A Safety andTolerability Study of Multiple Doses of ISIS-DMPKRx in Adults With Myotonic Dystrophy Type 1

A Phase 1/2a Blinded, Placebo-Controlled Study to Assess the Safety, Tolerability, and Dose-range Finding of Multiple Ascending Doses of ISIS 598769 Administered Subcutaneously to Adult Patients With Myotonic Dystrophy Type 1

This study will test the safety, tolerability, and pharmacokinetics of multiple escalating doses of ISIS-DMPKRx administered subcutaneously to adult patients with DM1.

This is a Phase 1/2a multicenter, blinded, placebo-controlled study of ISIS-DMPK Rx in adult patients with DM1.

Inclusion Criteria:

1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements

2. Males or females aged 20 to 55 years old at the time of informed consent

3. Satisfy the following:

   1. Females: non-pregnant and non-lactating, surgically sterile, post menopausal, abstinent, or if engaged in sexual relations of child-bearing potential, subject is using an acceptable contraceptive method from the time of signing the informed consent until at least 14 weeks after the last dose of Study Drug.
   2. Males: surgically sterile, abstinent or if engaged in sexual relations with a female of child-bearing potential, the subject must be using an acceptable contraceptive method from the time of signing the informed consent form until at least 14 weeks after the last dose of Study Drug.

4. BMI <35.0 kg/m2

5. Genetic confirmation of DM1 with DMPK CTG repeat length ≥ 100

6. Onset of DM1 symptoms after the age of 12

7. Clinically apparent myotonia equivalent to hand opening time of at least 2 seconds, in the opinion of the Investigator

8. Ambulatory (orthoses allowed, canes and walkers not allowed) and able to walk at least 25 meters at screening

Exclusion Criteria:

1. Clinically significant abnormalities in medical history (e.g., previous acute coronary syndrome within 6 months of screening, major surgery within 3 months of screening) or physical examination
2. Clinically significant abnormalities in screening laboratory values that would render the subject unsuitable for inclusion
3. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
4. Unwilling or unable to comply with study procedures (e.g., muscle biopsies), including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
5. Known history of or previous positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B
6. Active malignancy or history within last 5 years, except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix that has been successfully treated, or pilomatricoma
7. Treatment with another investigational drug, biologic agent, or device within one month of screening, or 5 half-lives of investigational agent, whichever is longer; any history of previous treatment with an oligonucleotide (including siRNA)
8. Recent history of or current drug or alcohol abuse
9. History of bleeding tendency or ongoing oral anticoagulation
10. Developmental delay, intellectual disability, or significant behavioral neuropsychiatric manifestations
11. Thyroid dysfunction that is untreated (if on thyroid hormone replacement therapy, need to have adequate and stable replacement over the previous 6 months)
12. Implanted device for the treatment of cardiac problems (i.e., pacemaker or defibrillator)
13. Clinically significant abnormal ECG or echocardiogram, or significant symptoms of cardiac dysfunction at Screening
14. Have a seizure disorder
15. If being treated with testosterone, on a stable replacement dose (i.e., for hypogonadism)
16. Treatment with corticosteroids within 8 weeks prior to the first dose of Study Drug
17. History of hypersensitivity to local anesthetics to be used in the biopsy procedure or components thereof
18. Treatment with anti-myotonia medication within 30 days prior to screening. May include, but not be limited to: Phenytoin, Carbamazepine, Procainamide, Disopyramide, Nifedipine, Acetazolamide, Clomipramine, Imipramine, Amytriptiline, Taurine, Quinine, Mexiletine
19. Have any condition, which, in the opinion of the investigator would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the study