Tapencarium (RZL-012) for Flank Fat Reduction: A Proof-of-Concept Study.

Background: RZL-012 is a novel cytolytic drug that has shown promise in reducing localized fat deposits in a single treatment session. Objectives: To assess the safety and efficacy of injecting RZL-012 to the flanks. Methods: A double-blind, placebo-controlled, proof of concept study randomized 12 patients to receive RZL-012 injections in 1 flank and placebo injections in the contralateral flank. After 12 weeks of follow-up, patients could receive RZL-012 in the placebo-treated flank and undergo follow-up for 12 weeks in the open-label phase. Results: At 12 weeks, Investigator Global Aesthetic Improvement Scale assessments showed improvement for 90.9% of RZL-012-treated flanks and 0% of placebo-treated flanks (P < .0001), 81.8% of patients were satisfied with the RZL-012-treated flanks, and 9.1% were satisfied with the placebo-treated flanks (P = .0019). Volume reduction measured on 3-dimensional images was a mean 37.27 mL, which was significantly greater than placebo (P = .0052). The product was well tolerated, with no clinically significant trends in laboratory values, electrocardiograms, or vital signs. Pharmacokinetic analyses demonstrated that RZL-012 is quickly absorbed, reaches maximum concentration in approximately 1.67 h, and has a half-life of 9.1 h. The mean maximal concentration of RZL-012 found in the blood was <1 µg/mL. Conclusions: RZL-012 is a promising option for injectable fat reduction of the flanks in a single treatment session. The drug was well tolerated in this small patient population, with no concerning safety signals, and it had indications of efficacy. Further research is needed in large Phase 2 studies with robust efficacy measurements to confirm these early findings.

Efficacy and Safety of Tapencarium (RZL-012) in Submental Fat Reduction.

BACKGROUND: Tapencarium (RZL-012) (5-(3.6-dibromo-9H-carbazol-9-yl)-N, N, N-trimethylpentan-1-aminium chloride) is a novel injectable synthetic molecule with cytolytic properties, capable of reducing subcutaneous fat volume. OBJECTIVES: The goal of this 3-armed, randomized, double-blind, placebo-controlled phase 2b study was to determine the safety and efficacy of low- and high-dose RZL-012 vs placebo on submental fat (SMF) reduction. METHODS: Patients (n = 151, age 18-65 years) with excess SMF received a single treatment session of RZL-012 or placebo in the submental area, after which they were monitored for 84 days. SMF was assessed at baseline and after dosing with newly developed scales, namely the Clinician Chin Assessment Tool (C-CAT) and Subject Chin Assessment Tool (S-CAT). SMF was also assessed by magnetic resonance imaging (MRI) at screening and on Day 84 after treatment. RESULTS: The proportion of patients who had a 1-grade or 2-grade improvement in C-CAT and/or S-CAT on Day 84 vs baseline was significantly higher in the high-dose RZL-012 group vs the placebo group (P < .002). The relative percentage reduction in MRI-measured SMF volume (Day 84 vs screening) was significantly greater in the high-dose RZL-012 group vs the low-dose RZL-012 or the placebo group (P < .0001). Local injection site reactions were the most common adverse events (AEs). CONCLUSIONS: A single administration of RZL-012 into SMF resulted in significant improvement in submental appearance as assessed by clinicians, patients, and MRI. From a safety perspective, there were no serious AEs and no clinically significant changes in vital signs or laboratory tests over the course of the study.

Mode of Action of RZL-012, a New Fat-Reducing Molecule.

BACKGROUND: RZL-012 (5-[3,6-dibromo-9H-carbazol-9-yl]-N,N,N-trimethylpentan-1-aminium chloride) is a novel investigational drug injected subcutaneously into fat tissues in patients with fat-related disorders (Dercum disease) or subjects seeking aesthetic changes. OBJECTIVE: Preclinical studies were undertaken to understand RZL-012's mechanism of action. MATERIALS AND METHODS: The effects of RZL-012 were tested in vitro by measuring adipocyte cell killing, membrane integrity, cytosolic calcium, and mitochondrial membrane potential (MMP). In vivo studies in pigs evaluated RZL-012's adipocyte killing effect and measured pig fat thickness in the injected areas. RESULTS: RZL-012 triggered adipocyte cell killing with IC50 values ranging from 25 to 106 µM. RZL-012 demonstrated initial effects on membrane integrity and calcium levels with delayed alterations in MMP. Incubation of RZL-012 with nanoghosts increased membrane permeability, culminating in full membrane destruction. Analysis of injected areas in pigs revealed liponecrosis 24 hours after dosing followed by an inflammatory response and formation of fibrotic tissue. Three months after dosing, an 18% reduction in mean fat thickness was observed in RZL-012 treated pigs. CONCLUSION: RZL-012 destroys adipocytes by directly disrupting cell membrane integrity. Replacement of dead fat tissue by fibrotic tissue enables healing and causes contraction of the injected area. These effects are translated into significant reduction in fat tissue volume.