colesevelam (IW-3718) / Ironwood Pharma - LARVOL DELTA

Leveraging bile solubilization of poorly water-soluble drugs by rational polymer selection. (PubMed, J Control Release) - "Eudragit E, Soluplus, and a therapeutically used model polymer, Colesevelam, impacted the bile-colloidal geometry and molecular interaction. These polymer-induced changes reduced the flux of poorly water-soluble and bile interacting drugs (Perphenazine, Imatinib) but did not impact the flux of bile non-interacting Metoprolol. Non-bile interacting polymers (Kollidon VA 64, HPMC-AS) neither impacted the flux of colloid-interacting nor colloid-non-interacting drugs. These insights into the drug substance/polymer/bile colloid interplay potentially point toward a practical optimization parameter steering formulations to efficient bile-solubilization by rational polymer selection."

Journal

Diabetogenic effects of cardioprotective drugs. (PubMed, Diabetes Obes Metab) - "Dihydropyridine calcium channel blockers, low dose diuretics, vasodilating beta blockers, alfa-blockers and pitavastatin have little or no effect on glycemic control. Blockers of the renin-angiotensin-aldosterone system, colesevelam, ranolazine and verapamil through slowing breakdown of bradykinin, vasodilation, increasing cholecystokinin levels, blocking sodium channels, and decreasing beta cell apoptosis may improve glycemic control and avoid the development of diabetes. Dihydropyridine calcium channel blockers, low dose diuretics, vasodilating beta blockers, alfa-blockers and pitavastatin have little or no effect on glycemic control. Blockers of the renin-angiotensin-aldosterone system, colesevelam, ranolazine and verapamil through slowing breakdown of bradykinin, vasodilation, increasing cholecystokinin levels, blocking sodium channels, and decreasing beta cell apoptosis may improve glycemic control and avoid the development of diabetes."

Journal • Review • Cardiovascular • Diabetes • Metabolic Disorders

A Trial of IW-3718 for 8 Weeks in Patients With Persistent Gastroesophageal Reflux Disease (GERD) Receiving Proton Pump Inhibitors (clinicaltrials.gov) - P3; N=495; Terminated; Sponsor: Ironwood Pharmaceuticals, Inc.; Trial completion date: Jun 2021 ➔ Nov 2020; Recruiting ➔ Terminated; Trial primary completion date: Jun 2021 ➔ Oct 2020; Parallel IW-3718 Phase III trial did not meet pre-specified criteria.

Clinical • Trial completion date • Trial primary completion date • Trial termination • Gastroenterology • Gastroesophageal Reflux Disease

Trial of IW-3718 for 8 Weeks in Patients With Persistent Gastroesophageal Reflux Disease (GERD) Receiving Proton Pump Inhibitors (clinicaltrials.gov) - P3; N=609; Completed; Sponsor: Ironwood Pharmaceuticals, Inc.; Active, not recruiting ➔ Completed

Clinical • Trial completion • Gastroenterology • Gastroesophageal Reflux Disease

A Study of Colesevelam in Fecal Incontinence (clinicaltrials.gov) - P3; N=60; Recruiting; Sponsor: Mayo Clinic; Trial completion date: Oct 2020 ➔ Dec 2022; Trial primary completion date: Oct 2020 ➔ Jun 2022

Clinical • Trial completion date • Trial primary completion date

Effect of Bile Acids and Bile Acid Sequstrants on GLP-1 Secretion After Roux-en-Y Gastric Bypass (clinicaltrials.gov) - P4; N=8; Completed; Sponsor: Hvidovre University Hospital; Recruiting ➔ Completed; Trial completion date: Feb 2017 ➔ Nov 2020

Trial completion • Trial completion date • Genetic Disorders • Obesity • FGF • FGF19

Effects of Bile Acids and Bile Acid Sequestrants on GLP-1 Secretion After Roux-en-Y Gastric Bypass (clinicaltrials.gov) - P4; N=12; Completed; Sponsor: Hvidovre University Hospital; Recruiting ➔ Completed; Trial completion date: Feb 2019 ➔ Nov 2020

Trial completion • Trial completion date • Genetic Disorders • Obesity • FGF19

[VIRTUAL] SEVERE HYPERTRIGLYCHERIDEMIA IN A PATIENT WITH GRAFT DISEASE AGAINST HOST IN TREATMENT WITH RUXOLITINIBE, SIROLIMUS AND CORTICOIDE (HEMO 2020) - "Female patient, 22 years old, diagnosed with refractory Hodgkin's lymphoma after autologous BMT in December 2016 with Fludarabine, Cyclophosphamide and total body irradiation protocol...There was no control of GVHD, being initially treated with Basiliximab, three doses, also without clinical response. Cyclosporine was suspended due to renal failure and later replaced by Sirolimus...On 06/27, Sirolimus and Ruxolitinib were suspended and Ezetimibe, Fenofibrate and Atorvastatin started...In cases of moderate to severe hypertriglyceridemia, the use of omega-3 and fibrates may be considered, as well as second-line treatments include niacin, Ezetimibe or Colesevelam...The interactions between immunosuppressive medications and lipid-lowering drugs used to treat side effects from previous treatment need to be regularly monitored, as changes are clinically important. In case of association of corticosteroids Sirolimus and Ruxolitinib, strict control of the lipid profile must..."

Clinical • Cardiovascular • Dyslipidemia • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Hepatology • Hodgkin Lymphoma • Hypertriglyceridemia • Immunology • Lymphoma • Metabolic Disorders • Oncology • Pain • Renal Disease • Respiratory Diseases • Transplantation

The novel phosphate and bile acid sequestrant polymer SAR442357 delays disease progression in a rat model of diabetic nephropathy. (PubMed, J Pharmacol Exp Ther) - "In comparison, colesevelam, a BAS with poor phosphate binding property did not prevent DKD progression, while losartan, an angiotensin II receptor blocker that is widely used to treat DKD, showed no effect on hyperglycemia. Significance Statement A new non-absorbed polymeric sequestrant with optimum phosphate and bile salt sequestration properties was developed as a treatment option for DKD. The new polymeric sequestrant offered combined pharmacological benefits including glucose regulation, lipid lowering and attenuation of DKD progression in a single therapeutic agent."

Journal • Preclinical • Cardiovascular • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Dyslipidemia • Gastrointestinal Disorder • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus

Effects of Fish Oil and Colesevelam (STAIR7007) (clinicaltrials.gov) - P=N/A; N=13; Active, not recruiting; Sponsor: University of Manitoba; Trial completion date: Apr 2020 ➔ Jul 2021; Trial primary completion date: Apr 2020 ➔ Apr 2021

Combination therapy • Trial completion date • Trial primary completion date • Dyslipidemia

Prevention of the rise in plasma cholesterol and glucose levels by kaki-tannin and characterization of its bile acid-binding capacity. (PubMed, J Sci Food Agric) - "Our findings indicate that kaki-tannin binds preferentially to bile acids with fewer hydroxy groups and has beneficial effects on glucose metabolism as well as cholesterol metabolism."

Journal • Genetic Disorders • Obesity

Real-world Effectiveness of treatments for type 2 diabetes, hypercholesterolemia, and hypertension in Canadian routine care - Results from the CardioVascular and metabolic treatment in Canada: Assessment of REal-life therapeutic value (CV-CARE) registry, 12-months results. (PubMed, Diabetes Res Clin Pract) - "In a real-world Canadian setting, MetER, C, AZI, AZI/CHL, and TXC show improvement of the cardiometabolic profile of T2D, HCh, and HTN patients."

Clinical • Journal • Real-World Evidence • Cardiovascular • Diabetes • Dyslipidemia • Hypertension • Metabolic Disorders • Type 2 Diabetes Mellitus

Diagnosis and management of bile acid diarrhoea: a survey of UK expert opinion and practice. (PubMed, Frontline Gastroenterol) - "Colestyramine was the usual sequestrant, starting between 2 g and 8 g daily; colesevelam was an alternative. In patients who had an incomplete response, increasing the dose, changing to an alternative sequestrant, use of loperamide and a low fat diet were suggested. Recommendations for follow-up and to improve the overall patient experience were made. This expert survey indicates current best practice in the diagnosis and management of BAD."

Journal • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease

Trial of IW-3718 for 8 Weeks in Patients With Persistent Gastroesophageal Reflux Disease (GERD) Receiving Proton Pump Inhibitors (clinicaltrials.gov) - P3; N=550; Active, not recruiting; Sponsor: Ironwood Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting

Enrollment closed • Gastroenterology • Gastroesophageal Reflux Disease

[VIRTUAL] Multiple Recurrent Lipomatoses with Thiazolidinedione Therapy in Familial Partial Lipodystrophy, Dunnigan Variety (FPLD2) (ENDO-I 2020) - "She developed diabetes at age 30 and was started on pioglitazone 45 mg daily, which was switched to rosiglitazone 8 mg daily at age 43 years...Her other medications included colesevelam, atorvastatin, metformin, glimepiride, lisinopril, losartan, hydrochlorothiazide, aspirin, insulin and dulaglutide. Her 54-year-old younger sister with FPLD2 (heterozygous p.R482Q LMNA mutation) was treated with lisinopril, metoprolol, atorvastatin, liraglutide, and insulin glargine and aspart, but no history of taking thiazolidinediones, and she never developed any lipomatoses...Her other medications included atorvastatin, aldactone and vitamin D3... Thiazolidinediones are selective peroxisomal proliferator-activated receptor-γ agonists and induce weight gain by increasing fat mass, especially subcutaneous depots. Our cases suggest that thiazolidinediones can cause undesired growth of non-lipodystrophic adipose tissue in patients with FPLD2 and thus should be avoided."

Aesthetic Medicine • Diabetes • Dyslipidemia • Lipodystrophy • Metabolic Disorders • LMNA

Bempedoic acid (Nexletol) for lowering LDL-cholesterol. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal

Lipoprotein Apheresis and Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors in Patients With Heterozygous Familial Hypercholesterolemia: A One Center Study. (PubMed, J Cardiovasc Pharmacol Ther) - "The PCSK9i treatment (evolocumab 420 mg/4 weeks, alirocumab 150 mg/2 weeks, or alirocumab 75 mg/2 weeks: 9, 6, and 2 patients, respectively) was initiated in patients with HeFH (n = 17; aged 35-69 years, 10 men, previously treated with statins + ezetimibe ± colesevelam and LA sessions for 2-12 years). PCSK9i therapy may reduce the frequency of LA. Larger trials are required to establish the clinical implications of PCSK9i in patients previously on LA."

Clinical • Journal • Dyslipidemia • Genetic Disorders • Metabolic Disorders

Table: Safety of drugs for IBS in pregnancy and lactation (online only). (PubMed, Med Lett Drugs Ther) - No abstract available

Clinical • Journal • Immunology • Inflammatory Bowel Disease

Drugs for Irritable Bowel Syndrome. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Constipation • Immunology • Inflammatory Bowel Disease

WELKid DM: Colesevelam for Children With Type 2 Diabetes (clinicaltrials.gov) - P4; N=230; Completed; Sponsor: Daiichi Sankyo, Inc.; Active, not recruiting ➔ Completed

Clinical • Monotherapy • Trial completion • Diabetes • Metabolic Disorders • Pediatrics • Type 2 Diabetes Mellitus

Colesevelam Versus Placebo in the Treatment of Nonalcoholic Steatohepatitis (clinicaltrials.gov) - P2; N=59; Completed; Sponsor: University of California, San Diego; Enrolling by invitation ➔ Completed

Clinical • Trial completion • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • MRI

"Ironwood Announces Updates Designed to Strengthen IW-3718 Phase III Program for Refractory Gastroesophageal Reflux Disease (GERD) https://t.co/gl7yxAt9zl" (@NewsFromBW)

Gastroenterology • Gastroesophageal Reflux Disease

Goal achievement of A1C and LDL in a Randomized Trial Comparing Colesevelam vs. Ezetimibe: GOAL-RCT. (PubMed, Diabetes Obes Metab) - P4 | "Among subjects with T2D, the initiation of colesevelam or ezetimibe led to similar achievement of primary composite outcome (LDL-c and A1c within target), with ezetimibe recording a greater LDL-c reduction and better toleratability than colesevelam."

Clinical • Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

[VIRTUAL] Bile Acid Sequestration Synergistically Accelerates Glucagon Receptor-Stimulated Body Weight Loss in Diet-Induced Obese Mice (ENDO-I 2020) - "Thus, to elucidate the role of BA in GCGR-mediated weight loss, we utilized anion-exchange BA-binding resins (BARS; Cholestyramine and Colesevelam) to prevent intestinal (ileal) re-uptake and reduce plasma total cholesterol, LDL, and BAs via fecal excretion. Together these studies suggest BARS may enhance the anti-obesity effect of GCGR agonism, beneficially regulate feeding behaviors, and prevent GCGR-stimulated glucose dysregulation in DIO mice. Furthermore, these studies argue that GCGR agonsim combined with BARS treatment may represent a novel therapeutic approach for obesity and obesity-associated glucose intolerance."

Preclinical • Genetic Disorders • Obesity

Integrative roles of microRNAs in lipid metabolism and dyslipidemia. (PubMed, Curr Opin Lipidol) - "miRNAs are not just fine-tuners of lipid metabolism, but critical regulatory factors in lipid homeostasis and health. Loss of these miRNA regulatory modules very likely contributes to the underlying metabolic defects observed in lipid disorders."

Journal • Dyslipidemia • Hepatology