Familial Hypercholesterolemia

August 14, 2017

Gemphire Therapeutics released results of a phase IIb, double-blind, placebo-controlled, randomized study of oral gemcabene 600mg dosed once daily in hypercholesterolemic patients. ROYAL-1 enrolled patients who were not adequately controlled, with an existing LDL-C value ≥100mg/dL (2.59mmol/L) and a TG value < 500mg/dL (5.65 mmol/L), on stable high- or moderate-intensity statin and/or ezetimibe therapy. Patients were stratified according to background statin intensity and diabetes status. One hundred and five subjects were enrolled at sites in the U.S. and randomized to either gemcabene 600mg or placebo for a total of 12 weeks. The primary endpoint was the percent change in LDL-C from baseline. Secondary endpoints included safety as well as the percent change from baseline in non-HDL-C, TC, TG, HDL-C, VLDL-C, Apo B, hsCRP and several other biomarkers. Fifty-six females and 49 males with a mean age of 61 years were enrolled. The mean baseline LDL-C was 130mg/dL. Gemcabene 600mg produced a mean percent change in LDL-C of -17.2% vs -5.5% for placebo (ANCOVA: p=0.0057). Gemcabene 600mg produced a median percent change in hsCRP of -40.0% (ranked ANCOVA: p<0.0001) vs -6.1% for placebo. Additional secondary results and subpopulations assessments will be provided once the full dataset has been analyzed. There were no serious adverse events in the study.

September 6, 2016

Amgen issued results of three phase III studies of Repatha (evolocumab) in patients across cardiovascular (CV) risk subgroups or with familial hypercholesterolemia (FH). The 12-week studies enrolled a total of 2,532 patients. Analysis showed that treatment with Repatha 140mg every two weeks or 420mg monthly consistently reduced levels of low-density lipoprotein cholesterol (LDL-C) and other lipids from baseline to the mean of weeks 10 and 12 across all risk categories compared to placebo or ezetimibe controls. For example, among very high-risk patients, Repatha reduced LDL-C levels from baseline 65.2% more than placebo and 40.7% more than ezetimibe. The rates of overall adverse events were similar for the three groups, occurring in 43.1%, 50.5% and 40.8% of patients on Repatha, ezetimibe and placebo, respectively.

April 4, 2016

Regeneron Pharmaceuticals and Sanofi released positive results from the phase III ODYSSEY ESCAPE trial evaluating Praluent (alirocumab) Injection in patients with an inherited form of high cholesterol known as heterozygous familial hypercholesterolemia (HeFH), whose cholesterol levels required chronic, weekly or bi-weekly apheresis therapy. The completed, placebo-controlled trial involved 62 patients from 14 treatment centers in the U.S. and Germany. These patients were receiving regular baseline apheresis therapy at fixed intervals of every week or every 2 weeks prior to randomization. Patients were randomized to receive Praluent 150mg (n=41) subcutaneously every 2 weeks or placebo (n=21), in addition to their existing treatment regimen. The double-blind treatment period comprised two intervals: for the first six weeks, patients remained on their established apheresis schedule at baseline, and for the following 12 weeks, apheresis frequency was adjusted based on the patient’s LDL cholesterol response to treatment. ODYSSEY ESCAPE is part of the overarching phase III ODYSSEY program, which includes more than 25,000 patients. The trial met its primary endpoint, demonstrating that patients who added Praluent to their existing treatment regimen significantly reduced the frequency of their apheresis therapy by 75%, compared to placebo (p< 0.0001). Sixty-three percent of patients treated with Praluent no longer required apheresis, compared to 0% of placebo patients. The most common adverse events in the trial were fatigue (15% Praluent; 10% placebo), nasopharyngitis (10% Praluent; 10% placebo), diarrhea (10% Praluent; 0% placebo), myalgia (10% Praluent; 5% placebo), upper respiratory infection (7% Praluent; 19% placebo), headache (7% Praluent; 5% placebo), arthralgia (7% Praluent; 10% placebo) and back pain (5% Praluent; 10% placebo).

September 28, 2015

Regeneron Pharmaceuticals and Sanofi have released results of a phase III study of Praluent (alirocumab) for heterozygous familial hypercholesterolemia (HeFH) patients to reduce low-density lipoprotein cholesterol (LDL-C). The analysis compared Praluent to placebo in 1,257 patients with HeFH. Data from four phase III ODYSSEY trials were included in the analysis. In those trials, patients either received Praluent or placebo, in addition to standard-of-care, which included maximally tolerated statins with or without other lipid-lowering therapies such as ezetimibe. In ODYSSEY LONG TERM and HIGH FH, patients were treated with Praluent 150mg (n=348) every two weeks administered as a single 1-milliliter (mL) injection or placebo (n=174). In those patients, the average LDL-C at baseline was 168mg/dL and 162mg/dL in the Praluent and placebo groups respectively. In ODYSSEY FH I and FH II, patients were treated with Praluent 75mg (n=490) every two weeks administered as a single 1mL injection or placebo (n=245). In ODYSSEY FH I and FH II, patients had their dose adjusted to 150mg at week 12 if they did not achieve their pre-specified LDL-C goal at week eight. In those patients, the average LDL-C level at baseline was 141mg/dL in both the Praluent and placebo groups. Across all primary and secondary endpoints assessed, there were statistical differences in favor of Praluent compared to placebo. Patients treated with Praluent achieved average LDL-C levels of less than 85mg/dL at week 12 and maintained reductions through 78 weeks of therapy. The effect of Praluent on CV morbidity and mortality has not been determined. In July, the EMA recommended the approval of Praluent in certain adult patients with hypercholesterolemia; a final decision from the European Commission is anticipated in September.

March 30, 2015

Esperion Therapeutics released results of a phase IIb study of ETC-1002 (bempedoic acid) compared with placebo in patients with hypercholesterolemia on stable statin therapy. The 12- week, multicenter, randomized, double-blind, placebo-controlled, parallel group study enrolled 134 subjects. Forty-three patients received ETC-1002 120mg; 45 patients received ETC-1002 180mg; 45 patients received placebo. One patient was randomized but did not receive study drug. ETC-1002-treated patients achieved 17% and 24% incremental reductions in LDL-cholesterol at doses of 120mg and 180mg, respectively, compared with patients on stable statin therapy alone. These reductions were significantly different from placebo (p=0.0055 and p<0.0001, respectively), occurred within the first two weeks of initiating therapy and continued throughout the treatment period. Consistent with prior studies, ETC-1002 demonstrated reductions of up to 30% in high-sensitivity C-reactive protein (hsCRP), an important marker of inflammation in coronary disease. ETC-1002 produced no increases in muscle-related adverse events (AEs). There was one reported serious adverse event (SAE) in the ETC-1002 treatment arms, which was not drug-related. Discontinuation rates were low overall and lower in ETC-1002-treated patients than those seen in placebo, and were not muscle-related.

March 23, 2015

Regeneron Pharmaceuticals and Sanofi issued results of a phase III trial of Praluent (alirocumab) involving 2,341 high-risk patients with hypercholesterolemia. The 78-week trial evaluated Praluent 150mg (n=1,553) every two weeks compared to placebo (n=788). At week 24, Praluent reduced LDL-C from baseline by an additional 62% v. placebo (p<0.0001) when added to the current standard-of-care, which included maximally-tolerated statins. Efficacy remained consistent throughout treatment, and at week 78 there was a 56% reduction from baseline in LDL-C for Praluent v. placebo (p<0.0001). At week 24, 81% of patients in the Praluent group achieved their pre-specified LDL-C goal (either 70mg/ deciliter [mg/dL] or 100mg/dL depending on baseline CV risk) compared to 8.5% for placebo (p<0.0001). Adverse events (AEs) occurred in 81% of Praluent and 83% of placebo patients, leading to discontinuation in 7.2% and5.8% of patients, respectively. Earlier this year, Regeneron and Sanofi announced the FDA accepted the BLA for Praluent for priority review.

August 4, 2014

Regeneron and Sanofi reported results of a phase III trial of alirocumab for hypercholesterolemia. The 2,341-patient, ongoing trial has two dosing regimens: 150mg every two weeks or 75mg every two weeks increasing to 150mg if needed to reach protocol-specified LDL-C targets. A pre-specified interim safety analysis was performed when all patients reached one year and approximately 25% of patients reached 18 months of treatment. A lower rate of adjudicated major cardiovascular events (cardiac death, myocardial infarction, stroke and unstable angina requiring hospitalization) was observed in the alirocumab arm compared to placebo in a post-hoc analysis (p<0.05). The potential of alirocumab to demonstrate cardiovascular benefit is being prospectively assessed in an ongoing 18,000-patient trial.