Methods of treatment of myotonic dystrophy type 1

Abstract

A method of treating myotonic dystrophy type 1 (DM1) by administering a peptide-PMO conjugate (Compound 1).

Description

METHODS OF TREATMENT OF MYOTONIC DYSTROPHY TYPE 1FIELD

[0001] The present disclosure relates to methods for treatment of myotonic dystrophy type 1.INTRODUCTION

[0002] Myotonic dystrophy type 1 (DM1) is a serious, progressive, disabling genetic disease that leads to early death in many patients. DM1 is inherited in an autosomal dominant manner and is characterized by progressive muscle weakness, myotonia (delayed muscle relaxation after contraction), and other systemic manifestations. DM1 affects at least 1 in 10,000 people worldwide or approximately 110,000 people in the United States and Europe (see Ashizawa T, Gagnon C, Groh WJ, Gutmann L, Johnson NE, Meola G, et al. Consensus-based care recommendations for adults with myotonic dystrophy type 1. Neurol Clin Pract, 2018;8(6):507-20; Myotonic Dystrophy Foundation. Myotonic Dystrophy Clinical Research Network.Available at: myotonic.org / myotonic-dystrophy-clinical-research-network; and Johnson NE, Butterfield RJ, Mayne K, Newcomb T, Imburgia C, Dunn D, et al. Population-based prevalence of myotonic dystrophy type 1 using genetic analysis of statewide blood screening program. Neurology. 2021;96(7):e1045-53).

[0003] The clinical presentation of DM1 varies considerably among patients with the disease, but in nearly all cases multiple systems throughout the body are affected. Muscular weakness and myotonia are the cardinal clinical symptoms of DM1. Fatigue is among the most impactful symptoms of DM1, due to the combination of muscle weakness, respiratory failure, sleep disordered breathing, and excessive daytime sleepiness (see Heatwole C, Bode R, Johnson N, Quinn C, Martens W, McDermott MP, et al. Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1). Neurology. 2012;79(4):348-57; and Johnson NE. Myotonic Muscular Dystrophies. Continuum (Minneap Minn). 2019;25(6): 1682-95). Symptom onset is typically in the third decade of life, with progressive weakness leading to approximately 50% of patients being wheelchair bound by time of death (see Turner C, Hilton-Jones D. Myotonic dystrophy: diagnosis, management and new therapies. Curr Opin Neurol. 2014;27(5):599-606; and de Die-Smulders CE, Hbweler CJ, Thijs C, Mirandolle JF, Anten HB, Smeets HJ, et al. Age and causes of death in adult-onset myotonic dystrophy Brain. 1998, 121 (Pt 8): 1557-63 ) Theaverage age of death in non-congenital forms of DM I is 54 years of age. with 70% of early mortality caused by cardio-respiratory complications.

[0004] The underlying molecular cause of DM1 is an expanded CTG repeat sequence in the 3’ untranslated region in one allele of the DM1 Protein Kinase (DMPK) gene. The CTG trinucleotide repeat is transcribed into an RNA containing a toxic CUG repeat, where it forms "hairpins" that sequester multiple proteins involved in splicing of various downstream transcripts into “nuclear foci”, including muscleblind-like protein 1 (MBNL1). The resulting systemic missplicing leads to downstream consequences in many cell types including muscle.

[0005] Currently, there is no cure for DM1. Treatments focus on managing the symptoms of DM1 manifested on a patient basis. No US Federal and Drug Administration approved treatments exist that target the cause of DM1, the expanded CTG.

[0006] Biologic macromolecules, such as oligonucleotides, hold enormous potential as therapeutic agents, for example, to treat DM1. However, a challenge in bringing biologic macromolecule therapies to the clinic is their limited ability to access the intracellular compartment when administered systemically. As such there is a need for administration of effective DM1 treatments, such as, for example, biological macromolecule treatments.SUMMARY

[0007] The present disclosure describes methods of treatment of myotonic dystrophy type 1 using Compound 1 in a human patient.DETAILED DESCRIPTION

[0008] The present disclosure describes treatment of myotonic dystrophy type 1 (DM1) in a patient comprising administering a pharmaceutical composition comprising Compound 1 to the patient. In some embodiments, 2-8 mg of Compound 1 is administered per kg of the patient. In some embodiments, more than one dose of a pharmaceutical composition comprising 2-8 mg / kg of Compound 1 is administered to the patient to treat DM1. In some embodiments, a second dose of a pharmaceutical composition comprising Compound 1 is administered to the patient six weeks after a first dose In some embodiments, multiple doses of a pharmaceutical composition comprising 2-8 mg / kg of Compound 1 are administered to the patient at dosing intervals of six weeks.

[0009] The underlying molecular cause of DM1 is an expanded CTG repeat sequence in the 3' untranslated region in one allele of the DM1 protein kinase (DMPK gene. The CTG trinucleotide repeat is transcribed into an RNA containing a toxic CUG repeat. The CUG repeats bind various proteins involved in splicing, including muscleblind-like protein 1 (MBNL1). Protein-bound DMPK mRNA can aggregate in the nucleus to form nuclear foci. Due to the sequestration of splicing factors, the splicing of various genes is disrupted including MBLN1, CLCN1, AP2A1, RYR1, KIF13A, VSP39, NFIX, CLASP, BINI, and others. The resulting systemic mis-splicing leads to downstream consequences that can manifest as DM1 clinical symptoms.Compound 1

[0010] Compound 1 has the structure:Compound 1

[0011] Compound I is designed to target the cause of DM1. It is hypothesized that hybridization of the phosphorodiamidate morpholino oligomer (PMO) portion of Compound 1 to at least a portion of the CUG repeat of a DMPK transcript can sterically block proteins (e.g., MBNL1) from binding to the expanded CUG repeat regions. The free proteins, which are not bound to the CUG repeat of the DMPK transcript, are available to affect proper splicing of various downstream genes. Additionally, hybridization of the PMO portion to at least a portion of the CUG repeat of a DMPK transcript can prevent the formation of the DMPK transcript containing nuclear foci associated with the DM1 disease state. As such, in embodiments, Compound 1 can be used to rescue the mis-splicing of downstream genes / transcripts, thereby, reducing the level of downstream transcripts associated with the DM1 disease phenotype, increasing the level of dowmstream genes / transcripts associated with a healthy phenotype, or both.

[0012] Compound 1 may be a free base or in the form of a pharmaceutically acceptable salt. In the context of pharmaceutical compositions that include a liquid carrier (such as those described herein), the free base or pharmaceutically acceptable salt forms of Compound 1 may be ionized Unless otherwise stated. Compound 1 is described as its form before formulation with at least a carrier to form a pharmaceutical composition.

[0013] Compound 1 can be a pharmaceutically acceptable salt of Compound 1. For example, the drug substance can be a pharmaceutically acceptable acid addition salt of Compound 1. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66. 1-19. In instances where a drug substance is in the form of a pharmaceutically acceptable salt, the salt may be classified in view of the counterion that is used to neutralize the charge of the ionized drug substance. Pharmaceutically acceptable counterions include, for example, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bicarbonate, bisulfate, bitartrate, borate, butyrate, bromide, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, cyclopentanepropionate, dihydrochloride, digluconate, dodecyl sulfate, edetate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glutamate, glucoheptonate, glycollyl arsanilate, glycerophosphate, 2-hydroxy-ethanesulfonate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, iodide, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nitrate, nicotinate, oleate, oxalate, palmitate, pamoate, pectinate,persulfate, 3 -phenyl propionate, phosphate, picrate, pivalate, propionate, pantothenate, polygalacturonate, stearate, succinate, salicylate, sulfate, subacetate, tartrate, tannate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0014] In one or more embodiments, the drug substance may be a Compound 1 acid addition salt Non-limiting examples of pharmaceutically acceptable acid addition salts include salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art, such as ion exchange.

[0015] In some embodiments the compound may be a bis (ionized at two positions) or tris (ionized at three positions) salt.

[0016] As used herein, unless otherwise specified, reference to Compound 1 includes the free base (free form) of Compound 1, pharmaceutically acceptable salts of Compound 1, and hydrates of Compound 1.

[0017] Compound 1 can be synthesized in any suitable manner. For example, the PMO portion of Compound 1 can be synthesized by solid phase synthesis (see, e.g., Contini A, et al. Biochem Biophys Res Comm. 2021. 549(16): 8; Paul S., Caruthers MH. Molecules. 2023. 28(14):5380; U.S. Patent No. 8,299,206; and U. S. Patent No. 5,185,444). The peptide portion of Compound 1 may be synthesized in any suitable manner and may be conjugated to the PMO portion in any suitable manner (see, e.g., U.S. Patent No. 11,225,506; U. S Published Patent Application Nos.2023 / 0020092 Al, 2024 / 0358845 Al, and 2023 / 0312653 Al, and PCT Patent Application Publication No. WO 2022 / 271818 Al.Pharmaceutical Compositions

[0018] Compound 1 can be formulated into a pharmaceutical composition comprising a pharmaceutically acceptable carrier. The pharmaceutical composition can be administered to a patient in need of treatment. The pharmaceutical composition can be administered to a patient as a treatment for DM1.

[0019] The pharmaceutical composition can include a pharmaceutically acceptable carrier. A carrier is a solvent, dispersion medium, vehicle, diluent, carrier solution, suspension, colloid, or the like. The use of carriers in pharmaceutical compositions is well known in the art. Except insofaras any conventional media or agent is incompatible with Compound 1, its use in the pharmaceutical composition is contemplated,

[0020] In embodiments, the pharmaceutically acceptable carrier includes water. In embodiments, the water carrier is a buffered aqueous solution, that is, the solution includes one or more agents that allow the solution to resist change in pH when exposed to certain amounts of acid and / or base. A buffered aqueous solution includes at least one weak acid and its conjugate base or at least one weak base and its conjugate acid. The weak acid and its conjugate base or the weak base and its conjugate acid are derived from buffering agents that are weak acids, weak bases, or salts thereof. As such, in embodiments, the pharmaceutical composition includes one or more buffering agents and the ions thereof. Buffering agents are salts of weak acids and / or salts of weak bases. Examples of buffering agents include, but are not limited to, acetic acid or salts thereof (e.g., acetate salts); monosodium and / or disodium phosphate or other phosphate salts; maleic acid or salts thereof (e.g., maleate salts), citric acid or salts thereof (e.g., citrate salts), histidine or salts thereof (e.g., histidine sodium salt); tartaric acid or salts thereof (e.g., tartrate salts); lactic acid or salts thereof (e.g., lactate salts); succinic acid or salts thereof (e.g., succinate salts); carbonic acid or salts thereof (e g, bicarbonate salts), and tromethamine and salts thereof.

[0021] In embodiments, the carrier includes water, and the water solution is not buffered, that is, the water solution does not include buffering agents.

[0022] In embodiments, the carrier includes various salts such as, for example, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium hydroxide, or any combination thereof.

[0023] In embodiments, the pharmaceutical composition includes one or more isotonic agents, such as sodium chloride, dextrose, mannitol, glycerol, or a combination thereof. In embodiments, the pharmaceutical composition includes sodium chloride. In embodiments, the pharmaceutical composition includes normal saline (e.g., isotonic saline) that includes about 0.9% (w / v) sodium chloride. In embodiments, the pharmaceutical composition includes 0.86% (w / v) to 0.94% (w / v) sodium chloride. In embodiments, the pharmaceutical composition includes 0.88% (w / v) to 0.92% (w / v) sodium chloride. In embodiments, the pharmaceutical composition includes 0.89% to 0.91% (w7'v) sodium chloride.

[0024] In embodiments, the pharmaceutical composition includes dextrose. In embodiments, the pharmaceutical composition includes about 5% (w / v) dextrose

[0025] In embodiments, the pharmaceutical composition includes both sodium chloride and dextrose. In embodiments, the pharmaceutical composition includes half-normal saline which includes about 0.45% (w / v) sodium chloride and about 5% (w / v) dextrose. In embodiments, the pharmaceutical composition includes quarter-normal saline which includes about 0.22% (w / v) sodium chloride and about 5% (w / v) dextrose.

[0026] The pharmaceutical composition may have a certain pH. The pH may enhance the solubility of the drug substance. The pH of a solution can be measured or calculated using techniques known in the art, for example, according to US Pharmacopeia 791. In embodiments, the pharmaceutical composition has a pH of 6.5 to 7.5.

[0027] Various acids and / or bases may be used to adjust the pH of a pharmaceutical formulation. In the case that the pH of the pharmaceutical composition is adjusted using an acid and / or base or salt thereof, the pharmaceutical composition includes the ions of the acid and / or base or salt thereof used to adjust the pH. In embodiments where the pH of the pharmaceutical composition is adjusted, sodium hydroxide and / or hydrochloric acid is used to adjust the pH.

[0028] In embodiments, the concentration of Compound 1 in a pharmaceutical composition is 30 mg / mL to 70 mg / mL. In embodiments, the concentration of Compound 1 in a pharmaceutical composition is 30 mg / mL or greater, 35 mg / mL or greater, 40 mg / mL or greater, 45 mg / mL or greater, 50 mg / mL or greater, 55 mg / mL, or greater, 60 mg / mL or greater, or 65 mg / mL or greater In embodiments, the concentration of Compound 1 in a pharmaceutical composition is 40 mg / mL to 60 mg / mL. In embodiments, the concentration of Compound 1 in a pharmaceutical composition is 45 mg / mL to 55 mg / mL. In embodiments, the concentration of Compound 1 in a pharmaceutical composition is 50 mg / mL.

[0029] In embodiments, the pharmaceutical composition is a sterile solution prepared by incorporating Compound 1 in the required amount in the appropriate carrier with or without various other ingredients, followed by filter sterilization.

[0030] In embodiments, the pharmaceutical composition may be in a form in which it will be administered to a patient. In embodiments, the pharmaceutical composition is in a form that will be diluted prior to administration to a patient. For example, the pharmaceutical composition may be in a form that will be added to an intravenous infusion bag to be delivered to a patient.

[0031] In embodiments, kits comprising the pharmaceutical composition are provided. In embodiments, the pharmaceutical composition is in a concentrated form to be diluted prior toadministration, and the kit comprises a pharmaceutically acceptable carrier and / or diluent that may be used to dilute the pharmaceutical composition. The pharmaceutically acceptable carrier or diluent may be a pure substance such as water or may include additional components of the pharmaceutical composition such as isotonic agents, buffers, or other agents In embodiments, a kit includes instructions or packaging materials that describe how to use the components of the kit, for example, how to dilute the pharmaceutical composition prior to administration. In embodiments, the kit comprises an ampoule or syringe containing the pharmaceutical composition described herein.Methods of Administration

[0032] The present disclosure describes methods of administering Compound 1 or a pharmaceutical composition containing the same to a patient having DM1. The administration may be for treatment of myotonic dystrophy type 1 (DM1). As such, in embodiments, the present disclosure describes a method for treating DM1 in a patient, the method including administering Compound 1 or a pharmaceutical composition containing the Compound 1 to the patient.

[0033] The terms “treat,” “treatment,” “treating,” and the like generally mean the administration of Compound 1 to a patient to reduce, correct, limit progression, ameliorate, or resolve, to any extent, a symptom, clinical sign, or biophysical manifestation related to DM1. The terms, “improve,” “increase,” “correct,” “reduce,” “decrease,” and the like, as used herein, indicate values that are relative to a control. In embodiments, a suitable control is a baseline measurement, such as a measurement in the same individual prior to administration of Compound 1 a pharmaceutical composition containing the Compound 1 to the patient.

[0034] Compound 1 or a pharmaceutical composition containing the Compound 1 may be administered to treat a patient that is diagnosed with DM1.

[0035] Compound 1 or a pharmaceutical composition containing the Compound 1 can be administered after the patient first exhibits a symptom or clinical sign of DM1. Treatment initiated after the patient first exhibits a symptom or clinical sign associated with DM1 may result in decreasing the severity of symptoms and / or clinical signs of DM1, and / or completely resolve the symptoms of DM1.

[0036] Compound 1 or a pharmaceutical composition containing the Compound 1 can be administered in any suitable manner. In embodiments, the pharmaceutical composition is administered intravenously. In embodiments where the pharmaceutical composition isadministered intravenously, the pharmaceutical composition is administered as a bolus or as an infusion. A bolus is typically administered using a syringe or an intravenous drip over a short period of time. In embodiments, the bolus is administered in a time period of 30 minutes or less, for example, less than 5 minutes, less than 1 minute, or less than 30 seconds. An infusion is the administration over a longer period of time. In embodiments, Compound 1 or a pharmaceutical composition containing Compound 1 is administered by infusion over a time period of 30 min or greater. Infusion may be continuous. In embodiments Compound 1 or a pharmaceutical composition containing Compound I is infused at a constant rate. In embodiments, Compound 1 or a pharmaceutical composition containing Compound 1 is infused at rates that change over the course of the infusion.

[0037] In embodiments, the method includes administering to a patient 2 mg / kg to 8 mg / kg dose of Compound 1. In embodiments, the method includes administering to a patient a 2 mg / kg dose of Compound 1. In embodiments, the method includes administering to a patient a 4 mg / kg dose of Compound 1. In embodiments, the method includes administering to a patient a 8 mg / kg dose of Compound 1. The dose administered may be in the form of a pharmaceutical composition.

[0038] In embodi ments, the time between any two doses of Compound 1 is referred to herein as a dosing interval. The amount of Compound 1 in each dose of a dosing interval can be the same or different. When more than two doses are administered, the dosing interval between sets of doses may be the same or different. For example, a first dosing interval may be 3 weeks, and a second dosing interval may be 4 weeks.

[0039] In embodiments, two or more doses of Compound 1 are administered at a dosing interval of 6 weeks.

[0040] In embodiments, the method of administration further includes preparing a dosage. In embodiments, the method includes diluting a concentrated drug product from a kit. In embodiments, the drug product is diluted with normal saline to achieve a desired concentration in a desired volume for administration.Clinical Outcomes

[0041] Administration of Compound 1 to a subject can result in a variety of clinical outcomes. For example, treatment may result in an increase of correctly spliced mRNA in various genes whose mis-splicing is associated with DM1. Treatment may improve one or more clinical symptoms associated with DM1. For example, treatment may improve pulmonary and / or muscle function.

[0042] A clinical outcome may be observed or measured at any time post-administration of a dose of Compound 1 to a subject. For example, a clinical outcome may be observed or measured 1 hour, 1 day, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks post administration of a dose of Compound 1 to a subject.

[0043] The terms, “improve,” “increase,” “correct,” “reduce,” “decrease,” and the like, as used herein, indicate values that are relative to a control. In embodiments, a suitable control is a baseline measurement, such as a measurement in the same individual prior to administration of Compound 1.

[0044] Treatment of myotonic dystrophy type-1 (DM1) with Compound 1 can be assessed by a number of methods, for example, but not limited to:• Change from baseline in percent predicted quantitative myometry testing (ppQMT) over time;• Change from baseline in video hand opening time (vHOT) over time;• Proportion of subjects with normalized myotonia, as defined by vHOT time of <2 seconds;• Change from baseline in the timed up and go (TUG) over time;• Change from baseline in 10-meter walk / run (10MWR) over time; and• Pulmonary function over time,

[0045] QMT measures isometric force using dynamometer, and can be improved in a 12-week exercise study with associated quality of life improvement in individuals with DM1 (see, Roussel MP, et ah Neuromuscul Disord. 2020;30(4):283-93; and Mikhail AI, et al. J Clin Invest.2022;132(10):e156125). HOT is a measurement of the time to open the hand from a grip position, is linked to splicing correction (see, Mulders SA, et al. Proc Natl Acad Sci U S A.2009; 106(33): 13915-20). HOT can be video recorded (vHOT). TUG measures the time it takes for a seated individual to stand, walk 3 meters, turn around, return to the chair, and sit (see, Knak KL, et al. Ann Clin Transl Neurol. 2020;7(8): 1382-91; and Nicolini-Panisson RD and Donadio MV. Rev Paul Pediatr. 2013;31(3):377-83). TUG measures balance and fall risk, one of the top symptoms impacting quality of life in individuals with DM1 (see, Shumway-Cook A, et al.Physical Therapy. 2000;80(9):896-903). The 10MWR test captures the time to travel 10 meters at comfortable and maximal safe speeds and is a recommended muscle function endpoint in individuals with DM1 (see, Knak KL, et al. Ann Clin Transl Neurol. 2020;7(8): 1382-91; Gagnon C, et al. J Neuromuscul Dis. 2018;5(4):523-37; Horrigan J, et al. Pediatr Neurol. 2020,112:84-93; and Knak KL, et al. Neurology. 2020;94(24):e2508-20).

[0046] The effect of Compound 1 on disease burden in subjects with DM1 can be evaluated utilizing DM1 -ActivC, MDHI-SF, PGI-S, and PGI-C assessments. DMl-ActivC is a 25-item self-administered questionnaire that covers a wide range of daily and social activities and represents the preliminary 146 items based on the WHO-ICF classification of activities and participation from which it was derived. This scale captures personal ability to execute a task where the patient is requested to determine whether he / she can complete such a task independently. It was initially developed in 2010 (see, Hermans MC, et al. Neuromuscul Disord.2010;20(5):310-8.), but re-constructed in 2015 (see, Hermans et al. PLoS One.2015; 10(10):e0139944), and the current version encompasses a total of 25 items, each described in three levels. The mean item scores ranged from 0 (“Not possible to perform”) to 2 (“Possible, without any difficulty”), with a mean transformed total instrument score ranging between 0 and 100, where a higher / lower score indicates a higher / lower ability to perform activities of daily living (ADL). MDHI-SF is a 17-item self-administered questionnaire designed to measure the overall level of disease burden in a patient with myotonic dystrophy type- 1 (,«?<?, Heatwole C, et al. Muscle Nerve. 2014;49(6):906-14, and Heatwole C, et al. Muscle Nerve. 2016;53 (2): 183- 90.) It covers 17 domains relevant to the adult myotonic dystrophy population on a 6-point scale: mobility, upper extremity function, ability to perform activities, fatigue, pain, gastrointestinal issues, vision, communication, sleep, emotional issues, cognitive impairment, social satisfaction, social performance, myotonia, breathing, swallowing, and hearing. This is a short version of the original scale MDHI that consists of 114 items across these 17 domains and can be completed rapidly by patients in approximately 1 to 2 minutes The total score ranges from 0 to 100 with a higher score reflecting a greater degree of symptoms. PGI scales measure disease severity (PGI- S) and change in clinical condition (PGI-C) (Official PGI-C, PGI-I, PGI-S | Patient Global Impressions scale - Change, Improvement, Severity distributed by Mapi Research Trust | ePROVIDE, accessed 7 March 2025 at https: / / eprovide. mapi-trust.org / instruments / patient-global-impressions-scale-change-improvement-severity ). PGI-S is a self-administeredquestionnaire that rates the severity of the patient’s overall status over the past week. The rating uses 5 responses ranging from “None” to “Very severe.” PGI-C is a self-administered questionnaire that addresses the patient’s overall status since the start of the study. The rating uses a 7-point scale that range from 1 (“Very much improved”) to 7 (“Very' much worse”).Certain Definitions

[0047] In the description and claims, the term “and / or” means one or all of the listed elements or a combination of any two or more of the listed elements: the terms “comprises,” “comprising,” and variations thereof are to be construed as open ended — i.e., additional elements or steps are optional and may or may not be present; unless otherwise specified, “a,” “an,” “the,” and “at least one” are used interchangeably and mean one or more than one; and the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0048] As used herein, “have,” “has,” “having,” “include,” “includes,” “including,” “comprise,” “comprises,” “comprising” or the like are used in their open-ended inclusive sense, and generally mean “include, but not limited to,” “includes, but not limited to,” or “including, but not limited to.”

[0049] As used in the description and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such compositions, reference to “an agent” includes mixtures of two or more such agents, reference to “the component” includes mixtures of two or more such components, and the like.

[0050] In the description, particular embodiments may be described in isolation for clarity. Reference throughout this specification to “embodiments,” “one embodiment,” “an embodiment,” “certain embodiments,” “one or more embodiments,” or “some embodiments,” etc., means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments. Thus, features described in the context of one embodimentmay be combined with features described in the context of a different embodiment except where the features are necessarily mutually exclusive.

[0051] In several places throughout the above description, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

[0052] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and / or animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0053] A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

[0054] All publications, patents and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications, patents and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

CLAIMS1. A method of treating myotonic dystrophy type-1 (DM1) in a patient in need thereof comprising:administering to the patient 2-8 mg of Compound 1 per kg of the patient’s weight.

2. The method of claim 1, wherein 2 mg / kg of Compound 1 is administered.

3. The method of claim 1, wherein 4 mg / kg of Compound 1 is administered.

4. The method of claim 1, wherein 8 mg / kg of Compound 1 is administered.

5. The method of any one of claims 1 to 4, wherein Compound 1 is administered to the patient every 6 weeks.

6. The method of any one of claims 1 to 5, wherein administering Compound 1 to the patient comprises administering a pharmaceutical composition comprising Compound 1 to the patient.

7. The method of claim 6, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier8. The method of claim 7, wherein the pharmaceutically acceptable carrier is saline,9. The method of any of claims 1 to 8, wherein the administration is intravenousadministration.

Images