CUR: Neuralstem Analysis and Research Report
2018-05-07 - by Asif , Contributing Analyst - 195 views
Neuralstem is focused on the research and development of nervous system therapies based on its proprietary human neural stem cells and its small molecule compounds with the ultimate goal of gaining approval from the United States Food and Drug Administration or FDA, and its international counterparts, to market and commercialize such therapies. Neuralstem is headquartered in Germantown, Maryland.
The company's patented technology platform has three core components:
- Over 300 lines of human, regionally specific neural stem cells, some of which have the potential to be used to treat serious or life-threatening diseases through direct transplantation into the central nervous system;
- Proprietary screening capability – its ability to generate human neural stem cell lines provides a platform for chemical screening and discovery of novel compounds against nervous system disorders; and
- Small molecules that resulted from Neuralstem’s neurogenesis screening platform that may have the potential to treat wide variety of nervous system conditions
The company's technology platform to date has produced two lead assets in clinical development: its NSI-189 phosphate small molecule program and NSI-566 stem cell therapy program.
Neuralstem has developed and maintain what the company believe is a strong portfolio of patents and patent applications that form the proprietary base for its research and development efforts. The company own or exclusively license over 10 U.S. issued and pending patents and over 70 foreign issued and pending patents related to its stem cell technologies for use in treating disease and injury. The company own over 15 U.S. issued and pending patents and over 70 foreign issued and pending patents related to its small molecule compounds.
The company believe its technology, in combination with its expertise, and established collaborations with major research institutions, could facilitate the development and commercialization of products for use in the treatment of a wide array of nervous system disorders including neurodegenerative conditions and regenerative repair of acute and chronic disease.
Recent Clinical and Business Highlights
- On November 6, 2017, the company strengthened its clinical research team with the appointment of David Recker, MD, as Chief Medical Officer. Dr. Recker has more than 20 years of experience in drug development in multiple therapeutic areas including CNS and cell therapy and has been involved in numerous aspects of clinical strategy development, including product registration and marketing support, clinical trial development and execution, data interpretation, key opinion leader development and support.
- On September 18, 2017, the company strengthened its board of directors with the appointment of Cristina Csimma, Pharm.D, MHP. Dr. Csimma has considerable experience in the biopharmaceutical industry and in drug development. In addition, on December 18, 2017, Tianjin Pharmaceuticals Group International Holdings Co., LTD (the sole holder of the Series A Preferred Stock) appointed Xi Chen, PhD as their designated director per the terms of the Series A Preferred Stock. Dr. Chen has extensive healthcare management and research experience in both China and North America.
- On September 5, 2017 the company were awarded two additional patents by the United States Patent and Trademark Office (USPTO). These patents broadly protect methods for using neural stem cells to treat neurodegenerative disorders, a key component of the Company’s platform. The first new patent, U.S. Patent No. 9,744,194, covers methods of treating neurodegenerative disorders through transplantation of neural stem cells. The second new patent, U.S. Patent No. 9,750,769, covers neural stem cells engineered to express IGF-1, a neurotrophic molecule with broad therapeutic potential in the treatment of neurodegenerative disorders.
- On August 2, 2017, Neuralstem was awarded a Small Business Innovation Research (SBIR) grant by the National Institutes of Health (NIH) to evaluate in preclinical studies the potential of NSI-189, a novel small molecule compound, for the prevention and treatment of diabetic neuropathy. The award of approximately $1 million will be paid over a two-year period, if certain conditions are met.
- On August 1, 2017, the company closed a public offering of 3,000,000 shares of common stock and 2,250,000 common stock purchase warrants at a public purchase price of $2.00 per share and accompanying warrant. The company received gross proceeds of $6.0 million and approximately $5.4 million of net proceeds from this offering.
- In June 2017, Neuralstem (NASDAQ: CUR) was added to the Russell Microcap® Index as part of the FTSE’s annual reconstitution of its family of U.S. indexes. The Russell Microcap® Index measures the performance of the microcap segment of the U.S. equity market.
Neuralstem has devoted substantially all of its efforts and financial resources to the pre-clinical and clinical development of its small molecule compounds and its stem cell therapeutics. Below is a description of its most advanced clinical programs, their intended indication and current stage of development:
NSI-189 (Small Molecule Pharmaceutical Compound)
The company's lead asset, NSI-189, is a new chemical entity with what the company believe to be a novel mechanism of action.
The company believe that NSI-189 may provide an effective treatment for patients suffering from Major Depressive Disorder or MDD by promoting synaptogenesis or neurogenesis in the hippocampus. Results to date indicate that NSI-189 promotes neurogenesis in mice and exerts anti-depression effects in MDD patients. Data suggests that chronic exposure to stress hormones (glucocorticoids) inhibits release of neurotrophins, thereby inhibiting neurogenesis in the dentate gyrus, which results in hippocampal atrophy and depressive disease symptoms. NSI-189 stimulates neurogenesis of human hippocampus derived neural stem cells in vitro and stimulates neurogenesis in mouse hippocampus in vivo therefore the company believe NSI-189 may have anti-depressant and pro-cognitive properties. NSI-189’s neurogenesis effect is believed to have a highly specific effect in the hippocampus and subventricular zone, the two well-known neurogenic regions in adult CNS,
In a Phase 1B study in subjects with MDD, NSI-189 showed strong potential for efficacy on both depression and cognition scales. Additionally, data from the study indicated that the compound appears to impart a durable effect. While the molecular mechanism of action is not yet fully understood, its data suggest that NSI-189 works by a different mechanism of action than current antidepressants. Accordingly, the company believe that NSI-189 may have a positive therapeutic response as well as a favorable side-effect profile when compared to currently marketed products.
Major Depressive Disorder (MDD)
Major depressive disorder (also known as recurrent depressive disorder, clinical depression, major depression, unipolar depression, or unipolar disorder) is a mental disorder characterized by episodes of all-encompassing low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. MDD is the leading cause of disability in the U.S. for persons age 15 to 44. In 2015, an estimated 16.1 million adults aged 18 or older in the United States had at least one major depressive episode in the prior year. This number represented 6.7% of all U.S. adults. Treatment of MDD is characterized by a high level of patient turnover due to low efficacy and high side effects. It is estimated that 67% of patients will fail their first line therapy, 75% will then fail their second line prescription and 80% will then fail their third line prescription . These factors combine to create a significant opportunity for a differentiated therapeutic agent, particularly one that may act through a novel mechanism of action.
Clinical Experience with NSI-189
Neuralstem has completed an exploratory Phase 2 randomized, placebo-controlled, double-blind clinical trial for the treatment of MDD in an outpatient setting.
The study randomized 220 subjects into three cohorts: NSI-189 40 mg twice daily (BID), NSI-189 40 mg once daily (QD), or placebo. After the initial screening period, the dosing portion of the trial was 12 weeks in duration. There was a two week wash out period for those subjects enrolled who were taking an anti-depressant at the time of screening.
The study was 80% powered to show an improvement in the primary endpoint, compared to placebo, with an assumed effect size of Cohen’s d=0.5 (p ≤ 0.05). Subjects eligible for the study had to be diagnosed with major depressive disorder, recurrent, as per Diagnostic and Statistical Manual of Mental Disorders V, scoring 20 or greater on the MADRS, at screening and baseline and experiencing at least one eight-week MDD episode. The MADRS score was confirmed to be 20 or greater via remote SAFER interview by an independent rater prior to the baseline visit. After the 12-week trial period, eligible subjects were given the opportunity to enroll in a separate six-month observational study to assess the durability of effect defined as the time until the start of a new antidepressant treatment (ADT). Both the interventional and the observational studies were/are being conducted under the direction of study principal investigator (PI) Maurizio Fava, MD, Executive Vice Chair, Department of Psychiatry and Executive Director, Clinical Trials Network and Institute, Massachusetts General Hospital.
On July 25, 2017, the company announced top-line results from its exploratory Phase 2 clinical trial examining the efficacy of NSI-189 compared to placebo for the treatment of MDD. The study did not meet its primary efficacy endpoint of a statistically significant reduction in depression symptoms on the Montgomery-Asberg Depression Rating Scale (MADRS), compared to placebo. Both doses were well-tolerated with no serious adverse events reported.
On December 5, 2017, the company presented an updated analysis – including reports on all secondary scales – from the Phase 2 study of NSI-189 in MDD at the 56th American College of Neuropsychopharmacology (ACNP) Annual Meeting. Two additional patient reported outcomes showed statistically significant improvements in depressive and cognitive symptoms: Cognitive and Physical Functioning Questionnaire (CPFQ): 40 mg; p = 0.035 and Quick Inventory of Depressive Symptomatology Scale (QIDS-SR): 40 mg; p = 0.040 (Stage 2). Thus, with all three patient reported outcome scales (SDQ, CPFQ, and QIDS-SR) NSI-189 reached statistical significance over placebo.
In addition, the company presented data on NSI-189’s effect on cognition as measured by computer-administered objective tests of cognition in the MDD patients. Two different test methods were used: Cogstate® and CogScreen®. Cogstate did not yield statistically significant results. In CogScreen® test, NSI-189 40 mg showed statistically significant improvement (p<0.05) on objective measures of executive functioning, attention, working memory, and memory.
In safety, NSI-189 appeared to be safe and well tolerated with no serious adverse events. There were no clinically meaningful changes in body weight or BMI, or in sexual function inventory.
Phase 1 Pharmacokinetics and Safety in Healthy Subjects
In February of 2011 the company commenced a two-part Phase 1A clinical trial to evaluate the safety and pharmacokinetics of NSI-189 in healthy volunteers. The first part of the study enrolled thirty-one healthy male and female subjects into a single ascending dose phase. Subjects were administered a single dose (40mg, 60mg, or 80mg) of NSI-189 or placebo. In the second part of the study, 10 subjects received single doses of 40mg oral NSI-189 under fed and fasting conditions in an open label cross-over design. All subjects completed the study. There were no clear gender effects on NSI-189 pharmacokinetics. No dose-limiting toxicity was observed, and no serious adverse events (AE) were noted. All AEs were considered mild in intensity and none were considered to have a reasonable causal relationship to study drug. NSI-189 was found to be safe and well tolerated at the tested doses.
In December of 2011, the company received authorization from the FDA to commence a Phase 1B randomized, double-blind, placebo-controlled, multiple-dose escalation study to evaluate safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) effects of NSI-189 in subjects with MDD. The primary outcome measure was to assess drug safety by number and severity of adverse events in drug versus the placebo group. A safety protocol also included a comparison between NSI-189 and placebo of vital signs, standard physical examination, ECG, EEG, standard clinical laboratory tests (hematology and biochemistry), standard neurological exam and the Columbia Suicide Severity Rating Scale. Secondary measurements included pharmacokinetics, and exploratory assessments included clinical scales such as the MADRS, CGI-I, SDQ, and the MGH CPFQ.
Criteria for subjects to be eligible to participate in the study included: a MADRS score of 15 to 30, inclusive, at screening and baseline; and diagnosed with MDD, or recurrent MDD, per DSM-IV-TR criteria and reconfirmed by SCID-CT. Subjects must have had at least two prior depressive episodes and have been currently or had historically been treated with antidepressants. The first cohort received 40 mg QD, the second cohort 40 mg BID, and the third cohort 40 mg three times per day (TID). 24 subjects with MDD were studied, with their diagnosis and illness severity confirmed through an independent, remote SAFER interview from Massachusetts General Hospital Clinical Trial Network, Inc. (MGH CTNI) raters. Each cohort included at least 3 female subjects. Each subject underwent a screening for eligibility (Day -37 to Day -6 or -3) and eligible subjects were admitted into the unit on Day -5 to complete their wash-out before being confirmed for eligibility and for baseline assessments. Eligible subjects received daily dosing of investigational medicinal product (NSI-189 or placebo) for 28 days starting on Day 1 and were followed for safety, PK, and PD until discharge. Subjects returned to the unit for extensive follow-up on Day 56 (± 3) and Day 84 (± 3) (End-of-study).
Trial data was presented in June 2014 at the American Society of Clinical Psychopharmacology Annual Meeting (ASCP), and published in the journal Molecular Psychiatry (Fava et al., 2015). NSI-189 was well tolerated and there were no serious (grade 4 or 5) adverse events.
At the end of dosing, efficacy measurements showed statistically significant improvement over placebo on one subject-reported depression scale (SDQ) and one subject-reported cognition scale (CPFQ) and showed a medium to large size effect on all scales studied.
Efficacy measurements (MADRS, SDQ, CGI-I and, CPFQ), showed a promising reduction in depressive and cognitive symptoms across all measures with statistically significant improvement in the SDQ and CPFQ scales, and a medium to large effect size for all measures at the cessation of dosing (day 28). These improvements persisted to day 84, 8 weeks after cessation of drug administration. In particular, depression symptoms showed a significant decrease at day 28 as measured by SDQ (P=0.02), with large effect size (Cohen's d = 0.90), which persisted to day 84, 8 weeks after cessation of drug administration (P=0.03), also with large effect size (Cohen's d = 1.10). In addition, CPFQ also showed a significant decrease at day 28 (P= 0.01) with large effect size (Cohen's d = 0.94) and at day 84, (P<0.01, Cohen's d = 1.20).
In summary, NSI-189, a novel neurogenic compound, has shown promise as a potential treatment for MDD in this Phase 1B, double-blind, randomized, placebo-controlled, multiple-dose study. It is its belief that NSI-189 may have a significant benefit on depressive and cognitive symptoms in patients with MDD and other related disorders.
Pre-Clinical Experience with NSI-189
The company's preclinical research on NSI-189 is focused on elucidating its mechanism of action and investigating its potential utility as a broad neuroregenerative drug that can prevent or reverse various types of central and peripheral nervous system disorders. Additionally, data to date indicate that NSI-189 may have a significant cognitive benefit in diseases that affect memory and cognition. Preclinical data support the potential benefits of NSI-189 in indications beyond MDD.
Supportive data include the following results obtained in collaboration with academic partners:
NSI-189 and cognition:
- Treatment of normal mouse brain slices with NSI-189 produced a concentration and time dependent increase in the magnitude of long term potentiation (LTP) and short-term potentiation (STP), a measure of synaptic plasticity which is an in vitro biomarker of memory.
- NSI-189 treatment of brain slices from mice with a genetic defect that models Angelman Syndrome (a severe neurogenetic disorder – inherited, orphan condition – that shares symptoms and characteristics similar to those associated with other disorders including autism, cerebral palsy, Prader-Willi syndrome) restored LTP to normal levels.
- NSI-189 treatment preserved brain function and hippocampal proliferation at normal levels in a rat model of cognitive impairment induced by irradiation.
NSI-189 and neuroregeneration:
- NSI-189 was demonstrated to be effective in the prevention and reversal of peripheral neuropathies in mouse models of Type 1 and preventative in Type 2 diabetes. Data from these studies, which includes reversal of neuropathic pain and decreased nerve conductance associated with the onset of diabetic symptoms, suggest that NSI-189 may have broad applicability in the treatment of central and peripheral neuropathies arising from diverse etiologies.
NSI-189 and neurogenesis.
- Oral administration of NSI-189 to mice with ischemic stroke led to a significant increase in neurogenesis in the hippocampus accompanied by a significant recovery from motor deficit. This evidence suggests that NSI-189 can induce recovery from stroke-induced brain damage. The improvements were maintained post cessation of dosing for the additional 12-week observational period. The sustained improvement suggests that NSI-189 initiated a host brain repair mechanism enabling tissue remodeling of the stroke brain. In cultured mouse hippocampal cells, NSI-189 lead to the upregulation of growth factors such as Stem Cell Factor (SCF) and Brain Derived Neurotrophic Factor (BDNF), as well as increasing neurite outgrowth.
The company believe that these data support its view that NSI-189 may be effective in the treatment of a broad range of cognitive and neuroregenerative applications.
Mechanism of Action Studies with NSI-189
Evidence to date suggests that NSI-189 has a novel mechanism of action when compared to currently marketed therapies. Screening assays indicate that NSI-189 does not bind appreciably to known neurotransmitter receptors or transporters. These tests have included 48 neurotransmitter related receptors, ion channels, and enzymes, plus in excess of 450 protein kinases. The resulting data lead it to believe that NSI-189 acts via a mechanism that is distinct from currently marketed SSRI, SNRI, or NDRI compounds
Discovery of NSI-189: The company's Proprietary and Novel Screening Platform
NSI-189’s potential was identified using its stem cell-based screening platform. The company's human neural stem cell lines form the foundation for functional cell-based assays used to screen for small molecule compounds that can affect biologically relevant outcomes such as neurogenesis, synapse formation, and protection against toxic insults. Neuralstem has developed over 300 unique stem cell lines representing multiple regions of the developing brain and spinal cord at different time points in development, enabling the generation of almost unlimited numbers of physiologically relevant human neural cells for screening, target validation, and mechanism-of-action studies. This platform provides it with a unique and powerful tool to identify new chemical entities to treat a broad range of nervous system conditions.
The discovery process for NSI-189 started with the initiation of a high content screen of 10,269 small molecules and led to the identification of 16 compounds that were capable of inducing neurogenesis, the birth of new neurons in hippocampal stem cells in culture. These 16 compounds were then tested for toxicity in vitro and in mice, and were evaluated for their ability to induce neurogenesis in healthy adult mice after oral administration. Seven of the starting 16 compounds, representing three structural classes, were advanced as orally active neurogenic leads. Compounds were evaluated in three mouse models of depression and NSI-189 was advanced as the lead small molecule candidate due to its anti-depressant behavioral effect, and its ability to both induce hippocampal neurogenesis and increase hippocampal volume.
NSI - 566 (Stem Cells)
The human central nervous system (CNS) has limited capacity for regeneration following injury or the onset of disease. Traditional therapies have mainly focused on minimizing the progression or symptoms of CNS disease or injury, but have not been effective at repairing the underlying cause of such disease. The focus of its cell therapy initiatives is the regeneration of neural function which has been lost to disease or injury. The company believe that neuroprotection, neuroregeneration, and/or bridging of damaged neural circuitry may be accomplished by implantation of NSI-566 at the injury site.
The company's proprietary technology enables the isolation and large-scale expansion of regionally specific neural stem cells from all areas of the developing human brain and spinal cord and enables the generation of commercially useful quantities of highly characterized allogeneic human neural stem cells that can be transplanted into patients to mitigate the consequences of CNS diseases or injury. Neuralstem has developed and optimized processes that allow it to manufacture these cells under Good Manufacturing Practices or cGMP compliant conditions as required by the FDA for use in clinical trials and have generated cell banks which the company believe are sufficient to provide material to meet all its requirements through to completion of Phase 3 studies. Neuralstem has exclusive licenses for manufacture and use of the surgical platform and cannula that enable administration of the cells to the spinal cord for treatment utilizing its stem cells. Based on its preclinical data the company believe that its human neural stem cells will differentiate into neurons and glia after grafting into the patient and will provide neuroprotection and stimulate neuroregeneration.
The company's lead stem cell program is the spinal cord-derived neural stem cell line, NSI-566, which is being tested for treatment of paralysis due to Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig’s disease), stroke, and spinal cord injury. To date Neuralstem has completed Phase 1 and Phase 2 safety and dose escalation studies in subjects with ALS and a Phase1 safety and dose escalation study in subjects with motor deficits due to ischemic stroke. Each of these studies are currently in their long-term follow-up stage. Recently the Phase 1 safety study in subjects with chronic spinal cord injury (cSCI) AISA A thoracic spinal cord injury subjects was expanded – under the auspices of UC San Diego – to include cervical spinal-cord injury subjects.
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement. In 2016 the Centers for Disease Control and Prevention estimated that between 14,000 and 15,000 Americans have ALS. In ALS, nerve cells (motor neurons) waste away or die, and can no longer send messages to muscles. This eventually leads to muscle weakening, twitching, and an inability to move the arms, legs, and body. As the condition progresses, muscles in the chest area stop working, making it difficult or impossible to breathe. NSI-566 is under development as a potential treatment for ALS by providing cells designed to nurture and protect the patient’s remaining motor neurons; and possibly repair some motor neurons which have not yet died but which are diseased. The company received orphan designation by the FDA for NSI-566 in ALS.
Motor Deficits Due to Ischemic Stroke
Ischemic stroke, the most common type of stroke, occurs as a result of an obstruction within a vessel supplying blood to the brain. In the US, approximately 1.8 million people live with paralysis due to stroke. Post-stroke motor deficits include paralysis in arms and legs and speech impairment and can be permanent. The company believe that NSI-566 may provide an effective treatment for restoring motor deficits resulting from ischemic stroke by both creating new circuitry in the area of injury and through repairing and or nurturing diseased cells to improve function in patients.
Chronic Spinal Cord Injury
Spinal cord injury, or SCI, generally refers to any injury to the spinal cord that is caused by trauma instead of disease, although in some cases it can be the result of diseases. It is estimated that there are 17,00014 new cases of SCI per year and that at any given time, there are between 243,000 and 347,000 people in the United States that are living with SCI. Chronic spinal cord injury (cSCI) refers to the time after the initial hospitalization. SCIs are most often traumatic, caused by lateral bending, dislocation, rotation, axial loading, and hyperflexion or hyperextension of the cord or cauda equina. Motor vehicle accidents are the most common cause of SCIs, while other causes include falls, work-related accidents, sports injuries, and penetrating injuries such as stab or gunshot wounds. In certain instances, SCIs can also be of a non-traumatic origin, as in the case of cancer, infection, intervertebral disc disease, vertebral injury and spinal cord vascular disease. The company believe that NSI-566 may provide an effective treatment for cSCI by “bridging the gap” in the spinal cord circuitry created in traumatic spinal cord injury and providing new cells to help transmit the signal from the brain to points at or below the point of injury.
Clinical Experience with NSI-566
Amyotrophic Lateral Sclerosis
In January 2010, the company commenced a Phase 1 trial of NSI-566 in ALS at Emory University in Atlanta, Georgia. The purpose of the trial was to evaluate the safety of its proposed treatment and procedure in a total of 15 subjects. The dosing of subjects in the Phase 1 trial, as designed, was completed in August of 2012. The company commenced a Phase 2 clinical trial in subjects suffering from ALS in September of 2013 to further test the feasibility and safety of the treatment and procedure, and maximum tolerated dose of cells. The Phase 2 dose escalation trial enrolled 15 ambulatory subjects in five different dosing cohorts. Each patient in the final cohort had two separate surgeries.
Neuralstem has completed all of the transplantations and the observation period of 24 months after the last surgery. The Phase 2 ALS clinical trial met the primary safety endpoints and established what the company believe to be the maximum safe tolerated dose of 16 million cells delivered in 40 injections over two surgeries. In June 2017, 24-month Phase 2 and combined Phase 1 and Phase 2 data from its ALS trials were presented at the International Society for Stem Cell Research (ISSCR) Annual Meeting, Approaches to Treating ALS, Boston, Massachusetts, by principal investigator Eva Feldman, MD, PhD, Russell N. DeJong Professor of Neurology and Director of Research of the ALS Clinic at the University of Michigan Health. The data showed that the intraspinal transplantation of the cells was safe and well tolerated. Subjects from both the Phase 1 and Phase 2 continue to be monitored for long-term follow-up evaluations.
To provide guidance for future studies the company undertook additional analyses of the Ph1/Ph2 NSI-566 ALS data using a matched controls approach. In order to facilitate this analysis, the company utilized Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT). The PRO-ACT platform houses the largest ALS clinical trials dataset ever created. PRO-ACT contains over 8,500 ALS de-identified patient records from multiple completed clinical trials. The PRO-ACT initiative merges data from existing publicly- and privately-conducted ALS clinical trials to generate an invaluable resource for accelerating discovery in the field of ALS. Post-hoc analyses of ambulatory limb-onset ALS participants in Phase 1 and 2 (Ph1/2) open-label intraspinal NSI-566 transplantation studies were compared to participants in PRO-ACT dataset who had complete data >1 month follow-up and matched Ph1/2 participants based on gender, age, disease duration, and baseline ALS functional rating scale-revised (ALSFRS-R). ALSFRS-R and a composite statistic (ALS/SURV), which combines survival and ALSFRS-R functional status, were analyzed. Mean ALSFRS-R at 24 months significantly differed between Ph1/2 and PRO-ACT (Ph1/2 30.1±8.6 vs. PRO-ACT 24.0±10.2, p=0·048). Using ALS/SURV, the median PRO-ACT participants did not live to 24-months, whereas the median Ph1/2 participant’s ALSFRS-R was 23 (p=0.0038). Neuralstem is continuing to analyze the data.
NSI-566: ALS Phase I and II, 2-Year Follow-Up vs Historical Data
To date, substantially all the clinical costs of its ALS studies have been funded by grants.
In 2013 the company commenced an open label, non-GCP, Phase I safety and dose escalation study in human subjects for treatment of motor deficits due to ischemic stroke. The trial was conducted at BaYi Brain Hospital in Beijing, China utilizing NSI-566, its spinal cord stem cells. This study was intended to evaluate safety of direct injections of NSI-566 into the brain and to determine the maximum safe tolerated dose.
In March 2016, the company completed dosing the final planned cohort, for a total of nine subjects. Subjects are currently being monitored through their 24-month observational follow-up period. The trial is being conducted by Suzhou Neuralstem, a wholly owned subsidiary of Neuralstem in China.
At the twelve-month interim assessment delivery of NSI-566 cells by this mechanism in this population appeared to be safe and well tolerated at all doses. While not powered for efficacy, pre-specified endpoints (Fugl-Meyer, Modified Rankin Score and NIH Stroke Scale) showed statistically significant improvement in all scales compared to baseline as analyzed using the Wilcoxon signed rank test. Longitudinal MRI studies showed evidence of graft survival and cavity-filling in all 9 patients.
Fugl-Meyer Motor Score
Chronic Spinal Cord Injury
In 2013, the company received authorization from the FDA to commence its proposed Phase 1 clinical trial to treat chronic spinal cord injury. The trial, which is taking place at The University of California, San Diego or UCSD, commenced in 2014 and the first subject was treated in October 2014. The study enrolled four AISA A thoracic spinal cord injury subjects (motor and sensory complete), one to two years’ post-injury at the time of stem cell treatment. In January of 2016 the company reported six-month follow-up data on all four subjects. The stem cell treatment was found to be safe and well-tolerated by the subjects enrolled and there were no serious adverse events. A self-reported ability to contract some muscles below the level of injury in one of the four subjects treated was confirmed via clinical and electrophysiological follow-up examinations. All subjects will be followed for five years.
FDA has approved the protocol amendment to treat an additional cohort of four cervical spinal cord injury patients. This study, under the supervision of UCSD is actively seeking subjects.
Substantially all of the clinical costs of this study have been, and will continue to be, funded by grants arranged through UCSD.
Pre-Clinical Experience with NSI-566 and other candidates for its stem cell pipeline
The company's preclinical studies with NSI-566 have served to provide a solid foundation for its ongoing clinical trials by demonstrating performance and efficacy of this cell line in animal models for ALS (Yan et al., 2006; Hefferan et al., 2011; Xu et al., 2006; Xu et al., 2009; Xu et al., 2011), spinal cord injury (Cizkova et al., 2007; Lu et al., 2012; van Gorp et al., 2013), and ischemic stroke (Tajiri et al., 2014), and demonstrated safety in large animals (Usvald et al., 2010; Raore et al., 2011). Additional studies involving NSI-566 or other proprietary cell lines are directed at identifying new therapeutic candidates.
In addition to NSI-566 Neuralstem has developed an inventory of over 300 unique stem cell lines. These stem cell lines include cortex, hippocampus, midbrain, hindbrain, cerebellum, and spinal cord. The company believe these lines possess unique properties and represent candidates for both transplantation-based strategies to treat disease and for screening of compound libraries to discover novel drug therapies.
Traumatic Brain Injury (TBI)
TBI occurs when a sudden mechanical force induces damage to the brain. TBIs result in cognitive and motor deficits or death. Damage may come from the forceful collision of the skull with a solid object, such as during a fall or car accident, or may be caused by an object penetrating the skull and disrupting brain tissue. The Company is in the midst of a collaboration with investigators at the Miami Project to Cure Paralysis to determine if transplantation of NSI-566 can lead to an improvement in motor function in an animal model for penetrating TBI (such as may occur from a gunshot).
Alzheimer’s disease (AD)
Neuralstem’s HK532-IGF-1 is a proprietary line of cortical neural stem cells engineered to over-express insulin-like growth factor-1 (IGF-1), which has been shown to have wide-ranging neuroprotective properties. AD is a progressive neurodegenerative disorder of the brain that leads to cognitive decline and memory loss which is the most common cause of dementia in older adults. Researchers at the University of Michigan evaluated the ability of the human neural stem cell line NSI-532.IGF1 to reverse the cognitive impact of neurodegeneration in AD (McGinley et al., 2016). In a mice model, mice with HK532-IGF-1 transplanted in the peri-hippocampus, performed better on hippocampal-dependent behavioral tasks than untreated mice, demonstrating both enhanced learning cognitive processes and memory consolidation.
Multiple Sclerosis (MS) and demyelinating diseases
In the case of MS and other demyelinating diseases, the myelin sheath that wraps and insulates axons in the central nervous system can become damaged, leading to inefficient transmission of signals along the nerves of the brain and spinal cord. This loss of conductivity may lead to profound symptoms, including loss of vision, sensation, and muscle strength, Myelin is generated in the CNS by a neural cell type called oligodendrocytes. The Company has developed a human neural stem cell line, NSI-777, that gives rise to large quantities of these myelin-generating cells after grafting in animals. In collaboration with researchers at Johns Hopkins University, Neuralstem has recently shown that NSI-777 has high capacity for myelinating axons after grafting into animal models for demyelination. The company will continue to pursue NSI-777 to further develop this candidate for potential use in treatment of human demyelinating diseases.
The company's stem cell-based technology has both therapeutic and screening characteristics.
From a therapeutic perspective, its stem cell-based technology enables the isolation and large-scale expansion of regionally specific, human neural stem cells from all areas of the developing human brain and spinal cord thus enabling the generation of physiologically relevant human neurons of all types. The company believe that its stem cell technology will assist the body in producing a neurotrophic environment to support weakened/diseased cells and/or assist the body in producing new cells to replace malfunctioning or dead cells as a way to treat disease and injury. Many significant and currently untreatable human diseases arise from the loss or malfunction of specific cell types in the body. The company's focus is to develop effective methods to protect, repair, and regenerate the damaged neural circuits with implantation of neural stem cells.
Small Molecule Pharmaceutical Compounds
Utilizing its proprietary stem cell derived screening capability, Neuralstem has discovered and patented a series of neurogenic small molecule compounds. The company believe its low molecular weight organic compounds can efficiently cross the blood/brain barrier. In mice, research indicated that the small molecule compounds can both stimulate neurogenesis of the hippocampus and increase its volume. The company believe the small molecule compounds may promote synaptogenesis or neurogenesis in the human hippocampus in indications such as MDD.
Substantial resources have been and will be devoted to its research programs. The company's efforts are directed at developing therapies utilizing its stem cells and small molecule regenerative drug candidates. This research is conducted internally, through the use of third party laboratories, consulting companies under its direct supervision, and through collaboration with academic institutes.
The company currently manufacture its cells both in-house and on an outsourced basis. The company outsource the manufacturing of its pharmaceutical compounds and its clinical supply of stem cells to cGMP compliant third-party manufacturers. The company manufacture neural stem cells in-house for use in its research and collaborative programs.
Neuralstem has developed and maintain what the company believe is a strong portfolio of patents and patent applications that form the basis for its research and development efforts. The company own or exclusively license over 10 U.S. issued and pending patents and over 70 foreign issued and pending patents related to its stem cell technologies for use in treating disease and injury. The company own over 15 U.S. issued and pending patents and over 70 foreign issued and pending patents related to its small molecule compounds. The company's issued patents have expiration dates ranging from 2018 through 2034.
When appropriate, the company seek patent protection for inventions in its core technologies and in ancillary technologies that support its core technologies or which the company otherwise believe will provide it with a competitive advantage. The company accomplish this by filing patent applications for discoveries the company make, either alone or in collaboration with scientific collaborators and strategic partners. Typically, although not always, the company file patent applications both in the United States and in select international markets. In addition, the company plan to obtain licenses or options to acquire licenses to patent filings from other individuals and organizations that the company anticipate could be useful in advancing its research, development and commercialization initiatives and its strategic business interests.
In addition to patenting its technologies, the company also rely upon trade-secret protection for its confidential and proprietary information and take active measures to control access to that information, including the use of confidentiality agreements with its employees, consultants and certain of its contractors.
The company's policy is to require its employees, consultants and significant scientific collaborators and sponsored researchers to execute confidentiality and assignment of invention agreements upon the commencement of an employment or consulting relationship with it. These agreements generally provide that all confidential information developed or made known to the individual by it during the course of the individual's or entity’s relationship with it, is to be kept confidential and not disclosed to third parties except in specific circumstances. In the case of employees and consultants, the agreements generally provide that all inventions conceived by the individual or entity in the course of rendering services to it shall be its exclusive property.
The patent positions of pharmaceutical and biotechnology companies, including ours, are uncertain and involve complex and evolving legal and factual questions. The coverage sought in a patent application can be denied or significantly reduced before or after the patent is issued. Consequently, the company do not know whether any of its pending applications will result in the issuance of patents, or if any existing or future patents will provide significant protection or commercial advantage or will be circumvented by others. Since patent applications are secret until the applications are published (usually eighteen months after the earliest effective filing date), and since publication of discoveries in the scientific or patent literature often lags behind actual discoveries, the company cannot be certain that the company were the first to make the inventions covered by each of its pending patent applications or that the company were the first to file patent applications for such inventions. There can be no assurance that patents will issue from its pending or future patent applications or, if issued, that such patents will be of commercial benefit to it, afford it adequate protection from competing products, or not be challenged or declared invalid.
In the event that a third party has also filed a patent application relating to inventions claimed in its patent applications, the company may have to participate in interference proceedings declared by the United States Patent and Trademark Office or USPTO, to determine priority of invention, which could result in substantial uncertainties and costs, even if the eventual outcome is favorable to it. There can be no assurance that its patents, if issued, would be held valid by a court of competent jurisdiction.
A number of pharmaceutical, biotechnology and other companies, universities and research institutions have filed patent applications or have been issued patents relating to cell therapy, stem cells and other technologies potentially relevant to or required by its proposed products. The company cannot predict which, if any, of such applications will issue as patents or the claims that might be allowed.
If third party patents or patent applications contain claims infringed by its technology and such claims are ultimately determined to be valid, there can be no assurance that the company would be able to obtain licenses to these patents at a reasonable cost, if at all, or be able to develop or obtain alternative non-infringing technology. If Neuralstem is unable to obtain such licenses or develop or obtain alternative non-infringing technology at a reasonable cost, the company may not be able to develop certain products commercially. There can be no assurance that the company will not be obliged to defend itself in court against allegations of infringement of third party patents. Patent litigation is very expensive and could consume substantial resources and create significant uncertainties. An adverse outcome in such a suit could subject it to significant liabilities to third parties, require it to seek licenses from third parties, or require it to cease using such technology.