A new study on mice published in Nature Neuroscience finds that fingolimod (Novartis brand name Gilenya) a first-in-class sphingosine-1-phosphate-receptor modulator currently used in treating persons with severe relapsing remitting MS, may also have therapeutic value in treating Post Traumatic Stress Disorder (PTSD).
The Nature Neuroscience study is titled “Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory” (Nature Neuroscience (2014) doi:10.1038/nn.3728). Corresponding author is Dr. Sarah Spiegel, Professor and Chair at the Virginia Commonwealth University School of Medicine Department of Biochemistry and Molecular Biology in Richmond, with primary authors Nitai C Hait and Laura E Wise, and Jeremy C Allegood, Megan O’Brien, Dorit Avni, Thomas M Reeves, Pamela E Knapp, Junyan Lu, Cheng Luo, Michael F Miles, Sheldon Milstien, and Aron H Lichtman, variously of the Departments of Medicine, Pharmacology and Toxicology, Biochemistry and Molecular Biology, Anatomy and Neurobiology, and the Massey Cancer Center at the Virginia Commonwealth University School of Medicine in Richmond, Virginia, and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Details of the Study:
The coauthors note that they’ve found FTY720 (fingolimod) has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking. In their study they show that FTY720 enters the nucleus, where it is phosphorylated by sphingosine kinase 2 (SphK2), and that nuclear FTY720-P binds and inhibits class I histone deacetylases (HDACs), enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in the brain, including the hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning, and rescues memory deficits independently of its immunosuppressive actions.
Research in the Spiegel/Milstien laboratory at Virginia Commonwealth University is focused on the enigmatic lipid mediator, sphingosine-1-phosphate (S1P), whose role as a signalling lipid was discovered in Dr. Spiegel’s lab two decades ago. Dr. Spiegel notes that many physiological and pathophysiological processes, including cancer, inflammation and asthma, are regulated by S1P, and that the puzzle is how such a simple molecule as S1P can have such diverse roles has been resolved by the lab’s finding that S1P functions not only as a ligand for S1P receptors, but also inside cells to regulate histone deacetylase activity and gene transcription. They also developed a new paradigm of “inside-out” signalling by S1P which has important implications for proliferation, directed cell movement, angiogenesis, tumorigenesis, inflammation and allergic responses. The Spiegel/Milstien lab was the first to suggest that S1P plays important roles in allergic responses, including asthma and anaphylaxis, the incidence of which is rising worldwide especially in industrialized urban populations. The lab team are studying how S1P is formed and released, and how it acts at many cellular levels, including mast cells, the airway epithelium, airway smooth muscle and many immune cells. Since the actions of S1P on all of these cells could exacerbate allergic responses, the proteins that synthesize, release and respond to S1P offer plausible targets for a new generation of anti-inflammatory therapeutics.
In the study published in Nature Neuroscience, the researchers found that Sphk2″/” mice have lower levels of hippocampal sphingosine-1-phosphate, an endogenous HDAC inhibitor, and reduced histone acetylation, and display deficits in spatial memory and impaired contextual fear extinction. Thus, they say sphingosine-1-phosphate and SphK2 play specific roles in memory functions and FTY720 may not be an ideal agent for treating PTSD due to its side-effect profile (see below), what they’ve learned could be a start on developing new agents with greater specificity for the nuclear anti-HDAC action in the hippocampus that could potentially lead to useful adjuvant therapy to help facilitate control of aversive memories
FTY720/fingolimod Background
The Multiple Sclerosis Trust describes fingolimod as a disease modifying drug currently used in treating persons with rapidly evolving severe relapsing remitting MS (two or more relapses a year), and for people who continue to have relapses despite treatment with one of the beta interferon drugs. It is also undergoing trials as a potential treatment for primary progressive MS. The trust notes that laboratory investigations have provided evidence that, in addition to its effect on the immune system, fingolimod may have neuroprotective and remyelinating properties in the brain and spinal cord.
The Multiple Sclerosis Coalition Emerging Therapies Collaborative observes that Gilenya is the first oral medication approved by the U.S. Food and Drug Administration (FDA) to modify disease activity in multiple sclerosis, and that it appears to prevent some potentially damaging T cells from leaving the lymph nodes. The result is that there are fewer T cells traveling into the central nervous system to do damage. It is not known yet whether fingolimod helps or protects the cells in a person’s CNS. The drug appears to work by binding to the surface of white blood cells (lymphocytes) in the immune system, thereby causing a large proportion of the lymphocytes to be retained in the lymph nodes, reducing the number that can reach the central nervous system and attack nerve cells in the brain and spinal cord. In addition, there is evidence that fingolimod, which is taken orally in capsule form, may have a direct effect on nerve cell damage and enhance the repair of myelin, which could have implications for people with progressive MS.
On the downside, the MS Trust says fingolimod may cause as a side effect a temporary bradycardia (decrease in the heart rate) and may be associated with atrioventricular block (a type of heart rhythm disorder), and that other common side effects include headache, liver enzyme increases, influenza, diahorrea, back pain, and cough. Fingolimod may also cause macular oedema (a swelling in the eye affecting vision).
LAst August, the FDA issued a public alert that a patient in Europe diagnosed with possible multiple sclerosis (MS) had developed a rare and serious brain infection after taking the drug Gilenya (fingolimod). This is the first case of progressive multifocal leukoencephalopathy (PML), reported following administration of Gilenya to a patient who had not previously received Tysabri (natalizumab), an MS drug associated with a higher risk of PML.
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PML is a rare and serious brain infection caused by the John Cunningham (JC) virus that damages the fatty covering of the brain called myelin. PML usually causes death or severe disability. Gilenya is used to treat relapsing forms of MS, a nervous system disease that affects the brain and spinal cord. Novartis reports that approximately 71,000 patients worldwide have been treated with Gilenya.
The FDA recommends that patients should not stop taking Gilenya without first discussing any questions or concerns with their health care professionals, provided its alert while continuing to investigate the PML case, and is working with Gilenya’s manufacturer, Novartis, to obtain and review all available information about this occurrence. FDA will communicate its final conclusions and recommendations after the evaluation is complete.
For more information visit the FDA website at: http://www.fda.gov/Safety/MedWatch/SafetyInformation and http://www.fda.gov/Drugs/DrugSafety.
Two large fingolimod trials have been published. “A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis” (N Engl J Med 2010; 362:387-401February 4, 2010DOI: 10.1056/NEJMoa0909494), published in The New England Journal of Medicine, was coauthored by Ludwig Kappos, M.D., Ernst-Wilhelm Radue, M.D., Paul O’Connor, M.D., Chris Polman, M.D., Reinhard Hohlfeld, M.D., Peter Calabresi, M.D., Krzysztof Selmaj, M.D., Catherine Agoropoulou, Ph.D., Malgorzata Leyk, Ph.D., Lixin Zhang-Auberson, M.D., Ph.D., and Pascale Burtin, M.D., Ph.D. for the FREEDOMS Study Group. Three groups took part in a two-year study: pa low-dose (0.5-mg) fingolimod group, a higher-dose (1.25-mg) fingolimod group, and a control group that took a placebo
This study was designed to determine if people taking fingolimod would have fewer relapses (exacerbations or attacks) over the two-year study than the group taking the placebo, and whether the risk of disability progression over the two-year study period would lower in patients taking fingolimod than in the placebo control cohort. Additionally, would those taking fingolimod have fewer new lesions (damaged areas related to MS) on magnetic resonance imaging (MRI) scans and/or develop less brain tissue loss or shrinkage over the two-year study than people taking placebo? Finally, would the group taking the low dose of fingolimod have different results or side effects than the group taking the high dose of fingolimod?
The researchers found that the annual relapse rate was 0.18 for the group taking the 0.5-mg dose and 0.40 for those on placebo, which indicated that over the two years if the trial the group taking fingolimod had a 54% lower risk of relapse than the group taking the placebo. The risk of disability progression was 30% lower over the two years of the trial in people taking the 0.5-mg dose of fingolimod than in people taking the placebo, and patients taking fingolimod had fewer new lesions and developed less brain tissue loss, as shown on their MRI scans, than the group taking placebo.
The group taking the low dose of fingolimod and the group taking the high dose of fingolimod did equally well, but the higher-dose group had more side effects, including two deaths. The Emerging Therapies Collaborative notes that these findings informed he FDA’s decision to approve only the 0.5-mg dose of fingolimod.
In the second study, “Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis” (N Engl J Med. 2010 Feb 4;362(5):402-15. doi: 10.1056/NEJMoa0907839. Epub 2010 Jan 20.0), also published in the New England Journal of Medicine, coauthors Jeffrey A. Cohen, M.Dmof the Mellen Center at the Cleveland Clinic, Cleveland, Ohio with Frederik Barkhof, M.D., Giancarlo Comi, M.D., Hans-Peter Hartung, M.D., Bhupendra O. Khatri, M.D., Xavier Montalban, M.D., Jean Pelletier, M.D., Ruggero Capra, M.D., Paolo Gallo, M.D., Guillermo Izquierdo, M.D., Klaus Tiel-Wilck, M.D., Ana de Vera, M.D., James Jin, Ph.D., Tracy Stites, Ph.D., Stacy Wu, M.D., Shreeram Aradhye, M.D., and Ludwig Kappos, M.D. for the TRANSFORMS Study Group, found that fingolimod prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with MS.
In this 12-month, double-blind, double-dummy study, the researchers randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months.
A total of 1153 patients (89%) completed the study, and the researchers found that annualized relapse rate was significantly lower in both groups receiving fingolimod–0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group–than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P
The researchers observe that their trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a.
In the 12-month TRANSFORMS trial, three groups who had suffered a relapse during the year before entering the study took part Many of them had been taking an injectable disease modifying treatment for MS. During the study, one group took a weekly injection of interferon beta-1a (Avonex) and a daily capsule containing a placebo. One group took the daily 0.5-mg dose of fingolimod and a weekly injection containing a placebo. One group took the daily 1.25-mg dose of fingolimod and a weekly injection of placebo.
The objectives of this study included determination of whether people taking fingolimod would have fewer relapses over the one-year study than people taking interferon beta-1a (Avonex)? Would fingolimod therapy result in fewer new lesions showing up on MRI scans over the one-year study than with people taking interferon beta-1a (Avonex)? Finally, would risk of disability progression over the one-year study period be lower in people taking fingolimod than in people taking interferon beta-1a (Avonex)?
THe researchers found a relapse rate during the one-year study of 0.16 per year for the 0.5-mg fingolimod group and 0.33 per year for the group taking Avonex, indicating that the group taking fingolimod had a 52% lower risk of having a relapse during the study period than the group taking interferon beta-1a (Avonex). Also, 82.5% of subjects taking the 0.5-mg dose of fingolimod and 70% of those taking interferon beta-1a had no relapses during the 12 months of the study, and the group taking the 0.5-mg dose of fingolimod had fewer signs of disease activity on MRI than the group taking Avonex. There was no difference among the groups in the risk of disease progression over the course of the study.
Sources:
Nature Neuroscience
The New England Journal of Medicine
The Multiple Sclerosis Trust
The Multiple Sclerosis Coalition Emerging Therapies Collaborative
U.S. Food and Drug Administration (FDA)
Novartis