a newly hypothesized link between impaired growth of hippocampal neural stem cells and neuropsychiatric diseases.
Prior to the creation of Neuralstem's hippocampal cell lines, there was a lack of effective, predictive in vitro assays to find and select compounds with neurogenic activity for clinical drug development. Neuralstem's work in this area led to the filing of several patent applications, including USPTO#8,293,488, "Methods For Screening Neurogenic Agents," granted October 2012. In total, there are four groundbreaking patents that have come out of this work. Another patent, USPTO#7,560,553, "Use of Fused Nicotinamides To Promote Neurogenesis," granted in July 2009, gives insight into the screening process.
Identification and Preclinical Development of NSI-189
Preclinical research on NSI-189 shows the molecule was among the best screened by company scientists for promoting neurogenesis in preclinical animal (mice) studies. An abstract entitled, "Histological Assessment of Mouse Brains After 28-Day Chronic Oral Administration of Four Novel Neurogenic Compounds" was presented at the 2012 Annual Meeting for the Society of Neuroscience (SFN).
According to the abstract, the goal of the study was to examine hippocampal neurogenesis and behavioral depression indices in response to chronic oral treatment with 1 of 4 novel neurogenic compounds. NSI-144, -150, -158 or -189 was administered for 28 days by oral gavage, and compared with groups that received vehicle, water, or imipramine. The tail suspension, forced swim and novelty suppressed feeding tests were performed to determine behavioral changes. At the end of the study, all animals were injected with 5-bromo-2-deoxyuridine (BrdU), perfusion-fixed, and brains prepared for standard histology. BrdU positive cells were counted in the sub-granular zone (SGZ) of the Dentate Gyrus (DG), and volume of the hippocampal subfields (DG, CA1, CA2, and CA3) were measured. Quantitative results showed that while all NSI compounds induced neurogenesis, as based on BrdU counting in the DG, only NSI-158 and NSI-189 also showed a concomitant increase in the CA3 subfield. Additionally, NSI-158 treatment did not reveal changes in behavioral experiments, as compared to NSI-189 that did show improvements in the novelty-suppressed feeding test. Given these data, NSI-189 was selected for further studies where neurogenesis may be a possible mechanism of treatment.
Clinical Development
Based on encouraging preclinical data with NSI-189, Neuralstem filed an investigation new drug (IND) application with the U.S. FDA in November 2010. The FDA approved the application in December 2010, allowing the commencement of a Phase Ia study. The Phase Ia study (NCT01310881) began in February 2011 and completed in October 2011. Because the Phase Ia study tested only healthy volunteers, the only data that was released noted all doses to be well-tolerated with no drug-related serious adverse events. We note that this was a relatively large study (n=52) for a Phase Ia, but management at Neuralstem wanted to generate enough safety data so that all future indications beyond MDD can proceed directly into Phase II. It may have cost a little more upfront, but in the long run we think this was very prudent, as it will save time and accelerate partnership milestones in the future.
In December 2011, the FDA allowed Neuralstem to advance into a Phase Ib trial (NCT01520649). The trial is a randomized, double-blind, placebo-controlled, multiple-dose escalating trial evaluating the safety, tolerability, pharmacokinetics and pharmacodynamic effect of three escalating doses of NSI-189 over 28 days per dose in the treatment of MDD. The trial initiated in December 2011. The three NSI-189 dosing cohorts are: 40mg QD (once-daily), 40mg BID (twice-daily), and 40mg TID (three-times-daily). Patients will receive an MRI at baseline, during the trial, at completion of the trial (28 days), and 1 month post-trial. Neuralstem will be looking for signs of stabilization or growth in the hippocampus.
Dosing in the second cohort commenced in October 2012. Dosing in the third cohort commenced in April 2013. We are expecting the trial to complete by the start of the fourth quarter 2013. We note the efficacy endpoints are all blinded until the conclusion of the trial, but management has noted the safety and tolerability of the compound, through the increased dosage in the first two cohorts, remains excellent. We find it highly encouraging that management has been able to proceed so smoothly between the dosing cohorts with no hold up from the FDA's data safety monitoring board.
If successful, we think the outcome of this Phase Ib study will be highly intriguing to larger pharmaceutical partners that have previously funneled billions of dollars in research and development of drugs to treat depression and mood disorders. It's been decades since we have seen a true new mechanism of action to treat depression. New novel CNS candidates to treat tricky diseases like depression and schizophrenia are highly coveted assets in the pharmaceutical industry. Take for example the massive revaluation in shares of Acadia Pharmaceuticals (ACAD) based on the success of its novel Phase III candidate for psychosis, pimavanserin. Acadia's market value has soared from $73 million in June 2012 to $1.65 billion today.
Based on the mechanism of action, besides MDD, we believe that NSI-189 has significant potential to treat other CNS diseases and conditions where hippocampal atrophy may be the underlying cause of the disease. These include:
- Alzheimer's disease - currently in preclinical studies
- Anxiety - currently in preclinical studies
- Bipolar disorder - currently in preclinical studies
- Schizophrenia - currently in preclinical studies
- Post-Traumatic Stress Disorder - currently in preclinical studies
- Chronic Traumatic Encephalopathy - currently in preclinical studies
Following results of the Phase Ib study, if successful, we expect partnership talks to heat up between Neuralstem and a potential larger pharmaceutical company for future development and commercialization of NSI-189. We believe that management will be looking for a partner that can both fund NSI-189 through registration trials in multiple indications and bring the drug to commercialization. The market opportunity for MDD is large, estimated at over $5 billion in 2012. Most patients are under-treated, and bounce between both branded and generic SSRI and SNRI molecules. A novel compound with a new mechanism of action could gain significant market share in the right hands. Plus, we fully expect partnering discussions to include upside to the above listed CNS diseases.
Conclusion
Neuralstem's advances in human hippocampal neural stem cells have spring-boarded the company into the development of small molecule drugs for the treatment of various central nervous system disorders. The hippocampus is the part of the brain involved in memory and the generation of new neurons. The company's creation of stable neural stem cell lines from the human hippocampus, the world's only such cell lines, allows for the screening of vast libraries of chemical compounds that protect hippocampal neurons against various toxins. The disease modeling platform offers the ability to test small molecules on living human neurons in vitro, enhancing early-stage drug discovery.
One of these newly found candidates, NSI-189, has progressed into Phase Ib testing with data expected in the fourth quarter 2013. There has been a real lack of breakthrough innovation to treat depression for the past several decades. If NSI-189 works as Neuralstem scientists believed, then this potential new mechanism for treating major depressive disorder, or other CNS indications, is a potential game-changer.
Management has noted being in partnership discussions with interested parties on NSI-189, with a goal of closing a deal after the data have been released. We expect that upfront payment from such a deal, along with milestones on the development of NSI-189 will help fund the next wave of clinical studies with HSSC therapy NSI-566 ALS or SCI. This is a unique opportunity that many of Neuralstem's competitors are lacking - the ability to self-fund a potentially revolutionary breakthrough in stem cell technology through the advancement of a traditional small molecule platform. In our eyes, that makes Neuralstem an intriguing long-term investment
MFG
Chali |
Thread abonnieren
