Ipsen (United Kingdom)

<h3></h3> PBC is a rare, cholestatic liver disease characterized by inflammation, fibrosis, and destruction of intrahepatic bile ducts. Elafibranor, a peroxisome proliferator-activated receptor (PPAR) agonist exerting effects on PPAR alpha and delta, was efficacious and well-tolerated in patients with PBC in the phase III ELATIVE® trial (NCT04526665). Here, longitudinal protein expression profiles were evaluated in serum samples from patients in ELATIVE®, to provide insights into the immunoregulatory mechanism of elafibranor in PBC. For patients in ELATIVE® who consented, serum samples were collected at baseline, Week 26, and Week 52. Longitudinal protein expression profiles were analyzed using Olink® Proximity Extension Assay technology. Two Olink® panels, Target 96 Immune Response and Explore HT, were used, covering &gt;5,500 proteins. Quality control and data normalization were conducted by Olink®. Linear mixed models were fitted to each protein from baseline to Week 52. Statistically significant changes in protein expression were identified using the Benjamini-Hochberg method with a 5% false discovery rate. Proteins with statistically significant changes in expression were assessed in elafibranor-treated patients with and without biochemical response, according to the primary endpoint of ELATIVE®. Pathway analyses were conducted using QIAGEN® Ingenuity Pathway Analysis (IPA®). Serum samples were analyzed from 121 patients, of whom 87 received elafibranor; 46 with and 41 without biochemical response at Week 52. Expression of control proteins, gamma-glutamyl transferase-1 (GGT1) and 5’-nucleotidase (NT5E), decreased with elafibranor treatment when measured by Olink® and standard methodologies, validating the use of Olink®. A network of &gt;20 proteins involved in hepatic inflammation had statistically significant changes of expression in elafibranor-treated patients with biochemical response at Week 52. IPA® revealed a novel inflammatory signature, including downregulation of intercellular adhesion molecule 1 (ICAM-1), dipeptidyl peptidase 4 (DPP4) and SerpinA3. This network is known to be implicated in immune cell adhesion and inflammatory regulation, and maps to immunomodulation and fibrosis pathways. Similarly, biomarkers associated with itching and fibrosis, such as bone marrow stromal cell antigen 2 (BST2) or solute carrier family 39 member 14 (SLC39A14), were significantly downregulated. This is the first longitudinal proteomic analysis to characterize proteins with modulated expression in patients with PBC treated with elafibranor. These findings provide novel mechanistic insights into the anti-inflammatory effect of elafibranor in PBC, as well as the impact on proteins associated with PBC symptoms, through effects on PPAR alpha and delta.

LBA4175 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is an aggressive malignancy with a median overall survival (mOS) of between 8 and 11 months. With the use of modern chemotherapy regimens, some patients with mPDAC have been shown to achieve long‐term survival of 18 months or longer (Rochefort et al. Oncol. 2019;24:1543–8). The aim of this analysis was to describe long‐term survivors among the North American population treated with liposomal irinotecan plus 5-fluorouracil/leucovorin and oxaliplatin (NALIRIFOX) in the NAPOLI 3 trial and to explore clinical and pathological factors that might be associated with prolonged survival. Methods: Patients with confirmed untreated mPDAC randomized to receive NALIRIFOX in NAPOLI 3 were treatment on days 1 and 15 of a 28-day cycle. In this post hoc analysis of patients enrolled from centers in North America (n = 120), baseline characteristics and NALIRIFOX dosing patterns were evaluated for individuals who survived for 18 months of longer (long-term survivors; n = 15). The analysis was descriptive; no statistical tests were performed. Kaplan–Meier methods were used to estimate mOS (interquartile range [IQR]). Results: Among the long-term survivors, the mOS was 19.5 (IQR: 18.8–22.6) months and 53.3% were male. At baseline, long-term survivors had a median age of 61.0 (IQR: 49.0–70.5) years, had a median CA 19-9 level of 166.8 U/ml (IQR: 32.7–1728.4), 53.3% had Eastern Cooperative Oncology Group Performance Score (ECOG PS) 0, 53.3% had the main pancreatic tumor located in the body of the pancreas, 66.7% had liver metastasis, and 53.3% had ≥ 3 metastatic sites. Liposomal irinotecan and oxaliplatin dose reductions were experienced by 66.7% and 80.0% of long-term survivors, respectively, and dose delays by 86.7% and 80.0%, respectively. Median cumulative dose of liposomal irinotecan was 1229.4 (IQR: 821.9–1513.9) mg/m 2 for long-term survivors and median cumulative dose of oxaliplatin was 962.3 (655.0–1470.3) mg/ml. Median duration of exposure was 65.1 (IQR: 40.1–89.0) weeks for liposomal irinotecan and 39.9 (26.6–76.4) weeks for oxaliplatin. Conclusions: This post hoc analysis investigated characteristics and dosing patterns of long-term survivors from NAPOLI 3 treated with NALIRIFOX in North America. Patients with prolonged OS were generally younger (vs typical mPDAC diagnosis), few had tumors in the head or tail of the pancreas and, overall, CA19-9 levels and ECOG PS were low. A large proportion of long-term survivors experienced liposomal irinotecan and/or oxaliplatin dose reductions or treatment delays, but had prolonged exposure and high cumulative doses of both drugs. Despite liver metastasis and ≥ 3 metastatic sites in a substantial proportion of long-term survivors, dose modifications and an otherwise good clinical profile enabled attainment of a long mOS. Small sample size limits the generalizability of these results. Clinical trial information: NCT04083235 .

IntroductionElafibranor, a dual peroxisome proliferator-activated receptor (PPAR) alpha/delta agonist, is under investigation as a treatment for primary biliary cholangitis (PBC). In vitro studies demonstrated that elafibranor and its major active metabolite GFT1007 inhibit organic anion transporter polypeptide (OATP) 1B3. A phase I trial was conducted to evaluate the drug-drug interaction (DDI) potential of elafibranor as a perpetrator with atorvastatin, an OATP1B3, OATP1B1 and cytochrome P4503A (CYP3A) clinical substrate.MethodsIn this phase I, randomised, open-label trial (EudraCT: 2015–000723-88), healthy participants received single doses of atorvastatin 40 mg (Days 1 and 17) and once-daily doses of elafibranor 180 mg (Days 4–19) under fasting conditions. Pharmacokinetic (PK) parameters derived for each treatment included observed maximum plasma concentration (Cmax), area under the plasma concentration curve from administration up to the last quantifiable concentration at 72 hours (AUC0–72 h), and time to reach Cmax (tmax). All adverse events (AEs) were recorded.ResultsOf 25 white male participants, 24 completed the trial; median (range) age was 32.0 (19–45) years. There was no increase in the overall exposure of atorvastatin. Compared with atorvastatin administration alone, Cmax was 28% lower following co-administration with elafibranor, with a geometric mean ratio (GMR) of 72 (90% confidence interval [CI]: 60.1–87.2); mean (standard deviation [SD]): 19.7 (11.0) ng/mL vs 14.8 (11.4) ng/mL. Median (range) tmax increased from 0.67 (0.50–3.00) hours (h) to 1.00 (0.67–4.50) h. There was a small decrease of mean (SD) AUC0–72 h (12%) following co-administration, and the 90% CIs indicated similarity between the regimens: 81.3 (42.1) ng/mL*h vs 75.0 (51.5) ng/mL*h; GMR: 88 (90% CI: 82.2–93.3). Observed differences between the two regimens were not deemed clinically significant. A total of 16 non-serious and mild to moderate treatment-emergent AEs were reported by 11 participants; all were resolved without treatment discontinuation.ConclusionsCo-administration of atorvastatin and elafibranor 180 mg had minimal impact on the overall exposure of atorvastatin. Therefore, co-administration of elafibranor 80 mg (clinical dose) with OATP1B1, OATP1B3 and CYP3A substrates, such as other statins, is unlikely to cause clinically significant PK DDIs. Furthermore, co-administration of atorvastatin and elafibranor was well tolerated.

People with neuroendocrine neoplasms (NENs) face a multitude of challenges, including delayed diagnosis, low awareness of the cancer among healthcare professionals and limited access to multidisciplinary care and expert centres. We have developed the first patient care pathway for people living with NENs in England to guide disease management and help overcome these barriers. The pathway was developed in two phases. First, a pragmatic review of the literature was conducted, which was used to develop a draft patient care pathway. Second, the draft pathway was then updated following semi-structured interviews with carefully selected expert stakeholders. After each phase, the pathway was discussed among a multidisciplinary, expert advisory group (which comprised the authors and the Deputy Chief Operating Officer, West Suffolk NHS Foundation Trust), who reached a consensus on the ideal care pathway. This article presents the outputs of this research. The pathway identified key barriers to care and highlighted how these may be addressed, with many of the findings relevant to the rest of the UK and international audiences. NENs are increasing in incidence and prevalence in England, compounding pre-existing inequities in diagnosis and disease management. Effective integration of this pathway within NHS England will help achieve optimal, equitable care provision for all people with NENs, and should be feasible within the existing expert multidisciplinary teams across the country.

Microbioreactors have been proven to be a useful tool in high-throughput applications, such as clone screening, synthetic library testing, and media optimization. Most were designed for low cell density applications, where the optical density of the cultures typically does not exceed an OD600 of 10. In microbial applications, where protein is to be expressed, such a scale is not sufficient to produce material for extensive target molecule testing. Here, we present a method for growing high-cell density Escherichia coli cultures in milliliter-scale bioreactors, to produce milligram quantities of target protein. We used a micro-Matrix system with a starting volume of 3ml per culture. A combination of defined medium, a fed-batch feeding strategy at low temperature, and an advanced self-adapting control algorithm achieved up to 0.7g of wet cell weight (WCW) in a 5.7ml final culture volume, which corresponds to 123g/L WCW. This translates to an estimated protein yield of 1150mg of target protein per liter final volume.