apraglutide (FE 203799) / Asahi Kasei, Ironwood Pharma - LARVOL DELTA

Ironwood Pharmaceuticals Provides Clinical and Regulatory Update on Apraglutide (Businesswire) - "Ironwood Pharmaceuticals, Inc...announced that, based on a recent discussion with the U.S. Food and Drug Administration (FDA), a confirmatory Phase 3 trial is needed to seek approval of apraglutide for patients with short bowel syndrome (SBS) with intestinal failure (IF) who are dependent on parenteral support....In preparation for the new drug application (NDA) submission, pharmacokinetic analysis indicated that the exposure and dose delivered in the STARS Phase 3 trial were lower than planned due to dose preparation and administration. Based on the strength of the STARS Phase 3 results, Ironwood believed that there was a regulatory path forward. However, following recent dialogue with the FDA it became clear that a confirmatory Phase 3 trial is needed to seek approval. Ironwood plans to work with the FDA on the design of a confirmatory Phase 3 trial and the regulatory path forward."

FDA event • Short Bowel Syndrome

COMPARISONS OF GLUCAGON-LIKE PEPTIDE-2 ANALOG APRAGLUTIDE IN COMBINATION WITH RUXOLITINIB FOR STEROID-REFRACTORY GASTROINTESTINAL ACUTE GRAFT-VERSUS-HOST DISEASE WITH MAGIC CONTROL COHORT: THE PHASE 2 STARGAZE TRIAL (EBMT 2025) - P2 | "STARGAZE short- and long-term interim results compared favourably to a MAGIC control cohort. More patients with SR lower-GI aGvHD treated with ruxolitinib had response at day 28, more patients maintained their response over time, and fewer patients experienced day 180 NRM compared with ruxolitinib alone. These findings are encouraging but should be interpreted with caution, given that the control arm was constructed from observational data and the small sample size."

Combination therapy • P2 data • Acute Graft versus Host Disease • Gastrointestinal Disorder • Graft versus Host Disease • Immunology

SAFETY AND EFFICACY OF THE GLUCAGON-LIKE PEPTIDE 2 ANALOG APRAGLUTIDE IN COMBINATION WITH RUXOLITINIB IN STEROID-REFRACTORY GASTROINTESTINAL ACUTE GRAFT-VERSUS-HOST DISEASE: THE PHASE 2 STARGAZE TRIAL (EBMT 2025) - P2 | "In STARGAZE, apraglutide was well tolerated and efficacious when added to ruxolitinib in the 2L setting. Most patients receiving apraglutide plus ruxolitinib had an overall response (all-organ and lower-GI) at days 28 and 56. Notably, durable ORs were observed from day 28 to 56 and from day 56 to 91."

Clinical • Combination therapy • P2 data • Acute Graft versus Host Disease • Gastrointestinal Disorder • Graft versus Host Disease • Immunology

Apraglutide/Ruxolitinib Provides Efficacy Benefit vs Ruxolitinib Alone in Refractory GI aGVHD (OncLive) - P2 | N=31 | STARGAZE (NCT05415410) | Sponsor: VectivBio AG | "The selective GLP-2 analog apraglutide plus ruxolitinib (Jakafi) generated improved short- and long-term efficacy outcomes vs ruxolitinib alone in patients with steroid-refractory gastrointestinal (GI) acute graft-vs-host disease (aGVHD), according to findings from a study comparing efficacy outcomes from the phase 2 STARGAZE trial (NCT05415410) vs a control cohort from the observational MAGIC trial....The data, which were presented at the 51st Annual EBMT Meeting, showed that the all-organ overall response rates (ORRs) were higher in the STARGAZE cohort (n = 31; apraglutide vs ruxolitinib) vs the MAGIC cohort (n = 31; ruxolitinib monotherapy) at days 28 (STARGAZE, 58.1%; MAGIC, 38.8%), 56 (45.1%; 32.2%), and 91 (45.1%; 25.8%). The complete response (CR) rates at these respective time points were also higher in STARGAZE (25.8%; 29.0%; 29.0%) vs MAGIC (19.4%; 16.1%; 16.1%)."

P2 data • Acute Graft versus Host Disease

Ironwood Pharmaceuticals…Updates Corporate Structure to Position for the Future (Businesswire) - "Strategic Reorganization:...Ironwood also has decided to wind down the Phase 2 exploratory study, STARGAZE, of apraglutide in Graft-versus-Host Disease to further focus its resources and investments. Ironwood expects to incur restructuring charges of approximately $20 to $25 million, which are anticipated to be incurred primarily in the first half of 2025. Ironwood expects to realize, as a result of the strategic reorganization, approximately $55 to $60 million of annual operating expense savings, resulting in $40 to $45 million benefit to annual profits, net of impact to collaborative arrangements revenue."

Commercial • Trial termination • Acute Graft versus Host Disease

Ironwood Pharmaceuticals…Highlights Compelling New Data… (Businesswire) - P3 | N=158 | STARS extend (NCT05018286) | Sponsor: VectivBio AG | "Apraglutide Open Label Extension Study, STARS Extend: The extension study data demonstrate that more patients weaned off parenteral support with longer exposure to apraglutide. An analysis of long-term extension data also showed that 27 apraglutide-dosed patients achieved enteral autonomy, which is the ultimate goal of SBS patients who are dependent on parenteral support."

P3 data • Short Bowel Syndrome

Ironwood Pharmaceuticals Initiates Apraglutide NDA Submission… (Businesswire) - "...'We have made important progress by initiating our rolling new drug application ('NDA') submission and announcing new data from our open label extension study, STARS Extend, demonstrating an increased number of patients on apraglutide achieving enteral autonomy over time. We plan to include the long-term extension data in our NDA submission, in addition to the robust efficacy and tolerability data from STARS, the largest Phase 3 clinical trial ever conducted in SBS-IF patients'....Submission completion expected in Q3 2025."

FDA filing • Short Bowel Syndrome

The Phase 2 Stargaze Trial of the Glucagon-like Peptide 2 (GLP-2) Analog Apraglutide in Combination with Ruxolitinib for Steroid-Refractory Gastrointestinal (GI) Acute Graft-Versus-Host Disease (aGvHD): Comparisons with a MAGIC Control Cohort (TCT-ASTCT-CIBMTR 2025) - P2 | "More pts with SR lower-GI aGvHD treated with RUX + APRA had response at day 28, more pts maintained their response over time, and fewer pts experienced day 180 NRM compared with RUX alone. These findings are encouraging but should be interpreted with caution, given that the control arm was constructed from observational data and the small sample size."

Combination therapy • P2 data • Acute Graft versus Host Disease • Gastrointestinal Disorder • Graft versus Host Disease • Immunology

STARGAZE: Proof-of-concept Trial of Apraglutide in GVHD (clinicaltrials.gov) - P2 | N=31 | Terminated | Sponsor: VectivBio AG | Trial completion date: Aug 2025 ➔ Dec 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Aug 2025 ➔ Dec 2024; Company decision

Trial completion date • Trial primary completion date • Trial termination • Acute Graft versus Host Disease • Gastrointestinal Disorder • Graft versus Host Disease • Immunology

Safety and Efficacy of the Glucagon-like Peptide 2 (GLP-2) Analog Apraglutide in Patients with Steroid-Refractory Gastrointestinal Acute Graft-Versus-Host Disease (aGvHD) in Combination with Best Available Therapy: Results from a Multicenter, Randomized, Single-Blind, Proof-of-Concept, Phase 2 Stargaze Trial (ASH 2024) - P2 | "GI aGvHD is often steroid-refractory, and despite recent improvements with the availability of ruxolitinib (RUX) as second-line therapy, an unmet need remains for non-immunosuppressive treatments. Notably, durable overall responses were observed from Day 28 to Day 56 and from Day 56 to Day 91. The outcomes, based on the novel regenerative mechanism of action of APRA, are encouraging in this severely ill population."

Clinical • Combination therapy • P2 data • Acute Graft versus Host Disease • Gastrointestinal Disorder • Graft versus Host Disease • Immunology

Use of glucagon-like polypeptide 2 analogs for intestinal failure. (PubMed, Expert Opin Pharmacother) - "More recently, ultralong acting GLP-2 analogs with half-lives of 70-80 hours can improve gastrointestinal function in surgically foreshortened bowel with only one injection every three to seven days. Future research is likely to focus upon the potential complementary role of GLP-1 and GLP-2 in treating short bowel syndrome."

Journal • Gastrointestinal Disorder • Pediatrics • Short Bowel Syndrome

The Long-Acting Glucagon-Like Peptide-2 Analog Apraglutide Enhances Intestinal Protection and Survival After Chemotherapy and Allogeneic Transplantation in Mice. (PubMed, Ann Transplant) - "CONCLUSIONS Apraglutide protects intestinal function and improves survival in mice following allogeneic transplantation or chemotherapy with cytarabine or melphalan. The potential effect of apraglutide on chemotherapy efficacy and on engraftment following allogeneic transplantation has been investigated in a parallel manuscript."

Journal • Preclinical • Fatigue • Gastrointestinal Disorder • Infectious Disease • Septic Shock • Transplantation

Safety, Tolerability, PK/PD of FE 203799 in Adults With Lymphomas (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: GlyPharma Therapeutics | Phase classification: P1b/2a ➔ P1/2

Phase classification • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • CD34

Safety and Tolerability of Once-Weekly Glucagon-Like Peptide-2 Analog Apraglutide in Patients With Short Bowel Syndrome and Intestinal Failure: Results From a Global, Phase 3, Randomized, Double-Blind Trial (ACG 2024) - P3 | "Incidence of AEs, serious AEs, and AEs of Grade ≥3 was similar between treatment arms ( Table 1 ). Dose interruptions due to AEs were also similar between APRA and PBO (10.9% vs 11.3%). The incidence of AEs associated with gastrointestinal (GI) tolerability was low and similar between treatment arms."

Clinical • P3 data • Cardiovascular • Gastrointestinal Disorder • Oncology • Short Bowel Syndrome

Phase 3, Double-Blind, Randomized STARS Trial of Apraglutide Once-Weekly in Patients with Short Bowel Syndrome and Intestinal Failure (SBS-IF): Subgroup Analyses by Baseline Demographics and SBS Disease Characteristics (ACG 2024) - P3 | "The primary endpoint was met at Wk 24 (n=163; overall population), with a significantly larger reduction in weekly PS volume from BL with APRA vs PBO (-25.5% vs -12.5%, p=0.001). These results have been presented previously. Subgroup analyses showed consistent treatment effect for APRA vs PBO across all subgroups in the overall population ( Figure 1 )."

Clinical • P3 data • Gastrointestinal Disorder • Short Bowel Syndrome

Efficacy and safety of apraglutide in short bowel syndrome with intestinal failure and colon-in-continuity: A multicenter, open-label, metabolic balance study. (PubMed, Clin Nutr) - P2 | "Apraglutide had an acceptable safety profile and was associated with significant reductions in PS needs and days off PS, improvements in intestinal absorption, and structural and functional intestinal changes in patients with SBS-IF-CiC."

Journal • Gastrointestinal Disorder • Short Bowel Syndrome

DISCOVERY OF AN ORAL, LONG-ACTING GLUCAGON-LIKE PEPTIDE 2 AS BEST-IN-CLASS TREATMENT FOR SHORT BOWEL SYNDROME (UEGW 2024) - "Overall, 1037331 demonstrated better in vitro and in vivo potencies, and better PK profiles than apraglutide. Most importantly, 1037331 with fatty acid conjugation showed oral bioavailability, which may improve patient compliance and convenience."

Gastrointestinal Disorder • Short Bowel Syndrome

EFFICACY AND SAFETY OF APRAGLUTIDE ONCE-WEEKLY IN PATIENTS WITH SHORT BOWEL SYNDROME AND INTESTINAL FAILURE (SBS-IF): RESULTS FROM THE STARS STUDY – A GLOBAL PHASE 3 DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL (UEGW 2024) - P3 | "APRA is the first once-weekly GLP-2 analogue to demonstrate efficacy in a phase 3 trial in SBS-IF. At Wk 24, APRA demonstrated significantly greater relative reductions in weekly PS volume from BL and a higher proportion of pts achieved an additional ≥1 day off PS, with comparable treatment effects in pts with stoma or CIC. APRA showed a favourable safety profile consistent with prior APRA studies in SBS-IF.EndpointPopulationApraglutide (n=110)Placebo (n=53)APRA vs PBO Difference [LSM or % (95% CI)]p-valuePrimary EndpointLSM or n (%)Relative % change from BL in actual PS weekly volume at Wk 24, Least Square Mean (LSM)Overall-25.5-12.5-13.0 (-20.9, -5.0)0.001Key Secondary Endpoints Percentage of subjects achieving a reduction of ≥1 day/wk off PS from BL at Wk 24, n (%) *Overall46 (43.0)14 (27.5)15.6 (0.7, 30.5)0.040Relative % change from BL in actual PS weekly volume at Wk 24, meanStoma (n=80)-25.6-7.8-17.8 (-28.4, -7.3)<0.001Percentage of subjects achieving a..."

Clinical • P3 data • Gastrointestinal Disorder • Short Bowel Syndrome

MAGNETIC RESONANCE IMAGING (MRI) SHOWS CHANGES IN BOWEL MORPHOLOGY AND MOTILITY IN SHORT BOWEL SYNDROME WITH INTESTINAL FAILURE (SBS-IF) AND COLON-IN-CONTINUITY (CIC) AFTER TREATMENT WITH THE LONG-ACTING GLUCAGON-LIKE PEPTIDE-2 (GLP-2) ANALOG APRAGLUTIDE (UEGW 2024) - "Using static and cine MRI sequences in pts with SBS-IF-CIC, STARS Nutrition shows that APRA treatment was associated with small bowel lengthening and increased duodenal wall thickness suggesting an intestinotrophic effect. Both effects may contribute to an increased surface area for absorption. The reduced motility, especially in the proximal colon may reduce transit time, allowing more time for absorption of nutrients, fluids and electrolytes; and reduced fecal output."

MRI • Gastrointestinal Disorder • Short Bowel Syndrome

ONE-YEAR TREATMENT WITH THE LONG-ACTING GLUCAGON-LIKE PEPTIDE-2 (GLP-2) ANALOG APRAGLUTIDE RESULTS IN PARENTERAL SUPPORT WEANING, CLINICAL BENEFIT AND IMPROVED PATIENT REPORTED OUTCOMES IN SHORT BOWEL SYNDROME WITH INTESTINAL FAILURE (SBS-IF) AND COLON-IN-CONTINUITY (CIC) (UEGW 2024) - "STARS Nutrition prospectively shows evidence for clinical benefit of a long-acting GLP-2 analog in SBS-IF–CiC. APRA has an acceptable safety profile and is associated with significant reductions in PS needs in pts with SBS-IF–CiC resulting in days without PS and subjective improvement based on PRO."

Clinical • Patient reported outcomes • Gastrointestinal Disorder • Hepatology • Short Bowel Syndrome

48-WEEK TREATMENT WITH THE LONG-ACTING GLUCAGON-LIKE PEPTIDE-2 (GLP-2) ANALOG APRAGLUTIDE IS ASSOCIATED WITH INCREASED ORAL INTAKE AND IMPROVED ENERGY AND CARBOHYDRATE ABSORPTION IN SHORT BOWEL SYNDROME WITH INTESTINAL FAILURE (SBS-IF) AND COLON-IN-CONTINUITY (CIC) (UEGW 2024) - "The STARS Nutrition MBS findings confirm the role of the colon in energetic recovery of carbohydrates and maintenance of the fluid balance in SBS-IF-CiC. In pts with SBS-IF-CiC, APRA treatment resulted in an early reduced fecal output and improved wet weight absorption. After 48 weeks, oral intake was increased despite stable fecal output, leading to increased energy and carbohydrate absorption."

Gastrointestinal Disorder • Short Bowel Syndrome

THE EFFECT OF APRAGLUTIDE ON GASTRIC EMPTYING IN HEALTHY INDIVIDUALS: A PHASE 1 RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, SINGLE-CENTRE TRIAL (UEGW 2024) - "Full abstracts will be published on 21 September 2024"

Clinical • P1 data • Inflammatory Bowel Disease • Pediatrics

Intestinal adaptation and rehabilitation in adults with short bowel syndrome. (PubMed, Curr Opin Clin Nutr Metab Care) - "Real-world data confirmed the teduglutide efficacy not only in weaning off IVS in accurately selected patients but also increased the alert on the risk of development of gastrointestinal polyps related to the drug; the impact of the therapy on patients' QoL deserves further studies and the cost-utility of the treatment is still uncertain. Some case reports highlighted the potential benefit of treatment with teduglutide in non-SBS gastrointestinal diseases, such as graft-versus-host disease, primary amyloidosis and refractory microscopic colitis. Phase 2 RCTs on safety and efficacy of two new long-acting GLP-2 analogues, glepaglutide and apraglutide, were published, and phase 3 RCTs have been completed."

Journal • Amyloidosis • Gastroenterology • Gastrointestinal Disorder • Graft versus Host Disease • Immunology • Short Bowel Syndrome

EFFICACY AND SAFETY OF APRAGLUTIDE ONCE-WEEKLY IN PATIENTS WITH SHORT BOWEL SYNDROME AND INTESTINAL FAILURE (SBS-IF): RESULTS FROM THE STARS STUDY - A GLOBAL PHASE 3 DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL (DDW 2024) - No abstract available

Clinical • Late-breaking abstract • P3 data • Gastrointestinal Disorder • Short Bowel Syndrome

THE EFFECT OF APRAGLUTIDE ON GASTRIC EMPTYING IN HEALTHY INDIVIDUALS: A PHASE 1 RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, SINGLE-CENTER TRIAL (DDW 2024) - "The two-sided 90% confidence intervals of the ratios (acetaminophen + apraglutide or acetaminophen + placebo vs acetaminophen alone) of the geometric means derived for the second period were not different ( Table 1 ). Conclusions : These results suggest that apraglutide does not affect gastric emptying of liquids in healthy individuals as measured by acetaminophen PK and can therefore be used in a broad patient population."

Clinical • P1 data • Graft versus Host Disease • Immunology • Short Bowel Syndrome