Ascendis Pharma (Denmark)

ContextAdult 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.ObjectiveThis work aimed to evaluate the efficacy and safety of lonapegsomatropin vs placebo as treatment for adults with GHD.MethodsThe 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.ResultsAt 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.ConclusionThe 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.

IntroductionHypoparathyroidism (HypoPT) is an endocrine disease caused by insufficient levels of parathyroid hormone and is associated with impaired health-related quality of life. This study assessed the clinical burden among individuals with postsurgical chronic HypoPT in Medicare Fee-For-Service.MethodsAdults (aged ≥ 18 years) with newly diagnosed HypoPT (N = 1166) were identified from the Medicare 100% Limited Data Set between July 1, 2017, and March 31, 2020. All had a confirmed diagnosis within 6–12 months after index diagnosis and were required to be continuously enrolled for ≥ 6 months pre index and ≥ 12 months post index. A random sample of non-HypoPT controls (N = 11,258) was synthetically assigned an index date of diagnosis to ensure similar baseline and follow-up periods as individuals with postsurgical chronic HypoPT. The two cohorts were compared before and after matching with respect to the risk of cardiovascular (CV) events, renal complications, urinary tract infections (UTIs), upper respiratory tract infections (URTIs), and mortality.ResultsIndividuals with postsurgical chronic HypoPT were older than non-HypoPT controls (mean age 69 vs. 64 years), more were female (76% vs. 57%), had higher Charlson Comorbidity Index scores (3.24 vs. 0.73), and a higher prevalence of moderate-to-severe renal disease (28.8% vs. 5.6%), nephrocalcinosis (59.9% vs. 0.6%), and nephrolithiasis (8.3% vs. 1.0%). They also had significantly greater mortality (hazard ratio [HR] 2.75). The incident risks of composite CV events (HR 1.35), renal complications (HR 4.92), UTIs (HR 2.09), and URTIs (HR 1.46) were greater in subcohorts without those conditions prior to index. After matching for baseline characteristics, the elevated risk of renal complications, UTIs, and URTIs remained while there was no difference in the risk of CV events or death between individuals with postsurgical chronic HypoPT and controls.ConclusionThe substantial clinical burden of postsurgical chronic HypoPT in Medicare patients highlights the treatment gaps associated with current therapy and the need for parathyroid hormone replacement therapies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-025-03264-x.

e14597 Background: TransCon IL-2 β/γ is a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 analog (IL-2 β/γ) designed to optimally address the drawbacks of interleukin-2 (IL-2) therapy. IL-2 β/γ was created by permanently attaching a 5 kDa mPEG in the IL-2Rα binding site. To improve the pharmacokinetic (PK) properties, IL-2 β/γ was transiently attached to a 40 kDa mPEG carrier via a TransCon linker creating a prodrug, TransCon IL-2 β/γ. Under physiological conditions, TransCon IL-2 β/γ releases active IL-2 β/γ from the carrier via autocleavage in a controlled manner. The associated long effective half-life and sustained IL-2 β/γ exposure results in robust activation of IL-Rβ/γ+ cytotoxic immune cells, at a lower Cmax compared to IL-2 therapy. The primary objectives of the IL-Believe trial are to evaluate safety and tolerability, and to define the maximum tolerated dose and recommended Phase 2 dose of TransCon IL-2 β/γ alone or in combination with pembrolizumab. Methods: In dose escalation (3+3 design), patients aged ≥18 with advanced solid tumors receive TransCon IL-2 β/γ as monotherapy or in combination with pembrolizumab with IV dosing every 3 weeks. Disease is assessed every 9 weeks using RECIST 1.1. Safety, PK, and pharmacodynamics (PD) are evaluated. Results: As of 25 Jan 2023, 27 patients were treated in dose escalation: 18 in monotherapy (Dose Levels (DL) 1-4) and 9 in combination therapy (DL1, DL2). The most common tumor types in monotherapy and in combination therapy were head &amp; neck (19%), colorectal (11%) and endometrial (11%). Patients received a median of 3 prior lines of therapy in monotherapy. The most common Treatment Related Adverse Events (TRAEs) in monotherapy and in combination therapy were pyrexia (30%), Cytokine Release Syndrome (CRS) (26%) and fatigue (22%). Grade 3 (G3) TRAEs in monotherapy were anemia (17%), CRS (6%), thrombocytopenia (6%), hypoxia (6%), all reported at DL4. 1 Dose Limiting Toxicity of G3 CRS was reported at DL4. Preliminary PK results showed systemic drug exposure of TransCon IL-2 β/γ with a half-life of ~ 35 hours and no PK interaction with pembrolizumab was observed. PD data were consistent with sustained activation and dose dependent expansion of cytotoxic effector cells, in comparison, Tregs were only expanded minimally. Absolute lymphocyte counts increased in a dose dependent manner while eosinophils remained low. Prolonged stable disease ( &gt; 32 weeks) was observed in one pancreatic cancer patient on monotherapy. Conclusions: TransCon IL-2 β/γ is generally well-tolerated as monotherapy and in combination with pembrolizumab. The pharmacodynamics data confirm a durable activation and expansion of IL-2Rβ/γ+ cytotoxic immune cells over IL-2Rα+ eosinophils and Tregs. Clinical trial information: NCT05081609 .

El objetivo del estudio fue investigar la innovación y su influencia en el rendimiento empresarial mediante análisis bibliométrico de la producción científica desde el año 2000 al año 2022. Se procedió a revisar publicaciones científicas especializadas en la base de datos Web of Science. Se identificaron un total de 1996 documentos, de las cuales se seleccionó una muestra base de 548 para el desarrollo del análisis bibliométrico. Se analizó la contribución científica internacional. Se examinó la producción anual científica, las revistas con más publicaciones, la producción por país, los documentos más citados, las palabras más relevantes, la red de palabras claves utilizadas por los autores, la red de colaboración por países, entre otras variables. Los resultados destacaron que la producción científica más significativa fue entre 2018 y 2021, con 344 registros. La mayor producción la tuvieron China con 591 y los Estados Unidos con 460 productos. El autor más citado es Teece, D.J. con 4,794 citas, seguido de Jiménez-Jiménez, D. con 650, y Matsuno, K. con 498. Se concluyó que la innovación impacta el rendimiento empresarial con una tendencia ascendente porque fortalece el desarrollo de las organizaciones.

As high-cost and innovative therapies continue to enter the market, health care decision makers (HCDMs) are expressing a need for early information on a product's clinical and economic impacts. Preapproval information exchange (PIE) fulfills these data needs by allowing manufacturers to share drug information with HCDMs prior to US Food and Drug Administration approval. With recent regulatory milestones, such as the Pre-approval Information Exchange Act of 2022, HCDMs look to leverage PIE to forecast budgets and inform reimbursement decisions. However, a lack of stakeholder alignment has challenged the evolving applications of PIE. In addition, manufacturers are still seeking regulatory clarity regarding best practices, and many are developing their own policies for content dissemination. Varying practices have led to heterogeneity of preapproval communications across manufacturers, which may not fully align with HCDM needs and interests. However, recently collected survey data from FormularyDecisions, which focused on HCDM perceptions of both PIE webinars and other formats of PIE (eg, PIE decks and dossiers), indicate that HCDMs have strong preferences regarding the timing and content shared in preapproval engagements. Additionally, product indication and clinical trial information are highly valued, and although desired by HCDMs in other studies, in FormularyDecisions survey data, exact pricing data do not currently appear to be a critical component of PIE. Preapproval communications are expected less than 1 year before anticipated product approval, and PIE webinars, specifically, should prioritize therapeutic areas and products anticipated to have a significant impact on organizational budgets. Although HCDMs prefer nonmanufacturer representatives for PIE webinars and virtual presentations, health outcome liaisons or medical science liaisons are ideal among manufacturer representatives for in-person preapproval engagements. The expectations of HCDMs should be considered as manufacturers establish PIE practices to ensure the exchange of quality and relevant information. DISCLOSURES: This study was funded by Xcenda. Dr Dodda, Dr Bannister, Dr Hydery, Ms Gorey, Ms Dunlap, and Dr Mody report personal fees from Xcenda during the conduct of the study.

PurposeThe purpose of this study was to conduct cognitive debriefing (CD) interviews with adults diagnosed with chronic hypoparathyroidism (HP) to assess the content validity of the SF-36v2® Health Survey Acute (SF-36v2) measure in this population.MethodsCD interviews were conducted with adults with HP in the United States (US). Interviews were conducted by a trained moderator using a semi-structured interview guide, employing a think-aloud method in conjunction with verbal probing. Participants were asked whether each item was understandable, relevant, important, and sensitive to change in relation to HP. Additionally, comprehension of instructions, response options, and the appropriateness of a 1-week recall period was assessed.ResultsSixteen adults with HP participated in individual CD telephone interviews. All items in the SF-36v2 were reported to be understood, relevant, important, and sensitive to change by at least half, and in most cases, by a strong majority of study participants. Most of the study sample confirmed comprehension of the instructions and the entire sample understood all response options.ConclusionThe study findings show that the items in the SF-36v2® are applicable to adults with HP. The overall high levels of endorsement of items provide strong evidence of the measure’s content validity for this population. The SF-36v2 is therefore recommended for usage in clinical trials examining adults with HP, although it is recommended that this generic measure be supplemented with disease-specific instruments such as the recently developed Hypoparathyroidism Patient Experience Scale—Symptom (HPES-Symptom) and Hypoparathyroidism Patient Experience Scale—Impact (HPES-Impact) measures.

Self-assembly and fibril formation play important roles in protein behaviour. Amyloid fibril formation is well-studied due to its role in neurodegenerative diseases and characterized by refolding of the protein into predominantly β-sheet form. However, much less is known about the assembly of proteins into other types of supramolecular structures. Using cryo-electron microscopy at a resolution of 1.97 Å, we show that a triple-mutant of the anti-microbial peptide plectasin, PPI42, assembles into helical non-amyloid fibrils. The in vitro anti-microbial activity was determined and shown to be enhanced compared to the wildtype. Plectasin contains a cysteine-stabilised α-helix-β-sheet structure, which remains intact upon fibril formation. Two protofilaments form a right-handed protein fibril. The fibril formation is reversible and follows sigmoidal kinetics with a pH- and concentration dependent equilibrium between soluble monomer and protein fibril. This high-resolution structure reveals that α/β proteins can natively assemble into fibrils.