Neurology Division

Cleveland, OH, United States

Neurology Division

Cleveland, OH, United States

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Flex Pharma, Inc. (NASDAQ: FLKS), a clinical-stage biotechnology company that is developing innovative and proprietary treatments for cramps and spasticity associated with serious neurological diseases including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Charcot-Marie-Tooth (CMT), today announced that the US Food and Drug Administration (FDA) has granted Fast Track designation for the development of FLX-787, the Company’s co-activator of TRPA1 and TRPV1, to treat severe muscle cramps in patients with ALS. There are currently no drugs approved in the US for this condition. Fast Track designation is intended to accelerate the clinical development and review of drugs to treat serious conditions that address an unmet medical need. “We believe the receipt of Fast Track designation from the FDA highlights the serious nature of cramps for patients suffering from ALS and the current lack of safe and effective treatments. The Fast Track designation represents an opportunity for even closer collaboration with FDA and an important catalyst for our development program for FLX-787,” stated William McVicar, Ph.D., Flex Pharma interim President and CEO. “With Phase 2 clinical trials in both ALS and CMT expected to initiate this quarter in the US, FLX-787 will be amongst the most advanced, novel compounds in the clinic for these degenerative neurological diseases. The R&D team is focused on the execution of these new Phase 2 IND studies, as well as completion of the ongoing exploratory Phase 2 spasticity study in MS in Australia. These studies are expected to yield several important data readouts in 2018.” “Our COMMEND trial, which is a Phase 2 study of primarily ALS patients in the US, has certain advantages to our ongoing ALS study in Australia, including longer run-in and treatment periods, increased dosing, a parallel design, and of course a much larger population from which patients can be recruited. As a result, we have elected to prioritize and focus our efforts on the COMMEND study and will end the exploratory Australian ALS study early, with roughly a dozen patients,” noted Flex Pharma Chief Medical Officer Thomas Wessel, M.D., Ph.D. “The data from the Australian study will inform our larger COMMEND clinical trial, particularly regarding baseline cramp frequency and intra-subject variability, which could influence sample size calculation and other aspects of trial conduct for this important US study.” Fast Track designation allows for a more frequent dialogue with the Neurology Division at FDA on the company's drug development plan, data requirements and clinical trial design, throughout the drug development and review process, with the goal of getting important new drugs to patients more rapidly. Through the Fast Track program, a product may be eligible for priority review at the time of a New Drug Application (NDA) filing and may also be eligible to submit completed sections of the NDA on a rolling basis, before the complete application is submitted. The COMMEND trial is a Phase 2 clinical trial designed to evaluate FLX-787 in patients with motor neuron disease (MND), focused on ALS, who suffer from cramps. The COMMIT trial is a Phase 2 clinical trial designed to evaluate FLX-787 in patients with CMT. These randomized, controlled, double-blinded, parallel design trials in the US will include a run-in period to establish a baseline in cramp frequency. Patients will then be randomized to 30 mg of FLX-787 administered three times a day, or control, for 28 days. Patients will be evaluated for changes in cramp frequency as the primary endpoint, with a number of secondary endpoints. Flex Pharma, Inc. is a clinical-stage biotechnology company that is developing innovative and proprietary treatments for cramps and spasticity associated with the severe neurological diseases of ALS, MS and peripheral neuropathies such as Charcot-Marie-Tooth (CMT). Flex Pharma was founded by National Academy of Science members Rod MacKinnon, M.D. (2003 Nobel Laureate), and Bruce Bean, Ph.D., recognized leaders in the fields of ion channels and neurobiology, along with Chair Christoph Westphal, M.D., Ph.D. This press release contains forward-looking statements for purposes of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things, the design and timing of ongoing and anticipated clinical trials, including the timing for results of our clinical trials, and our expectations regarding the level of interaction with the FDA and other benefits associated with FLX-787 having been granted Fast Track status. These forward-looking statements are based on management's expectations and assumptions as of the date of this press release and are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those expressed or implied by such statements. These risks and uncertainties include, without limitation: the status, timing, costs, results and interpretation of our clinical studies; the uncertainties inherent in conducting clinical studies; our ability to enroll patients in each of clinical studies on a timely basis; expectations of our ability to make regulatory filings and obtain and maintain regulatory approvals; availability of funding sufficient for our foreseeable and unforeseeable operating expenses and capital expenditure requirements; the inherent uncertainties associated with intellectual property; and other factors discussed in greater detail under the heading "Risk Factors" in our Annual Report on Form 10-K for the year ended December 31, 2016 and subsequent filings with the Securities and Exchange Commission (SEC). You are encouraged to read our filings with the SEC, available at www.sec.gov, for a discussion of these and other risks and uncertainties. Any forward-looking statements that we make in this press release speak only as of the date of this press release. We assume no obligation to update our forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release.


LONDON, UK / ACCESSWIRE / July 27, 2017 / Pro-Trader Daily takes a look at the latest corporate events and news making the headlines for Flex Pharma, Inc. (NASDAQ: FLKS), following which we have published a free report that can be viewed by signing up at http://protraderdaily.com/optin/?symbol=FLKS. The clinical-stage biotechnology Company announced on July 25, 2017, that the US Food and Drug Administration (FDA) has granted Fast Track designation for the development of FLX-787, i.e. the Company's co-activator of TRPA1 and TRPV1 to treat severe muscle cramps in patients with amyotrophic lateral sclerosis (ALS). For immediate access to our complimentary reports, including today's coverage, register for free now at: Discover more of our free reports coverage from other companies within the Biotechnology industry. Pro-TD has currently selected RedHill Biopharma Ltd (NASDAQ: RDHL) for due-diligence and potential coverage as the Company reported on July 25, 2017, its financial results for Q2 2017 which ended on June 30, 2017. Tune into our site to register for a free membership, and be among the early birds that get our report on RedHill Biopharma when we publish it. At Pro-TD, we make it our mission to bring you news that matter about the stock you follow. Today, our research desk covers a blog story on FLKS; also brushing on RDHL. Go directly to your stock of interest and access today's free coverage at: As of now, no drugs have been approved in the US for this condition. Flex Pharma has been developing innovative and proprietary treatments for cramps and spasticity associated with serious neurological diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Charcot-Marie-Tooth (CMT). The above mentioned fast track designation is expected to speed up the clinical development and review of drugs required to address the unmet medical need and treat serious conditions related to ALS. FDA Approval Driven by Current Lack of Effective Treatments for ALS William McVicar, Ph.D., Flex Pharma interim President, and CEO stated that the receipt of Fast Track designation from the FDA underlines the grave nature of cramps for patients suffering from ALS and the existing lack of safe and effective treatments for them. The Fast Track designation also signifies an opportunity for greater collaboration with FDA. This will also act as an important catalyst for their development program for FLX-787. It is anticipated that the Phase-2 clinical trials in ALS and CMT will initiate this quarter, which will make FLX-787 one of the most advanced, novel compounds in the clinic for degenerative neurological diseases. He mentioned that his R&D team is focused on the execution of these new Phase-2 IND studies as well as completion of the ongoing exploratory Phase-2 spasticity study in MS in Australia. These studies are expected to yield several important data readouts in 2018. The COMMEND trial is a Phase-2 clinical trial that has been designed to assess FLX-787 in patients with motor neuron disease (MND), primarily focused on ALS, who suffer from cramps. On the other hand, the COMMIT trial is a Phase-2 clinical trial that is designed to evaluate FLX-787 in patients with CMT. These randomized, controlled, double-blinded, parallel design trials in the US will include a run-in period to establish a baseline in cramp frequency. After which, patients will be randomized to 30 mg of FLX-787 administered three times a day, or control, for 28 days; on this basis, patients will be evaluated for changes in cramp frequency as the primary endpoint, with a number of other secondary endpoints. Flex Pharma to Prioritize US Phase-2 COMMEND Trial over its Australian Study Flex Pharma Chief Medical Officer Thomas Wessel, M.D., Ph.D. stated that the COMMEND trial, primarily focused on ALS patients in the US, has certain advantages to the Company's ongoing ALS study in Australia, including longer run-in and treatment periods, increased dosing, a parallel design, and of course a much larger population from which patients can be recruited. Therefore, the Company has decided to prioritize and focus its efforts on the COMMEND study and end the exploratory Australian ALS study early, with around a dozen patients. He believes that the data from the Australian study will apprise the Company's larger COMMEND clinical trial, mainly about baseline cramp frequency and intra-subject variability, which could impact the calculation of sample size and other aspects of trial conduct for the US study. How will the Fast Track Designation Help? The Fast Track designation will enable Flex Pharma to have a more frequent dialogue with the Neurology Division at FDA about its drug development plan, data requirements, and clinical trial design, throughout the drug development and review process. This will allow the Company to offer important new drugs to its customers more rapidly. Through this Fast Track program, a product might be eligible for priority review at the time of a New Drug Application (NDA) filing and might also be eligible for submitting completed sections of the NDA on a rolling basis, before the complete application is submitted. At the closing bell, on Wednesday, July 26, 2017, Flex Pharma's stock tumbled 5.77%, ending the trading session at $4.08. A total volume of 325.52 thousand shares have exchanged hands, which was higher than the 3-month average volume of 138.92 thousand shares. The Company's stock price surged 14.61% in the last three months. The stock currently has a market cap of $76.17 million. 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Plaud-Valentin M.,University of Puerto Rico at San Juan | Skolasky R.L.,University of Baltimore | Wojna V.,Neurology Division | Wojna V.,University of Puerto Rico at San Juan | Melendez L.M.,University of Puerto Rico at San Juan
AIDS | Year: 2013

OBJECTIVE: HIV-1-associated neurocognitive disorders (HAND) is triggered by immune activation of brain cells and remain prevalent during progressive viral infection despite antiretroviral therapy. Cathepsins and cystatins are lysosomal proteins secreted by macrophages and microglia, and may play important roles in neuroregulatory responses. Our laboratory has shown increased secretion and neurotoxicity of cathepsin B from in-vitro HIV-infected monocyte-derived macrophages, and increased expression in postmortem brain tissue with HIV encephalitis and HAND. We hypothesized that cystatin B and cathepsin B could represent potential biomarkers for HAND. METHODS: Monocytes, plasma, and cerebrospinal fluid (CSF) from retrospective samples from 63 HIV-seropositive Hispanic women were selected for this study. These were stratified as 27 normal, 14 asymptomatic, and 22 HIV dementia, and as 14 progressors and 17 nonprogressors. Samples were evaluated for cystatins B and C and cathepsin B expression and activity. RESULTS: Increased cathepsin B and cystatins B and C were found in plasma of HIV-seropositive women. Higher intracellular expression of cathepsin B and cystatin B were found in monocytes from women with HIV-associated dementia (P<0.05). Significant increase in cystatin B concentration in CSF was found in women with dementia compared with HIV-seropositive asymptomatic women. CONCLUSION: These results demonstrate that dysregulation of cystatin B-cathepsin B system is operative in HIV-associated neurocognitive impairment and suggests that intracellular expression of cystatin B and cathepsin B in monocytes could be potential candidate biomarkers for HIV dementia, whereas increased cathepsin B and cystatins B and C in plasma are potential candidate markers of chronic HIV-1 activation. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Stahl J.S.,Neurology Division | Stahl J.S.,Case Western Reserve University | Thumser Z.C.,Neurology Division | Oommen B.S.,Case Western Reserve University
Journal of Vestibular Research: Equilibrium and Orientation | Year: 2012

Downbeat nystagmus (DBN) is a common eye movement complication of cerebellar disease. Use of mice to study pathophysiology of vestibulocerebellar disease is increasing, but it is unclear if mice can be used to study DBN; it has not been reported in this species. We determined whether DBN occurs in the ataxic mutant tottering, which carries a mutation in the Cacna1a gene for P/Q calcium channels. Spontaneous DBN occurred only rarely, and its magnitude did not exhibit the relationship to head tilt seen in human patients. DBN during yaw rotation was more common and shares some properties with the tilt-independent, gaze-independent component of human DBN, but differs in its dependence on vision. Hyperactivity of otolith circuits responding to pitch tilts is hypothesized to contribute to the gaze-independent component of human DBN. Mutants exhibited hyperactivity of the tilt maculo-ocular reflex (tiltMOR) in pitch. The hyperactivity may serve as a surrogate for DBN in mouse studies. TiltMOR hyperactivity correlates with hyperdeviation of the eyes and upward deviation of the head during ambulation; these may be alternative surrogates. Muscimol inactivation of the cerebellar flocculus suggests a floccular role in the tiltMOR hyperactivity and provides insight into the rarity of frank DBN in ataxic mice. © 2012 - IOS Press and the authors. All rights reserved.


Stahl J.S.,Neurology Division | Stahl J.S.,Case Western Reserve University | Thumser Z.C.,Neurology Division | May P.J.,University of Mississippi | And 3 more authors.
Journal of Neurophysiology | Year: 2015

Rigorous descriptions of ocular motor mechanics are often needed for models of ocular motor circuits. The mouse has become an important tool for ocular motor studies, yet most mechanical data come from larger species. Recordings of mouse abducens neurons indicate the mouse mechanics share basic viscoelastic properties with larger species but have considerably longer time constants. Time constants can also be extracted from the rate at which the eye re-centers when released from an eccentric position. The displacement can be accomplished by electrically stimulating ocular motor nuclei, but electrical stimulation may also activate nearby ocular motor circuitry. We achieved specific activation of abducens motoneurons through photostimulation in transgenic mice expressing channelrhodopsin in cholinergic neurons. Histology confirmed strong channelrhodopsin expression in the abducens nucleus with relatively little expression in nearby ocular motor structures. Stimulation was delivered as 20- to 1,000-ms pulses and 40-Hz trains. Relaxations were modeled best by a two-element viscoelastic system. Time constants were sensitive to stimulus duration. Analysis of isometric relaxation of isolated mouse extraocular muscles suggest the dependence is attributable to noninstantaneous decay of active forces in non-twitch fibers following stimulus offset. Time constants were several times longer than those obtained in primates, confirming that the mouse ocular motor mechanics are relatively sluggish. Finally, we explored the effects of 0.1- to 20-Hz sinusoidal photostimuli and demonstrated their potential usefulness in characterizing ocular motor mechanics, although this application will require further data on the temporal relationship between photostimulation and neuronal firing in extraocular motoneurons. © 2015 the American Physiological Society.


Stahl J.S.,Neurology Division | Stahl J.S.,Case Western Reserve University | Thumser Z.C.,Neurology Division
Journal of Neurophysiology | Year: 2014

Mutation of the Cacna1a gene for the P/Q (CaV2.1) calcium channel invariably leads to cerebellar dysfunction. The dysfunction has been attributed to disrupted rhythmicity of cerebellar Purkinje cells, but the hypothesis remains unproven. If irregular firing rates cause cerebellar dysfunction, then the irregularity and behavioral deficits should covary in a series of mutant strains of escalating severity. We compared firing irregularity in floccular and anterior vermis Purkinje cells in the mildly affected rocker and moderately affected tottering Cacna1a mutants and normal C57BL/6 mice. We also measured the amplitude and timing of modulations of floccular Purkinje cell firing rate during the horizontal vestibuloocular reflex (VOR, 0.25–1 Hz) and the horizontal and vertical optokinetic reflex (OKR, 0.125–1 Hz). We recorded Purkinje cells selective for rotational stimulation about the vertical axis (VAPCs) and a horizontal axis (HAPCs). Irregularity scaled with behavioral deficit severity in the flocculus but failed to do so in the vermis, challenging the irregularity hypothesis. Mutant VAPCs exhibited unusually strong modulation during VOR and OKR, the response augmentation scaling with phenotypic severity. HAPCs exhibited increased OKR modulation but in tottering only. The data contradict prior claims that modulation amplitude is unaffected in tottering but support the idea that attenuated compensatory eye movements in Cacna1a mutants arise from defective transfer of Purkinje cell signals to downstream circuitry, rather than attenuated synaptic transmission within the cerebellar cortex. Shifts in the relative sizes of the VAPC and HAPC populations raise the possibility that Cacna1a mutations influence the development of floccular zone architecture. © 2014 the American Physiological Society.


Stahl J.S.,Neurology Division | Stahl J.S.,Case Western Reserve University | Thumser Z.C.,Neurology Division
PLoS ONE | Year: 2013

The potassium channel antagonist 4-aminopyridine (4-AP) improves a variety of motor abnormalities associated with disorders of the cerebellum. The most rigorous quantitative data relate to 4-AP's ability to improve eye movement deficits in humans referable to dysfunction of the cerebellar flocculus. Largely based on work in the ataxic mouse mutant tottering (which carries a mutation of the Cacna1a gene of the P/Q voltage-activated calcium channel), 4-AP is hypothesized to function by enhancing excitability or rhythmicity of floccular Purkinje cells. We tested this hypothesis by determining whether systemic or intrafloccular administration of 4-AP would ameliorate the eye movement deficits in tottering that are attributable to flocculus dysfunction, including the reductions in amplitude of the yaw-axis vestibulo-ocular reflex (VOR) and vision-enhanced vestibulo-ocular reflex (VVOR), and the optokinetic reflex (OKR) about yaw and roll axes. Because tottering's deficits increase with age, both young and elderly mutants were tested to detect any age-dependent 4-AP effects. 4-AP failed to improve VOR, VVOR, and OKR gains during sinusoidal stimuli, although it may have reduced the tendency of the mutants' responses to VOR and VVOR to decline over the course of a one-hour recording session. For constant-velocity optokinetic stimuli, 4-AP generated some enhancement of yaw OKR and upward-directed roll OKR, but the effects were also seen in normal C57BL/6 controls, and thus do not represent a specific reversal of the electrophysiological consequences of the tottering mutation. Data support a possible extra-floccular locus for the effects of 4-AP on habituation and roll OKR. Unilateral intrafloccular 4-AP injections did not affect ocular motility, except to generate mild eye elevations, consistent with reduced floccular output. Because 4-AP did not produce the effects expected if it normalized outputs of floccular Purkinje cells, there is a need for further studies to elucidate the drug's mechanism of action on cerebellar motor dysfunction.


PubMed | Case Western Reserve University and Neurology Division
Type: Comparative Study | Journal: Journal of neurophysiology | Year: 2014

Mutation of the Cacna1a gene for the P/Q (CaV2.1) calcium channel invariably leads to cerebellar dysfunction. The dysfunction has been attributed to disrupted rhythmicity of cerebellar Purkinje cells, but the hypothesis remains unproven. If irregular firing rates cause cerebellar dysfunction, then the irregularity and behavioral deficits should covary in a series of mutant strains of escalating severity. We compared firing irregularity in floccular and anterior vermis Purkinje cells in the mildly affected rocker and moderately affected tottering Cacna1a mutants and normal C57BL/6 mice. We also measured the amplitude and timing of modulations of floccular Purkinje cell firing rate during the horizontal vestibuloocular reflex (VOR, 0.25-1 Hz) and the horizontal and vertical optokinetic reflex (OKR, 0.125-1 Hz). We recorded Purkinje cells selective for rotational stimulation about the vertical axis (VAPCs) and a horizontal axis (HAPCs). Irregularity scaled with behavioral deficit severity in the flocculus but failed to do so in the vermis, challenging the irregularity hypothesis. Mutant VAPCs exhibited unusually strong modulation during VOR and OKR, the response augmentation scaling with phenotypic severity. HAPCs exhibited increased OKR modulation but in tottering only. The data contradict prior claims that modulation amplitude is unaffected in tottering but support the idea that attenuated compensatory eye movements in Cacna1a mutants arise from defective transfer of Purkinje cell signals to downstream circuitry, rather than attenuated synaptic transmission within the cerebellar cortex. Shifts in the relative sizes of the VAPC and HAPC populations raise the possibility that Cacna1a mutations influence the development of floccular zone architecture.


PubMed | University of Padua, Eo Galliera Hospital, University of Verona, Anglia Ruskin University and 3 more.
Type: | Journal: Journal of neurology, neurosurgery, and psychiatry | Year: 2016

We conducted a systematic review and meta-analysis investigating the influence of acetylcholinesterase inhibitors (AChEIs) therapy on nutritional status and weight across observational and interventional studies. Two authors searched major electronic databases from inception until 10/14/2015 for longitudinal, open-label and randomised double-blind placebo controlled (randomised controlled trials (RCTs)) studies of AChEIs in patients with dementia reporting nutritional status outcome data. Out of 3551 initial hits, 25 studies (12 open-label trials, 9 RCTs and 4 longitudinal studies) including 10792 patients with dementia were meta-analysed. In longitudinal studies (median follow-up 6months), a significant cumulative incidence of weight loss between baseline and follow-up evaluation was observed (studies=2; 5%; 95% CI 1% to 34%, p<0.0001; I


PubMed | University of Sheffield, University of Kentucky, University of Mississippi, Case Western Reserve University and Neurology Division
Type: Journal Article | Journal: Journal of neurophysiology | Year: 2015

Rigorous descriptions of ocular motor mechanics are often needed for models of ocular motor circuits. The mouse has become an important tool for ocular motor studies, yet most mechanical data come from larger species. Recordings of mouse abducens neurons indicate the mouse mechanics share basic viscoelastic properties with larger species but have considerably longer time constants. Time constants can also be extracted from the rate at which the eye re-centers when released from an eccentric position. The displacement can be accomplished by electrically stimulating ocular motor nuclei, but electrical stimulation may also activate nearby ocular motor circuitry. We achieved specific activation of abducens motoneurons through photostimulation in transgenic mice expressing channelrhodopsin in cholinergic neurons. Histology confirmed strong channelrhodopsin expression in the abducens nucleus with relatively little expression in nearby ocular motor structures. Stimulation was delivered as 20- to 1,000-ms pulses and 40-Hz trains. Relaxations were modeled best by a two-element viscoelastic system. Time constants were sensitive to stimulus duration. Analysis of isometric relaxation of isolated mouse extraocular muscles suggest the dependence is attributable to noninstantaneous decay of active forces in non-twitch fibers following stimulus offset. Time constants were several times longer than those obtained in primates, confirming that the mouse ocular motor mechanics are relatively sluggish. Finally, we explored the effects of 0.1- to 20-Hz sinusoidal photostimuli and demonstrated their potential usefulness in characterizing ocular motor mechanics, although this application will require further data on the temporal relationship between photostimulation and neuronal firing in extraocular motoneurons.

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