Gilis‐Januszewska, Aleksandra

Abstract Context Adult growth hormone (GH) deficiency (GHD) is characterized by metabolic abnormalities caused by insufficient GH production. Lonapegsomatropin, a prodrug administered once weekly, was designed to provide sustained release of unmodified somatropin to reduce the burden of daily somatropin injections. Objective This work aimed to evaluate the efficacy and safety of lonapegsomatropin vs placebo as treatment for adults with GHD. Methods The foresiGHt trial was a multicenter, randomized, parallel-arm, placebo-controlled (double-blind) and active-controlled (open-label) trial (NCT04615273) conducted at 116 centers in North America, Europe, and Asia-Pacific. The trial randomly assigned and dosed 259 adults with GHD. Participants were randomly assigned 1:1:1 to receive once-weekly lonapegsomatropin, once-weekly placebo, or daily somatropin for 38 weeks. The primary efficacy end point was change from baseline in trunk percent fat at week 38. Secondary efficacy end points included change from baseline in trunk fat mass and total body lean mass. Results At week 38, lonapegsomatropin significantly reduced trunk percent fat (−1.68% vs +0.37%; least squares [LS] mean difference −2.04%; P < .001), increased total body lean mass (+1.60 kg vs −0.11 kg; LS mean difference 1.70 kg; P < .0001), and reduced trunk fat mass (−0.48 kg vs +0.22 kg; LS mean difference −0.70 kg; P = .0053) vs placebo. The safety and tolerability profile of lonapegsomatropin was comparable to somatropin. Conclusion The foresiGHt trial met its primary efficacy end point by demonstrating superiority of lonapegsomatropin vs placebo with similar safety and tolerability, supporting its potential as a once-weekly treatment option for adults with GHD.

Abstract Disclosure: B.M. Biller: Consulting Fee; Self; HRA Pharmaceuticals, Novartis Pharmaceuticals, Sparrow, Strongbridge Biopharma. Grant Recipient; Self; Strongbridge Biopharma. A. Gilis-Januszewska: Speaker; Self; Ipsen, Novartis Pharmaceuticals, Novo Nordisk, Recordati, Teva Pharmaceutical Industries Ltd.. M. Doknic: None. A.M. Pico: None. M. Fleseriu: Consulting Fee; Self; Ascendis, GlaxoSmithKline, Johnson &Johnson, Karyopharm, Novo Nordisk, Pfizer, Inc., Pharmacosmos. Research Investigator; Self; Ascendis. G. Raverot: None. A.M. Isidori: None. Y. Takahashi: None. J.M. Garcia: None. J.M. Silverstein: None. I. Bancos: None. E. Huang: Employee; Self; Ascendis Pharma, Inc. J. Kang: Employee; Self; Ascendis Pharma, Inc. A.S. Komirenko: Employee; Self; Ascendis Pharma, Inc. L. Domrzalski: Employee; Self; Ascendis Pharma, Inc. A. Shu: Employee; Self; Ascendis Pharma, Inc. K. Yuen: Advisory Board Member; Self; Amryt, Ascendis, Corcept, Crinetics, Novo Nordisk, Recordati, Strongbridge, Xeris. Grant Recipient; Self; Amryt, Ascendis, Corcept, Crinetics. Speaker; Self; Corcept, Novo Nordisk, Recordati. Background: Adult GHD (aGHD) is characterized by metabolic abnormalities due to insufficient growth hormone (GH) production. Lonapegsomatropin was designed to provide sustained release of unmodified somatropin, with the identical amino acid sequence as endogenous GH, and once-weekly injection reduces the burden of daily GH replacement therapy. MethodsForesiGHt was a randomized, parallel-3-arm, placebo(PL)-controlled (double-blind) and active-controlled (open-label) trial designed to establish the efficacy and safety of lonapegsomatropin in aGHD. It evaluated 259 adults with GHD across 21 countries who were GH treatment-naïve or not treated with GH in the prior year, randomized 1:1:1 to receive lonapegsomatropin, once-weekly PL, or daily somatropin (dGH). Fixed dosing was based on age and oral estrogen intake, and designed to be comparable across lonapegsomatropin and dGH arms. Following a 12-week (w) titration period to target maintenance dose, fixed doses were administered for 26w. ResultsBaseline (BL) characteristics were similar between arms. Lonapegsomatropin demonstrated superiority on the primary efficacy endpoint of change from BL in trunk percent fat at Week 38 vs PL (lonapegsomatropin -1.7% vs PL 0.4%, LS mean difference -2.0%, p < 0.0001) and on the key secondary efficacy endpoints of change from BL in total body lean mass (lonapegsomatropin 1.6 kg vs PL -0.1 kg, LS mean difference 1.7 kg, p < 0.0001) and change from BL in trunk fat mass (lonapegsomatropin -0.5 kg vs PL 0.2 kg, LS mean difference -0.7 kg, p = 0.0053). Mean total exposure and maintenance doses were similar for lonapegsomatropin and dGH arms, with larger changes from BL in average IGF-I SDS mean at Week 38 in the lonapegsomatropin arm (1.4) vs dGH arm (0.5). To assess outcomes at comparable weekly IGF-I exposure, a post-hoc analysis was performed in a subset of participants with average IGF-I SDS ≤1.75 SDS at Week 38. Mean IGF-I SDS for these subsets were similar (lonapegsomatropin -0.1, dGH -0.5), and comparable effects in fat and lean tissue compartments were demonstrated (change from BL in trunk percent fat mean -2.4% and -2.6% respectively; change from BL in total body lean mass mean 1.7 kg and 1.4 kg respectively). In the safety population, the incidence of severe AEs was low (lonapegsomatropin, 3.4%; placebo, 1.2%; dGH, 2.3%) and the incidence of treatment-related AEs was similar (lonapegsomatropin 24.7%, dGH 22.1%). Injection site reaction incidence was low and similar for lonapegsomatropin (4.5%), dGH (5.8%) and placebo (4.8%), and A1c levels remained stable in all treatment arms. ConclusionsThe results of the foresiGHt trial indicate that lonapegsomatropin is a safe, efficacious, and tolerable replacement for endogenous GH. Once-weekly dosing may be impactful for adults with GHD who typically manage multiple other medical therapies. Presentation: 6/3/2024

Abstract Disclosure: D. Ferone: Consulting Fee; Self; Camurus AB, Ipsen, Novartis-AAA, Recordati. Grant Recipient; Self; Camurus AB, Ipsen, Novartis-AAA, Recordati. Research Investigator; Self; Camurus AB. J.L. Spencer-Segal: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. G. Fidan Yaylali: None. M. Doknic: Speaker; Self; Pfizer, Inc., Novo Nordisk, Merck, Sandoz. E. Isaeva: None. A. Dreval: None. A. Gilis-Januszewska: None. E. Gezer: None. I. Bancos: Advisory Board Member; Self; Diurnal, Spruce, Neurocrine, Adrenas, Sparrow, Corcept, HRA Pharmaceuticals, Recordati, Xeris, AstraZeneca, Novo Nordisk. Grant Recipient; Self; Recordati, HRA Pharmaceuticals. L. Katznelson: Advisory Board Member; Self; Camurus AB, Recordati. M. Harrie: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A. Svedberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A.M. Pedroncelli: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. F. Tiberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. Background: Acromegaly is a rare, serious disorder characterized by overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). There is a need for new, convenient therapies that provide effective disease control. CAM2029 is a novel subcutaneous octreotide depot designed for convenient once-monthly self-administration (ready-to-use syringe or injection pen). In a 24-week, Phase 3 trial (ACROINNOVA 1), CAM2029 was superior to placebo at attaining IGF-1 response (≤upper limit of normal [ULN] at week 22/24: 72.2% vs 37.5%; P=0.0018) in patients with acromegaly previously controlled under standard of care (SoC; octreotide long-acting repeatable [LAR]/lanreotide Autogel). Here, we report interim data from another Phase 3 trial of CAM2029 (ACROINNOVA 2; NCT04125836), focusing on the “New to CAM2029” subgroup of patients whose acromegaly was either controlled or uncontrolled under SoC. Methods: This 52-week, Phase 3, open-label trial (with a 52-week extension) enrolled patients who had received CAM2029 or placebo in ACROINNOVA 1 (reported separately) and “New to CAM2029” patients who were adequately or inadequately controlled (IGF-1 ≤2x ULN) on a stable dose of octreotide LAR/lanreotide Autogel for ≥3 months (data reported here). In the main part of the trial, new patients received once-monthly CAM2029 20 mg for up to 52 weeks. The primary endpoint was adverse events (AEs). Secondary endpoints included (i) the proportion of patients with IGF-1 ≤1x ULN (weeks 50/52 mean), (ii) the change from baseline in IGF-1, and (iii) the combined IGF-1 and GH response. Baseline values reflected SoC treatment. Data cutoff: May 23, 2023. Results: Eighty-one new patients were enrolled (mean age 51.8 years; 59.3% female). No new or unexpected safety signals were observed. The most common treatment-emergent AEs were injection site erythema (n=22) or swelling (n=13), and headache (n=12). AEs were mostly mild (grade 1/2); there were no serious or Grade 3 treatment-related AEs attributed to CAM2029. IGF-I response increased from 14.8% at baseline SoC (12/81) to 33.3% (20/60 patients with available data) at weeks 50/52. The estimated increase in IGF-1 response (linear probability model) from baseline at week 52 was 21.9% (95% CI: 9.6, 34.1). Biochemical control for both IGF-1 and GH improved over time: 30.0% of patients (18/60) had a combined IGF-1 and GH response at the end of the main part of trial, vs 11.7% (7/60) at baseline. Conclusion: CAM2029 was well tolerated with a safety profile consistent with that of SoC. Biochemical control rates improved from SoC baseline over 52 weeks of CAM2029 treatment in the “New to CAM2029” patients. These findings reinforce the efficacy and safety of CAM2029 in patients with acromegaly, including patients with uncontrolled disease with current SoC treatment (octreotide LAR/lanreotide Autogel). Presentation: 6/1/2024