aleglitazar (R1439) / Roche - LARVOL DELTA

Chronic PPARα/γ and CB2R agonist treatments attenuated visceral adipose tissue (VAT)-derived extracellular vesicle-related VAT and intestinal abnormalities in NASH mice. (PubMed, Am J Pathol) - "In vitro experiments revealed that PPARα/γ and CB2R activation attenuated NASH AT-derived EV (EVnash)-induced pathogenic changes in the J774/SVEC4-10/Caco2 /3T3-L1 cell system. This study suggested that VAT-derived EVs contribute to the pathogenesis of NAFLD and that combined PPARα/γ and CB2R agonist treatment reduces VAT-released EV release and HIF1/MCP-1 signals to ameliorate hepatic steatosis and VAT/intestine abnormalities of NASH mice."

Journal • Preclinical • Genetic Disorders • Hepatology • Immunology • Inflammation • Inflammatory Bowel Disease • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • CD31 • HIF1A • PECAM1 • PPARA • PPARG • TGFB1

Diabetic dyslipidaemia and insulin resistance are more closely associated with liver steatosis than liver fibrosis in type 2 diabetes patients (EASD 2024) - P3 | "This Alecardio analysis suggests that diabetic dyslipidemia and insulin resistance are more closely associated with liver steatosis than liver fibrosis in patients with T2DM."

Clinical • Diabetes • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Type 2 Diabetes Mellitus • APOB

Prevalence of hepatic fibrosis and effect of PPAR-α/γ agonism in type 2 diabetes patients of different ethnicities (EASD 2024) - P3 | "AF seems prevalent among T2DM subjects from African-American origin compared to other ethnicities. The prevalence of AF in this non-selected population is lower than reported in previous studies. Treatment with a PPAR-α/γ agonist for 24 months significantly decreased FIB-4 as compared to placebo for Caucasian and Asian subjects."

Clinical • Diabetes • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Type 2 Diabetes Mellitus

Hepatic fibrosis and not hepatic steatosis determines cardiovascular risk in type 2 diabetes independent from other cardiovascular risk factors: a report from the AleCardio trial (EASD 2024) - P3 | "NITs for hepatic fibrosis help to identify the subjects with T2DM at the highest CV risk. These data may help in the current discussion on defining targets for therapy in specific subgroups of patients in whom high intensity CV risk management is necessary."

Clinical • Diabetes • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Type 2 Diabetes Mellitus

Impact of age on the predictive value of NT-proBNP in patients with diabetes mellitus stabilised after an acute coronary syndrome. (PubMed, Diabetes Res Clin Pract) - "Among patients with T2DM stabilised after an ACS, NT-proBNP level predicts death irrespective of age."

Journal • Acute Coronary Syndrome • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • Type 2 Diabetes Mellitus

Improvement of non-invasive tests of liver steatosis and fibrosis as indicators for non-alcoholic fatty liver disease in type 2 diabetes mellitus patients with elevated cardiovascular risk profile using the PPAR-α/γ agonist aleglitazar. (PubMed, PLoS One) - "This post-hoc analysis showed improvement of non-invasive tests of liver steatosis and fibrosis after starting dual PPAR-α/γ agonist treatment, adding to the evidence that this pathway has potential in non-alcoholic fatty liver disease treatment."

Clinical • Journal • Cardiovascular • Coronary Artery Disease • Diabetes • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Type 2 Diabetes Mellitus

The Glitazars Paradox: Cardiotoxicity of the Metabolically Beneficial Dual PPARα and PPARγ Activation. (PubMed, J Cardiovasc Pharmacol) - "The objective of this review article pertains to the understanding of how combined PPARα and PPARγ activation, which successfully targets the major complications of diabetes, causes cardiac dysfunction. Furthermore, it aims to suggest interventions that will maintain the beneficial effects of dual PPARα/γ agonism and alleviate adverse cardiac outcomes in diabetes."

Journal • Cardiovascular • Congestive Heart Failure • Diabetes • Dyslipidemia • Heart Failure • Metabolic Disorders • Type 2 Diabetes Mellitus

Cardiovascular risk and safety evaluation of a dual peroxisome proliferator-activated receptor-alpha/gamma agonist, aleglitazar, in type 2 diabetes patients: A meta-analysis. (PubMed, J Cardiovasc Pharmacol) - "In comparison with the placebo or pioglitazone, the aleglitazar treatment significantly improved %HbA1c, high-density lipoprotein-cholesterol (HDL-chol), and triglycerides. Incidence of hypoglycemia, gastrointestinal hemorrhage, bone fractures, heart failure, cardiovascular death, and malignancy was higher in the aleglitazar group. Despite efficacy in glycemic and lipidic control, the aleglitazar treatment was associated with a poor safety profile."

Journal • Retrospective data • Cardiovascular • Congestive Heart Failure • Diabetes • Gastrointestinal Disorder • Heart Failure • Hematological Disorders • Hypoglycemia • Metabolic Disorders • Musculoskeletal Diseases • Oncology • Orthopedics • Renal Disease • Type 2 Diabetes Mellitus

Dual PPARα/γ agonist aleglitazar confers stroke protection in a model of mild focal brain ischemia in mice. (PubMed, J Mol Med (Berl)) - "Beneficial effects of aleglitazar independent of glucose regulation. Aleglitazar provides extended window of opportunity for stroke treatment."

Journal • Preclinical • Cardiovascular • Gene Therapies • Immunology • Ischemic stroke • Reperfusion Injury

The cardiovascular effects of peroxisome proliferator-activated receptor agonists (Am J Med) - Article discusses on randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes; The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance

Literature review • Diabetes

Effects of the dual PPAR-α/γ agonist aleglitazar on glycemic control and organ protection in the Zucker diabetic fatty rat (Diabetes Obes Metab) - Glycated hemoglobin (5.4% vs 9.2%) and blood glucose (8.3±0.3 vs 26.1±1.0mmol/l) were significantly reduced at 12 weeks with aleglitazar vs vehicle-treated ZDF rats (both p<0.01), while aleglitazar preserved near-normal plasma insulin levels; Aleglitazar prevented the development of hypertriglyceridemia (1.4±0.1 vs 8.5±0.9mmol/l) and reduced plasma non-esterified fatty acids (0.09±0.02 vs 0.26±0.04mmol/l) relative to vehicle-treated animals (both p<0.01); Urinary glucose and protein concentrations were significantly reduced at 13 weeks with aleglitazar vs vehicle-treated rats (both p<0.01)

Preclinical • Diabetes

A study of aleglitazar in monotherapy in patients with type 2 diabetes mellitus who are drug-naïve to anti-hyperglycemic therapy (clinicaltrials.gov) - P3, N=400 -> 13; Sponsor: Hoffmann-La Roche; Recruiting -> Completed; Completion date: Dec 2014 -> Aug 2013.

Enrollment change • Trial completion • Trial completion date • Diabetes

A study to evaluate the effect of aleglitazar on cardiac energetics and function in patients with type 2 diabetes mellitus and no history of coronary artery disease (clinicaltrials.gov) - P2, N=18; Sponsor: Hoffmann-La Roche; Completed -> Active, not recruiting; Primary completion date: Sep 2013 -> Jan 2015.

Trial primary completion date • Trial status • Acute Coronary Syndrome • Diabetes

A study of aleglitazar in combination with metformin in patients with type 2 diabetes mellitus who are inadequately controlled with sulfonylurea alone or sulfonylurea plus metformin therapy (clinicaltrials.gov) - P3, N=197; Sponsor: Hoffmann-La Roche; Recruiting -> Active, not recruiting; Completion date: May 2014 -> Dec 2013.

Enrollment closed • Diabetes

The drugs are working for Roche (WSJ) -

Drugs such as aleglitazar and dalcetrapib are still several years away from a potential market launch, increasing the likelihood that these drugs could fail to meet goals;

Analyst’s opinion • Diabetes

A pharmacodynamic/pharmacokinetic study of aleglitazar in patients with type 2 diabetes mellitus on treatment with lisinopril (clinicaltrials.gov) - P1, N=55; Sponsor: Hoffmann-La Roche; Completed; Completion date: NA -> Mar 2013.

Trial completion date • Diabetes

Genome-wide changes in microRNA expression during short and prolonged heat stress and recovery in contrasting rice cultivars. (PubMed) - J Exp Bot - "Expression of osa-miR1439, osa-miR1848, osa-miR2096, osa-miR2106, osa-miR2875, osa-miR3981, osa-miR5079, osa-miR5151, osa-miR5484, osa-miR5792, and osa-miR5812 was observed only in Nagina 22 during high temperature, suggesting a specific role of these miRNAs in heat stress tolerance. This study provides details of the repertoire of miRNAs expressed in root and shoot of heat susceptible and tolerant rice genotypes under heat stress and recovery."

Journal • Biosimilar

A study to investigate the effects of rifampicin on the pharmacokinetics of aleglitazar in healthy volunteers (clinicaltrials.gov) - P1, N=24; Sponsor: Hoffmann-La Roche; Completed; Completion date: NA -> Apr 2013.

Trial completion date • Acute Coronary Syndrome

A pharmacodynamic/pharmacokinetic study of aleglitazar in patients with type 2 diabetes mellitus on treatment with lisinopril (clinicaltrials.gov) - P1, N=44; Recruiting; Completion date: May 2012 -> Dec 2012

Trial completion date • Diabetes

Roche: Q1 2013 Results (Roche) - Anticipated regulatory submission in US for type 2 diabetes in 2015; Anticipated regulatory submission in China for type 2 diabetes in 2015; Anticipated regulatory submission in US for cardiovascular risk reduction in post acute coronary syndrome patients with type 2 diabetes in 2015; Anticipated regulatory submission in EU for cardiovascular risk reduction in post acute coronary syndrome patients with type 2 diabetes in 2015; Anticipated regulatory submission in US for cardiovascular risk reduction in patients with stable cardiovascular disease and type 2 diabetes/pre-type 2 diabetes in 2016 or after; Anticipated regulatory submission in EU for cardiovascular risk reduction in patients with stable cardiovascular disease and type 2 diabetes/pre-type 2 diabetes in 2016 or after

Anticipated EU regulatory • Anticipated FDA event • Anticipated non-US regulatory • Diabetes

Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: The AleCardio randomized clinical trial (JAMA) - P3, N=7,226; AleCardio (NCT01042769); Sponsor: Hoffmann-La Roche; “The primary end point occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo group (hazard ratio, 0.96 [95% CI, 0.83-1.11]; P = .57). Rates of serious adverse events, including heart failure (3.4% for aleglitazar vs 2.8% for placebo, P = .14), gastrointestinal hemorrhages (2.4% for aleglitazar vs 1.7% for placebo, P = .03), and renal dysfunction (7.4% for aleglitazar vs 2.7% for placebo, P &lt; .001) were increased.”

P3 data • Diabetes

Roche halts investigation of aleglitazar following regular safety review of phase III trial (Roche Press Release) - P3, N=7,227; NCT01042769; Sponsor: Hoffmann-La Roche; "...following the results of a regular safety review of the aleglitazar AleCardio phase III trial, the independent Data and Safety Monitoring Board (DSMB) has recommended to halt the trial due to safety signals and lack of efficacy. Based on this recommendation, Roche has decided to terminate the AleCardio trial and all other trials involving aleglitazar"

Discontinued • DSMB • Trial termination • Acute Coronary Syndrome • Diabetes

Roche stops developing a new drug for diabetes (NY Times) - "Roche...discontinued development of a potentially important diabetes drug, a move that could raise safety questions about the entire category of drugs...The failure of aleglitazar could influence the federal Food and Drug Administration’s deliberations over GlaxoSmithKline’s diabetes drug Avandia, which works similarly."

Discontinued • Diabetes

Comparative effects of aleglitazar- a PPAR-α/γ agonist- versus pioglitazone on glycemia, insulin sensitivity and lipids in patients with type 2 diabetes and stage 3 chronic kidney disease (ADA 2013) - Presentation time: Sun 6/23 12:00 PM; Abstract #1142-P; P2, N=301; NCT01043029; Sponsor: Hoffmann-La Roche; “…reductions in HbA1c were similar in patients taking/not taking metformin at baseline but greater in those on sulfonylurea at baseline vs those without…In AleNephro, while ALE 150 µg/d had comparable effects to PIO 45 mg/d on diabetes control and insulin sensitivity.”

P2 data • Acute Coronary Syndrome • Diabetes

Investor Day (Roche) - "Lowering TG/HDL ratio was associated with a beneficial impact of pioglitazone on progression of coronary atherosclerosis in diabetic patients"

P3 data • Diabetes