Erytech Pharma (France)

CHRONOS is a multicenter, retrospective, cohort study involving acute graft-versus-host disease (aGvHD) adult patients with gastrointestinal (GI) symptoms, steroid- and ruxolitinib refractory, who initiated third-line therapy between 30 May 2019 and 30 September 2024. Primary endpoints were all-organ overall response rate (ORR) and GI-specific ORR (GI-ORR) around 28 days after treatment initiation. Secondary endpoints included duration of response, real-world progression-free survival (rwPFS) of underlying malignancy, and overall survival (OS). Fifty-nine patients from 16 sites in Europe were included. On Day 28, ORR was 36% (95% CI: 24-49%), GI-ORR was 37% (95% CI: 25-51%); 29% (95% CI: 11-49%) of responders lost response within 30 days, and 52% (95% CI: 29-72%) within 90 days. Median rwPFS and median OS were both 86 days (95% CI: 54-128 days). Median OS was higher in responders than in non-responders (186 versus 45 days). Over the 12-month follow-up period, 41 patients died, mainly due to aGvHD progression (n = 25), and infectious complications (n = 9). Within 3 months, Grade ≥ 2 infectious events occurred in 51% of patients; Grade 3-4 thrombocytopenia and neutropenia in 64% and 32%, respectively. These findings demonstrate limited effectiveness of third-line therapy in this cohort of steroid- and ruxolitinib-refractory aGvHD patients with GI symptoms.

BackgroundMultiple studies have evaluated fecal microbiota transfer (FMT) in patients with ulcerative colitis (UC) using single-donor (SDN) and multidonor (MDN) products. Systematic review and meta-analysis were performed to compare the safety of SDN and MDN products.MethodsSystematic searches were performed in Web of Science, Scopus, PubMed, and Orbit Intelligence to identify studies that compared FMT products manufactured using SDN or MDN strategies against control treatment in patients with UC. Fifteen controlled studies were selected for meta-analysis (11 randomized controlled trials and 4 controlled cohort trials). Safety of each treatment type was assessed using the counts of adverse events and serious adverse events using fixed- and random-effects models. Significance of the indirect difference between FMT preparations was assessed using a network approach. Benefit-risk ratios were calculated by multiplicative utility model, incorporating geometric mean of risk ratios (RRs) of efficacy and safety.ResultsSafety data was collected for a total of 587 patients (193 exposed to SDN products, 114 exposed to MDN products and 280 exposed to control treatment). The 12 studies showed similar overall safety event counts for MDN and SDN versus placebo (RRs: 0.90 and 1.09, respectively [P = 0.206 and P = 0.420, respectively]). Results indicated similar risk of safety events for MDN compared to SDN (RR: 0.83, P = 0.159). Positive benefit-risk ratios were demonstrated for MDN and SDN versus placebo (RRs: 1.70 and 1.16, respectively [P = 0.003 and P = 0.173, respectively]). MDN had a greater benefit-risk ratio compared to SDN (RR: 1.46, P = 0.072).ConclusionSimilar safety profiles were observed for MDN and SDN strategies. Alongside previously described superior efficacy, treatment with MDN has greater benefit-risk ratio than SDN in patients with UC. Further development of MDN FMT treatment for UC should be considered.

Abstract Disclosure: S. Allas: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. G. Ravel: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. C. Farrell: Employee; Self; ICON plc. S. Fillon: Employee; Self; Amolyt Pharma. O. Taha: Employee; Self; Amolyt Pharma. M.D. Culler: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. M. Ovize: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. M. Sumeray: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. A.J. Van der Lely: Consulting Fee; Self; Amolyt Pharma. Acromegaly is a rare disease typically caused by a benign growth hormone (GH)-secreting pituitary adenoma that stimulates over-production of insulin-like growth factor-1 (IGF1) from the liver. Treatment with somatostatin analog (SSA) monotherapy does not provide optimal control of circulating IGF-1 levels in the majority of patients. AZP-3813, a 16-amino acid, bicyclic GH receptor antagonist (GHRA) binds to the GH receptor and prevents endogenous GH from stimulating the production of IGF-1. The compound is being developed as an add-on therapy for the treatment of acromegaly in patients insufficiently controlled with SSAs. In normal animals, AZP-3813 potently decreases circulating levels of IGF-1 and further suppressive effects are observed when combined with the SSA, octreotide. Randomized double-blind placebo-controlled single and multiple ascending dose studies (SAD and MAD, respectively) are being conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZP-3813 in healthy subjects. Here we report data from all SAD cohorts and the first 3 MAD cohorts. In the SAD study, 5 subjects received a single subcutaneous administration of 3 mg AZP-3813 or placebo (3:2) and 8 subjects received 10, 20, 40, 60, 90, 120 mgAZP-3813 or placebo (6:2). In the MAD study, 8 subjects received 10, 20, 40 mg AZP-3813 or placebo (6/2) QD for 14 consecutive days. In both SAD and MAD studies, treatment was well tolerated in all subjects with no safety concerns. Cmax and AUC increased in a dose-proportional manner. The half-life of AZP-3813 was estimated to be 18-22 hours. In the SAD study, AZP-3813 induced a dose-related decrease in circulating IGF-1 levels at doses of 10 mg and above with a more prolonged reduction up to 72 hours at higher doses. In the MAD study, AZP-3813 induced a gradual and sustained dose-related decrease in circulating IGF-1 levels at 20 and 40 mg/day, with a larger effect after 2 weeks of dosing as compared to single administration at the same dose, consistent with a cumulative effect of repeated administration. Mean placebo-adjusted % change from baseline for the 20 and 40 mg cohorts were 19% and 44%, respectively. This study is ongoing, and updates on additional MAD cohorts will be reported at the meeting. These data clearly demonstrate that AZP-3813, the novel GHRA, substantially decreases circulating IGF-1 levels in healthy individuals, thereby supporting further testing in patients with acromegaly. Presentation: 6/1/2024

BackgroundHypoparathyroidism (HPT) is a rare condition in which the parathyroid glands fail to produce enough parathyroid hormone (PTH) or the PTH produced lacks biologic activity. The aim of this study was to explore the patient experience of HPT.MethodsAdult patients with HPT, recruited via a medical recruitment agency and the US hypoPARAthyroidism Association, participated in web-based, semi-structured, qualitative interviews that were audio-recorded and transcribed. Thematic analysis identified key symptoms and health-related-quality-of-life (HRQOL) impacts of HPT.ResultsInterviews were conducted with 16 patients with self-reported HPT for ≥ 12 months (15 females; age range 26-76 years). Key HPT symptoms reported included: fatigue (n=16, 100%), cognitive dysfunction (n=15, 94%), pain (n=15, 94%), tingling (n=14, 88%), muscles twitches/spasms (n=13, 81%), muscle cramps (n=12, 75%), temperature sensitivity (n =12, 75%), muscles weakness (n=12, 75%), cardiovascular issues (n =10, 63%), and eye problems (n= 9, 56%). Patients experienced intra-day symptom variability and unpredictability depending on treatment (Tx) regime. This erratic symptom experience hindered daily planning, and interactions with family/friends, resulting in emotional distress. Patients reported that HPT had a detrimental impact on their daily lives including impacts on physical functioning (n=11, 69%), sleep (n=10, 63%), daily activities (n=16, 100%), and work (n=13, 81%) as well as on relationships and social functioning (n=16, 100%). Fifteen patients (94%) reported emotional impacts; a key issue was the patient-perceived "invisibility" of HPT, specifically patients’ disease experience was often dismissed by family/friends as HPT is rare, with "no visible" symptoms. Patients also noted the burden of HPT management (e. g., Tx regimens, potential effects from long-term medication use). The need for constant vigilance associated with symptoms monitoring and medication use could be onerous. The absence of "at-home calcium monitoring" required patients to adhere to self-imposed "medication timetables": any deviations caused emotional distress as patients feared triggering a "calcium crash". Seven patients noted that Tx effects were not sustained throughout the day, leading to a re-emergence of symptoms as the day progressed. Patients reported that symptom reduction, improved Tx longevity and at-home calcium self-monitoring were key factors that could improve wellbeing and HRQOL.ConclusionsThe interviews provided valuable insights on the patient lived experience of HPT. Patients’ lives were significantly disrupted by their HPT symptoms regardless of Tx regime. This disruption was exacerbated by the unpredictability of symptoms which challenged patients’ ability to live their lives. These findings highlight the need for durable effective Tx for patients with HPT.Presentation: No date and time listed

TPS453 Background: FOLFIRINOX remains the standard of care for the first line treatment of patients with locally advanced and metastatic pancreatic adenocarcinoma, however the prognosis remains poor, thus novel treatment options are indicated. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. A randomized phase IIb study in patients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180) was previously conducted. Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. A second line pivotal randomized phase III trial (Trybeca-1) is currently enrolling (NCT03665441). We design this phase I study to determine the safety of mFOLFIRINOX combined with Eryaspase in the first line of treatment. Methods: Patients with locally or metastatic biopsy proven pancreatic adenocarcinoma will be treated with the combination of mFOLFIRINOX plus Eryaspase. This will be a standard 3+3 design with 4 possible doing levels. mFOLFIRINOX dosing will include 5-Fluorouracil 2400 mg/m2 over 46 hours, Oxaliplatin 85 mg/m2, Irinotecan 150 mg/m2 plus Eryaspase 75 Units/kg at dose level 0. Eryaspase will be dose escalated up to 100 Units/kg. The study will enroll at three academic centers. Key eligibility criteria include performance status 0 or 1; locally advanced or metastatic tumor disease; adequate organ function. The primary objective is to determine the maximum tolerated dose and safety of this novel combination. Key secondary objectives include objective response rate, progression-free survival, overall survival, pharmacokinetics, pharmacodynamics, and biomarker research. A data safety monitoring committee will review data every 3 months. Clinical trial information: 04292743.

The human gut microbiota performs functions that are essential for the maintenance of the host physiology. However, characterizing the functioning of microbial communities in relation to the host remains challenging in reference-based metagenomic analyses. Indeed, as taxonomic and functional analyses are performed independently, the link between genes and species remains unclear. Although a first set of species-level bins was built by clustering co-abundant genes, no reference bin set is established on the most used gut microbiota catalog, the Integrated Gene Catalog (IGC). With the aim to identify the best suitable method to group the IGC genes, we benchmarked nine taxonomy-independent binners implementing abundance-based, hybrid and integrative approaches. To this purpose, we designed a simulated non-redundant gene catalog (SGC) and computed adapted assessment metrics. Overall, the best trade-off between the main metrics is reached by an integrative binner. For each approach, we then compared the results of the best-performing binner with our expected community structures and applied the method to the IGC. The three approaches are distinguished by specific advantages, and by inherent or scalability limitations. Hybrid and integrative binners show promising and potentially complementary results but require improvements to be used on the IGC to recover human gut microbial species.

Blood rheology is a key determinant of tissue perfusion at rest and during exercise. The present study investigated the effects of race distance on hematological, blood rheological, and red blood cell (RBC) senescence parameters. Eleven runners participated in the Martigny–Combes à Chamonix 40 km race (MCC, elevation gain: 2300 m) and 12 others in the Ultra-Trail du Mont Blanc (UTMB, 171 km, elevation gain: 10,000 m). Blood samples were collected before and after the races. After the UTMB, the percentage of RBC phosphatidylserine (PS) exposure was not affected while RBC CD235a levels decreased and RBC-derived microparticles increased. In contrast, after the MCC, RBC PS exposure increased, while RBC CD235a and RBC-derived microparticles levels were not affected. The free hemoglobin and hemolysis rate did not change during the races. RBC aggregation and blood viscosity at moderate shear rates increased after the MCC. RBC deformability, blood viscosity at a high shear rate, and hematocrit decreased after the UTMB but not after the MCC. Our results indicate that blood rheology behavior is different between a 40 km and a 171 km mountain race. The low blood viscosity after the ultra-marathon might facilitate blood flow to the muscles and optimize aerobic performance.

La prévalence des dysfonctions somatiques cervicales (DSC) est temporairement augmentée durant le traitement orthodontique. L’objectif de cette étude est de rechercher les facteurs prédictifs des DSC inhérents au patient et au traitement. Matériel et méthodes : Nous avons réalisé une étude rétrospective comparative sur 68 patients en cours de traitement multi-attache entre un groupe ayant développé des DSC sévères versus un groupe témoin (DSC absentes, légères à modérées). Les critères étudiés étaient la typologie verticale et la classe molaire, le disjoncteur, le ressort ouvert, les cales de surélévation, les extractions. Nous avons effectué une étude uni- et multivariée. Résultats : Les facteurs de risque pourvoyeurs de DSC sont l’hypo ou l’hyperdivergence, la classe II molaire, les cales de surélévation molaire, les ressorts ouverts. Le disjoncteur serait protecteur. Les extractions constituent un facteur non significatif. Conclusion : L’étude corrobore l’importance de la classe I molaire et de la normodivergence. Une étude complémentaire est nécessaire pour évaluer si ce sont les dispositifs de traitement ou les caractéristiques diagnostiques qu’ils traitent qui sont reliés aux DSC.

Abstract Background : Anti-PD-1 immunotherapy, although efficient in several cancer indications; has shown some limitations due to the appearance of resistance mechanisms. More specifically, the overexpression of A2A receptor (adenosine receptor) on the surface of infiltrated CD8 T cells following anti-PD-1 treatment blunts the immune response in an adenosine-rich tumor microenvironment (TME). In addition, increased evidence of immune escape has been described through gene hypermethylation processes. Erymethionase (methionine-gamma-lyase encapsulated into red blood cells) is an innovative experimental therapy designed to directly reduce systemic levels of L-methionine, an amino-acid nutrient needed for tumor growth and metastasis. Erymethionase is expected to indirectly decrease adenosine levels in TME and to reduce hypermethylation reactions. This bimodal action makes of erymethionase a promising agent to combine with immune checkpoint inhibitors. The benefit of such combination (erymethionase and PD-1 blockade agent) was investigated in a TNBC-like syngeneic mouse model. Methods : Mice bearing orthotopic EMT-6 syngeneic breast carcinoma were intravenously injected once weekly for 4 consecutive weeks with vehicle or mouse erymethionase at 30 or 60 U/kg alone or in combination with anti-mouse PD-1 antibody (RMP1-14 clone, intraperitoneal route, 10 mg/kg, twice weekly for 3 consecutive weeks) from D7 (D0 referring to injection of tumor cells). Erymethionase treatment was associated to daily oral vitamin B6 (pyridoxine, PN) uptake to maintain enzyme activity. The body weight, the length and width of the tumor were measured twice a week. Animal behavior was checked every day. Satellite animals receiving 60 U/kg of erymethionase or vehicle were sacrificed to collect 500-1000 m3 size-tumors to perform immunophenotyping, measure metabolites and/or assess biomarkers. Results : Analysis of health parameters revealed that all treatments were well tolerated along the experiment. A delayed start of exponential growth was reported for the combination at the highest dose of erymethionase vs single agents leading to a significant tumor growth inhibition and an increased survival (median survival time of 35 days for the combination vs 23 days for anti-PD-1 or erymethionase 60 U/kg alone; statistically significant). The antitumor effects were less pronounced at the lower dose level of erymethionase in combination with anti-PD1. Analysis of collected tumors to investigate on the mechanism(s) of action is ongoing. Conclusion : To our knowledge, this is the first in vivo demonstration of anti-PD-1 therapy potentiation using a L-methionine-restricting agent. The data are supportive of the planned erymethionase first-in-human study. Citation Format: Karine Sénéchal, Sylvie Maubant, Marie Leblanc, Séverine Ciré, Fanny Gallix, Aurély Andrivon, Olivier Duchamp, Fabrice Viviani, Françoise Horand, Alexander Scheer, Vanessa BOURGEAUX. Erymethionase (methionine-gamma-lyase encapsulated into red blood cells) potentiates anti-PD-1 therapy in TNBC syngeneic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2258.