A Phase 1 Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Single Dose of SRP-5051 in Patients with Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping Treatment
Study ID: STU 112017-056
This is a first-in-human, open-label, single-dose trial evaluating a single dose (0.3, 1.0, 2.0, 4.0, or 6.0 mg/kg) of SRP-5051 in up to 30 patients with genetically confirmed DMD who have deletion mutations amenable to exon 51 skipping treatment. each patient will complete 3 trial periods: Screening Period will be up to 2 weeks in duration, Treatment and observation Period will be 4 weeks in duration, and 8 week Safety Follow-up Period. on Day 1, patients will receive a single dose of SRP-5051 (either 0.3, 1.0, 2.0, 4.0, or 6.0 mg/kg) administered as an intravenous (iV)infusion over 60 (+-) 5 minutes. Patients will remain inpatient during Days 1 and 2, and return to the clinic on Day 3, Week 2, and Week 4 for continued safety monitoring. at Week 4, a muscle biopsy will be collected to assess exon skipping and dystrophin protein levels. assignment of patients to the 5 treatment groups will occur sequentially, starting with the 0.3 mg/kg dose. escalation to the next dose will occur based on a safety data review performed by a Safety Review Committee (SRC). The safety and tolerability of a single dose of SRP-5051 dosed at 0.3, 1.0, 2.0, 4.0, or 6.0 mg/kg will be assessed through a review and evaluation of the following: * adverse events * Serious adverse events * Dose-limiting toxicities * Clinical laboratory testing (hematology, coagulation, chemistry, immunogenicity, and urinalysis findings). * Kidney injury safety biomarkers (including kidney injury marker [KiM]-1, urine albumin, and clusterin) * other clinical assessments (eCG and eCHo findings, vital signs, and physical examination findings). From the plasma PK samples, the following PK parameters will be determined, as appropriate, using noncompartmental analysis: * Maximum plasma concentration (Cmax) * Time to maximum plasma concentration (Tmax) * area under the plasma concentration-curve (auC0-t and auC0- [?]) * Volume of distribution at the terminal phase (Vz) * Volume at steady state (Vss) * elimination half-life (t[1/2])) * Plasma clearance (CL) From the urine collections the following PK parameters will be determined, as appropriate, using noncompartmental analysis: * amount excreted in urine over 24 hours (ae0-24) * Renal clearance (CLR) * Percent of administered dose excreted renally * Percent of total clearance due to renal clearance The following pharmacodynamics assessments will be performed using tissue from a biopsy of the gastrocnemius muscle collected at Week 4 (+-) 1 week. * exon 51 skipping using polymerase chain reaction (PCR) methods * Dystrophin levels by Western blot and iHC, if feasible
1. Is male. 2. Has a genetic diagnosis of DMD and an out-of-frame deletion mutation of the DMD gene amenable to exon 51 skipping treatment. 3. Be >=12 years of age. 4. Has been on a stable dose of oral corticosteroids for at least 12 weeks prior to study drug administration, or has not received corticosteroids for at least 12 weeks prior to study drug administration. 5. If sexually active, agrees to use, a male condom during such activity for the entire duration of the study and for 90 days after the last dose. The sexual partner must also use a medically acceptable form of contraceptive during this time frame. The approved methods of contraception include: male condom with spermicide (foam, gel, film, cream, or suppository); sterile sexual partner (eg, tubal ligation, tubal occlusion, hysterectomy and/or bilateral oophorectomy, or bilateral salpingectomy); or by female sexual partner, established use of hormonal contraceptives, use of an intrauterine device with copper or intrauterine system with progestogen, barrier contraceptive (condom, diaphragm, or cervical/vault caps) used with spermicide. Abstinence (eg, calendar, ovulation, symptothermal post-ovulation methods) is not an acceptable method of contraception. Patients sexually active with a pregnant partner must agree to use condoms until 90 days following drug administration. 6. Is willing to provide informed consent or informed assent (if applicable) and has (a) parent(s) or legal guardian(s) who is (are) willing to provide written informed consent for the patient to participate in the study.
- Cancer Related
- Healthy Volunteers
- UT Southwestern Principal Investigator
- DIANA PATRICIA CASTRO
Primary objective: evaluate the safety and tolerability of 5 escalating doses of SR-5051 (0.3, 1.0, 2.0, 4.0,or 6.0 mg/kg) administered as a single dose to patients with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping treatment. Secondary objective: Determine the pharmacokinetic (PK) profile of 5 escalating doses of SR-5051 (0.3, 1.0, 2.0, 4.0,or 6.0 mg/kg) administered as a single dose to patients with DMD amenable to exon 51 skipping treatment. exploratory objectives: Demonstrate evidence of mechanism of action (exon skipping and dystrophin production)following a single dose of SRP-5051 (0.3, 1.0, 2.0, 4.0, or 6.0 mg/kg; and, identify major metabolites of SRP-5051 in the plasma and urine.