In May 2022, Medpace experts participated in Digestive Disease Week in San Diego, CA. Learn more from Medical Department Vice Presidents Dr. Piotr Krzeski and Dr. Bruce Yacyshyn, as they recap highlights from the event.
GI and Liver Highlights from DDW 2022
Inflammatory bowel disease, like other disorders of the GI tract due to inflammation, has not established standardized disease activity criteria. This is found for both ulcerative colitis (UC) and Crohn’s disease (CD). Benjamin Click and his Target-IBD investigators (Su1537) showed that histologic risk revealed by findings of inflammation on index biopsy predicted in 513 evaluable US patients predicted loss of response to medical management. These biopsy changes occurred at a mean of 11.8 months (IQR 5.3-20.1 months). However, no specific histologic scoring system was used (e.g., Nancy, Robarts, or Geboes) to put the findings in the context of many IBD clinical trials. These scoring methods were used by Verstockt and the group from Belgium (Su462), who used all of them to identify a one-year post-treatment outcome of refractory ulcerative colitis treated with tofacitinib. They found a median histologic remission rate of 3-3, 17-26.3, and 13-17, respectively for the 40 patients studied. Patients had an endoscopic remission rate at one year of 32.5%. A correlation between histologic remission and endoscopic remission was found at year 1 (p=0.006).
Miguel Regueiro reinforced the clinical applications of markers in UC including fecal calprotectin, CRP, and endoscopic/histologic healing during his IBD theatre presentation on May 22.
Some new techniques for Crohn’s disease activity scoring included the use of ultrasound. De Cristofaro and team from Rome (Sa458) presented a poster of distinction evaluating 100 patients. Their technique used small intestine contrast ultrasonography (SICUS), and compared this to clinical activity using the Harvey Bradshaw index (HBI), CRP, and fecal calprotectin. They found that different echo behaviors correlated with different CD behaviors, with a hypoechoic pattern, in particular, correlating well (p=0.0017) with a greater HBI.
IBD clinical improvement continues to be guided by gut flora. A presentation by Hacker from the University of Munich (Sa1639) found that enteric enteral nutrition (EEN) drove a multi-OMIC panel including a group of protective bacteria, correlating with improved clinical responses.
Furthermore, man’s best friend (dog) has been found to be associated with a lower incidence of altered gut barrier with changes in microbiome composition. Williams Turpin from the University of Toronto presented this finding during the IMIBD section, distinguished abstract plenary on May 23. This session was excellent in the range and depth of presenters, who covered a wide range of IBD research topics.
Amongst the posters presented that were of interest included Tu1474, showing a clinical response in an open-label enema study of an anti-helminth, Niclosamide given by enema for ulcerative proctitis/proctosigmoiditis.
Another luminal disorder also associated with the disassociation of PRO scoring and histologic response to treatment was presented by Dellon et al., (867a), who evaluated clinical and histologic improvements in eosinophilic esophagitis from the 3-part liberty EOE TREET study. This study evaluated treatment response to dupilumab for EoE patients at week 24. Interestingly, the study showed a disconnect between histologic response to treatment (Histologic scoring system) and the absolute change in the Dysphagia symptom questionnaire (DSQ), a PRO -coprimary outcome for the study. This finding is of interest given the similarities to IBD scoring, where lack of correlation with PRO guidance has been an issue.
A presentation by the VQ-HP trialists of a p-CAB (Vonoprazan) was given by a Thai group of investigators led by Tungtrongchitr from Samut Prakan. (Tu1070). The p-CABs represent a new treatment class, different from PPIs in that they are more rapidly acting and efficacious than PPI medications. This group found that a quadruple therapy regimen (including bismuth subsalicylate, metronidazole, and tetracycline) eradicated 84.4 % at seven days and 94% at 14 days. This study was significant because these rates were achieved in a geography with high rates of clarithromycin resistance regardless of CYP3A4/5 genotype. Clearly more to come from this class of drugs!
Gastroparesis has remained an underserved indication (and a challenging field for drug development), leaving metoclopramide formulations among the few drugs available for clinicians yet tinged with safety concerns related to the risk of tardive dyskinesia (TD). We welcomed the retrospective analysis of Truen health MarketSacn Commercial Database on TD incidence from 2011-2020 (Sa1470). While it showed that TD is significantly less frequent in metoclopramide prescribed patients (33.4/100 000) than previously thought, the figure rose to almost 0.1% of gastroparetics on metoclopramide, potentially reflecting the more chronic use in this population (TD incidence was associated with longer duration of metoclopramide use and was the highest among those on 24-48 months of treatment). We are eagerly awaiting data on nasal vs. oral metoclopramide TD incidence, although do not hold our breath given the essentially similar pharmacokinetics and pharmacodynamics of the two formulations. TD historically is the #1 medication AE facing gastroenterologists and has a true human cost.
Since the seminal Angulo et al. study, we have known about the prognostic significance of liver fibrosis in patients with NAFLD/NASH. Here, a study by Lam et al. (Su1368) added obesity as an independent clinical risk variable associated with the development of clinical outcomes such as liver decompensation or liver-related events in a multivariable Cox-proportional hazard model in a large single-center cohort.
De novo HCC development in non-cirrhotic NASH has been described previously. A new meta-analysis of 58 studies by Hao Tan et al. (Su1385) quantified the proportion of HCC associated with non-cirrhotic NAFLD/NASH demonstrating that nearly 40% of incident NAFLD-related HCC cases occurred in patients without cirrhosis. This study calls for a revision in HCC surveillance strategies in this population.
Hu et al. (Su1397) provided evidence on how fast-food consumption is associated with NAFLD/NASH severity based on a cross-sectional analysis of NHANES cohort. Predictably, frequent, defined as seven or more, meals from fast food or pizza places per week were associated with more severe NAFLD. We are what we eat seems to hold true…
Polycystic ovary syndrome (PCOS) tends to be underestimated in our search for NAFLD/NASH risk factors. Suffice to note that the vast majority of NAFLD/NASH drug development research does not list PCOS among the usual metabolic syndrome components of HTN, dyslipidemia, obesity or t2DM in screening for NASH patients. This is predictably similar in patient screening in clinical practice. The study by Maldonando et al. (Su1406) provided arguments for a change in the approach showing that PCOS conferred 22% higher odds of NASH independent of the typical metabolic risk factors (which were more common in PCOS/NAFLD than in NAFLD alone).
Confirmation of NASH as causative of liver cirrhosis is sometimes challenging and the diagnosis calls for the exclusion of other causes. Alpha-1 antitrypsin deficiency is one of them. A challenging dilemma in clinical practice and NASH drug development ensues in A1AT MZ genotype NASH patients who may present with borderline low A1AT. While they do not qualify for A1AT-specific treatment, their risk of liver disease progression, decompensation or treatment response is different from those with MM type. An abstract from Prakash et al. (Su1380) confirmed the significantly increased risk of developing hepatic events in patients with MZ heterozygotes and obesity, while another one from the same group (Su1381) characterized A1AT levels in CLD patients across the spectrum of A1ATD genotypes. Going a step further, a study from Park et al. (Tu1294) provided basic background on the role of proteolytic enzyme regulation in pathogenesis of NASH in a transgenic mouse model.
Liver Cholestatic Diseases
In the quest for new targets in PSC, Zhou et al. (Su1345) identified the role of growth hormone (GH) and growth hormone receptor signaling in cholangiocytes in PSC. In the elegant paper, they initially demonstrated increased serum GH levels and GH receptor expression in cholangiocytes in PSC patients compared to healthy individuals. The same phenomena were confirmed in appropriate mouse models of mechanistic cholestatic liver injury (bile duct ligation) and PSC (Mdr2 knock-out). The Mdr2-/- were then exposed to growth hormone and GH receptor antagonist, Somavert (pegvisomant), demonstrating exacerbation and improvement in liver injury, respectively. We will eagerly await similar signal of efficacy in clinical experiments, which should be quick in coming given the significant unmet need and the fact that the product (or similarly acting somatostatin analogues) has already been available for clinical use in endocrine indications.
Seladelpar, a selective ppar-delta agonist has had its hiccups in development but we could see further encouraging data on its sustained efficacy in 101 PBC patients with inadequate response or intolerance to UDCA after 2 years of open-label dosing in extension of the phase 2 study (presentation 323). The initial GLOBE score improvement (driven by alkaline phosphatase decrease) was sustained and even deepened after 1 and 2 years of on-treatment follow-up. Safety and efficacy after 3 months of seladelpar treatment in patients with compensated PBC cirrhosis (Su1348) as well as in 2nd line non-responders to OCA or fibrates (Su1351) were presented in pooled subgroup analyses of phase 2 and 3 studies. We are all looking forward to the new drug in the PBC armamentarium.
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