Lipocine Inc. announced results from a Phase 2 clinical trial (NCT04134091) which includes LPCN 2401, an oral proprietary combination of anabolic androgen receptor agonist and a-tocopherol, an antioxidant. The results showed significant improvement in body composition through decreased FM and increased LM or fat free mass (FFM) in patients with BMI 30 (obese) or BMI 27 with at least one weight-related comorbidity. This multi-center prospective, blinded Phase 2 study included participants with obesity (BMI 30) and participants with BMI 27 with at least oneweight-related comorbidity (e.g. hypertension, type 2 diabetes, dyslipidemia), a population consistent with FDA guidance for developing products for weight management.

Participants were randomized to receive one of three treatments for 36 weeks: A) testosterone ester monotherapy capsule, B) T ester + a-tocopherol capsule (LPCN 2401), or C) matching placebo. Participants underwent Dual-Energy X-Ray Absorptiometry (DEXA) scans to measure body composition at baseline and Weeks 20 and 36. Safety and tolerability were monitored throughout the 36 weeks.

Analyses of body composition parameters, including prespecified endpoints of whole body LM and whole-body FM. Among treatments B and C, 27 participants were randomized and completed the baseline and at least one post-baseline DEXA. At baseline, mean BMI was 36.0 kg/m2 and mean age was 52.4 yrs.

LPCN 2401 intervention resulted in significant FM lost and LM gained compared to placebo; a significant improvement was noted as early as Week 20. A significant reduction in AF (fat in the area roughly between the pelvis and ribs) and a significant increase in BMC were observed in treatment B, the LPCN 2401 intervention arm. The intervention was observed to be weight neutral, with fat lost offset by lean mass gained.

An overall improvement in body composition is evidenced by substantial decrease in the fat mass to lean mass ratio. Analyses set includes all randomized participants (ITT) who have baseline DEXA data and at least one post-baseline DEXA scan. Data are arithmetic means, last observation carried forward (LOCF).

LPCN 2401 resulted in numerically greater fat mass loss than Treatment A (monotherapy). Numerical trends towards improvement in blood pressure and HbA1c with LPCN 2401 support the benefit of Treatment B relative to both placebo and Treatment A. LPCN 2401 was well-tolerated with the frequency and severity of observed treatment-emergent AEs comparable to placebo. No GI or muscle spasm adverse events were reported by participants receiving LPCN 2401.

Approximately 74% of US adults age 20 and older are either obese or overweight, and an estimated 30% of the US adult population have BMI = 30 kg/m2. Obesity is a chronic, relapsing health risk defined by excess body fat. Excess body fat increases the risk of death and major comorbidities such as type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, osteoarthritis of the knee, sleep apnea, and some cancers (Caterson and Hubbard et al.

2004; Calle and Thun et al. 1999). Reportedly (Flynn et al.

Morgan Stanley, February 27, 2024), approximately 24M obese elderly are most vulnerable to losing muscle mass. The rapid weight loss observed with the approved weight management medications includes unwanted LM loss, up to 40% of the patient's total weight lost. Moreover, discontinuation of these therapies frequently results in a rapid regain in weight.

Loss of LM has multiple negative health implications including weakness/fatigue, lowered metabolism which can cause a regain in fat mass, declines in neuromuscular function, potential effects on emotion and psychological states, and increased risk of injury. Several recent studies showed that body composition, especially lean body mass (muscle) may play an independent role in survival of patients with diseases such as cancer and cardiovascular diseases (DH Lee and EL Giovannucci, Exp Biol Med. 2018).

Therefore, a focus on body composition in obesity management to sustainably lose FM while maintaining LM should be an essential goal. There is a significant unmet need for an oral, efficacious, muscle preserving/gaining option for chronic obesity/weight management that ameliorates the loss of LM associated with GLP-1/GIP agonist treatment, resulting in a higher quality weight loss. Moreover, there is a need for a chronic long-term pharmacotherapy option to maintain weight upon cessation of incretin mimetic therapy, prevent fat/weight rebound "overshoot" and minimize lag in muscle recovery to prevent collateral fattening.

LPCN 2401 is an oral formulation of a proprietary combination of anabolic androgen receptor agonist and a-alpha tocopherol, an antioxidant metabolic modifier. Data from preclinical and clinical studies support the potential of LPCN 2401 in gaining lean mass while losing fat mass. As adjunct therapy to incretin mimetics, LPCN 2401 has potential to attenuate weight rebound, ameliorate loss of muscle mass, improve muscle quality and functionality, amplify fat mass loss with improved body composition, and potential to maintain weight, prevent "fat overshoot," and accelerate muscle rebound post incretin mimetic discontinuation.