Slide 1: Intervention with oral LPCN 1148 improves sarcopenia and HE in cirrhosis: 52-week phase 2 trial
Intervention with oral LPCN 1148 improves sarcopenia and hepatic encephalopathy (HE) in patients with cirrhosis: a 52-week phase 2 randomized clinical trial Dr. Arun Sanyal Director, Stravitz-Sanyal Institute for Liver Disease & Metabolic Health Virginia Commonwealth University
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation contains “forward-looking statements” that are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and include statements that are not historical facts regarding our product development efforts, our product
Slide 3: Sarcopenia is common in cirrhosis and impacts clinically meaningful outcomes
Sarcopenia is common in cirrhosis and impacts clinically meaningful outcomes • How patients feel: • Health related quality of life • How patients function: • Frailty • Activities of daily living • How patients survive: • Hepatic encephalopathy • Mortality • Peri-transplant outcomes • Health care res
Slide 4: Multiple mechanisms contribute to sarcopenia in cirrhosis
Multiple mechanisms contribute to sarcopenia in cirrhosis Androgens: • Linked to muscle mass • Inhibits myostatin • Modulates mTOR • Increases protein synthesis • Decreases turnover - 90% of males with cirrhosis have low free testosterone 1. Sinclair et al, Aliment Pharmacol Ther, Volume: 43, Issue:
Slide 5: LPCN 1148: A novel MOA for management of cirrhosis
LPCN 1148: A novel MOA for management of cirrhosis Product Oral androgen receptor agonist Candidate Dosage form comprising testosterone dodecanoate, a unique prodrug of the endogenous hormone Attributes Targeted Mechanism of Action Anabolic1 Ammonia Lowering Androgenic Increase muscle mass and Via I
Slide 6: Central Hypothesis
Central Hypothesis: LPCN 1148 will improve sarcopenia, sarcopenia related outcomes and clinically significant outcomes in patients with cirrhosis
Slide 7: Aims and objectives
Aims and objectives Specific Aims Objectives • To perform a phase 2 proof of • To generate proof of concept concept study to establish the of overall benefit of LPCN short term safety and efficacy 1148 to support further of LPCN 1148 in male development of this drug in patients with advanced the stu
Slide 8: Study population
Study population Inclusion criteria Exclusion criteria • Adult males • Failure to obtain consent • Cirrhosis • Active severe encephalopathy • Sarcopenia – defined by BMI- • Active infection adjusted SMI* • Uncontrolled or recurrent GI • Listed for liver transplantation bleed in past 6 months • Prior
Slide 9: Study design
Study design Two-arm, two stage (1:1 randomization, N=29) • Oral LPCN 1148, T dodecanoate, vs. Placebo • Standard of care treatments allowed, including HE therapies Stages: 1. 24-week placebo-controlled 2. 28-week open-label extension (OLE) • All subjects receive LPCN 1148 during OLE SCREENING TREAT
Slide 10: Endpoints
Endpoints Primary endpoint Secondary endpoints (p values not adjusted for multiplicity) • Baseline-adjusted change in Week 24 and week 52: Skeletal Muscle Index (L3 • Feel and function: region, L3-SMI) at Week 24 in • patient reported outcomes (PGI-C) LPCN 1148 treated • Survives: • acute worsening
Slide 11: Baseline characteristics
Baseline characteristics LPCN 1148 Placebo (N=15) (N=14) Age (years) 58.3 ± 7.5 58.8 ± 9.5 BMI (kg/m2) 29.2 ± 5.3 29.0 ± 8.6 L3-SMI (cm2/m2) 47.8 ±7.0 44.8 ± 8.5 MELD Score 15.9 ± 3.7 18.1 ± 4.6 Medical History ≥ 1 Decompensation Event# 14 (93%) 14 (100%) ≥ 2 Decompensation Event 13 (87%) 12 (86%) H
Slide 12: Participant disposition
Participant disposition Assessed for eligibility (N=48) Allocated LPCN 1148 (N=15) Allocated Placebo (N=14) Study discontinuation: • Withdrawal of consent following liver transplant (n=2) • Death (n=2) Completed Week 24 (n=15) Completed Week 24 (n=10) Study discontinuation: Entered Stage 2: Open lab
Slide 13: Analysis datasets
Analysis datasets LPCN 1148 switch LPCN 1148 Placebo from placebo (N=15) (N=14) (N=10) Safety set* Stage 1 15 14 --- Stage 2 11 --- 8 Modified intent-to-treat (mITT)# Stage 1 15 10 --- Stage 2 15 --- 6 • For LPCN 1148 switch from placebo, change from baseline during Stage 2 is calculated using week
Slide 14: Primary endpoint met: LPCN 1148 improves L3-SMI at week 24
Primary endpoint met : LPCN 1148 improves in L3-SMI at week 24 L3-SMI Absolute Change from Baseline Data are LS mean (SE). mITT set based on study drug compliance and having at least one post-baseline CT with LOCF. * p < 0.05 for change from baseline; ** p =0.005 vs. placebo
Slide 15: LPCN 1148 improvement in L3-SMI observed during OLE
LPCN 1148 improvement in L3-SMI observed during OLE L3-SMI Change from Baseline 12 LPCN 1148 Placebo Placebo to 1148 (n=15) (n=10) (n=6) * Change from baseline (cm2/m2) 10 * • Increased muscle area was maintained 8 through 52 weeks of treatment with 6 * LPCN 1148 * * 4 • Placebo participants signifi
Slide 16: LPCN 1148 improved myosteatosis and muscle quality at week 24
LPCN 1148 improved myosteatosis and muscle quality at week 24 Substantial Changes in Muscle Quality seen with LPCN 1148 Therapy • Significant increase in high quality muscle (HQM, +30 to +150 Hounsfield Units, HU) • Decrease in intramuscular adipose tissue (IMAT, -190 to -30 HU) Data are LS mean (SE
Slide 17: Recurrence of Overt HE was decreased with LPCN 1148
Recurrence of Overt HE was decreased with LPCN 1148 while on HE standard medication(s) LPCN 1148 switch from Placebo LPCN 1148 LPCN 1148 placebo Parameter (Through Week 24) (Through Week 24) (Week 24 to EOS) (Week 24 to EOS) N=14 N=15 N=11 N=8 History of HE prior to 11 (79%) 11 (73%) 7 (64%) 6 (75%)
Slide 18: LPCN 1148 improved hemoglobin and anemia in cirrhosis
LPCN 1148 improved hemoglobin and anemia in cirrhosis LPCN 1148 switch Placebo LPCN 1148 from placebo (Through Week 24) (Through Week 24) (Week 24 to EOS) N=14 N=15 N=8 Baseline; mean (SE) 13.2 (0.6) 11.4 (0.8) Hemoglobin (g/dL) Week 24 CFB; mean (SE) 0.0 (0.3) 0.9 (0.3)*,** -- Week 52 CFB; mean (SE
Slide 19: LPCN 1148 improved patient reported symptoms severity
LPCN 1148 improved patient reported symptoms severity Placebo LPCN 1148 LPCN 1148 switch (Through Week (Through Week from placebo 24) 52) (Week 24 to EOS) N=14 N=15 N=8 Patient Global Week 24 mean (SD) 3.8 (0.3) 3.1 (0.3)** -- Impression of Change (PGI-C) Week 52 mean (SD) -- 2.9 (0.3) 3.9 (0.7) Dat
Slide 20: LFI changes were comparable between LPCN 1148 and placebo
LFI changes were comparable between LPCN 1148 and placebo Placebo LPCN 1148 LPCN 1148 switch (Through Week (Through Week from placebo 24) 52) (Week 24 to EOS) N=14 N=15 N=8 Baseline; mean (SE) 4.0 (0.3) 4.1 (0.2) -- Liver Frailty Index Week 24 CFB; mean (SE) -0.17 (0.18) -0.17 (0.14) -- (LFI) Week 5
Slide 21: LPCN 1148: trends towards improvement in other secondary endpoints
LPCN 1148: trends towards improvement in other secondary endpoints LPCN 1148 switch Placebo LPCN 1148 LPCN 1148 from placebo (Through Week 24) (Through Week 24) (Week 24 to EOS) (Week 24 to EOS) N=14 N=15 N=11 N=8 Deaths; n (%) 2 (14%) 0 1 (9%) 0 Hospitalizations; n (%) 5 (36%) 5 (33%) 5 (45%) 1 (13
Slide 22: Overall, LPCN 1148 was well tolerated up to 52 weeks of treatment
Overall, LPCN 1148 was well tolerated up to 52 weeks of treatment LPCN 1148 switch Placebo LPCN 1148 LPCN 1148 from placebo (Through Week 24) (Through Week 24) (Week 24 to EOS) (Week 24 to EOS) N=14 N=15 N=11 N=8 Total AEs; n (%) 9 (64%) 9 (60%) 7 (64%) 7 (88%) Serious AEs; n (%) 5 (36%) 5 (33%) 5 (
Slide 23: Summary and conclusions
Summary and conclusions • Oral androgen receptor agonist LPCN 1148 improved sarcopenia in adult male patients with cirrhosis • This improvement was maintained through 52 weeks of treatment • LPCN 1148 was further associated with improvement in encephalopathy, anemia, total number of days hospitalize
Slide 24: Acknowledgements
Acknowledgements • We acknowledge the contribution of all of the investigators and staff for this trial and express our gratitude to the patients who participated in this study