Efficacy and Safety of RZL-012 on Submental Fat Reduction

A Double Blind, Randomized, Three Arm, Placebo-Controlled Phase 2b Study to Evaluate the Efficacy and Safety of RZL-012 in Subjects Seeking for Submental Fat Reduction

A total of 135 eligible male or female subjects will be randomized according to a predetermined randomization scheme (1:1:1 ratio) to receive a single multi-injection treatment of high dose RZL-012, low dose RZL-012, or placebo on Day 0. They will be monitored for safety and efficacy over 84 days.

Each subject will be randomized to either active treatment (high or low dose RZL-012) or placebo at a ratio of 1:1:1 per group and receive one of the following:

• low dose (concentration of injected solution 34 mg/mL RZL-012) of 5.1 mg/0.15 mL/injection point that results in a dose/volume of 163.2±20.4 mg/4.8±0.6 mL RZL-012,
• high dose (concentration of injected solution 50 mg/mL RZL-012) of 7.5 mg/0.15 mL/injection point that results in a maximum total dose/volume of 240±30 mg/4.8±0.6 mL RZL-012,
• placebo of 0.15 mL/injection point that results in a total maximum volume of 4.8±0.6 mL.

Subjects treated with RZL-012 will undergo a single treatment session with 32±4 injections. The maximal number of injections will be 36 with maximal doses of 183.6 mg and 270 mg for the low and high doses, respectively. Each injection point will be dosed with 5.1 mg RZL-012 for the low dose or 7.5 mg for the high dose in a volume of 0.15 mL/injection site. Placebo (vehicle) subjects will be injected with a 0.15 mL vehicle per each injection site. The maximal injection volume for all groups will be up to 5.4 mL.

Inclusion Criteria:

1. Is a male or female subject between the ages of 18 and 65 years, inclusive.

2. Has body mass index (BMI) between >22 and <40.

3. Has SMF area that is contiguous and fits to 32±4 injections sites according to a grid with 1 cm distance between injection points.

4. Has moderate to severe grade 3 to 4 of SMF as rated by the C-SFS.

5. Has moderate to severe grade 3 to 4 of SMF as rated by the P-SFS.

6. Has stable weight, with no fluctuation of >5 kg in the past 12 months.

7. If female, is not pregnant or breastfeeding based on the following:

   • agree to the use of highly effective contraceptive methods for at least 2 weeks before baseline until 7 days after the last day of study drug and a negative serum pregnancy test (ß-hCG) at screening and negative urine pregnancy test at baseline; or
   • is of nonchildbearing potential defined as clinically infertile as the result of surgical sterilization (hysterectomy, bilateral tubal ligation, and/or bilateral oophorectomy); or
   • is confirmed postmenopausal status (defined as either having amenorrhea for ≥ 12 consecutive months without another cause and documented serum follicle-stimulating hormone (FSH) level > 40 mIU/mL or another documented medical condition (e.g., was born without a uterus)) NOTE: The following are considered highly effective contraceptive methods: hormonal oral contraceptives, injectables, and patches; intrauterine devices; double-barrier methods (synthetic condom, diaphragm, or cervical cap used with spermicidal foam, cream, or gel); and male partner sterilization.

8. If male (with or without vasectomy), agree to the use of highly effective contraceptive methods (as listed in Criterion #7 above) from study check-in until 7 days after the last day of study drug.

9. Is willing to avoid strenuous exercise for seven (7) days post treatment.

10. Is able to adhere to the visit schedule and protocol requirements and be available to complete the study.

11. Is willing and able to sign an Institutional Review Board (IRB) approved informed consent form (ICF) indicating that they are aware of the investigational nature of the study.

Exclusion Criteria:

Subjects must NOT meet any of the following Exclusion criteria to be eligible for enrollment:

1. Is unable to tolerate subcutaneous injections.
2. Has dysfunctional gallbladder activity (e.g., underwent cholecystectomy or cholecystitis).
3. Has any uncontrolled systemic disease that is not stabilized (i.e., cardiovascular disease, mental illness).
4. Has had treatment with botulinum toxin injections in the neck or chin area within nine (9) months prior to screening.
5. Has used anticoagulation therapies that may increase bleeding or bruising (i.e., aspirin, ibuprofen, vitamins, and herbal preparations) for seven (7) days prior to treatment.
6. Has skin laxity (i.e., elastosis, skin crepiness, skin redundancy, skin draping, vertical and/or horizontal skin bands and folds, blunting of cervical mental angle, loss of opposition of skin to underlying neck structures due to skin laxity) that could obscure the evaluation and treatment of SMF.
7. Has an extreme fat bulge under the chin and the submental fat was previously rated as 'very severe'.
8. Has fat extends down the neck beyond the Adam's Apple, towards the base of the neck where the fat extends laterally along the jawline making the jawline indistinguishable from the neck.
9. Has any scars, unshaven hair, tattoos, facial hair or jewelry on or near the proposed treatment area.
10. Has presence of structures or confounding factors that may interfere with assessing SMF such as but not limited to enlarged submandibular salivary and/or parotid glands, micrognanthia, chin implant, soft tissue volume augmentation of chin and/or jawline, pronounced platysmal bands and deep necklace lines or presence of facial jowls that could obscure the evaluation of SMF.
11. Has significant history or current evidence of a medical, psychological or other disorder that, in the Investigator's opinion, would preclude enrollment in the study.
12. Has an active dermatitis or open wound in the proposed treatment area.
13. Has abnormal coagulation tests (PT, PTT)
14. Has D-dimer value >0.64mg/L in screening visit
15. Has an active bacterial, fungal, or viral infection in the proposed treatment area.
16. Has a pre-existing skin condition in the submental region that, at the Investigator's discretion, may confound evaluation or analysis.
17. Has previously had treatments or surgery in the submentum, such as but not limited to, focused ultrasound, radiofrequency, cryolipolysis, liposuction, sodium deoxycholate, or neck lift.
18. Has pre-existing neurological or gastrointestinal condition leading to dysphagia, dysphonia, or facial nerve palsy.
19. Has Dercum's Disease
20. Has any pre-existing medical condition other than increased SMF that, at the Investigator's discretion, may result in increased submental fullness, such as but not limited to, thyroid enlargement, goiter, cervical lymphadenopathy, etc.
21. Has a planned fat reduction procedure of any variety to the submental region for the duration of the study.
22. Has medication or a history of coagulopathy.
23. Has a history or family history of venous thrombotic disease.
24. Has been treated chronically at least three (3) months prior to study entry with systemic steroids or immunosuppressive drugs.
25. Has been treated chronically at least one (1) week prior to study entry with non-steroidal anti-inflammatory drugs (NSAIDs).
26. Current participation or participation within three (3) months prior to the start of this study in a drug or other investigational research study.
27. Has claustrophobia or an MRI incompatible device or implant.