Cardiovascular Abnormalities

March 19, 2018

MyoKardia announced positive results from the Phase IIPIONEER-HCM clinical study of the investigational agent mavacamten in symptomatic, obstructive hypertrophic cardiomyopathy (oHCM) patients, including results from a low-dose patient cohort (“Cohort B”), which studied once-daily 2mg and 5mg oral doses of mavacamten. PIONEER-HCM is a Phase II open-label study to assess the efficacy, safety, pharmacokinetics, pharmacodynamics, and tolerability of mavacamten in patients with symptomatic oHCM. PIONEER-HCM consists of two dosing cohorts: in the first cohort, subjects received a once-daily 10mg, 15mg or 20mg dose of mavacamten and were required to discontinue background therapy including beta blockers prior to study entry; and Cohort B, in which subjects received a once-daily 2mg or 5mg oral dose of mavacamten and nine out ten patients remained on beta blocker therapy. Baseline patient characteristics were similar across both patient cohorts.

March 12, 2018

Esperion announced positive top-line results from the first pivotal, Phase III study (Study 4 or 1002-048) of bempedoic acid. The 12-week study met its primary endpoint with LDL-C lowering totaling 28 percent (p<0.001). The LDL-C lowering for the bempedoic acid group was 23 percent from baseline, as compared to an LDL-C increase of five percent for the placebo group. Patients treated with bempedoic acid also achieved a significantly greater reduction of 33 percent in high-sensitivity C-reactive protein (hsCRP), compared to the placebo group which had an increase of two percent (p<0.001). The 12-week, global, pivotal, Phase III randomized, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of bempedoic acid 180 mg/day versus placebo as add-on therapy in patients with atherosclerotic cardiovascular disease (ASCVD), or at a high risk for ASCVD. The primary objective was to assess the 12-week LDL-C-lowering efficacy of bempedoic acid versus placebo when added to ezetimibe and up to the lowest starting dose of a statin.

January 27, 2014

Resverlogix reported results of two trials (SUSTAIN and ASSURE) of RVX-208 for the treatment of major adverse cardiac events (MACE) over six months. When MACE data (n=499) from both SUSTAIN and ASSURE trials were combined, it demonstrated that treatment with RVX-208 lead to a significant reduction in MACE. RVX-208 treated patients (n=331) had fewer cumulative events of 6.74% v. 15.09% (p=0.02) in the placebo treated group (n=168). Furthermore, in patients who had elevated CRP > 2mg/dL (n=283), the benefit of RVX-208 treatment of patients (n=179) appeared more striking with a cumulative event rate of 6.42% v. 20.53% (p=0.007) in the placebo group (n=104). One analysis was performed by an independent firm.

September 30, 2013

Resverlogix released results of a phase IIb trial evaluating RVX-208 using intravascular ultrasound (IVUS) for the treatment of 281 high-risk cardiovascular patients. The below median HDL (<39mg/dL) baseline population consisted of 92 patients who were taking either Rosuvastatin (Crestor) or Atorvastatin (Lipitor) together with RVX-208. Rosuvastatin and RVX-208 patients had a highly statistically significant Percent Atheroma Volume (PAV) plaque regression of -1.43% with probability value of p<0.002. This PAV regression exceeded the trial's pre-specified PAV endpoint (-0.6%) by more than two-fold. Those patients taking Atorvastatin (Lipitor) with RVX-208 had a PAV plaque progression of +0.19% with a non-significant probability value. The synergistic effect of the Rosuvastatin and RVX-208 combination is the basis for two recent provisional patent applications by Resverlogix.

October 29, 2012

Bayer HealthCare released data from a phase III trial of riociguat for pulmonary arterial hypertension (PAH). This randomized, double-blind, placebo-controlled, multinational study enrolled 445 patients with symptomatic PAH. Subjects received titrated doses of riociguat three times daily in increments of 0.5mg, with doses as low as 1.0mg and as high as 2.5mg, over eight weeks, followed by a four-week follow-up period. The study met its primary endpoint by demonstrating a statistically significant improvement in the six-minute walk distance (6MWD) with patients treated with riociguat showing an improvement of 36 meters 95%-CI [20-52 meters] (p<0.0001) after 12 weeks compared with placebo. Results also showed a statistically significant improvement in 6MWD, both in the treatment-naive patient group (38 meters after 12 weeks compared with placebo [95%-CI 15-62 meters]) and the pre-treated patient group (36 meters after 12 weeks compared with placebo [95%-CI 15-56 meters]). The drug was well tolerated.

September 3, 2012

Pozen issued results from a phase I trial of PA32540 for the treatment of cardiovascular disease. This randomized, openlabel, two-arm crossover study enrolled 30 patients with cardiovascular disease at risk for aspirin-associated gastric ulcers. Subjects were divided into two arms. The first arm received PA32540 in the morning plus 300mg clopidogrel over 10 hours later on Day One, and PA32540 in the morning plus 75mg clopidogrel 10 hours later on day two through seven. The second arm received 81mg enteric-coated aspirin, 300mg clopidogrel and 40mg EC omeprazole all in the morning on day one, followed by 81mg enteric-coated aspirin, 75mg clopidogrel and 40mg EC omeprazole all in the morning on day two through seven. When subjects completed treatment, they had a 14-day washout period and then crossed over to the alternate treatment. Data showed the PA32540 arm resulted in greater antiplatelet effects than the EC aspirin arm (46.5% versus 39.9%, respectively, at day seven: 95% confidence interval of the difference [2.57, 11.91]; p=0.004). The drug was well tolerated.

August 6, 2012

Bristol-Myers Squibb and AstraZeneca issued results from five phase III trials of Onglyza (saxagliptin) for the treatment of cardiovascular disease. These randomized, placebo-controlled studies enrolled 1,681 patients with type 2 diabetes and varying degrees of cardiovascular risk. Subjects received Onglyza 5mg or placebo for 24 weeks. Data demonstrated improvements across key measures of blood sugar control (glycosylated hemoglobin levels, or HbA1c; fasting plasma glucose, or FPG and postprandial glucose, or PPG) compared to placebo in patients at high risk for cardiovascular disease. Decreases in FPG for Onglyza at week 24 ranged from -14.2 mg/dL to -16.0 mg/dL versus placebo. Similarly, PPG results at week 24 ranged from -36.1 mg/dL to -47.0 mg/dL compared to placebo. Finally, achievement of target HbA1c (less than 7.0%) ranged from 15.7% to 21.8% versus placebo. The drug was well tolerated. The most frequent adverse event was hypoglycemia. BMS and AZ did not note their future plans for Onglyza.

March 26, 2012

POZEN released results from two phase III trials of PA32540, a coordinated-delivery tablet of immediate-release omeprazole and delayed release aspirin, under development for the secondary prevention of cardiovascular disease in subjects at risk for aspirin-induced ulcers. The randomized, double-blind, multi-center studies enrolled 1,049 subjects at risk for developing aspirin-associated ulcers and already taking aspirin at a dose of 325 mg once daily for at least three months. The subjects received treatment with either PA32540 or 325 mg enteric-coated aspirin once daily. The primary endpoint, a significant reduction in the cumulative incidence of gastric ulcers following administration of PA32540 versus 325 mg enteric-coated aspirin over six months, was met in both studies. Secondary endpoints were also reached, including a reduction in gastroduodenal ulceration as well as a reduction in discontinuation due to upper gastrointestinal adverse events.

April 4, 2011

Pozen issued results from the phase I trial of PA32540, a tablet for the secondary prevention of cardiovascular disease in patients at risk for aspirin-associated gastric ulcers. The randomized, open-label, two-arm crossover study, Co-Rx, was designed to compare PA32540 to current standard of care, Prilosec, both in conjunction with clopidogrel. Thirty healthy subjects were treated with one of the following: A) PA32540 in the morning plus clopidogrel (300 mg) over 10 hours later on day 1, and PA32540 in the morning plus clopidogrel (75 mg) 10 hours later on days two through seven; B) enteric-coated aspirin (81 mg) plus clopidogrel (300 mg) plus Prilosec (40 mg) all in the morning on day 1 followed by enteric-coated aspirin (81 mg) plus clopidogrel (75 mg) plus Prilosec (40 mg) all in the morning on days two through seven. Each treatment was separated by a 14 day washout period. The primary endpoint was the percent inhibition of platelet aggregation (IPA) after morning dosing on day seven of each period. The PA32540 treatment arm resulted in a significantly greater IPA than the standard of care arm, with an approximate 20% improvement in the anti-clotting effects.

February 28, 2011

Isis released results from a phase I trial of ISIS CRPRx, under development for the treatment of inflammatory and cardiovascular disorders. The blinded, randomized, placebo-controlled, dose-escalation study enrolled 80 healthy subjects who received single and multiple doses ranging from 50 mg per week to 600 mg per week. In all but one cohort, the subjects had normal (generally undetectable to less than 2 mg/L) CRP levels. In the 600 mg per week multi-dose cohort, eight subjects with elevated levels of CRP were enrolled. The subjects enrolled in this cohort had an average CRP level at baseline of approximately 3.0 mg/L. After three weeks of dosing, the six subjects who received ISIS-CRPRx had an average CRP level of 0.76 mg/L, which is within the normal range of CRP and represents an average reduction of greater than 70% compared to placebo. Subjects receiving placebo remained elevated above 3.0 mg/L. ISIS-CRPRx was well tolerated in all cohorts, with no serious adverse events.

March 22, 2010

Portola issued positive results from a phase IIb trial of betrixaban, a Factor Xa inhibitor. This multi-national, randomized, double-blind, dose-finding study, dubbed EXPLORE Xa, enrolled 508 subjects with non-valvular atrial fibrillation or atrial flutter and at least one risk factor for stroke. The subjects received betrixaban 40, 60 or 80 mg or open-label warfarin, the current standard of care. The primary study endpoint, the time to occurrence of major or clinically relevant non-major (CRNM) bleeding, was reached. The incidence of major or CRNM bleeding was 0.8%, 3.9%, 3.9% and 5.5% for the betrixaban 40 mg, 60 mg, and 80 mg and warfarin groups, respectively. The once daily dose of betrixaban 40 mg demonstrated significantly less major and CRNM bleeding than open label warfarin (p≡0.035). Secondary endpoints were also reached. The incidence of any bleeding was significantly lower compared to warfarin (31.5%) for betrixaban 40 mg (17.3%, p≡0.011) and 80 mg (18.9%, p≡0.022). Treatment was well tolerated.

September 7, 2009

AstraZeneca reported results from a head-to-head study evaluating ticagrelor versus clopidogrel for the prevention of complications due to acute coronary syndrome. This international, double-blind, randomized trial, PLATO (A Study of Platelet Inhibition and Patient Outcomes), enrolled 18,624 patients with ACS with or without ST-segment elevation. The subjects received ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter). The primary endpoint was percentage of reported cardiovascular events (CV death, myocardial infarction, stroke) at 12 months. Ticagrelor achieved greater efficacy over clopidogrel (9.8% vs. 11.7%; p<0.001), without an increase in major bleeding (11.6% vs. 11.2%, p≡0.43). A statistically significant reduction in both CV death (4.0% vs. 5.1%, p≡0.001) and heart attacks was also observed (5.8% vs. 6.9%, p≡0.005) with no difference in stroke (1.5% vs. 1.3%, p≡0.22). Ticagrelor also demonstrated significant results across multiple secondary efficacy endpoints including all-cause mortality, transient ischemic attack, recurrent cardiac ischemia, severe recurrent cardiac ischemia, and other arterial thrombotic events. When minor bleeding was added to the major bleeding results, ticagrelor showed an increase versus clopidogrel (16.1% vs. 14.6%, p≡0.008). There was also an increase in non-procedural related bleeding with ticagrelor.

April 6, 2009

Gentium reported positive results from a phase II/III trial of defibrotide for the prevention of Veno-Occlusive Disease (VOD). This European, open-label, randomized study enrolled 360 pediatric patients undergoing stem cell transplantation who were at high risk for hepatic VOD. The subjects were placed in one of two treatment arms: the defibrotide prophylaxis arm received 25mg/kg/day in four divided doses beginning at the time of conditioning and finishing 30 days after stem cell transplantation (SCT) or upon discharge; the control arm did not receive VOD prophylactic measures. The primary endpoint was development of VOD within 30 days post-SCT based on the modified Seattle criteria. In the intent-to-treat analysis (n≡356), defibrotide led to a 40% reduction in incidence of VOD within 30 days after SCT (p≡0.0539). In addition, in subjects who completed 30 days in the study (n≡333) a 40% reduction rate of the incidence of VOD was observed within 30 days (p≡0.0366). Defibrotide was well tolerated and no difference in adverse events was observed between the two arms.

March 2, 2009

AstraZeneca issued positive results from a phase III trial of Crestor for the prevention of major cardiovascular events. This long-term, randomized, double-blind, placebo-controlled study, dubbed JUPITER (Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin), enrolled 17,802 subjects at increased risk for a cardiovascular event. The study was designed to determine if Crestor 20 mg decreases the risk of heart attack, stroke and other major cardiovascular events when administered over a long period of time. Crestor significantly reduced the risk of stroke by 48% compared to placebo (p≡0.002), There was no increase in the risk of hemorrhagic stroke versus placebo (p≡0.44) and combined risk of heart attack, stroke or cardiovascular death was reduced by 47% compared to placebo (p<0.00001).

October 29, 2007

Anthera announced positive preliminary results from a phase II trial of A-002 for the treatment of cardiovascular disease. This multi-center, randomized, double-blind, placebo- controlled trial, dubbed PLASMA (Phospholipase Levels And Serological Markers of Atherosclerosis), enrolled 400 subjects with stable coronary heart disease, in the US and Ukraine. The subjects received one of four different doses of A-002 or placebo for up to eight weeks, in addition to standard of care therapies. Statistical significance was reached in the primary endpoint, a reduction in secretory phospholipase A2 (sPLA2) levels. Significant decreases in cholesterol levels (LDL-C, non-HDL and total cholesterol), as well as reductions in C-Reactive Protein, were also observed. Full results are expected in 2008, to be followed by phase III trials.

The Medicines Company announced positive results from a phase III trial of Cleviprex for the treatment of acute hypertension. This open-label, single-arm, multi-center study enrolled 126 subjects in an emergency room setting, presenting with acute hypertension (average baseline systolic blood pressure (SBP) of 203 mmHg). For each subject, the investigators determined a target SBP range to be achieved within the first 30 minutes of Cleviprex infusion. The target SBP levels were reached by a median of 10.9 minutes, with 89% of subjects achieving their target within 30 minutes. Following initial blood pressure control, Cleviprex was infused continuously for a median of 21 hours to maintain blood pressure within target limits. Among subjects who received 18 hours of continuous Cleviprex therapy, 92% did not require the addition of other intravenous antihypertensive agents during the 18-hour period. A NDA is currently under review by the FDA.

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