Congestive Heart Failure

October 19, 2015

Mesoblast has issued results of a phase II trial of a mesenchymal precursor cell (MPC) therapy for the treatment of chronic heart failure (CHF). A post-hoc analysis was performed in 30 patients randomized to receive either placebo or a single administration of 150 million MPCs (MPC-150-IM). Control patients with baseline LVESV greater than 100ml had the greatest deterioration (adverse remodeling) over six months in terms of worsening in both LVESV and left ventricular end diastolic volume (LVEDV), and loss of left ventricular ejection fraction (LVEF). Over a six-month followup period, the 150 million MPC dose resulted in placebo-corrected significant reductions in LVESV of 57ml (p=0.007) and LVEDV of 54ml (p=0.004), and an increase in LVEF of 8.1 absolute percentage points (p=0.068) in patients with baseline LVESV greater than 100ml. All of the heart failure-related major adverse cardiovascular events (HF-MACE) seen over 36 months in the trial occurred in control patients with baseline LVESV greater than 100ml; the annualized HF-MACE rate was 24% in that group, with an overall 71% HF-MACE rate over 36 months. In contrast, no HF-MACE were seen over the entire 36 months in 150 million MPC-treated patients with baseline LVESV greater than 100ml (p=0.0007 when analyzed by Kaplan-Meier time-to-first-event analysis and p<0.0001 by incidence analysis for total/recurrent HF-MACE, 0 v. 11 events). An ongoing phase III trial, using a time-to-first-event analysis of HF-MACE as the primary endpoint, is being conducted in 1,165 patients by Mesoblast’s partner Teva in North America to investigate MPC-150-IM in patients with advanced CHF.

August 3, 2015

esoblast reported results of a phase II study of Mesenchymal Precursor Cells (MPCs) for the treatment of congestive heart failure (CHF). The dose-escalation, placebo-controlled study enrolled 60 subjects. Patients treated with the highest dose, MPC 150m, showed the greatest improvement in left ventricular remodeling compared to controls; this was evidenced by significant reductions in left ventricular end systolic volume (LVESV), p=0.015, and left ventricular end diastolic volume (LVEDV), p=0.02, at month six post treatment relative to controls. Patients treated with the highest dose, MPC 150m, showed the greatest improvement in functional exercise capacity compared to controls (6MTW: p=0.062) at month 12 post treatment. In a post-hoc analysis after all patients had completed 36 months of follow up, treatment with MPC 150m was shown to be associated with a significantly lower incidence of heart failure-related major adverse cardiovascular events (HF-MACE) events compared to the control group (0% v. 33% HF-MACE by Kaplan-Meier, p=0.026 by log-rank). A randomized, placebo-controlled, phase III trial using Mesoblast’s high-dose MPC 150m is being conducted by Mesoblast’s development and commercial partner, Teva Pharmaceutical Industries, and is actively enrolling patients across multiple clinical sites in North America.

September 1, 2014

Biotronik reported results of a worldwide, randomized, controlled trial of Biotronik Home Monitoring for the detection of heart failure at an early stage. 274 patients received an ICD and 390 patients received a CRT-D in adherence with European guidelines, and were followed for one year. The primary outcome, worsening heart failure, was based on a composite score including death, hospitalization, NYHA class and patient self-assessment. Secondary outcomes included all-cause mortality and hospitalization. Home Monitoring reduced all-cause mortality by over 50%. Only 18.9% of patients using Home Monitoring experienced the worsening of heart failure, compared to 27.2% in the control arm (p=0.013). The prospective study randomized 664 patients with chronic heart failure, NYHA class II or III symptoms, ejection fraction ≤35%, and optimal drug therapy in groups with or without telemonitoring in a 1:1 ratio.

September 3, 2012

Novartis issued results from a phase II trial of LCZ696 for the treatment of heart failure with preserved ejection fraction (HF-PEF). This randomized, double-blind, multicenter,parallel group, active-controlled study, PARAMOUNT, enrolled 301 patients with HFPEF who also had elevated NT-proBNP (>400pg/ml). After halting any treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, subjects received 50mg LCZ696 or 40mg valsartan twice-daily for 36 weeks. Doses of both drugs were doubled after one week and doubled again after another week to a maximum dose of 200mg LCZ696 and 160mg valsartan twice-daily. Results demonstrated that after 12 weeks of treatment, reduction in NT-proBNP was 23% greater with LCZ696 than valsartan (p=0.005). In addition, there was a greater reduction (p=0.003) in left atrial size (cardiac remodeling) in LCZ696-treated patients at the end of the 36-week study. The drug was well tolerated. Novartis is also conducting phase II and III studies of LCZ696 for the reduction of blood pressure and treatment of hypertension, respectively.

January 17, 2011

Mesoblast released positive interim results from a phase II trial evaluating their proprietary adult stem cell product Revascor for congestive heart failure. This randomized, placebo-controlled trial enrolled 60 subjects with moderate to severe heart failure. The subjects received Revascor as a single injection at one of three progressively increasing doses plus standard of care, or standard of care alone. Data are from six months of follow-up. Efficacy endpoints showed that a single injection of Revascor significantly reduced the number of subjects who developed any severe adverse cardiac events over the follow-up period from 93.3% in the control group to 44.4% in the Revascor treated group (p≡.001). Revascor also significantly reduced the number of subjects who developed any major adverse cardiac events from 40% to 6.7% (p≡0.005). A single injection of Revascor reduced the overall monthly event rate of a MACE by 84% compared with controls (p≡0.01), and every dose tested demonstrated a similar protective effect. Death from cardiac causes was reduced from 13.3% to 0% over this period (p≡0.059) and the overall monthly rate of cardiac-related hospitalizations was reduced by 48% (p≡0.07). There have been no cell-related adverse events at any of the Revascor doses tested.

April 7, 2008

Bioheart issued positive results from a phase IIa trial of MyoCell for the improvement of heart function among patients with congestive heart failure. This European based, randomized, controlled study, dubbed SEISMIC, enrolled forty subjects previously fitted with implanted cardiac defibrillators (ICDs), receiving standard medical therapy and who were experiencing congestive heart failure. The subjects were randomized on a two-to-one ratio into the treatment or control groups. Both groups were evaluated at three- and six-month intervals using digital imaging and standard quality of life measurement such as the six-minute walking test and New York Heart Association (NYHA) heart failure classification. At six months, 84% of subjects in the MyoCell group experienced improved or unchanged six-minute walking test scores compared to 16% of the control group. NYHA classification improved or remained unchanged in 94% of the MyoCell treated subjects compared to 58% of the control group. In addition, 69% of the control group's results worsened, versus only 16% of the treated group. Arrhythmia was no different between the treatment and control arms in the study. A phase II/III study of MyoCell is currently underway.

August 20, 2007

Biogen released positive top-line results from a phase II trial of Adentri for the treatment of congestive heart failure. This randomized, double-blind, placebo-controlled trial enrolled 50 subjects who received oral Adentri (3, 15, 75 or 225 mg) or placebo, in combination with standard heart failure therapy, once daily for 10 days. Treatment was well tolerated, with no reported adverse events in during the 10 day treatment period or at the 30-day follow-up. Higher doses of Adentri were not associated with an increase in adverse events. Increased sodium excretion was observed from day 1 and continued for 10 days. Adentri did not cause renal impairment or increased potassium excretion. Body weight, edema, and physician global assessment improvements were also observed. The pharmacokinetic profile was consistent with once-daily dosing. Based on the results, Biogen plans to move forward with the development of oral and intravenous formulations of Adentri.

November 20, 2006

NovaCardia issued positive results from a phase II trial of KW-3902 for the treatment of congestive heart failure (CHF), at the American Heart Association's 79th Annual Scientific Sessions in Chicago, IL. The trial was designed to look at the effect of KW-3902 on renal function, measured by the glomerular filtration rate (GFR) and renal plasma flow. This randomized, double-blind, placebo-controlled, two-way crossover trial enrolled 32 stable CHF subjects with mild renal impairment. Subjects received furosemide with KW-3902 or furosemide with placebo. Data demonstrated that over an eight hour period, KW-3902 provided an increase in GFR of 32.1% over baseline, compared to an increase of 8.3% with placebo (p < 0.05). An increase in renal plasma flow of 47.7% with KW-3902 was observed, compared to an increase of 16.0% with placebo (p < 0.01). In addition, urine volume over eight hours was greater in the KW-3902 treated group versus the placebo group. NovaCardia is currently investigating KW-3902 in ongoing phase III trials.

August 22, 2005

Cardiome Pharma announced negative results of a phase II trial, dubbed "OPT-CHF," of oxypurinol for the treatment of congestive heart failure (CHF). Trial data failed to meet the primary composite endpoint relative to placebo (p= 0.357); this endpoint included improvement in NYHA functional class, rate of hospitalization or emergency intervention for worsening CHF, need for additional interventional treatment, withdrawal of drug treatment due to refractory disease and cardiovascular death. Trial data also failed to demonstrate drug efficacy in secondary endpoints, including Minnesota CHF Quality of Life assessment and time to acute clinical events. This randomized, double-blind, placebo-controlled study enrolled 405 CHF patients across 53 sites in the US and Canada, who received 600 mg oral oxypurinol or placebo daily for 24 weeks.

Myogen also reported result of a phase II trial of ambrisentan, for the treatment of pulmonary arterial hypertension (PAH), in the Journal of the American College of Cardiology. The drug met its primary efficacy endpoint, significantly increasing 6-minute walk distance across all dosing groups (mean increase: 36.1 m, range: 33.9 m - 38.1 m; p<0.0001). Secondary improvements were noted in Borg dyspnea index, WHO functional class, subject global assessment, mean pulmonary arterial pressure (-5.2 mmHg; p<0.0001), and cardiac index (+0.331/min/m2; p<0.0008). This double-blind, dose-ranging study enrolled 64 PAH patients, who received one of four daily regimens of ambrisentan (1 mg, 2.5 mg, 5 mg, or 10 mg) for 12 weeks.

Myogen has reported results of their phase IIb "DAR-201" trial of darusentan for the treatment of resistant hypertension. Administration of 300 mg daily produced significant, placebo-corrected reductions in both systolic (-11.6 mmHg; p=0.02) and diastolic (-7.0 mmHg; p<0.001) blood pressure at trial completion. Secondary efficacy was seen in reducing blood pressure at lower doses and at interim time measures. The drug did not produce significant changes in liver enzymes, with no incidences of serum aminotransferase levels above two times the upper limit of normal. This randomized, double-blind, placebo-controlled study enrolled 115 patients at 30 US sites, who were titrated up from 10 mg to 300 mg of the drug or placebo daily, with 2 week intervals between dose increases; once the 300 mg daily dose was reached, patients received treatment for 10 weeks. Based on these results, the company announced plans to initiate phase III trials of the drug in the near future.

April 25, 2005

Protein Design Labs and CardioPep Pharma GmbH announced positive results of a phase II trial, dubbed SIRIUS II, of ularitide, for the treatment of decompensated congestive heart failure (DHF). All 3 dose levels of the drug significantly improved both pulmonary capillary wedge pressure and dyspnea symptom severity at six hours vs. placebo (p < 0.05), the study's primary endpoints. Serious adverse event incidence was comparable between all 3 treatment groups and placebo. This randomized, double-blind, placebo-controlled trial enrolled 221 DHF patients across 19 centers in Europe, who received a 24 hour IV infusion of one of 3 doses of ularitide (7.5, 15, or 30 ng/kg/min) or placebo.

April 18, 2005

Cardiome Pharma issued positive results from a physician-sponsored clinical trial of their investigational xanthine oxidase inhibitor oxypurinol, for the treatment of congestive heart failure (CHF). Final results indicated that the drug produced a statistically significant increase in one-time left-ventricle ejection fraction (LVEF), a measure of disease severity (p=0.0008). Specifically, the drug produced a 3.5% increase in total ejection volume, which translated to a 19.2% increase in relative ejection fraction, relative to pre-treatment measurements. This open-label single-group assignment study enrolled 20 CHF patients at the Eppendorf Clinic at the University of Hamburg. Subjects received a single intravenous dose of 400 mg oxypurinol, followed by LVEF measurement. The company announced that these data would serve to support their ongoing phase II study of the drug, which recently completed dosing. Results from that study are expected in Q3, 2005.

February 22, 2005

Cardiome Pharma reported positive results of a investigator-sponsored clinical trial of oxypurinol, for the treatment of congestive heart failure. Trial data yielded significant evidence of efficacy, with patients receiving the drug demonstrating a 6.8% improvement in left ventricle ejection fraction (LVEF) vs. placebo (p=0.017). This improvement relative to placebo represented an average relative increase in cardiac output of 22.6%. Secondary efficacy was also observed, with oxypurinol producing a 17.0 mg/L decrease in serum uric acid levels, versus placebo (p<0.001). No significant improvements vs. placebo were noted in 6 minute walk distance, but improvement from baseline was seen in both treatment arms. No serious adverse events or safety concerns were noted. This double-blind, placebo controlled trial treated 47 patients with LVEFs below 40%. Subjects were randomized to receive oxypurinol or placebo via oral dosing for 28 days.

Encysive Pharmaceuticals has reported top-line results of a phase III trial of their drug Thelin (sitaxsentan), for the treatment of pulmonary hypertension. Results from the pivotal study met their primary endpoint, yielding a placebo-subtracted improvement in total distance in a 6 minute walk test of 31.4 meters at the 100 mg. trial dose (p=0.03). Patients in the bosentan group also experienced a significant improvement in placebo subtracted distance (29.5 meters, p=0.05), but neither the difference between 100 mg Thelin and bosentan nor the improvements seen with 50 mg Thelin (24.2 meters, p>0.05) were significant. Efficacy was also seen in secondary endpoints with 100 mg Thelin, including a significant improvement in WHO functional class (a mark not reached in any other study arm, p=0.04), a trend towards improvement in time to clinical worsening, and the lowest number of early discontinuations and incidences of liver enzyme abnormalities of any trial arm. This double-blind, placebo-controlled trial randomized 240 PAH patients across 55 sites in North America, Europe, Israel and Australia at a 1:1:1:1 ratio to receive one of two doses of Thelin (50 mg. or 100 mg.) or placebo once daily, or approved therapy with bosentan twice daily (per the bosentan label). Following these results, the company announced plans to file an NDA with the FDA in April 2005.

October 6, 2003

AVI BioPharma reported positive results from a phase II trial investigating Resten-NG, a Neugene antisense drug for the treatment of cardiovascular restenosis. Results showed a restenosis rate of 33.3% in both the control and 3 mg dose treatment groups, and a 8.3% rate in the 10mg dose group. The 10mg dose group showed a significant reduction of late loss, the decrease in vessel lumen diameter at six months, and lesion length compared with both the control and 3mg groups. There were no increases in toxicity or adverse events in either of the treatment groups. The multicenter, randomized, controlled study, called AVAIL, enrolled 57 subjects. The trial evaluated the safety and effectiveness of Resten-NG in subjects at high risk for cardiovascular restenosis following angioplasty and stent placement. Results were reported at the 15th annual scientific symposium of Transcatheter Cardiovascular Therapeutics in Washington, D.C.

Scios reported positive results from a pilot study investigating Natrecor (nesiritide), a recombinant human B-type natriuretic peptide for the treatment of congestive heart failure. Results showed that weekly infusions of Natrecor for 12 weeks were well tolerated. Less than 1% (11 of 1645) of infusions were discontinued due to side effects. Data demonstrated that the incidence of adverse events was similar in the three groups, and no adverse event occurred significantly more frequently in the Natrecor groups. The multi-center, randomized, three-treatment arm, open-label, study enrolled 210 subjects at high risk for rehospitalization. The study was designed to evaluate the safety and tolerability of weekly infusions of Natrecor administered in an outpatient setting to subjects who were at high risk for hospitalization. Results were presented at the 7th Annual Scientific Meeting of the Heart Failure Society of America in Las Vegas.<

August 4, 2003

Amylin Pharmaceuticals reported positive results from a phase II trial investigating AC2592, a glucagon-like peptide 1 (GLP-1) for the treatment of congestive heart failure. GLP-1 is a naturally occurring hormone produced in the gut. Results demonstrated that subjects showed general improvement in a composite quality of life score and cardiac function. Data showed that the severity of heart failure also improved during AC2592 administration. The most common adverse event reported was mild to moderate nausea. Outcome measures included peak oxygen consumption, left ventricular ejection fraction, quality of life assessment, and brain natriuretic peptide, or BNP (an indicator of heart dysfunction. The open-label, exploratory, dose-titration study enrolled 14 subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure.