High Blood Pressure (Hypertension)
October 10, 2016
Quantum Genomics issued results of a
phase IIa study of QGC001 in patients with
hypertension. In the double-blind crossover
study, a total of 34 patients with moderate
grade I to II hypertension were randomized,
and received two 28-day sequences alternating
the investigational product QGC001 versus
placebo, separated by a 14-day washout (no
treatment) period. The data show positive
signals on several endpoints, in particular on
the primary endpoint of the study, specifically
a drop in daytime systolic blood pressure
measured as ambulatory pressure in
hypertensive patients treated with QGC001 as
compared with placebo. The FDA has advised
the company on the design of a phase II trial to
be conducted in the U.S. to evaluate QGC001 in
a targeted population of hypertensive patients.
Quantum Genomics plans to submit an IND
application for the trial in the first half of 2017.
The company is also evaluating the possibility
of further clinical trials in Europe and Asia.
September 14, 2015
Gilead Sciences issued results of a phase
III/IV study of first-line combination therapy
Letairis and tadalafil to monotherapy
(Letairis or tadalafil) in patients with WHO/
NYHA functional class II and III pulmonary
arterial hypertension (PAH). The multicenter,
randomized, double-blind study enrolled 500
patients randomized (2:1:1) to receive Letairis
and tadalafil (n=253) or monotherapy with
Letairis (n=126) or tadalafil (n=121) (titrated
from 5mg to 10mg once-daily and from
20mg to 40mg once-daily for Letairis and
tadalafil, respectively). The treatment effect
for the composite primary endpoint of time to
clinical failure was driven mainly by a reduced
number of hospitalizations due to PAH, with
a reduced risk of hospitalization due to PAH
of 63% (hazard ratio=0.37; 95% CI: 0.22, 0.64;
p<0.001). Consistently favorable reductions
in clinical failure events were observed
based on etiology, WHO functional class, age,
geographical area and gender. The predefined
subgroup analysis of the primary endpoint
suggested that patients with WHO functional
class II (n=155; hazard ratio=0.21; 95% CI:
0.07, 0.63); p=0.005) responded even more
positively than patients with WHO functional
class III (n=345; hazard ratio=0.58; 95% CI:
0.39, 0.86; p=0.006). Statistically significant
improvements also were observed with the
following secondary endpoints v. the pooled
monotherapy arm: change from baseline at
week 24 in N-terminal pro-B-type natriuretic
peptide (NT-proBNP) (-67% v. -50%; p<0.001),
percentage of patients with satisfactory
clinical response at week 24 (39% v. 29%;
odds ratio 1.56; p=0.03) and median change
from baseline to week 24 in six-minute walk
distance (6MWD) (49 meters v. 24 meters;
p<0.001). There was no difference between
treatment groups in the change from baseline
to week 24 for WHO functional class. Letairis
is indicated in the U.S. to improve exercise
ability and delay clinical worsening and in the
E.U. under the tradename Volibris to improve
exercise capacity. Tadalafil 40mg is indicated
in the U.S. and the E.U. to improve exercise
ability and capacity, respectively.
August 10, 2015
Esperion Therapeutics released results of a
phase II study of ETC-1002 (bempedoic acid)
in patients with both hypercholesterolemia and
hypertension. The six-week, multicenter, randomized,
double-blind, placebo-controlled, parallel
group assessed the effect of ETC-1002 on systolic
blood pressure (SBP) and diastolic blood pressure
(DBP); the effect of ETC-1002 on additional lipid
and cardiometabolic risk markers, including
hsCRP; and characterized the safety and tolerability
of ETC-1002. A total of 143 patients with
hypercholesterolemia and hypertension were
washed out of any lipid-regulating and blood
pressure therapies. Seventy one patients received
ETC-1002 180mg and 72 patients received
placebo. ETC-1002-treated patients achieved
LDL-cholesterol lowering of 21% at six weeks,
compared with an increase of LDL-cholesterol of
3% in the placebo group. Levels of hsCRP were reduced
by 25% with ETC-1002, compared with an
increase of 20% in the placebo group. ETC-1002
was safe and well-tolerated, with no muscle-related
AEs or ETC-1002-related SAEs.
September 15, 2014
Mast Therapeutics reported results from
a phase II study of AIR001 (sodium nitrite)
inhalation solution for pulmonary arterial
hypertension (PAH). The multi-center,
open-label, randomized, parallel-dose study
randomized subjects into one of three treatment
arms and treated with AIR001 for 16
weeks: 80mg once daily after a two-week
“run-in” period of 46mg once daily; 46mg
four times daily after a two-week run-in period
of 46mg four times daily; or 80mg four
times daily after a two-week run-in period
of 46mg four times daily. The study enrolled
29 patients. All doses showed improvement
in median pulmonary vascular resistance
(PVR). In the secondary efficacy analysis, all
doses showed improvements in the median
distances obtained in the six-minute walk
test, including clinically meaningful improvements
at the highest dose level. AIR001 was
well-tolerated, with no treatment-related
serious adverse events. In particular, methemoglobin
levels remained normal (<1.5%),
which distinguishes AIR001 from safety
concerns associated with intravenously
administered nitrite. AIR001 has been
granted Orphan Drug status by the FDA
and the EMA for the treatment of PAH. The
company will proceed with phase IIa studies
and anticipates reporting preliminary study
results as early as the second half of 2015.
June 3, 2013
Novo Nordisk issued results from a phase IIIa trial of liraglutide for the treatment of obesity. This double-blind, randomized study enrolled 3,731 obese or overweight patients with co-morbidities such as prediabetes, hypertension and dyslipidaemia, but without diabetes. Subjects received liraglutide 3mg in combination with diet and exercise for 56 weeks, or placebo. Results showed from mean baseline weight of 106kg and a BMI of 38kg/m2, the average weight loss for people treated with liraglutide 3mg at 56 weeks was 8.0% compared to 2.6% for people treated with placebo. The proportion of people achieving a weight loss of at least 5% was 64% for liraglutide 3mg and 27% for placebo. The proportion of people achieving a weight loss of at least 10% was 33% for liraglutide 3mg and 10% for placebo treatment. All differences between liraglutide and placebo were statistically significant and the trial met all three co-primary endpoints. In addition, people treated with liraglutide 3mg experienced statistically significant improvements in obesity-related risk factors, including blood pressure, cardiovascular risk biomarkers, lipids and patient-reported quality of life, compared to people treated with placebo. The drug was well tolerated. The most frequent adverse events were related to the gastrointestinal system and diminished over time. Novo Nordisk expects to complete the remaining phase IIIa trial in the SCALE program in the third quarter of 2013 and to file liraglutide 3mg for regulatory review as a treatment for obesity in the U.S. and E.U. at the beginning of 2014.
September 10, 2012
The American Journal of Medicine published results from a phase III adjunctive trial of chlorthalidone for the treatment of hypertension. This 10-week, randomized, double-blind, titrate-to-target study enrolled 609 patients with stage two hypertension. Subjects received azilsartan medoxomil 40mg alone for two weeks, then 12.5mg of either diuretic, chlorthalidone or hydrochlorothiazide, for four weeks. At week six, subjects were titrated to 25mg chlorthalidone or hydrochlorothiazide for another four weeks. At week six, the clinic systolic blood pressure (SBP) reductions of the fixed dose combination of azilsartan medoxomil and chlorthalidone were -35.1mmHg. These data were statistically significantly (p<0.001) greater than those of azilsartan medoxomil and hydrochlorothiazide (-29.5mmHg), with a mean difference of -5.6mmHg. At the end of 10 weeks, greater clinic SBP reductions were maintained in patients taking the fixed-dose combination of azilsartan medoxomil and chlorthalidone (-37.8mmHg) versus those taking azilsartan medoxomil and hydrochlorothiazide (-32.8mmHg) with a mean difference of -5.0mmHg. Chlorthalidone was well tolerated.
May 7, 2012
Actelion Pharmaceuticals reported results from a long-term phase III trial of macitentan, a novel dual endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension. This multinational, multi-center, event-driven study, SERAPHIN, enrolled 742 patients. Subjects received macitentan 3mg, 10mg or placebo for up to three and a half years. The trial met a primary endpoint of decreasing the risk of a morbidity/mortality event over the treatment period, with the 3mg dose reducing risk by 30% (p≡0.0108) and the 10mg dose reducing risk by 45% (p<0.0001). The drug was well tolerated. The most frequent adverse events were elevations in liver alanine or aspartate aminotransferases and a decrease in hemoglobin. Based on these data, Actelion plans to submit the registration dossier to Health Authorities world-wide in the fourth quarter of 2012.
March 22, 2010
Novartis released positive results from a phase II trial of LCZ696 for the treatment of hypertension and other cardiovascular disorders. This randomized, double-blind, placebo and active controlled trial enrolled 1,334 subjects with mild-to-moderate uncomplicated essential hypertension. The subjects received eight weeks of treatment with one of three doses of LCZ696, three comparable doses of valsartan, AHU377 or placebo. All three active treatments achieved incremental blood pressure (BP) reductions on average over placebo. The subjects who received the two higher doses of LCZ696 achieved greater average reductions from baseline in both mean sitting systolic and diastolic BP than those in the comparator arms. In addition, subjects receiving the highest dose of LCZ696 also achieved superior BP control rates and significantly greater decreases in pulse pressure. LCZ696 was well tolerated, with no cases of angioedema reported.
June 1, 2009
Gilead released positive results from a phase III trial of ambrisentan for the treatment of pulmonary hypertension. This open-label, single-arm study, dubbed ARIES-3, enrolled 224 subjects with pulmonary hypertension due to a variety of etiologies. The subjects received ambrisentan at a dose of 5 mg once daily for 24 weeks. The primary endpoint was the change from baseline in six-minute walk distance (6MWD) at Week 24. In the overall study population, subjects experienced a mean 6MWD improvement of 21 meters (11.8 to 29.3; p<0.001) from baseline at 24 weeks. At the end of treatment, 97% of subjects were still alive. The probability of no clinical worsening at 24 weeks across the population was 90%. Treatment was generally well tolerated.
April 13, 2009
Gilead issued positive results from a phase III trial of darusentan for the treatment of resistant hypertension. This randomized, double-blind, placebo-controlled parallel group trial, DORADO/DAR-311, enrolled 379 subjects with resistant hypertension who were being treated with full doses of three or more antihypertensive medications. The subjects were randomized to once-daily doses of darusentan 50 mg, 100 mg, 300 mg or placebo for a 14-week treatment period. The co-primary endpoints were change from baseline to week 14 in trough sitting systolic blood pressure (SPB) and trough sitting diastolic blood pressure (DBP) as compared to placebo. Both primary endpoints were reached. At week 14, the reductions in mean trough sitting SBP from baseline were 8.6 mmHg, 16.5 mmHg, 18.1 mmHg and 18.1 mmHg for the placebo, darusentan 50 mg, 100 mg and 300 mg groups, respectively (p<0.001). Reductions in mean trough sitting DBP from baseline were 5.3 mmHg, 10.1 mmHg, 9.9 mmHg and 10.7 mmHg for the placebo, darusentan 50 mg, 100 mg and 300 mg groups, respectively (p<0.001). Darusentan was generally well tolerated.
February 9, 2009
Ligand issued positive results from a phase IIb trial of PS433540 for the treatment of hypertension. This randomized, double-blind, placebo- and active-controlled study enrolled 261 subjects with Stage 1 and Stage 2 hypertension. The subjects were randomized to once-daily doses of PS433540 at 200 mg, 400 mg, or 800 mg doses, placebo, or irbesartan (standard of care) at a 300 mg dose for 12 weeks. The primary endpoint was the change from baseline in mean seated systolic blood pressure for each dose of PS433540 compared with placebo and changes in blood pressure for each dose of PS433540 compared to irbesartan. PS433540 at 200 mg, 400 mg and 800 mg reduced systolic blood pressure by 13 mm Hg, 14 mm Hg, and 23 mm Hg, respectively. For diastolic blood pressure, the reductions with PS433540 were 7, 9, and 14 mm Hg respectively. All doses reduced blood pressure statistically significantly greater than placebo. The 800 mg daily dose of PS433540 produced a statistically significant reduction in systolic and diastolic blood pressure as compared to irbesartan. The percentages of subjects who reached a blood pressure goal of less than 140/90 at 12-weeks were 36%, 52%, and 62% with the PS433540 200 mg, 400 mg and 800 mg dose arms, respectively, compared to 32% of the irbesartan arm and 9% of the placebo arm. The 800 mg dose of PS433540 showed a statistically significantly higher percentage of patients achieving blood pressure control compared to irbesartan. PS433540 was generally well tolerated and there were no serious adverse events associated with therapy. Ligand is currently looking for a partner to continue the development of PS433540.
August 4, 2008
The Medicines Company released positive results from a phase III trial of Cleviprex for the treatment of acute hypertension after cardiac surgery. This randomized, double-blind, placebo-controlled trial, dubbed ESCAPE 2, enrolled 110 subjects with a systolic blood pressure (SBP) greater than 140 mm Hg following cardiac surgery. The subjects were randomized to a 30 to 60 minute infusion of Cleviprex or placebo. The primary end point was the incidence of treatment failure, defined as the inability to decrease SBP by 15% or more from baseline, or the discontinuation of study treatment for any reason within the 30 minute period after study drug initiation. The primary endpoint was reached: treatment success was achieved in significantly more Cleviprex-treated subjects than placebo-treated subjects (91.8% versus 20.4%, P <0.0001). The median time to achieving target systolic blood pressure with Cleviprex was 5.3 minutes. Treatment was generally well tolerated and no clinically significant increase in heart rate from baseline was observed. Adverse event rates were similar for both treatment groups. An NDA is currently under review by the FDA.
June 30, 2008
Speedel reported positive results from a phase IIa trial of SPP-635 for the treatment of hypertension. This double-blind, placebo-controlled, randomized, parallel design study enrolled 35 subjects with mild to moderate hypertension. The subjects received a single daily dose of SPP635 or placebo for 4 weeks. Sitting blood pressure and 24-hour ambulatory blood pressure (ABP) were the efficacy endpoints. Treatment with SPP635 decreased ABP compared to placebo (24-hour systolic ABP -12.5 1.70 mmHg versus +1.5 1.59 mmHg, diastolic ABP -8.4 1.09 mmHg versus -0.1 1.10 mmHg). Moreover, there was a significant decrease in ABP not only during the daytime (systolic blood pressure effects of SPP635 versus placebo: -14.4 2.01 mmHg vs. +0.9 2.17 mmHg; diastolic blood pressure lowering of SPP 635 versus placebo: -9.6 .38 mmHg versus -0.7 1.55 mmHg) but also during night-time (systolic blood pressure effects of SPP635 versus placebo: -9.7 1.80 mmHg versus +2.7 2.17 mmHg; diastolic blood pressure lowering of SPP 635 versus placebo: -6.9 1.20 mmHg vs. +2.4 2.26 mmHg). Similar results were observed for sitting blood pressure. Based on the results Speedel plans to move forward with the development of SPP-635.
November 5, 2007
Forest Laboratories issued positive results from a phase III trial of nebivolol for the treatment of hypertension. This twelve-week, randomized, double-blind trial enrolled 300 African-American subjects with stage I-II hypertension. The subjects received nebivolol (2.5, 5, 10, 20, or 40 mg) or placebo once daily. Results showed that nebivolol significantly reduced sitting diastolic and sitting systolic blood pressure at all daily doses compared to placebo. Nebivolol was well tolerated, with a low rate of the side effects commonly associated with beta blockers, including fatigue, sexual dysfunction, and depression. In addition, treatment did not lead to adverse changes in blood lipids and glucose levels. An NDA is currently under review by the FDA.
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.
October 15, 2007
Pharmacopeia issued positive results from a phase I trial of PS433540 for the treatment of hypertension. This double-blind, placebo controlled trial enrolled 17 healthy male subjects. All the subjects received placebo and four dose levels of PS433540 (20, 100, 250 and 500 mg) and open label 300 mg of irbesartan (current standard of care) once, at weekly intervals. At baseline and 2, 4, 12 and 24 hours post-dose, subjects received a six-minute infusion of angiotensin II (AII) and had their blood pressure measured. All doses of PS433540 produced a statistically significant inhibition of the expected AII-induced increase in blood pressure when compared to placebo (p<0.01). In addition, the data showed that the 250 mg and 500 mg doses of PS433540 were at least as effective in blocking the AII response as irbesartan. It was determined that PS433540 is suitable for once-daily oral dosing provided by its ability to block AII induced blood pressure increase for 24 hours. Pharmacopeia is currently conducting phase IIa trials of PS433540.
July 2, 2007
Speedel announced positive results from a phase IIa trialof SPP-635 for the treatment of hypertension. This double-blind,placebo-controlled, randomized, parallel design trial enrolled 35 subjects inEurope. Subjects received either placebo or a single dosage level of SPP635, once-dailyfor 4 weeks. Statistically significant results were observed in blood pressurechanges after four weeks compared to placebo. Sitting systolic blood pressurewas significantly reduced by 17.9 mmHg, from 156.6±9.1 mmHg at baseline(mean ± SD) to 138.7±13.3 mmHg in the SPP635 group (p<0.001).The placebo group remained unchanged (156.1±9.0 to 153.2±8.9 mmHg;baseline vs. end of treatment). Diastolic blood pressure was also significantlyreduced by 9.8 mmHg, from 91.3±7.8 to 81.5±8.2 mmHg (p<0.001)in the SPP635 treated group compared to 95.3±5.1 to 93.3±5.4 mmHgin the placebo group. Based on the results, Speedel plans to initiate a phaseII trial in Europe later in 2007.
June 25, 2007
Cytos released positive top-line results from a phase I/IIa trial of CYT-006 for the treatment of hypertension, at the 17th European Meeting on Hypertension. This randomized, double-blind and placebo-controlled trial enrolled 72 subjects with mild to moderate hypertension. Subjects were randomized into two arms to receive one of two doses of the vaccine or placebo administered via 3 subcutaneous injections at week 0, 4 and 12. Efficacy on systolic and diastolic blood pressure was assessed by 24-hour ambulatory blood pressure monitoring at baseline and post-treatment. All subjects who received the vaccine showed a strong antibody response on the first injection which was boosted by the subsequent injections. CYT-006 showed strong efficacy in the early morning hours. The early morning rise of blood pressure starting at 5 am was suppressed by the vaccine, leading at 8 am to a change from baseline of the blood pressure of - 25 / - 13 mm Hg compared to placebo (SBP / DBP, p<0.0001 / p=0.0035). This suppression of early morning rise blood pressure was associated with an exceptionally low increase in plasma renin concentration (PRC) from a mean renin concentration of 5.1 pg/ml at baseline to 6.3 pg/ml at week 14 (p=0.02). The induced anti-angiotensin antibody levels were significantly higher at the 300 microgram than at the 100 microgram dose (p=0.0098). Blood pressure reduction was much larger and only significant at the 300 microgram dose (p=0.0498). Based on the results Cytos plans to move forward with the development of CYT-006.
May 21, 2007
NicOx and Axcan announced negative results from a phase IIa trial of NCX 1000 for the treatment of portal hypertension. This double-blind, dose-escalating trial enrolled 11 subjects who were randomized to receive either placebo or escalating doses of NCX 1000 (500mg, 1000mg and 2000mg as the first three doses during the first two days). This was followed by 2000mg (or the maximum tolerated dose) three times a day for the following 14 days. The primary endpoint was portal pressure on day 16 compared to baseline. Secondary endpoints included the same comparison after consumption of a controlled meal as well as response rate, increase of liver blood flow, safety, tolerability and pharmacokinetics. Results revealed a positive safety and tolerability profile. However, treatment with NCX 1000 did not provide the efficacy required to continue this trial or move into future trials. Based on the results NicOx and Axcan have agreed to terminate the development of NCX 1000.
April 16, 2007
Pharmacopeia announced positive results from a phase I trial of PS433540 for the treatment of hypertension and diabetic nephropathy. This randomized, placebo-controlled, dose-escalation trial enrolled healthy subjects who were placed into six groups. Each group was comprised of eight individuals, with six receiving PS433540 and two receiving placebo. Treatment was administered in doses ranging from 20 mg to 1000 mg and the doses were increased for each successive group. Treatment was well tolerated across all six doses administered. PS433540 possessed linear pharmacokinetics and a half-life consistent with once daily administration. Based on the results, Pharmacopeia plans to initiate multiple ascending dose trials later in 2007.
February 26, 2007
BioMarin reported negative results from a phase IIa trial of Phenoptin for the treatment of hypertension. This randomized, double-blind, placebo-controlled trial enrolled 116 subjects with poorly controlled hypertension. Subjects received oral doses of Phenoptin (5 mg/kg) or placebo twice daily for eight weeks. The primary endpoint, a statistically significant drop in systolic blood pressure when compared to placebo, was not met. The subjects on placebo experienced a drop of 6.4 mm Hg while those receiving Phenoptin had a drop of 4.8 mm Hg. Statistical significance was not reached for any other safety or efficacy parameter relative to placebo. BioMarin plans to further analyze the data and does not anticipate altering the course of development at this time.
February 5, 2007
Cytos released positive results from a phase IIa trial of CYT006-AngQb, a vaccine for the treatment of hypertension. This randomized, double-blind and placebo-controlled trial enrolled 72 subjects with mild to moderate hypertension. Subjects were randomized into two arms to receive one of two doses of the vaccine or placebo administered via 3 subcutaneous injections at week 0, 4 and 12. Efficacy on systolic and diastolic blood pressure was assessed by 24-hour ambulatory blood pressure monitoring at baseline and post-treatment. Treatment was safe and well tolerated, with side effects mostly transient. The most commonly reported adverse events included injection site reactions and mild flu-like symptoms lasting for 1 to 2 days. All subjects who received the vaccine showed a strong antibody response on the first injection which was boosted by the subsequent injections. The antibody response had long half-life of 3-4 months. A significant reduction in ambulatory daytime blood pressure was observed, however these differences were not significant in nighttime blood pressure. Based on these results Cytos plans to initiate future trials exploring a more aggressive treatment regimen.
January 8, 2007
Actelion reported positive results from a clinical trial, dubbed EARLY (Endothelin Antagonist Trial in mildly Symptomatic PAH patients, NYHA modified functional class II), of Tracleer for the treatment of pulmonary arterial hypertension (PAH). This double-blind, placebo-controlled, multicenter trial enrolled 185 mildly symptomatic PAH subjects internationally. Subjects received placebo or Tracleer at an initial dose of 62.5 mg b.i.d. for four weeks and a target dose of 125 mg b.i.d. for five months, for an overall exposure to either active study drug or placebo of six months. After six months, subjects could opt to continue in an open-label extension study that was ongoing at this time. The co-primary endpoints were achieved, with the subjects on Tracleer therapy showing a significant reduction in pulmonary vascular resistance (PVR) and an improvement in 6-minute-walk test compared to those receiving placebo (p less than 0.0001and p=0.076, respectively). The secondary endpoint was met as well, with Tracleer treatment resulting in a 70% reduction in the time to clinical worsening when compared to placebo (p=0.018). Results were to be fully analyzed in anticipation of worldwide filings of Tracleer to include the treatment of mildly symptomatic PAH (NYHA modified functional class II).
Nuvelo and Bayer announced negative results from two phase III trials of alfimeprase. The first trial, dubbed NAPA-2 (Novel Arterial Perfusion with Alfimeprase-2) evaluated alfimeprase in the treatment of acute peripheral arterial occlusion. This randomized, double-blind trial enrolled 300 subjects internationally, who received 0.3 mg/kg of alfimeprase or placebo. The primary endpoint, avoidance of open vascular surgery within 30 days of treatment, was not met. The second trial, dubbed SONOMA-2 (Speedy Opening of Non-functional and Occluded catheters with Mini-dose Alfimeprase-2) evaluated alfimeprase in the treatment of catheter occlusion. This randomized, double-blind trial enrolled 303 subjects who received 3 mg of alfimeprase with placebo in a 2:1 ratio. The primary endpoint, restoration of function to the occluded catheter in 15 minutes, was not met. Based on these results, Nuvelo and Bayer decided to temporarily suspended enrollment in the ongoing Phase 3 trials, NAPA-3 and SONOMA-3, pending further analysis of the results.
April 17, 2006
Myogen has issued top line results of their phase III ARIES-1 trial of ambrisentan for the treatment of pulmonary arterial hypertension. Trial data met their primary efficacy endpoint, with both doses of the drug significantly improving placebo-corrected mean change in six-minute walk distance at week 12 compared to baseline (5 mg: 30.6 m, p=0.0084; 10 mg: +51.4 m, p=0.0001). Rates of clinical worsening were generally low among all treatment arms, and differences in this measure were not significant between groups. Safety data were generally positive, with no patients developing serum aminotransferase concentrations greater than three times the upper limit of the normal. The most commonly observed adverse event was peripheral edema. This randomized, double-blind, placebo-controlled study enrolled 202 subjects in the US, who received one of two doses of the drug (5 mg or 10 mg) or placebo once daily.
January 23, 2006
Novartis and Speedel announced positive results of three phase III trials of aliskiren (SPP-100), for the treatment of hypertension. The first study, which investigated the drug (150 mg) in combination with the approved calcium channel blocker amlodipine (5 mg), found the combination to be safe and efficacious: the combination had a positive tolerability profile, showed a reduced incidence of edema compared to amlodipine alone, and showed an increased reduction in blood pressure. Results of the second study, which investigated both aliskiren monotherapy and in combination with the ACE inhibitor ramipril, were also positive: the drug produced decreases in systolic and diastolic blood pressure from baseline as a monotherapy, and significantly improved both measures when added to ramipril, vs. ramipril alone; the combination was well tolerated. The third trial indicated a positive safety and tolerability profile for long term aliskiren monotherapy (>12 months).
August 22, 2005
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.
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.
February 7, 2005
Angiogenix reported negative efficacy results from a phase II trial of Acclaim (isosorbide mononitrate plus L-arginine), for the prevention of nitrate tolerance in patients with chronic stable angina. The trial failed to meet its primary efficacy endpoint, a statistically significant increase in treadmill walking time following treatment. The trial also failed to meet secondary endpoints, though positive, non-significant trends were observed for time to onset of angina, ST-segment depression, and improvement seen with concomitant ACE inhibitor therapy. Trial data did meet their primary safety endpoint, with acceptable profiles for both incidence of serious adverse events and tolerability. This randomized, double-blinded, placebo-controlled, multi-center study enrolled 204 subjects across 7 countries. The company announced plans to continue the development of Acclaim, with a re-assessment of dosing data based on these results prior to future studies.
Speedel Pharma announced positive results from phase I studies a pair of their investigational rennin inhibitors, SPP630 and SPP635, for the treatment of hypertension and protection of end-organs including the heart and kidneys. Data from the trials met pharmacokinetic endpoints, establishing a bio-availability of roughly 30%, an elimination half-life of more than 30 hours (suitable for once daily dosing), and an improved tissue distribution profile. These micro-dosing studies of both drugs used nano-molar doses to investigate their pharmacokinetics in healthy volunteers. Speedel announced that the completion of these trials allowed for the initiation of expanded, classical phase I studies in Q3, 2005.
January 3, 2005
Cardiome Pharma and Fujisawa Healthcare reported results from a phase III trial with RSD1235, an Ion channel modulator being investigated for the treatment of atrial fibrillation (AF). The study, called ACT 1, enrolled 426 subjects with AF at 45 sites in the U.S., Canada and Scandinavia. The study examined three sub-groups, including 237 subjects with recent-onset AF (more than 3 hrs but less than 7 days), 119 patients with longer-term AF (more than 7 days but less than 45 days) and 60 patients with atrial flutter. Results showed that 52% of the 234 subjects with recent-onset AF achieved a normal heart rhythm compared with 4% of subjects given placebo. In the overall population, 38% of RSD1235 treated subjects demonstrated termination of AF, compared to 3% of placebo patients. In addition, 8% of RSD1235 treated subjects in the longer-term AF population achieved AF termination compared to 0% of placebo subjects. In the recent-onset AF population, 52% of those who were dosed with RSD1235 achieved a normal heart rhythm, as compared to 4% of placebo patients. There were no cases of drug-related "Torsades de Pointes", an arrhythmia which is an occasional side effect of many current anti-arrhythmia drugs. Serious adverse events were reported in 13% of subjects receiving RSD1235 compared to 18% subjects on placebo. Serious drug-related adverse events occurred in 0% of placebo patients and 1.4% of patients receiving RSD1235. The primary endpoint in ACT 1 was conversion of recent-onset AF to normal heart rhythm for a period of at least 1 minute.
The Medicines Company reported primary results from a phase III trial investigating Clevelox (clevidipine), an intravenous drug being evaluated for the control of blood pressure. The placebo-controlled, doubled blind, randomized study, called ESCAPE-1, enrolled subjects before they underwent cardiac surgery. Results showed that patients with high blood pressure treated with Clevelox achieved treatment success 92.5% of the time versus 17.3% with placebo, measured by at least a 15% reduction in blood pressure. In November 2004, The company reported similar primary results of ESCAPE-2, a trial of Clevelox conducted in post-operative patients. The complete Clevelox phase III program consists of five clinical trials, including three trials, know as ECLIPSE, which are currently enrolling patients. Full data will be published and presented under scientific peer review. Pending positive results, the Medicines Company plans on filing an NDA with the FDA shortly.
December 6, 2004
Penwest Pharmaceuticals announced mixed results from a pivotal phase III study of low doses of its investigational beta blocker PW2101, for the treatment of hypertension and angina. Trial data failed to meet their primary efficacy endpoint, with a non-significant change in Mean Seated Office Cuff diastolic blood pressure from baseline to week six, compared to placebo (2.4 mmHg, p>0.05). The trial did meet secondary endpoints, including a significant increase in 24-hour Mean Ambulatory diastolic blood pressure from baseline to week six, compared with placebo. A previous phase III pivotal trial of low-dose PW2101 also produced significant evidence of efficacy. This randomized, double-blind, placebo-controlled study enrolled 110 hypertensive patients, who received low dose low-dose PW2101 or placebo for 6 weeks. The company announced plans to submit these data to the FDA as an expansion of the PW2101 NDA, which is currently under review, in hopes of broadening the dosing indications for the drug.
October 11, 2004
Encysive Pharmaceuticals reported top-line results of their STRIDE-6 clinical trial of Thelin (sitaxsentan), for the treatment of pulmonary arterial hypertension (PAH) in subjects failing standard therapy with bosentan. Trial data indicated that among subjects discontinuing bosentan for lack of efficacy (n=35), 10% in the low dose Thelin group and 33% in the high-dose Thelin group achieved symptom improvement, and unchanged disease state was noted for 75% and 47% of each group, respectively. Among subjects discontinuing bosentan due to safety concerns (n=13), primarily liver function abnormalities, only one was unable to safely undergo treatment with Thelin, due to a recurrence of liver abnormality. Tolerability concerns were similar for both doses, and included nausea, fatigue, headache, edema, and upper respiratory tract infection; one subject in the study died due to progressive PAH. This blinded, dose-ranging study randomized 48 bosentan-intolerant PAH patients to receive either 50 or 100 mg Thelin once daily for 24 weeks; following completion of the STRIDE-6 study, 45 of the 48 subjects continued into the STRIDE-3 long-term extension.
April 12, 2004
Forbes Medi-Tech reported positive preliminary results from a phase II trial investigating FM-VP4, a cholesterol absorption inhibitor for the treatment of high cholesterol. Results showed that the study reached its primary efficacy endpoint of significantly lowering low-density lipoprotein (LDL) cholesterol. Data showed that the reduction in LDL cholesterol was 11% as compared to placebo, with 33% of subjects at 400 mg per day achieving a greater than 15% reduction. FM-VP4 was shown to be safe with no difference seen between dosing and placebo groups. The double blind, placebo-controlled, dose-escalation study enrolled 25 subjects with hypercholesterolemia. Subjects were treated with placebo or escalating doses of FM-VP4 from 100, 200, 400, and 800 mg daily for 28 days.
Medicure reported positive preliminary results from a phase II trial investigating MC-4232, an ACE Inhibitor plus MC-1 for the treatment of hypertension. Results showed a trend towards the reduction in glycated hemoglobin (HbA1c), the primary measure of blood glucose control. Data showed 4.9% reduction in HbA1c compared to baseline levels. HbA1c reflects average blood glucose fluctuations over a 60 to 90 day period. The 14-week study enrolled 15 subjects with diabetic hypertension. Medicure plans to proceed with additional phase II trials.
July 21, 2003
Alteon reported negative results from a phase IIb trial investigating ALT-711, a crosslink breaker for the treatment of uncontrolled systolic hypertension. Results showed that ALT-711 did not demonstrate statistical significance as compared to placebo in the primary endpoint, the reduction of systolic blood pressure by ‘office cuff pressure’ measurement. The data showed a 6-10 mm Hg drop in systolic blood pressures in all groups during the first two weeks. The dose ranging, double-blind, placebo-controlled trials, called SAPPHIRE (Systolic And Pulse Pressure Hemodynamic Improvement by Restoring Elasticity) and SILVER (Systolic Hypertension Interaction with Left VEntricular Remodeling), enrolled 768 subjects having elevated systolic blood pressure at over 60 sites nationwide. Subjects were maintained on background hypertension medication during treatment.
EPIX Medical reported positive results from two phase III trials investigating MS-324, a blood pool contrasting agent for the use with magnetic resonance angiographs (MRA). The two trials were conducted on subjects with suspected vascular disease in the renal and pedal arteries. Results demonstrated that both studies met their primary clinical endpoint, demonstrating statistically significant improvement in accuracy for detecting renal and pedal vascular disease with MS-325 compared with non-contrast MRA. The renal study enrolled 145 subjects with suspected disease in the renal arteries and administered each a 0.03 mmol/kg dose of MS-325. Data showed that three individual MRA readers achieved an accuracy of 73%, 79% and 79%, with MS-324 enhancement compared with 45%, 56% and 51% for non-contrast MRAs. The pedal study enrolled 96 subjects with suspected pedal artery stenosis and administered each a 0.03 mmol/kg dose of MS-325. The three readers showed improved specificity of 21%, 34% and 34% with MS-325-enhanced MRA compared to non-contrast MRA. Results were announced at the 11th annual meeting of the International Society of Magnetic Resonance in Medicine (ISMRM) in Toronto.
Sanofi-Synthelabo reported positive results from a general surgery study investigating Arixtra (fondaparinux), a selective factor X inhibitor for the treatment of venous thromboembolism (VTE). Results showed that Arixtra was at least as effective and as safe as the low molecular weight heparin (LMWH) dalteparin for the prevention of VTE following major abdominal surgery. In abdominal cancer surgery subjects, fondaparinux was significantly more effective than the low molecular weight heparin. The randomized, double blind study, called PEGASUS (The PEntasaccharide in GenerAl SUrgery Study) enrolled 2,927 subjects who had undergone major abdominal surgery. Results were presented at the 19th Congress of the International Society on Thrombosis and Haemostasis.
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.
March 10, 2003
Biovail reported positive results from a phase IV trial investigating Cardizem LA (diltiazem), a recently approved drug for the treatment of hypertension. Results showed that Cardizem demonstrated better diastolic blood pressure control compared to the alternative drug amlodipine. There was a highly statistically significant reduction in DBP favoring Cardizem during the first four hours of awakening and between 6AM and 12 noon however over 24-hours the DBP reductions were comparable to amlodipine. The drug also showed superior reductions in the rate-pressure product, an index of myocardial oxygen demand. The randomized study enrolled African American subjects who had stage I and II hypertension.
May 20, 2002
Study results indicate that Forest Laboratories' lercanidipine provides comparable efficacy to the calcium channel blocker amlodipine while offering an improved tolerability profile. The double-blind COHORT trial included 828 hypertensive subjects and compared the tolerability of lercanidipine, lacidipine (an agent similar to lercanidipine) and amlodipine. Results showed that treatment with lercanidipine resulted in 75% fewer subject drop-outs due to edema compared to treatment with amlodipine. Furthermore, the incidence of edema was over 50% lower in subjects treated with lercanidipine compared to the incidence with amlodipine treatment.
April 8, 2002
Results from two phase III trials suggest that Pharmacia's eplerenone produces a greater reduction in proteinuria than enalapril in diabetic hypertensive subjects. Additionally, results showed that the two drugs similarly reduced left ventricular mass (LVM). Both trials evaluated treatment with eplerenone, enalapril, and eplerenone in combination with enalapril. The studies were designed to control blood pressure equally in all treatment groups to allow for evaluation of eplerenone's effect on proteinuria and left ventricular hypertrophy (LVH). In the first trial, which included diabetic subjects with hypertension and albuminuria, treatment with eplerenone resulted in a 62% reduction in proteinuria, compared to a 45% reduction with enalapril and a 74% reduction with the combination therapy. In the second trial, which included hypertensive subjects with LVH, eplerenone and enalapril treatment produced reductions of 14.5g and 19.7g in LVM, respectively. LVM reduction in the combination therapy group was 27.2g.