IP Library › Granted Patent US 12,226,413
Granted Patent B2
US 12,226,413 · App. 17/194,703 · Granted Feb 18, 2025

Early treatment of CMT disease

Inventors: Daniel Cohen (Saint Cloud, FR); Ilya Chumakov (Vaux le Pénil, FR); Rodolphe Hajj (St. Germain en Laye, FR); Aude Milet (Antony, FR); Serguei Nabirochkin (Chatenay Malabry, FR); Klaus-Armin Nave (Göttingen, DE); Thomas Prukop (Duderstadt, DE); Michael Sereda (Göttingen, DE)
Assignee: PHARNEXT
A61K31/485A61K31/047A61K31/197C12Q1/6883C12Q2600/156
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Quick Facts
Patent No.
US 12,226,413
App. No.
17/194,703
Granted
Feb 18, 2025
Kind
B2
Abstract

The present invention provides methods for treating, preventing, or delaying the onset of Charcot-Marie-Tooth Disease type 1A (CMT1A), by administering to a subject in need thereof a combination comprising baclofen, sorbitol and naltrexone, or a pharmaceutically acceptable salt thereof.

Claims (25)

1. A method of treating Charcot Marie Tooth type 1A disease (CMT1A) in a subject bearing a duplication or mutation of a PMP22 gene, comprising the step of administering to the subject a combination of baclofen, sorbitol, and naltrexone, or a pharmaceutically acceptable salt thereof, effective to treat CMT1A; wherein the subject is a human of 7 years of age or less; is at an early stage of the disease; and is showing no or few physiological or morphological signs of CMT1A; and wherein the method provides in said subject a long term reduction of a sign, symptom, or clinical manifestation of CMT1A for at least 1 year.

2. The method according to claim 1 , wherein the duplication or mutation of the PMP22 gene in the subject is identified by a genetic test.

3. The method according to claim 1 , wherein the subject has a Charcot-Marie-Tooth Neuropathy Score (CMTNS) below 8.

4. The method according to claim 1 , wherein the subject has a Charcot-Marie-Tooth Disease Pediatric Scale score (CMTPedS) below 30.

5. The method according to claim 1 , wherein the subject has an Overall Neuropathy Limitations Scale score (ONLS) of 0.

6. The method according to claim 1 , wherein the subject is asymptomatic.

7. The method according to claim 1 , wherein the subject is about 6 years of age or less.

8. The method according to claim 1 , wherein the subject has a Charcot-Marie-Tooth Neuropathy Score (CMTNS) below 8; a Charcot Marie Tooth Disease Pediatric Scale score (CMTPedS) below 30; and an Overall Neuropathy Limitations Scale score (ONLS) of 0.

9. The method according to claim 1 , comprising administering to the subject simultaneously or sequentially a combination of baclofen, naltrexone, and sorbitol, wherein the baclofen is administered at a dose of between about 0.3 mg and about 12 mg, sorbitol at a dose of between about 10.5 mg and about 420 mg, and naltrexone at a dose between about 0.035 mg and about 1.4 mg.

10. The method according to claim 1 , wherein the baclofen, sorbitol, and naltrexone are administered sequentially or simultaneously at a relative weight ratio of baclofen/sorbitol/naltrexone of x/y/1, wherein: x is between about 2 and about 20; and y is between about 100 and about 500.

11. The method according to claim 9 , wherein the baclofen, sorbitol, and naltrexone are administered sequentially or simultaneously at a relative weight ratio of baclofen/sorbitol/naltrexone of about 8.6/300/1.

12. The method according to claim 9 , wherein the subject is administered a combination of (R/S) baclofen, sorbitol, and naltrexone.

13. The method according to claim 11 , wherein the subject is administered a combination of (R/S) baclofen, sorbitol, and naltrexone.

14. The method according to claim 1 , wherein the combination is administered chronically to the subject.

15. The method according to claim 1 , wherein the combination is administered transiently for a period of 5 years or less to the subject.

16. The method according to claim 1 , wherein the method provides a reduction in a sign, symptom, or clinical manifestation of CMT1A for at least 1 year, as compared with a patient who is treated beginning at a more advanced stage of CMT1A with the combination of baclofen, sorbitol, and naltrexone, or pharmaceutically acceptable salt thereof.

17. The method according to claim 16 , wherein the method provides a reduction in a sign, symptom, or clinical manifestation of CMT1A for at least 5 years.

18. The method according to claim 16 , wherein the reduction in a sign, symptom, or clinical manifestation of CMT1A comprises an improvement in the subject's CMTNS and/or CMTPedS and/or ONLS and/or Compound Muscle Action Potential (CMAP) scores.

19. The method according to claim 17 , wherein the reduction in a sign, symptom, or clinical manifestation of CMT1A comprises an improvement in the subject's CMTNS and/or CMTPedS and/or ONLS and/or Compound Muscle Action Potential (CMAP) scores.

20. The method according to claim 1 , wherein the method provides a delay in a sign, symptom, or clinical manifestation of CMT1A for at least 1 year, as compared with a patient who is treated beginning at a more advanced stage of CMT1A with the combination of baclofen, sorbitol, and naltrexone, or pharmaceutically acceptable salt thereof.

21. The method according to claim 20 , wherein the method provides a delay in a sign, symptom, or clinical manifestation of CMT1A for at least 5 years.

22. The method according to claim 20 , wherein the delay comprises a Charcot-Marie-Tooth Neuropathy Score (CMTNS) below 8 for at least 1 year.

23. The method according to claim 20 , wherein the delay comprises a Charcot Marie Tooth Disease Pediatric Scale score (CMTPedS) below 30 for at least 1 year.

24. The method according to claim 20 , wherein the delay comprises an Overall Neuropathy Limitations Scale score (ONLS) of 0 for at least 1 year.

25. The method according to claim 21 , wherein the delay comprises an Overall Neuropathy Limitations Scale score (ONLS) of 0 for at least 5 years.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2022
From: COHEN, DANIEL; CHUMAKOV, ILYA; HAJJ, RODOLPHE; MILET, AUDE; NABIROCHKIN, SERGUEI; NAVE, KLAUS-ARMIN; PRUKOP, THOMAS; SEREDA, MICHAEL
To: PHARNEXT
Reel/Frame 060674/0543 →
Continuity (4)
Continuation 16505000 · Jul 8, 2019
Continuation 15619074 · Jun 9, 2017
Provisional Application 62348276 · Jun 10, 2016
Related Publication 20210260053A1 · Aug 26, 2021
References Cited (104)
US 7592372B2 · Osugi · 2009 [cited by applicant]
US 8716269B2 · Cohen et al. · 2014 [cited by applicant]
US 8992891B2 · Cohen et al. · 2015 [cited by applicant]
US 9393241B2 · Cohen et al. · 2016 [cited by applicant]
US 9427436B1 · Cohen et al. · 2016 [cited by applicant]
US 9566275B2 · Cohen et al. · 2017 [cited by applicant]
US 10300015B2 · Cohen et al. · 2019 [cited by applicant]
US 10322101B2 · Cohen et al. · 2019 [cited by applicant]
US 10383870B2 · Cohen et al. · 2019 [cited by applicant]
US 10441558B2 · Cohen et al. · 2019 [cited by applicant]
US 10463640B2 · Cohen et al. · 2019 [cited by applicant]
US 10583135B2 · Cohen et al. · 2020 [cited by applicant]
US 10849851B2 · Cohen et al. · 2020 [cited by applicant]
US 10905686B2 · Cohen et al. · 2021 [cited by applicant]
US 10940147B2 · Cohen et al. · 2021 [cited by applicant]
US 20030069213A1 · Ii et al. · 2003 [cited by applicant]
US 20050038062A1 · Burns et al. · 2005 [cited by applicant]
US 20050187290A1 · Fontes et al. · 2005 [cited by applicant]
US 20050220863A1 · Han · 2005 [cited by applicant]
US 20070099947A1 · Dean et al. · 2007 [cited by applicant]
US 20070110801A1 · Perovitch et al. · 2007 [cited by applicant]
US 20070299098A1 · Tanabe · 2007 [cited by applicant]
US 20080206332A1 · Kidney et al. · 2008 [cited by applicant]
US 20080255062A1 · Fernyhough et al. · 2008 [cited by applicant]
US 20120040940A1 · Cohen et al. · 2012 [cited by applicant]
US 20120270836A1 · Cohen et al. · 2012 [cited by applicant]
US 20130059676A1 · Angeli · 2013 [cited by applicant]
US 20130085122A1 · Cohen et al. · 2013 [cited by applicant]
US 20130090307A1 · Cohen et al. · 2013 [cited by applicant]
US 20170165256A1 · Cohen et al. · 2017 [cited by applicant]
US 20200155491A1 · Cohen et al. · 2020 [cited by applicant]
US 20200237750A1 · Cohen et al. · 2020 [cited by applicant]
CA 2727064A1 · 2009 [cited by applicant]
DE 102006016990A1 · 2007 [cited by applicant]
EP 0778023A1 · 1997 [cited by applicant]
EP 2065038A1 · 2009 [cited by applicant]
EP 2263665A1 · 2010 [cited by applicant]
TR 2007134136A2 · 2007 [cited by applicant]
WO 2000020024A2 · 2000 [cited by applicant]
WO 0249607A2 · 2002 [cited by applicant]
WO 2003077867A2 · 2003 [cited by applicant]
WO 2004006911A2 · 2004 [cited by applicant]
WO 2004019938A1 · 2004 [cited by applicant]
WO 2004103263A2 · 2004 [cited by applicant]
WO 2005032555A2 · 2005 [cited by applicant]
WO 2005053612A2 · 2005 [cited by applicant]
WO 2006117573A1 · 2006 [cited by applicant]
WO 2007134077A2 · 2007 [cited by applicant]
WO 2009068668A1 · 2009 [cited by applicant]
WO 2009153291A1 · 2009 [cited by applicant]
WO 2010139627A1 · 2010 [cited by applicant]
WO 2011054759A1 · 2011 [cited by applicant]
WO 2012117076A2 · 2012 [cited by applicant]
WO 2014195394A1 · 2014 [cited by applicant]
Fledrich et al., “Soluble neuregulin-1 modulates disease pathogenesis in rodent models of Charcot-Marie-Tooth disease 1A,” Nature Medicine, vol. 20, 2014, pp. 1055-1061. [cited by applicant]
Gabreëls-Festen et al., “Charcot-Marie-Tooth disease type 1A: morphological phenotype of the 17p duplication versus PMP22 point mutations,” Acta Neuropathologica, vol. 90, 1995, pp. 645-649. [cited by applicant]
Chumakov et al., “Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy,” Orphan… [cited by applicant]
Shy et al., “Reliability and validity of the CMT neuropathy score as a measure of disability,” Neurology, vol. 64, 2005, pp. 1209-1214. [cited by applicant]
Murphy et al., “Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease,” Journal of the Peripheral Nervous System, vol. 16, 2011, pp. 191-198. [cited by applicant]
Burns et al., “Validation of the Charcot-Marie-Tooth disease pediatric scale as an outcome measure of disability,” Annals of Neurology, vol. 71, 2012, pp. 642-652. [cited by applicant]
Graham et al., “A modified peripheral neuropathy scale: the Overall Neuropathy Limitations Scale,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 77, 2006, pp. 973-976. [cited by applicant]
Mandel et al., “A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment,” Orphanet Journal of Rare Diseases, vol. 10, 2… [cited by applicant]
Sereda et al., “A transgenic rat model of Charcot-Marie-Tooth disease,” Neuron, vol. 16, 1996, pp. 1049-1060. [cited by applicant]
Meyer Zu Horste et al., “Antiprogesterone Therapy Uncouples Axonal Loss from Demyelination in a Transgenic Rat Model of CMT1A Neuropathy,” Annals of Neurology, vol. 61, 2007, pp. 61-72. [cited by applicant]
Rivlin et al., “Objective clinical assessment of motor function after experimental spinal cord injury in the rat,” Journal of Neurosurgery, vol. 47, 1977, pp. 577-581. [cited by applicant]
Maxwell et al., “Two rapid and simple methods used for the removal of resins from 1.0 micron thick epoxy sections,” Journal of Microscopy, vol. 112, 1978, pp. 253-255. [cited by applicant]
Prukop et al., “An Experimental Trial of an Early Onset Treatment with a Combinational Drug (PXT3003) Consisting of Baclofen, Naltrexone, Sorbitol in the CMT1A Rat Model,” Peripheral Nerve Society Meeting, Presentation,… [cited by applicant]
No Author Listed, Peripheral Nerve Society Meeting Program, Jun. 27-Jul. 2, 2015 (238 pages). [cited by applicant]
Berenbaum et al., “Synergy, Additivism and Antagonism in Immunosuppression: A Critical Review,” Clinical & Experimental Immunology, vol. 28, No Month Listed 1977, pp. 1-18. [cited by applicant]
International Search Report and Written Opinion issued by the European Patent Office as International Searching Authority for International Application No. PCT/EP2008/066468 mailed Mar. 3, 2009 (14 pages). [cited by applicant]
International Search Report and Written Opinion issued by the European Patent Office as International Searching Authority for International Application No. PCT/EP2014/061664 mailed Jun. 30, 2014 (10 pages). [cited by applicant]
Li et al., “Effect of Baclofen Combined with Neural Facilitation Technique on the Reduction of Muscular Spasm in Patients with Spinal Cord Injury,” Neural Regeneration Research, vol. 2, No. 8, Aug. 2007, pp. 510-512. [cited by applicant]
MHRA, “Baclofen 5MG/5ML Oral Solution,” Retrieved from the Internet <http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con094157.pdf> Aug. 2, 2010 (22 pages). [cited by applicant]
Pharminfotech, “Baclofen,” Formulation in Pharmacy Practice—eMixt, Retrieved from the Internet <http://www.pharminfotech.co.nz/manual/Formulation/mixtures/baclofen.html> Aug. 31, 2011 (2 pages). [cited by applicant]
Weimer et al., “Medication-Induced Exacerbation of Neuropathy in Charcot-Marie-Tooth Disease,” Journal of Neurological Science, vol. 242, No. 1-2, No Month Listed 2006, pp. 47-54. [cited by applicant]
Slavik, J. et al. “In Vitro Correlates of in Vivo Rapamycin Therapy in Patients with Multiple Sclerosis,” Clinical Immunology, vol. 119, Jan. 1, 2006, p. S113. [cited by applicant]
Pomara, N. et al. “Mifepristone (RU 486) for Alzheimer's disease,” Neurology, vol. 58, No. 9., May 1, 2002, p. 1436. [cited by applicant]
Gallagher, P. et al. “Persistent effects of mifepristone (RU-486) on cortisol levels in bipolar disorder and schizophrenia,” Journal of Psychiatric Research, vol. 42, No. 12, Oct. 1, 2008, pp. 1037-1041. [cited by applicant]
Herrmann, D. N. et al. “Experimental Therapeutics in Hereditary Neuropathies: The Past, the Present and the Future,” Neurotherapeutics, vol. 5, No. 4, Jan. 1, 2008, pp. 507-515. [cited by applicant]
Gironi, M. et al. “A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis,” Multiple Sclerosis, vol. 14, No. 8, Sep. 1, 2008, pp. 1076-1083. [cited by applicant]
Cintas, P. et al. “Drug therapy for symptomatic relief in ALS-Quels sont les traitements medicamenteux syptomatiques?” Revue Neurologique, vol. 162, Jun. 1, 2006, pp. 4S235-4S243. [cited by applicant]
Norris, F. H. et al. “Trial of Baclofen in Amyotrophic Lateral Sclerosis,” Archives of Neurology, vol. 36, Nov. 1, 1979, pp. 715-716. [cited by applicant]
Lees, A. J. et al. “Baclofen in Parkinson's disease,” Journal of Neurology, Neurosurgery & Psychiatry, vol. 41, Jan. 1, 1978, pp. 707-708. [cited by applicant]
Chemidex Pharma Ltd. “Lyflex 5mg/5m1 Oral Solution” XP-002476376, retrieved from the Internet:http://emc.medicines.orq.uk/emc/assets/c/html/DisclavDoc.asp?document ID=14939, Apr. 14, 2008. [cited by applicant]
Wilcock, G. K. et al. “A placebo-controlled, double-blind trial of the selective AB-42 lowering agent, flurizan (MPC-7869, (R)-flurbiprofen) in patients with mild to moderate Alzheimer's disease,” Alzheimer's & Dementia… [cited by applicant]
Written Opinion in International Application No. PCT/EP2010/057438, Nov. 4, 2010, pp. 1-19. [cited by applicant]
Bassi et al., “Encephalomyelitis with Thyrotoxicosis,” Journal of Neurology, vol. 218, No Month Listed 1978, pp. 293-295. [cited by applicant]
Coffey et al., “Familial Trigeminal Neuralgia and Charcot-Marie-Tooth Neuropathy—Report of Two Families and Review,” Surgical Neurology, vol. 35, Jan. 1, 1991, pp. 49-53. [cited by applicant]
Colombo et al., “Effects of the Combination of Naltrexone and Baclofen on Acquisition of Alcohol Drinking Behavior in Alcohol-Preferring Rats,” Drug and Alcohol Dependence, vol. 77, No. 1, No Month Listed 2005, pp. 87-9… [cited by applicant]
Genetics Home Reference: Your Guide to Understanding Genetics Conditions. “Charcot-Marie-Tooth Disease,” Dec. 11, 2012 <http://ghr.nlm.nih.gov/condition/charcot-marie-tooth-disease/show/print> (15 pages). [cited by applicant]
Grandis et al., “Current Therapy for Charcot-Marie-Tooth Disease,” Current Treatment Options in Neurology, vol. 7, No. 1, No Month Listed 2005, pp. 23-31. [cited by applicant]
Magnaghi et al., “GABA Receptor-Mediated Effects in the Peripheral Nervous System—A Cross-Interaction with Neuroactive Steroids,” Journal of Molecular Neuroscience, vol. 28, No. 1, No Month Listed 2006, pp. 89-102. [cited by applicant]
RightDiagnosis.com http://www.rightdiagnosis.com/n/neuropathy/subtypes.htm. Accessed Feb. 28, 2014 (pp. 1-9). [cited by applicant]
Stella et al., “Prodrug Strategies to Overcome Poor Water Solubility,” Advanced Drug Delivery Reviews 59, No Month Listed 2007, pp. 677-694. [cited by applicant]
Zu Horste, G. M. et al. “Myelin disorders: Causes and Perspectives of Charcot-Marie-Tooth Neuropathy,” Journal of Molecular Neuroscience, vol. 28, No. 1, Jan. 1, 2006, pp. 77-88. [cited by applicant]
Keltner, J. L. “Myotonic Pupils in Charcot-Marie-Tooth Disease, Successful Relief of Symptoms with 0.025% Pilocarpine,” Achieves of Ophthalmology, vol. 93, No. 11, Jan. 1, 1975, pp. 1141-1148. [cited by applicant]
Chambliss, W.G., Sodium Acetate monograph in Handbook of Pharmaceutical Excipients 5th ed. (2006), pp. 654-655. [cited by applicant]
Jones, D., Chapter 1: Pharmaceutical Solutions for Oral Administration. In Pharmaceutics—Dosage Form and Design, 1E (2008). [cited by applicant]
SciFinder® Sorbitol Search Results (2018). Copyright © 2018 American Chemical Society (ACS). [cited by applicant]
Garcia et al., “Charcot-Marie-Tooth disease type 1A with 17p duplication in infancy and early childhood”, Neurology, 50 (4): 1061-1067 (1998). [cited by applicant]
CMTPEDS (http://calculator.cmtpeds.ord/,2015) (Year: 2018). [cited by applicant]
Haberlova et al., “Utility of Charcot-Marie-Tooth Neuropathy Score in children with type 1A disease”, Pediatr Neurol., 43(6): 407-10 (2010). [cited by applicant]
Bird (NCBI, GeneReviews, 1998, p. 1-41). [cited by applicant]
CMT-NINDS, 2017 (https://www.ninds.nih.gov/Disorders/Patient-caregiver-education/Fact-sheets/Charcot-Marie-Tooth-Disease-Fact-Sheet, 2017). [cited by applicant]