May 8, 2017
Cytokinetics issued results of a phase II trial evaluating omecamtiv mecarbil in patients with chronic heart failure. COSMIC-HF was conducted in two phases, a dose escalation phase followed by the previously reported dose expansion phase. The dose escalation phase was a randomized, placebo-controlled, multicenter, sequential cohort design. The purpose of the dose escalation phase was to select an oral, modified-release formulation to advance into the dose expansion phase. Approximately 40 patients were randomized 1:1:1:1 to receive placebo or one of three oral formulations twice daily (BID) (M-F1, M-F2, and SCT-F2) for seven days in each of two cohorts (25mg BID Cohort 1; 50mg BID Cohort 2). The pharmacokinetics (PK) of the three formulations were characterized following the first dose and after seven days of twice daily dosing. The PK of the three formulations were similar; however, the maximum plasma concentration (Cmax) and exposure over 12 hours (area under the curve or AUC12h) of M-F1 had the lowest coefficient of variability (CV), 23% and 21% respectively, at the 50mg BID dose compared to the two other formulations. Additionally, the peak to trough fluctuation of this formulation was the lowest (1.14±0.12) as calculated from the ratio of the Cmax measured after dosing to the plasma concentration just prior to dosing (Cmax/Cpredose) at 50mg BID. The terminal half-life was 24.6±8.7 h (25mg BID) and 28.6±7.4 h (50mg BID). Excessive concentrations of omecamtiv mecarbil occurred in one patient taking 50mg of M-F1 on day seven (Cmax = 1320 ng/mL) compared with the other subjects (n=9, Cmax: 349 to 654 ng/mL), which was associated with myocardial infarction characterized by symptoms of chest pain and an increased troponin. Overall, the dose escalation phase and the outlier informed the selection of the MF-1 formulation that was used in the expansion phase of COSMIC-HF and the implementation of PK-guided dose titration to further optimize plasma concentrations of omecamtiv mecarbil in patients with heart failure.
November 30, 2015
Amgen and Cytokinetics have reported
results of a phase II trial evaluating omecamtiv
mecarbil in patients with chronic heart failure.
COSMIC-HF was a double-blind, randomized,
placebo-controlled, multicenter trial. The
trial consisted of two parts, a dose escalation
phase and a larger and longer expansion
phase. In the dose escalation phase, 96
patients were randomized 1:1:1:1 to placebo
or one of three omecamtiv mecarbil oral
modified-release formulations in two cohorts
(25mg twice daily or 50mg twice daily). Each
patient cohort was followed for 35 days.
The expansion phase evaluated 448 chronic
heart failure patients with reduced ejection
fraction who were dosed with the selected
oral formulation of omecamtiv mecarbil for
20 weeks and followed for a total of 24 weeks.
Patients were randomized 1:1:1 to receive
either placebo or treatment with omecamtiv
mecarbil 25mg twice daily or 25mg with dose
escalation to 50mg twice daily depending on
plasma concentrations of omecamtiv mecarbil
after two weeks of treatment. Following 20
weeks of treatment, statistically significant
improvements were observed in pre-specified
secondary endpoint measures of cardiac function
in the dose titration group, compared to
placebo. Systolic ejection time increased by 25
msec (p<0.001), stroke volume increased by
3.63mL (p=0.022) and heart rate decreased by
2.97 beats per min (p=0.007). Left ventricular
end-systolic and end-diastolic dimensions
decreased by 1.79mm (p=0.003) and 1.29mm
(p=0.013), respectively, and were associated
with statistically significant reductions in left
ventricular end-systolic and end-diastolic
volumes. N-terminal pro-brain natriuretic
peptide (NT-proBNP) decreased by 970pg/mL
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.
June 3, 2013
Zensun Sci & Tech released results from a phase II trial of Neucardin for the treatment of chronic heart failure. This double-blind, placebo-controlled study enrolled 678 patients with NYHA class II-III chronic heart failure. The subjects received Neucardin via a mini pump for eight hours a day for 10 days, or placebo. The data demonstrated Neucardin reduced all-cause mortality, improved heart function, reduced heart volumes, improved exercise capacity and quality of life on top of current standard of care in patients with chronic heart failure (CHF). Overall, the phase II clinical studies demonstrated a 3% to 5% placebo corrected improvement in left ventricular ejection fraction, (LVEF) (p<0.05). The drug was well tolerated. Based on these trial data, Zensun Sci & Tech has filed a New Drug Application (NDA) in China to obtain accelerated market approval, and is planning a phase III clinical program in the U.S.
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.
May 28, 2012
Neurocrine Biosciences reported results from a phase II trial of urocortin 2 for the treatment of acute decompensated heart failure. This randomized study enrolled 53 patients. After initial stabilization, subjects received a four-hour infusion of either placebo or urocortin 2 in addition to standard-of-care treatments. Mean arterial pressures were significantly reduced (p<0.001) from 92 ±3mmHg at baseline to 80 ±3mmHg at end of the urocortin 2 infusion (n≡27) in contrast to placebo (n≡26) where the mean arterial pressure was 92 ±3mmHg at baseline and 89 ±4mmHg at the end of the placebo infusion. Infusion of urocortin 2 was generally well tolerated. Adverse events included transient flushing and lowering of systolic blood pressure below pre-set stop values. Neurocrine Biosciences plans to continue their studies of urocortin 2 and present findings in an upcoming scientific meeting.
May 2, 2011
Juventas Therapeutics issued preliminary results from a phase I trial of JVS-100 for treatment of heart failure. This open label trial enrolled 17 subjects with NYHA Class III heart failure, left ventricular ejection fractions less than 40% and an average time from heart attack of 7.3 years. Three escalating JVS-100 doses were evaluated: 5 mg (cohort 1), 15 mg (cohort 2) and 30 mg (cohort 3). Efficacy was assessed as changes from baseline in: echocardiographic parameters, cardiac perfusion via SPECT and clinical parameters including NYHA class, 6 minute walk distance (6MWd) and quality of life score (QOL). Four-month efficacy data was available from cohorts one and two. At four months post-therapy, the subjects demonstrated dose-dependent improvements in all clinical parameters, with clinically relevant improvements compared to baseline in QOL and 6MWd for subjects from cohort two. At one month after dosing in cohort three, subjects showed similar clinically relevant improvements in QOL and 6MWd, with some subjects improving a full NYHA class. The primary safety endpoint, the number of major adverse cardiac events at 30 days, was reached by all 17 subjects. There were no adverse events likely related to drug.
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.
August 9, 2010
Cardioxyl issued positive results from a phase I/IIa trial of CXL-1020 for the treatment of acute decompensated heart failure. This U.S-based, placebo-controlled, double-blind, dose-escalation study enrolled 28 subjects with chronic stable heart failure. A total of 67 exposures of a sustained intravenous infusion were administered across four dosing cohorts. CXL-1020 demonstrated positive safety profile and pharmacokinetic profiles, and was well tolerated. There were no serious adverse events and CXL-1020 was well tolerated at doses up to 10 ug/kg/min. In addition, CXL-1020 clearly demonstrated statistically significant hemodynamic activity in patients with relevant underlying disease.
June 7, 2010
Celladon issued positive results from a phase II trial of Mydicar, a genetically targeted enzyme replacement therapy for heart failure. This randomized, double-blind, placebo-controlled study, CUPID (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease), enrolled 37 subjects with severe forms of heart failure. The subjects received one of four doses of Mydicar (very low to high) or placebo delivered in a single dose directly to the heart muscle during a short outpatient procedure. The primary efficacy endpoint was a composite encompassing the simultaneous assessment of clinical outcomes, exercise tolerance, heart failure symptoms, biomarkers, and cardiac function. The highest dose of Mydicar was determined to be the most effective. High dose Mydicar resulted in 50% risk-reduction in cardiovascular events (p≡0.040). The mean duration of hospitalization in this Mydicar group during the six-month period was 0.2 days per patient versus 2.1 days per patient in the placebo treated group. Mydicar high dose also significantly improved heart failure symptoms, exercise tolerance, serum biomarkers and cardiac function.
September 21, 2009
Bioheart released interim results from a phase II/III trial of MyoCell (autologous skeletal myoblasts) for the treatment of cardiac heart failure post-myocardial infarction. This international, randomized, double-blind, placebo-controlled study, dubbed MARVEL, had enrolled 20 subjects to date. The subjects were randomized to three separate treatment groups: 400 million cells, 800 million cells or placebo, administered via injection (16 per patient) directly into parts of the ventricular wall specifically weakened by scar tissue from previous heart attacks. The primary endpoints were improvements on the 6 minute walk distance test (6MWD) and safety. The results are based on analyses of 3 and 6-month follow-up data. The 6MWD increased on average by more than 91 meters in MyoCell-treated population compared to a decrease of nearly 4 meters in the placebo-treated group. Safety endpoints were also reached. The occurrence of early (within 4 weeks of ASM implantation) ventricular tachyarrhythmias appeared in the ASM treated groups. However, the arrhythmias were detected and treated with no adverse results, and completely by six months post-treatment.
November 17, 2008
Celladon released positive interim results from a phase I/II trial of Mydicar, a genetically-targeted enzyme replacement therapy for advanced heart failure. This two-stage, dose-escalation trial was dubbed CUPID (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease). Data are from the first nine subjects enrolled in the open-label, dose escalation phase I stage. The subjects received one of four escalating doses of Mydicar delivered in a single dose directly to the heart muscle. Improvements from baseline to six months were observed across a number of parameters important in assessing heart failure status, including symptomatic (5 subjects), functional (4 subjects), biomarker (2 subjects) and left ventricular function/remodeling (6 subjects). Of the nine treated subjects, two with low levels of pre-existing antibodies to the adeno-associated viral (AAV) vector did not show improvement in these parameters. Mydicar was well tolerated.
October 20, 2008
Nile Therapeutics reported positive interim results from a phase IIa trial of CD-NP for the treatment of acute heart failure. This open-label, dose-escalation study enrolled 30 subjects in Russia. The subjects received standard-of-care heart failure treatment plus a 3 ng/kg/min 8-hour infusion of CD-NP, followed by a 14-hour washout and then a second 8-hour infusion of CD-NP at 10 ng/kg/min. Results from the first cohort of showed a statistically significant reduction in pulmonary capillary wedge pressure (PCWP). Infusion with 3 ng/kg/min of CD-NP resulted in a statistically significant reduction of 2.9 mmHg relative to baseline at eight hours (p=0.02). Infusion of 10 ng/kg/min CD-NP following a washout period resulted in a further reduction of PCWP, which reached statistical significance at two hours after initiation (p=0.02). In subjects who completed both doses of CD-NP, there was a statistically significant overall reduction in PCWP of 5.4 mmHg from the initial baseline PCWP of 23.7 mmHg (p=0.002). Minimal changes in blood pressure relative to baseline were observed and there were no hypotension or clinically significant blood pressure reductions. CD-NP also elicited a statistically significant increase in urine output during infusion at both dose levels administered. During the 3 ng/kg/min infusion of CD-NP, there was an increase in hourly urine output of 48 mL/hr compared to the pre-dose baseline period (p=0.01). Infusion of 10 ng/kg/min CD-NP resulted in an increase in the hourly urine output of 93 mL/hr compared to the pre-dose baseline period (p<0.01). Serum creatinine remained unchanged during the infusion period. Based on the results, plans for a phase IIb trial are underway.
August 18, 2008
Palatin Technologies released positive results from a phase II trial of PL-3994 for the treatment of heart failure. This randomized, double-blind, placebo-controlled, single ascending dose study enrolled 21 subjects with controlled hypertension. The subjects received PL-3994 or placebo subcutaneously. The study was designed to demonstrate that PL-3994 can be given safely in conjunction with antihypertensive medications. The primary endpoint, a pre-specified reduction in systemic blood pressure, was achieved. In addition, elevations in plasma cGMP levels were all observed for several hours after single subcutaneous doses. PL-3994 was well tolerated and there were no reports of serious adverse events. Additional phase II studies are planned for later in 2008.
April 7, 2008
Debiopharm and Sigma Tau reported positive results from a phase II trial of istaroxime for the treatment of acute heart failure. This randomized, double-blind, parallel-assignment study enrolled one hundred and twenty subjects requiring hospitalization for deterioration of chronic heart failure and left ventricular systolic dysfunction. The primary endpoints included change in pulmonary capillary wedge pressure from pre-infusion to the last assessment at six hours. Istaroxime treatment was able to significantly reduce pulmonary congestion, hemodynamicas and diastolic function without adversely affecting neurohormones or renal function. In thirty subjects who received three doses of istaroxime over six hours, a statistically significant decrease of pulmonary wedge pressure was observed (p<0.03 for all doses), with a reduction of the left ventricular diastolic volume (p=0.02 for the highest dose) and an increase in cardiac index (p=0.04 for the highest dose), compared to subjects treated with placebo. Based on the results the companies plan to move forward with the development of istaroxime.
October 22, 2007
Nile Therapeutics released positive results from a phase Ia trial of CD-NP for the treatment of heart failure. This study enrolled 22 healthy subjects who received CD-NP (10, 17.5 or 25 ng/kg/min) or placebo during a four-hour infusion. Placebo and CD-NP (10, 17.5 and 25 ng/kg/min) increased urine flow rate versus baseline (125%, 53%, 30% and 230% average change, respectively), increased sodium excretion versus baseline (28%, 138%, 55% and 158% average change, respectively) and increased plasma cGMP versus baseline (4%, 202%, 378% and 691% average change, respectively). Treatment was well tolerated; there was no effect on arterial blood pressure, serum potassium levels or renal function levels when compared to baseline. Based on the results Nile plans evaluate higher doses of CD-NP in upcoming phase Ib trials.
September 10, 2007
Merck announced positive results from a phase III trial of Cordaptive for the treatment of dyslipidemia. This double-blind, randomized trial enrolled 1,613 subjects who received Cordaptive (1 gram/day), extended-release niacin alone (1 gram/day) or placebo. After four weeks, the active treatment groups doubled their respective doses to 2 grams per day for an additional 20 weeks. The co-primary endpoints were the effects of 2 grams of Cordaptive versus placebo on percent changes in LDL-cholesterol (LDL-C) across weeks 12 to 24, and the effects of 1 gram of Cordaptive versus extended-release niacin on flushing symptom severity during the first week of treatment. In the subjects who advanced to 2 grams of Cordaptive, LDL-C levels were reduced from baseline by an average of 19% (versus a reduction of 0.5% with placebo). In addition, in the subjects receiving 1 mg of Cordaptive, 69% reported either no flushing symptoms or mild flushing symptoms during the first week of treatment compared to 44% of those who received extended-release niacin alone. Secondary endpoints included the effects of 2 grams of Cordaptive versus placebo on HDL-cholesterol (HDL- C) levels, triglyceride levels and other lipid parameters, and the flushing frequency and intensity of 2 grams of Cordaptive compared to extended-release niacin alone. In the subjects receiving Cordaptive 2 mg their HDL-C levels increased by an average of 19% (versus a reduction of 1.2% with placebo), and their triglyceride levels were reduced by an average of 22% (versus an increase of 3.6% with placebo). By week 24, the frequency of moderate or greater flushing was 2 days/week for subjects receiving 2 grams of Cordaptive or a placebo versus 7 days/week among those treated with 2 grams of extended-release niacin. A NDA for Cordaptive in the treatment of dyslipidemia is currently under review by the FDA.
Novartis reported positive results from a phase II trial of SPP100 for the treatment of heart failure. This trial, dubbed ALOFT (ALiskiren Observation of Heart Failure Treatment), enrolled 302 subjects who were treated with SPP100 150 mg once per day plus standard heart failure therapy or placebo plus standard therapy. Results revealed that subjects treated with SPP100 plus standard therapy showed significant reductions in B-type natriuretic peptide (BNP) which were nearly five times greater than reductions with standard therapy alone (-61 pg/mL versus -12 pg/mL, p= 0.016). Treatment with SPP100 was safe and well tolerated, with a profile similar to placebo. Based on the results, Novartis plans to proceed with the development of SPP100 into phase III trials.
Sanofi-Aventis issued positive long-term results from two clinical trials of Lovenox for the treatment of acute ST-segment elevation myocardial infarction (STEMI). The first trial, dubbed ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment, Thrombolysis in Myocardial Infarction -- Study 25), enrolled 4,676 subjects. The subjects received adjunctive anticoagulation therapy with either Lovenox or unfractionated heparin (UFH) in a blinded fashion during fibrinolysis and underwent subsequent percutaneous coronary intervention (PCI). Results at one year showed that the primary endpoint of death or nonfatal myocardial infarction remained significantly in favor or Lovenox versus UFH (15.8% versus 17.0%, p-0.01). Net clinical benefit, including all cause of death, nonfatal myocardial infarction and nonfatal disabling stroke, was also significantly in favor of Lovenox when compared to UFH through one year (16.0% versus 17.3%, p=0.007). The second trial, dubbed STEEPLE (Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention (PCI): An International Randomized Evaluation), enrolled 3,528 subjects. The trial was designed to evaluate a single intravenous dose of Lovenox (0.5 mg/kg and 0.75 mg/kg) versus Activated Clotting Time (ACT)-adjusted intravenous UFH in subjects undergoing non-emergency PCI. The primary endpoint was the incidence of major and minor bleeding. Results at one year showed that the composite of all cause death at 1 year and major bleeding was 3.1% for Lovenox 0.5 mg/kg (p=0.06 vs. UFH), 3.4% for Lovenox 0.75 mg/kg (p=0.07 vs. UFH), 3.3% for the two Lovenox arms combined (p=0.03 vs. UFH) and 4.7% for UFH. Lovenox has been approved for the treatment of acute coronary syndromes.
June 18, 2007
NovaCardia reported positive preliminary results froma phase III trial of KW-3902 for the treatment of acute congestiveheart failure (CHF). This double-blind, randomized trial enrolled 304 subjectswith CHF and renal impairment. Subjects received placebo or 10, 20 or 30 milligramdoses of intravenous KW-3902, administered daily for up to three days. All subjectsreceived intravenous furosemide. The primary endpoint was the proportion of subjectsin the categories of treatment success, treatment failure or no change. The 30mg dose of KW-3902 appeared to be the most efficacious, with higher rates of treatmentsuccess and lower rates of treatment failure compared to placebo. Twenty-fourhours post-treatment, self-reported marked or moderate improvement in dyspneawas reported in 66% of the KW-3902 (30 mg) group compared to 51% of the placebogroup. No statistically significant differences in adverse events were reportedbetween the groups. The 30 mg dose of KW-3902 was determined to be the optimaldose for NovaCardia's two 600-subject phase III trials, dubbed PROTECT-1 and PROTECT-2.Both trials are enrolling subjects in the US, Canada, Europe, Israel and Russia.
April 2, 2007
AstraZeneca reported positive results from a phase III trial, dubbedMETEOR (Measuring Effects on intima media Thickness: an Evaluation OfRosuvastatin), of Crestor for the treatment of atherosclerosis. This 24-month,randomized, double-blind, placebo-controlled trial enrolled 984 asymptomatic,hypercholesterolaemic subjects with a low-risk of coronary artery disease andevidence of sub-clinical atherosclerotic disease. Results demonstrated thatsubjects taking Crestor 40 mg experienced a 0.0014 mm/yr decrease in the meanmaximum carotid intima-media thickness, a marker of atherosclerotic burden,compared to a progression of 0.0131 mm/yr for those on placebo (p≤0. 0001). Inaddition, Crestor demonstrated a 48.8% reduction in LDL-C and an 8. 0% increasein HDL-C (both p≤0.0001 vs placebo). AstraZeneca plans to file a NDA and MAAfor Crestor in the treatment of atherosclerosis in the first half of 2007.
Scios issued positive results from a phase II trial, dubbed FUSION II(Follow-Up Serial InfusiOns of Natrecor in Advanced Heart Failure), for thetreatment of chronic decompensated heart failure (CDHF). This randomized,placebo controlled, double-blind trial enrolled 920 subjects internationally.Subjects received once- or twice-weekly infusions of Natrecor or placebo, alongwith optimized heart failure medications. The primary endpoint was a compositeof death and cardiorenal hospitalization at 12 weeks. Results revealed nostatistically significant difference in the primary endpoint between the twogroups when each was added to optimal heart failure medications, significantuse of indicated heart failure devices and intensive disease management. Basedon the results, Scios plans to move forward with future trials.
December 11, 2006
Astellas and CV Therapeutics released positive results from a phase III trial of regadenoson for the potential use as a pharmacologic stress agent in myocardial perfusion imaging (MPI) studies. This randomized, double-blind trial enrolled 1,231 subjects, all of who received a clinically indicated baseline MPI study using Adenoscan (adenosine injection). Subjects then received either regadenoson or Adenoscan in a second MPI study. The trial was designed to evaluate the comparability of MPI studies conducted with regadenoson and Adenoscan. Treatment was well tolerated with the most common adverse events including shortness of breath, headache, chest pain, flushing and gastrointestinal discomfort. The trial met the primary endpoint by showing with 95% confidence that MPI studies conducted with regadenoson were comparable to MPI studies conducted with Adenoscan. Based on the results of the phase III trials CV plans to file a NDA with the FDA in 2007.
Cytokinetics issued positive results from a phase I trial of CK-1827452 for the treatment of acute and chronic heart failure. This randomized, open-label, four way crossover trial enrolled 10 healthy subjects who received CK-1827452 at 0.125 mg/kg administered as a reference intravenous infusion at a constant rate over one hour, as a liquid solution taken orally in a fasted state, as an immediate-release solid formulation taken orally in a fasted state and as an immediate-release solid formulation taken orally following consumption of a standard, high-fat breakfast. The trial was designed to evaluate the absolute bioavailability and the effects of food on the bioavailability of CK-1827452 when administered orally. All four treatment administrations were well tolerated, with no reported serious adverse events. Pharmacokinetic data from this study demonstrated oral bioavailability of approximately 100% for each of the three conditions of oral administration. Oral absorption while fasting was rapid for the liquid solution and immediate-release solid formulation. The median time to maximum plasma concentration after dosing (Tmax) was 0.5 hours for the liquid solution and 1 hour for the immediate-release formulation. Food delayed the rate of absorption, with a median Tmax of 3 hours, but did not diminish the extent of absorption. Based on these results, Cytokinetics plans to initiate an international phase II trial of CK-1827452 in late 2006 or early 2007.
July 10, 2006
Cytokinetics reported positive results of a phase I trial of CK-1827452, their investigational cardiac myosin activator for the treatment of heart failure. The study found the maximum tolerated dose to be 0.5 mg/kg/hr for a 6 hour infusion. This dose produced significant and clinically relevant increases in ejection fraction and fractional shortening from baseline, vs. placebo; this corresponded to significant prolongation of systolic ejection time. The drug demonstrated linear, dose-proportional pharmacokinetics and pharmacodynamic effects were seen to be dose-dependent. This double-blind, randomized, placebo-controlled, dose-escalation study enrolled healthy volunteers, under the direction of the trial's lead investigator Dr. John R. Teerlink, M.D.
May 15, 2006
Cardiome issued additional results of a phase I trial of an oral formulation of RSD1235, for the treatment of atrial arrhythmia; preliminary results were announced in August 2005. The additional data concerned the drug's effects on QT interval: subjects receiving a 300 mg twice daily dose of the drug had a baseline QT interval of 396 +/- 25 msec, and a value at maximum plasma concentration (Cmax) of 394 +/- 13 msec; the 600 mg twice daily group had a baseline QT of 402 +/- 19 msec, and a Cmax value of 405 +/- 18 msec; and the 900 mg twice daily dose had a baseline QT of 413 +/- 19 msec and a Cmax value of 408 +/- 25 msec. Prolongation of QT interval is a frequent complication of antiarrhythmic therapy, and Cardiome was encouraged by the lack of this complication. The company announced plans to initiate a phase IIb trial of oral RSD1235 in the second half of 2006.
Scios issued positive results of a phase II trial, dubbed NAPA (Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery) of nesiritide for the maintenance of post-operative renal function following coronary artery bypass graft (CABG). These results were announced at the 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke meeting in Washington, DC. Trial data yielded significant improvements in both maximum mean increase in serum creatinine from baseline (0.15+/-0.29 mg/dl for nesiritide, vs. 0.34+/-0.48 mg/dl for placebo; p<0.001), and in maximum decrease in glomerular filtration rate from baseline (-10.8 mL/min/1.73 m2 vs. -17.2 mL/min/1.73 m2; p=0.001). This prospective, multi-center, randomized, double-blind pilot study enrolled 279 heart failure patients scheduled for CABG surgery across 54 sites, who received an infusion of the drug or placebo after induction of anesthesia, with subsequent 14 day follow-up.
October 10, 2005
Lumen Therapeutics issued positive interim results from the phase I portion of their phase I/II trial of LT-1951, for the prevention of graft failure following saphenous vein coronary artery bypass graft (CABG) surgery. Data from the ongoing study indicated that the drug was safe and generally well tolerated, with no serious adverse events reported and an expected incidence and profile of overall adverse events. These results were sufficiently positive to warrant expansion of the trial into its phase II portion. This placebo-controlled, two stage study enrolled 20 CABG patients in the first stage, with each subject receiving both drug- and placebo-treated venous grafts. The company announced that it planned to expand the enrollment to an additional 30 subjects in the phase II portion of the trial, which was designed to investigate the preliminary efficacy of the drug in preventing graft lumen loss.
September 12, 2005
Protein Design Labs issued positive results of their phase II "SIRIUS II" trial of ularitide, for the treatment of acute decompensated heart failure (ADHF), at the annual European Society of Cardiology (ESC) Congress in Stockholm. The drug demonstrated efficacy in both primary measures, significantly reducing dyspnea severity score (p<0.05) and pulmonary capillary wedge pressure (p<0.05) in all dosing groups, compared to placebo. This efficacy produced significant improvements in cardiac index, a measure of heart function, in the two higher dosing groups. Secondary endpoints were also positive, with no change in serum creatinine levels, no increase in mortality, and a reduction in median hospital stay. This randomized, double-blind, placebo- controlled study enrolled 221 subjects across 19 sites throughout Europe, who received one of 3 doses of ularitide (7.5, 15, or 30 ng/kg/min) or placebo via 24-hour infusion. Based on these results, the company announced plans to initiate additional trials of the drug in Europe and the US.
July 4, 2005
Myogen has issued negative results of a pair of phase III trials of enoximone, for the treatment of advanced chronic heart failure. Trial data failed to achieve success in any of the 3 co-primary endpoints: change in time to first hospitalization did not differ significantly from placebo in either trial (p=0.71); "marked improvement" in overall well- being was achieved by non-significantly fewer subjects with enoximone than placebo in both the first (43% vs. 46%; p= 0.79) and second trial (29% vs. 31%; p=0.11); and six- minute-walk distance failed to achieve significance in one trial (+1.5 meters; p=0.82). Significance was achieved in six-minute-walk distance in the second trial (+10.0 meters; p=0.025), but this value did not achieve the pre-established efficacy value of p<0.02. The drug did achieve its safety endpoint of non-inferior all-cause mortality vs. placebo. These parallel-design, randomized, double-blind, placebo- controlled trials, dubbed ESSENTIAL I & II, enrolled a total of 1,854 patients across 211 sites in 16 countries. Subjects were randomized 1:1 to receive thrice-daily low- dose enoximone (25 mg) or placebo for 6 months. Myogen announced that they were discontinuing development of enoximone, based on these results.
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.
November 15, 2004
AVI BioPharma reported positive phase II results for Resten-NG (AVI-4126), their third-generation antisense oligonucleotide for the treatment of cardiovascular restenosis. Results indicated that the drug met its primary endpoint, demonstrating significant efficacy in preventing restenosis following balloon angioplasty compared with subjects receiving standard therapy or sub-therapeutic doses of Resten-NG, as confirmed by quantitative angiography and ultrasound imaging. Secondary efficacy was seen in significantly reducing neointimal growth. This multi-center, double-blind, study randomized coronary artery disease patients at risk for restenosis to receive either a therapeutic or sub-therapeutic dose regimen of Resten-NG or standard therapy following balloon angioplasty. AVI announced plans to initiate a phase III clinical trial of the drug in Europe based upon these results.
NitroMed has issued results from a phase III study of BiDil (isosorbide dinitrate/hydralazine), for the treatment of heart failure in African American patients. Trial results demonstrate that the drug met its primary efficacy endpoints, with a 43% improvement in patient survival (p=0.01), a lower sudden death rate (6.2% vs. 10.2%; p=0.02), a 33% reduction in first hospitalization for heart failure (p=0.001), and a significant improvement in quality of life (p=0.02), vs. placebo. This double-blind, placebo-controlled trial enrolled 1,050 African American patients with heart failure across 170 investigative sites, who were randomized to receive either BiDil or placebo in addition to standard therapy for 18 months. NitroMed announced that it had submitted the data from the trial to the FDA, as required to amend their NDA for the treatment of heart failure in African American patients.
September 20, 2004
Vasogen announced preliminary results of their phase II study of Celacade, for the immunomodulatory treatment of advanced chronic heart failure. The study found that the drug significantly improved disease severity scores, including significant improvements in risk of death (p=0.022), all-cause hospitalization (p=0.008) and composite clinical score (p=0.006), and key electrocardiogram measurements (p=0.035), compared with placebo. Furthermore, the condition of subjects receiving Celacade improved significantly more often, and worsened significantly less often, than subjects receiving placebo. No significant difference from placebo was found in 6-minute walk endurance test or left-ventricular ejection fraction. This randomized, double-blind, controlled study enrolled a total of 75 chronic heart failure patients, who received either Celacade or placebo adjuvant to standard pharmacological therapy for six months. Vasogen announced that these results, which were published in the September 15th edition of the Journal of the American College of Cardiology, would be used as the basis for advancing Celacade into phase III trials.
April 5, 2004
Myogen reported negative preliminary results from a phase III trial investigating enoximone capsules, a PDE III inhibitor for the treatment of chronic heart failure. The study was designed to evaluate enoximone as an effective treatment to wean patients off of IV inotrope therapy. Results showed the study failed to meet its primary endpoint of intravenous inotrope therapy wean success at 30 days. Data showed a wean success rate of 61% in subjects treated with enoximone compared with 51% in subjects given placebo. The randomized, double-blind, placebo-controlled pivotal study, called EMOTE, enrolled 201 subjects with advanced chronic heart failure who are dependent on intravenous inotrope therapy.
September 15, 2003
AstraZeneca reported positive results from a trial investigating Atacand, an approved angiotensin receptor blocker for the new indication of chronic heart failure. Results demonstrated that Atacand reduced cardiovascular deaths or hospital admissions for heart failure by 16% when compared to placebo. The international, multi-center program, called CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) enrolled 7,601 subjects with symptoms of chronic heart failure. The program consisted of three independent, parallel, double blind, placebo-controlled trials. Treatment with Atacand was generally well tolerated but associated with a greater occurrence of discontinuation of study medication compared to placebo due to an increase in serum creatinine (6.2% vs. 3.0%) hypotension (3.5% vs. 1.7%), and hyperkalemia. Atacand is currently approved for the treatment of hypertension. Results were published in the September 6th edition of The Lancet.
NicOx reported positive results from a phase II endoscopy trial investigating NCX 4016, a nitric oxide for the treatment of peripheral arterial obstructive disease (PAOD). Data demonstrated that gastric safety, measured by endoscopy, was significantly better for NCX 4016 both as a monotherapy and in combination with aspirin compared to treatment with aspirin alone. Results also showed that NCX 4016 showed greater activity in the inhibition of inflammatory markers compared to aspirin. Endoscopic scores for NCX 4016 were similar to placebo. The study enrolled 48 subjects who were treated for 21 days. Results were reported in November 2003 at the American Heart Association meeting in Orlando.
April 7, 2003
Alteon reported preliminary results from a phase IIa trial investigating ALT-711, a glycosylation end product (AGE) crosslink breaker for the treatment of diastolic heart failure. Early results showed that subjects who received treatment for 16 weeks achieved a statistically significant reduction in left ventricular (LV) mass. LV mass was 125+35 gm at baseline and decreased to 119+35 gm at follow-up. Subjects also showed improvements in LV diastolic filling. However, measurements of exercise tolerance and aortic distensibility proved to be more variable than anticipated. The open-label, outpatient trial enrolled 23 subjects at least 60 years of age who received 210 mg of ALT-711 twice daily for 16 weeks in addition to their current medications. The DIAMOND (Distensibility Improvement and Remodeling in Diastolic Heart Failure) study was conducted at Wake Forest University Baptist Medical Center and the Medical University of South Carolina.
Pharmacia reported positive results from a phase III trial investigating Inspra (eplerenone), an approved hypertension drug for the new indication of post-myocardial infarction heart failure. Results showed a 15% reduction in ‘all cause mortality’ and a 13% reduction in the combined endpoint of ‘cardiovascular death and hospitalizations’ among Inspra treated subjects compared with current standard therapy. In addition, in subjects treated with Inspra there was a 21% reduction in sudden cardiac death and 15% fewer subjects hospitalized for heart failure. Inspra was generally well tolerated compared to placebo, with similar rates observed for adverse events such as menstrual disorder, gynecomastia and impotence. The randomized, double blind, placebo-controlled study, called EPHESUS (Eplerenone Post- AMI Heart Failure Efficacy and SUrvival Study), enrolled 6,632 subjects at 671 centers worldwide. The company plans to submit a sNDA for Inspra in the treatment of post-myocardial infarction heart failure.
January 27, 2003
Alteon reported fairly positive preliminary results from an ongoing phase IIa trial investigating ALT-711, an advanced glycosylation end product for the treatment of diastolic heart failure (DHF). Data showed that subjects experienced a statistically significant reduction in left ventricular mass after receiving the drug for 16 weeks. The primary endpoints, including changes in exercise tolerance and aortic distensibility, proved to be too variable to report. Additionally, results showed that the drug had a positive effect on the subjects' 'quality of life', which was measured by survey method. The open-label study enrolled 23 subjects at least 60 years of age or older with DHF.