Increlex (mecasermin) / Ipsen, Eton Pharma, Esteve - LARVOL DELTA

Long-Term Treatment With rhIGF-1 in GHIS (clinicaltrialsregister.eu) - P2/3 | N=92 | Sponsor: Ipsen Biopharmaceuticals Inc

New P2/3 trial

Real-World Effectiveness and Safety of Recombinant Human IGF-1 Treatment in Naïve Prepubertal Patients with Severe Primary IGF-I Deficiency at Near-Adult Height: Results from the Global IGFD Registry (ENDO 2025) - P | "Background: The Global Increlex® Growth Forum Database (IGFD) Registry monitors the real-world effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF-1; Increlex® [mecasermin]) in treating patients aged 2-18 years with growth failure due to severe primary insulin-like growth factor-I deficiency (SPIGFD)... There was a significant gain in HtSDS from rhIGF-1 initiation to NAH in NPP patients. Patients who initiated treatment at a younger vs older age had a marginally greater HtSDS gain to NAH."

Clinical • Real-world • Real-world effectiveness • Real-world evidence • Pediatrics

IC03. Diagnosis and Treatment of Severe Primary IGF-1 Deficiency (SPIGFD) (ENDO 2025) - "The Endocrine Society thanks the following supporters: Funded Eton Pharmaceuticals How to diagnosis Severe Primary IGF-1 Deficiency (SPIGFD) Safety and Efficacy of Increlex (mecasermin) Appropriate Utilization and Dosing of Increlex (mecasermin)"

IGF1

Near-adult height outcomes in patients treated with rhIGF-1 for severe growth failure: real-world IGFD Registry data. (PubMed, J Clin Endocrinol Metab) - P | "In a real-world setting, despite patients with SPIGFD initiating rhIGF-1 treatment at a relatively advanced age, rhIGF-1 treatment resulted in improved NAH. Greatest improvements in height outcomes were observed in NPP patients."

Journal • Real-world evidence • Endocrine Disorders

Two-Year-Old Dizygotic Twins Diagnosed With Rabson-Mendenhall Syndrome (ESPE-ESE 2025) - "Metformin was started at 100 mg once-daily and then Increlex (Mecasermin) injections were started at 0.04 mg/kg once-daily under inpatient observation, titrated to 0.04 mg/kg twice-daily after six weeks. Given the young age at diagnosis and the rarity of RMS, this case is being managed in collaboration with national experts however there is little evidence base for the treatments being offered. We hope this report will highlight the need for further research into novel therapeutic options and long-term management strategies for this challenging condition."

Developmental Disorders • Diabetes • Genetic Disorders • Hypoglycemia • Metabolic Disorders • Pediatrics

Eton Pharmaceuticals Out-Licenses International Rights to Increlex (GlobeNewswire) - "Eton Pharmaceuticals, Inc...announced the out-licensing of commercial rights to Increlex in territories outside of the U.S. to Esteve Pharmaceuticals, S.A....Esteve will license the ex-U.S. rights for up to ten years and will also be receiving an option to acquire the international rights in the future. Eton will supply product to Esteve at a fixed transfer price, and the transaction does not impact the Company’s expectation to exit 2025 at an approximately $80 million annual revenue run rate."

Commercial • Immunology

Long-term effectiveness and safety data from the Global Increlex® Registry in patients treated with rhIGF-1: Subgroup analysis of naïve pre-pubertal patients and patients with Laron syndrome (ESPE 2024) - P | "Background: The Global Increlex® Registry (NCT00903110) monitors real-world safety and effectiveness of recombinant human insulin-like growth factor (rhIGF-1; Increlex® [mecasermin]) in severe primary IGF-1 deficiency (SPIGFD)... Long-term HtSDS improvements in registry-enrolled patients with SPIGFD are encouraging. Five-year treatment data are likely enriched by treatment-responsive NPP patients, especially those with Laron syndrome. Safety data aligned with previous reports."

Clinical • Hematological Malignancies • Hypoglycemia • Myelodysplastic Syndrome • Oncology • IGF1

First line treatment evaluation in patients with severe primary insulin-like growth factor 1 deficiency (SPIGFD): Data from the Global Increlex® Registry (ESPE 2024) - P | "Some patients receive GH treatment before recombinant human IGF-1 (rhIGF-1; Increlex® [mecasermin])... With rhIGF-1 treatment in SPIGFD, GH-naïve patients gained more height versus patients previously treated with GH when adjusted for baseline parameters. Our assessment did not consider height response to GH or baseline characteristics at GH initiation."

Clinical • Endocrine Disorders • Hypoglycemia • IGF1

IGF-1 Treatment for Individuals With Short Stature Due to PAPP-A2 Deficiency (clinicaltrials.gov) - P1/2 | N=7 | Completed | Sponsor: Children's Hospital Medical Center, Cincinnati | Active, not recruiting ➔ Completed

Trial completion • IGF1 • PAPPA2

A Pilot Treatment Study of Insulin-Like Growth Factor-1 (IGF-1) in Autism Spectrum Disorder (clinicaltrials.gov) - P2 | N=3 | Terminated | Sponsor: Icahn School of Medicine at Mount Sinai | N=10 ➔ 3 | Recruiting ➔ Terminated; Decision made to terminate due to difficulty in procurement of adequate supply of treatment drug. Decision made on April 2023 to terminate study.

Enrollment change • Trial termination • Autism Spectrum Disorder • Genetic Disorders • IGF1

Frequency and predictive factors of hypoglycemia in patients treated with rhIGF-1: Data from the Eu-IGFD Registry. (PubMed, J Clin Endocrinol Metab) - P=N/A | "Hypoglycemia occurs more frequently in patients with prior history of hypoglycemia and/or Laron syndrome compared with patients without these risk factors, and these patients should be carefully monitored for this adverse event throughout treatment."

Biomarker • Journal • Hypoglycemia • IGF1

Capillary electrophoresis on-line hyphenated with mass spectrometry for analysis of insulin-like growth factor-1 in pharmaceutical preparations. (PubMed, Electrophoresis) - "Optimized and validated CZE-ESI-MS method was successfully applied for the determination of IGF-1 in injectable solutions (Increlex®), and its presence was also confirmed in nutritional preparations (tablets and liquid colostrum). This is the first validated CZE-ESI-MS method for the determination of IGF-1 in pharmaceutical matrices revealing the potential of capillary electrophoresis for its use in drug quality control laboratories with benefits, such as high separation efficiency, high-speed analysis, low sample consumption, as well as environmental and cost aspects."

Journal • IGF1

Pathway to assess severe primary IGF-1 deficiency diagnosis in a real-life setting: data from the Global Increlex® Registry (ESPE 2022) - P=N/A | "Background: Severe primary insulin-like growth factor-1 deficiency (SPIGFD) is a rare condition for which replacement therapy with recombinant human insulin-like growth factor-1 (rhIGF 1; mecasermin [Increlex®]) is approved for treatment in Europe and the USA... In children reported to have SPIGFD enrolled in the registry, HtSDS and baseline IGF-1 were reported in >90% of patients, while additional biochemical information including GH levels were less frequently reported, indicating that full reporting should be pursued. Recommendations on SPIGFD recognition and diagnosis should be produced and made available to the medical community in order to improve homogeneity in the diagnostic workup of these patients across countries."

Clinical • IGF1 • IGFBP3

Alterations in stem cell populations during rIgF-1 (Increlex) therapy in patients with SPIGF1D (ESPE 2022) - "For the first time we performed long-term observation of these populations in response to rhIGF-1 (mecasermin) therapy...In conclusion, here we provided novel insight into stem cells participation in IGF-1 deficiency in patients. Thus, we demonstrated basis for future studies in context of stem cells and IGF-1 role in growth disturbances."

Clinical • Pediatrics • CXCL12 • IGFBP3

Global Increlex® Registry, post-authorisation surveillance registry monitoring the long-term safety and effectiveness of mecasermin in children and adolescents with Severe Primary IGFD (SPIGFD): objectives and study design (ESPE 2022) - P=N/A | "The registry will allow for characterisation of the risk-benefit profile of mecasermin in patients presenting with SPIGFD in real-life settings."

Clinical • Endocrine Disorders • IGF1

Alterations in Stem Cell Populations in IGF-1 Deficient Pediatric Patients Subjected to Mecasermin (Increlex) Treatment. (PubMed, Stem Cell Rev Rep) - "In conclusion, here we provided novel insight into stem cells participation in IGF-1 deficiency in patients. Thus, we demonstrated basis for future studies in context of stem cells and IGF-1 role in growth disturbances."

Journal • Pediatrics • CXCL12 • IGF1 • IGFBP3

IGF-1 Treatment for Individuals With Short Stature Due to PAPP-A2 Deficiency (clinicaltrials.gov) - P1/2 | N=7 | Active, not recruiting | Sponsor: Children's Hospital Medical Center, Cincinnati | Trial completion date: Nov 2022 ➔ Jan 2023

Trial completion date • IGFBP3 • PAPPA2

IGF-1 Treatment for Individuals With Short Stature Due to PAPP-A2 Deficiency (clinicaltrials.gov) - P1/2 | N=7 | Active, not recruiting | Sponsor: Children's Hospital Medical Center, Cincinnati | Trial primary completion date: May 2022 ➔ Aug 2022

Trial primary completion date • IGFBP3 • PAPPA2

A Pilot Treatment Study of Insulin-Like Growth Factor-1 (IGF-1) in Autism Spectrum Disorder (clinicaltrials.gov) - P2 | N=10 | Recruiting | Sponsor: Icahn School of Medicine at Mount Sinai | Trial completion date: May 2022 ➔ Jul 2024 | Trial primary completion date: May 2022 ➔ Jul 2024

Trial completion date • Trial primary completion date • Autism Spectrum Disorder • Genetic Disorders • IGF1

Clinical Trial in 22q13 Deletion Syndrome(Phelan-McDermid Syndrome) (clinicaltrials.gov) - P2 | N=19 | Completed | Sponsor: Icahn School of Medicine at Mount Sinai | Recruiting ➔ Completed | N=35 ➔ 19

Enrollment change • Trial completion

IGF-1 Treatment for Individuals With Short Stature Due to PAPP-A2 Deficiency (clinicaltrials.gov) - P1/2 | N=7 | Active, not recruiting | Sponsor: Children's Hospital Medical Center, Cincinnati | Trial completion date: May 2022 ➔ Sep 2022 | Trial primary completion date: May 2021 ➔ May 2022

Trial completion date • Trial primary completion date • IGFBP3 • PAPPA2

Pubertal Timing and Growth Dynamics in Children With Severe Primary IGF-1 Deficiency: Results From the European Increlex Growth Forum Database Registry. (PubMed, Front Endocrinol (Lausanne)) - P=N/A | "Puberty is delayed in untreated children and adolescents with severe primary IGF-1 deficiency (SPIGFD); to date, it has not been reported whether recombinant human insulin-like growth factor-1 mecasermin (rhIGF-1) treatment affects this...Children and adolescents treated with rhIGF-1 for SPIGFD with growth failure experienced an increase in height SDS in prepubertal years compared with baseline. Despite 1.5 years delay in pubertal start and a delayed and slightly lower PPHV, height SDS gain during puberty was maintained."

Journal • IGF1

EuIGFD: Global Patient Registry to Monitor Long-term Safety and Effectiveness of Increlex® in Children and Adolescents With Severe Primary Insulin-like Growth Factor-1 Deficiency (SPIGFD). (clinicaltrials.gov) - P=N/A; N=500; Recruiting; Sponsor: Ipsen; N=330 ➔ 500; Trial completion date: Dec 2023 ➔ Dec 2027; Trial primary completion date: Dec 2023 ➔ Dec 2027

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Hypoglycemia • FGF • IGF1 • IGFBP3

[VIRTUAL] Assessment of genetic defects, baseline characteristics and adverse events reported in the Increlex® registry (ESPE 2021) - P=N/A | "Genetic testing was reported for >50% patients. Patients with versus without reported genetic abnormalities had shorter stature at first rhIGF-1 dose and more TEAEs. Further work is required to understand the role of genetic testing in clinical practice."

Adverse events • Hypoglycemia • PTPN11 • STAT5B

IGF-1 Treatment for Individuals With Short Stature Due to PAPP-A2 Deficiency (clinicaltrials.gov) - P1/2; N=7; Active, not recruiting; Sponsor: Children's Hospital Medical Center, Cincinnati; Trial completion date: Nov 2021 ➔ May 2022

Clinical • Trial completion date • IGFBP3 • PAPPA2