High Cholesterol (Hyperlipidemia)
April 4, 2016
Regeneron Pharmaceuticals and Sanofi
released positive results from the phase III
ODYSSEY ESCAPE trial evaluating Praluent
(alirocumab) Injection in patients with an
inherited form of high cholesterol known as
heterozygous familial hypercholesterolemia
(HeFH), whose cholesterol levels required
chronic, weekly or bi-weekly apheresis
therapy. The completed, placebo-controlled
trial involved 62 patients from 14 treatment
centers in the U.S. and Germany. These
patients were receiving regular baseline
apheresis therapy at fixed intervals of every
week or every 2 weeks prior to randomization.
Patients were randomized to receive
Praluent 150mg (n=41) subcutaneously
every 2 weeks or placebo (n=21), in addition
to their existing treatment regimen. The
double-blind treatment period comprised
two intervals: for the first six weeks, patients
remained on their established apheresis
schedule at baseline, and for the following
12 weeks, apheresis frequency was adjusted
based on the patient’s LDL cholesterol
response to treatment. ODYSSEY ESCAPE
is part of the overarching phase III ODYSSEY
program, which includes more than
25,000 patients. The trial met its primary
endpoint, demonstrating that patients who
added Praluent to their existing treatment
regimen significantly reduced the frequency
of their apheresis therapy by 75%, compared
to placebo (p< 0.0001). Sixty-three
percent of patients treated with Praluent
no longer required apheresis, compared to
0% of placebo patients. The most common
adverse events in the trial were fatigue (15%
Praluent; 10% placebo), nasopharyngitis
(10% Praluent; 10% placebo), diarrhea (10%
Praluent; 0% placebo), myalgia (10% Praluent;
5% placebo), upper respiratory infection
(7% Praluent; 19% placebo), headache
(7% Praluent; 5% placebo), arthralgia (7%
Praluent; 10% placebo) and back pain (5%
Praluent; 10% placebo).
July 27, 2015
Regeneron Pharmaceuticals and Sanofi
reported results of a phase III trial of Praluent
(alirocumab) Injection for low-density lipoprotein
cholesterol (LDL-C). ODYSSEY JAPAN evaluated
Praluent (n=144) compared to placebo
(n=72), on top of standard care, in Japanese
patients with hypercholesterolemia, with either
HeFH or at high CV risk, and who could not
reach their LDL-C treatment goal as defined by
the JAS guidelines despite lipid-lowering treatments
that included statins. The mean LDL-C
value at baseline was 141.2mg/dL. Patients
initially were randomized to receive either Praluent
75mg every two weeks administered as a
single 1mL injection, or placebo. At week 24,
97% of patients in the Praluent group reached
their LDL-C treatment goal, compared to 10%
for placebo (p<0.0001). Ninety-nine percent of
patients who received Praluent at week eight
remained on the initial 75mg dose, while 1%
of patients had their dose adjusted to receive
150mg every two weeks, also as a single 1mL
injection. The most common adverse events
(occurring in at least 5% of patients in the Praluent
group) were nasopharyngitis, injection site
reaction and back pain. The FDA has recommended
the approval of Praluent.
March 23, 2015
Regeneron Pharmaceuticals and Sanofi
issued results of a phase III trial of Praluent
(alirocumab) involving 2,341 high-risk patients
with hypercholesterolemia. The 78-week
trial evaluated Praluent 150mg (n=1,553)
every two weeks compared to placebo
(n=788). At week 24, Praluent reduced LDL-C
from baseline by an additional 62% v. placebo
(p<0.0001) when added to the current
standard-of-care, which included maximally-tolerated
statins. Efficacy remained consistent
throughout treatment, and at week 78 there
was a 56% reduction from baseline in LDL-C
for Praluent v. placebo (p<0.0001). At week 24,
81% of patients in the Praluent group achieved
their pre-specified LDL-C goal (either 70mg/
deciliter [mg/dL] or 100mg/dL depending on
baseline CV risk) compared to 8.5% for placebo
(p<0.0001). Adverse events (AEs) occurred in
81% of Praluent and 83% of placebo patients,
leading to discontinuation in 7.2% and5.8% of
patients, respectively. Earlier this year, Regeneron
and Sanofi announced the FDA accepted
the BLA for Praluent for priority review.
April 14, 2014
Sanofi and Regeneron Pharmaceuticals
released results of a phase II study of
alirocumab for the treatment of low-density
lipoprotein-cholesterol (LDL-C, or “bad” cholesterol)
in Japanese subjects. This multicenter,
placebo-controlled, phase II study randomized
approximately 100 patients with LDL-C greater
than or equal to 100mg/dL receiving lipidmodifying
therapy. 25 patients per group were
randomized to receive one of three doses of
alirocumab dosed subcutaneously every other
week (Q2W)—150mg, 75mg or 50mg, or
placebo, all in combination with statin therapy.
At week 12, the mean percentage reduction
in LDL-C from baseline in patients receiving
alirocumab 5 mg Q2W was 55%, alirocumab
75mg Q2W was 62% and alirocumab 150mg
Q2W was 72%, compared to 3% in the placebo
group (p<0.0001 v. placebo for all treatment
arms). All patients in each of the alirocumab
groups achieved LDL-C levels of <100mg/dL,
compared to 8% of patients in the placebo
group. Treatment emergent adverse events
(TEAEs) in this study were reported by 52% of
patients in the alirocumab 50mg group, 48%
of patients in the 75mg group, 64% of patients
in the 150mg group, compared to 32% in the
placebo group. The most frequently reported
TEAEs were nasopharyngitis, injection site reaction,
back pain, cystitis and ligament sprain.
April 7, 2014
Pfizer has reported results of a phase
IIb trial of bococizumab (RN316) for the
treatment of density lipoprotein cholesterol
(LDL-C). The dose-ranging, double-blind,
placebo-controlled, 24-week study in 354
patients examined two dosing regimens:
twice monthly (bococizumab 50mg, 100mg
or 150mg) and once monthly (bococizumab
200mg or 300mg). For both regimens, the
bococizumab dose was lowered if LDL-C
was reduced to =25 mg/dL. The first opportunity
for dose reduction was at week
six for the twice-monthly and week eight
for the once-monthly regimen. The primary
efficacy analysis was the placebo-adjusted
change from baseline in LDL-C at Week 12.1
The mean baseline LDL across doses was
109mg/dL. Bococizumab twice-monthly
and once-monthly dosing regimens were
associated with significant placebo-adjusted
reductions in LDL-C at week 12, with the
greatest reductions seen with 150mg for the
twice-monthly regimen and 300mg for the
once-monthly regimen. Prior to the majority
of dose reductions due to an LDL-C =25mg/dL,
the LDL-C changes seen with these regimens
were greater than those observed at
week 12. The phase III program for bococizumab
was initiated in October 2013.
February 3, 2014
Amgen reported results of a phase III trial of
evolocumab in patients with high cholesterol.
The randomized, multicenter, double-blind,
placebo- and ezetimibe-controlled trial evaluated
evolocumab in 307 hyperlipidemic patients
who could not tolerate effective doses
of at least two different statins due to musclerelated
side effects. Patients were randomized
to one of four treatment groups: subcutaneous
evolocumab 140mg every two weeks and
oral placebo daily; subcutaneous evolocumab
420mg monthly and oral placebo daily; subcutaneous
placebo every two weeks and oral
ezetimibe 10mg daily; or subcutaneous placebo
monthly and oral ezetimibe 10mg daily.
The most common adverse events (> 5% in
evolocumab combined group) were headache
(7.8% evolocumab; 8.8% ezetimibe), myalgia
(7.8% evolocumab; 17.6% ezetimibe), pain in
extremity (6.8% evolocumab; 1% ezetimibe)
and muscle spasms (6.3% evolocumab; 3.9%
ezetimibe). The phase III evolocumab program
includes 13 trials, with a combined planned
enrollment of more than 28,000 patients.
January 13, 2014
Amgen reported results of a phase III trial of
evolocumab for the treatment of high cholesterol.
The randomized, multicenter, doubleblind,
placebo-controlled study was designed
to evaluate the long-term (52-week) safety,
tolerability and efficacy of evolocumab in
patients with hyperlipidemia at risk for cardiovascular disease. Background lipid-lowering
therapy was optimized to one of four treatment
groups (diet alone; diet plus atorvastatin
10mg; diet plus atorvastatin 80mg; and
diet plus atorvastatin 80mg plus ezetimibe
10mg) for individual patients based on their
LDL-C and cardiovascular risk according to the
National Cholesterol Education Program Adult
Treatment Panel (NCEP ATP) III risk categories.
After optimization, patients were maintained
on therapy for at least four weeks. A total of
901 patients with a fasting LDL-C >= 75mg/dL
were then randomized and received monthly
subcutaneous evolocumab 420mg or placebo
in combination with background lipid-lowering
therapy. Evolocumab significantly reduced
LDL-C, as measured by the accepted standard,
preparative ultracentrifugation, from baseline
at week 52 compared to placebo. LDL-C
reduction at week 12 was consistent with the
long-term efficacy at week 52.
November 4, 2013
Sanofi and Regeneron Pharmaceuticals released results of a phase III trial of alirocumab for the reduction of low-density lipoprotein-cholesterol (LDL-C, or “bad” cholesterol). The global, randomized, doubleblind, active-controlled, parallel-group study to evaluate the efficacy and safety of alirocumab over 24 weeks in patients with primary hypercholesterolemia and moderate cardiovascular risk is expected to enroll more than 23,000 patients and currently includes 12 clinical trials of alirocumab both in combination with other lipid-lowering agents and as monotherapy. Patients in the trial were randomized to receive monotherapy with either ezetimibe 10mg, an alternative to statin therapy, or alirocumab. Alirocumab was self administered initially at its low dose of 75mg every two weeks, and was up-titrated at week 12 to 150mg if the LDL-C measurement at week eight was above 70mg/dL. The mean LDL-C reduction from baseline to week 24 was significantly greater in patients randomized to alirocumab, as compared to patients randomized to ezetimibe (47.2% v. 15.6%, p<0.0001). In the trial, which employed a dose increase (up-titration) for patients who did not achieve an LDL-C level of 70mg/dL, the majority of patients remained on the initial low dose of alirocumab of 75mg.
September 9, 2013
Esperion Therapeutics issued results of a phase IIa study of ETC-1002 when added to statin therapy in patients with elevated levels of low-density lipoprotein cholesterol (LDL-C or “bad cholesterol”). The randomized, double-blind, placebo-controlled, multicenter study in 58 patients with hypercholesterolemia involved 42 patients randomized to receive ETC-1002 plus 10mg atorvastatin. All ETC-1002 treated patients received escalating daily doses of 60mg, 120mg, 180mg and 240mg ETC-1002, each over a two-week period, for a total of eight weeks. Sixteen patients received placebo plus 10mg atorvastatin, also for eight weeks. ETC-1002 treated patients achieved incremental LDL-C lowering of 22% at eight weeks, compared with 0% in the placebo group, when added to 10mg of atorvastatin (p<0.0001). ETC-1002 was well-tolerated over eight weeks of treatment when added to a statin, and no serious adverse events (SAEs) were reported.
May 27, 2013
Genfit issued results from a phase IIa trial of GFT505 for the reduction of of non-HDL-cholesterol and triglycerides, or “remnant cholesterol,” in hypercholesterolemia. This study enrolled pre-diabetic and diabetic patients with hypercholesterolemia. Subjects received GFT505 80mg daily, or placebo. Analysis demonstrates treatment with GFT505 significantly reduces the level of “remnant cholesterol” in both pre-diabetic and diabetic populations. Data showed the effect of GFT505 on measured remnant cholesterol was -24% (p=0.0046) compared to the placebo group after 28 days of treatment. Consistently, after three months of treatment in diabetic patients, the effect of GFT505 on calculated remnant cholesterol compared to the placebo group was -46% (p=0.01). GFT505 was well tolerated. Genfit did not note its plans for GFT505.
May 13, 2013
Esperion Therapeutics reported results from a phase II trial of ETC-1002 for type 2 diabetes and hypercholesterolemia. This randomized, double-blind, placebo-controlled, parallel-group study enrolled 60 patients with type 2 diabetes (HbA1C 7-10%), a body mass index of 25-35kg/m2, and LDL-C≥100mg/dL. Subjects received ETC-1002 80mg for two weeks followed by ETC-1002 120mg for two weeks, or placebo for four weeks, and were treated in an inpatient unit where their diet and lifestyle were controlled. Results showed after two weeks of treatment with 80mg of ETC-1002, LDL-C was reduced by an average of 32% (p<0.0001), while after an additional two weeks of 120mg of ETC-1002, LDL-C was reduced by an average of 43% (p<0.0001) compared with 6% and 3% reductions, respectively, for those patients treated with placebo. ETC-1002 also significantly reduced non-HDL-C (by 30%; p=0.0001) and high sensitivity C-reactive protein (hsCRP) and blood pressure compared with placebo. ETC-1002 had neutral effects on other lipids, including triglycerides and HDL-C. The drug was well tolerated. The most frequent adverse events were headache, hyperglycemia, constipation, arthralgia, dry eye and viral upper respiratory tract infection. Esperion is currently evaluating ETC-1002 in multiple phase II trials in more targeted patient populations.
March 18, 2013
Kowa Pharmaceuticals America and Eli Lilly issued results from a phase IV trial of Livalo compared to pravastatin for reducing low-density lipoprotein cholesterol (LDL-C). This randomized, double-blind, double-dummy, active-controlled, parallel-group superiority study enrolled 252 HIV-infected patients with high cholesterol and with or without viral hepatitis B or C. Subjects received Livalo 4mg or pravastatin 40mg once daily. Results showed after 12 weeks of therapy, Livalo had a significantly greater decrease in LDL-C compared with pravastatin (Livalo -49.4mg/dL and pravastatin -33.6mg/dL, 31% versus 21% reduction, respectively, p<0.001). Livalo was well tolerated. The most frequent treatment emergent adverse events were diarrhea, upper respiratory tract infection, sinusitis, headache, nausea, nasopharyngitis and increase in blood creatine phosphokinase. Eleven subjects were discontinued from the study due to a TEAE.
November 12, 2012
Amgen released results from a phase II trial of AMG 145 for the treatment of heterozygous familial hypercholesterolemia (HeFH). This multi-arm, placebo-controlled, combination study enrolled patients with HeFH with high levels of low density lipoprotein cholesterol (LDL-C). Subjects received 350mg or 420mg AMG 145 and statin therapy, or placebo and statin therapy, every four weeks for 12 weeks. Data showed a significant LDL-C decrease with AMG 145 versus placebo. At week 12, LDL-C reduction, measured by preparative ultracentrifugation, was 43% and 55% with 350mg and 420mg AMG 145, respectively, compared to a 1% increase with placebo (p<0.001 for both dose groups). At week 12, treatment with 350mg and 420mg AMG 145 resulted in 70% and 89% of patients reaching LDL-C levels of <100mg/dL and 44% and 65% achieving <70mg/dL, respectively, compared to 2% and 0% of placebo subjects, respectively. Favorable reductions in total cholesterol, non-HDL-C, Lp(a) and ApoB were consistent with the reductions in LDL-C. AMG 145 was well tolerated. The most frequent adverse events were nasopharyngitis, injection-site reaction and headache. Amgen did not note its plans for AMG 145.
June 4, 2012
Sanofi and Regeneron Pharmaceuticals released additional results from a phase II trial of SAR236553/REGN727 for the treatment of heterozygous familial hypercholesterolemia (heFH). This randomized, double-blind, placebo-controlled, dose-finding study enrolled 77 subjects with heFH whose LDL-cholesterol levels remained uncontrolled on statin therapy with or without ezetimibe. Subjects were separated into five arms and received either placebo or SAR236553/REGN727 150mg, 200mg or 300mg at four-week intervals, or SAR236553/REGN727 150mg at two-week intervals. Subjects were treated for 12 weeks. Subjects dosed with SAR236553/REGN727 achieved a mean LDL-cholesterol reduction from baseline of 28.9% to 67.9%, compared to 10.7% in patients receiving placebo (p<0.05). In addition, in the most intense dose regimen tested where the greatest LDL-cholesterol reduction was observed (150mg every two weeks), 93.8% of patients achieved LDL-cholesterol levels lower than 100mg/dL (2.59mmol/L), compared to 13.3% of patients on placebo, and 81.3% reached LDL-cholesterol levels lower than 70mg/dL (1.81mmol/L), compared to none on placebo. The drug was well tolerated and the most common adverse events were injection-site reaction. Sanofi and Regeneron intend to initiate a global phase III program with SAR236553/REGN727 in June.
April 2, 2012
Amgen released results from a phase Ib trial of AMG 145 for the treatment of high cholesterol. Data are from 51 subjects who were on low to moderate stable doses of statins. The subjects received AMG 145 every two or four weeks or placebo. The subjects who received AMG 145 every two weeks had mean LDL-C reductions of up to 75% versus placebo at week six (three subcutaneous doses). The subjects who received AMG 145 every four weeks demonstrated up to a 66% reduction in LDL-C at week eight (two subcutaneous doses). A cohort of subjects on high doses of statins who received AMG 145 every two weeks had a mean reduction in LDL-C of up to 63% versus placebo at week six (three subcutaneous doses).
January 9, 2012
Alnylam issued interim results from a phase I trial of ALN-PCS for the treatment of severe hypercholesterolemia. Data are from the first 20 subjects enrolled into the trial. ALN-PCS resulted in a rapid, dose-dependent, and durable silencing of PCSK9 protein levels in plasma of up to 66% relative to baseline, with a statistically significant mean reduction of 60% at day four in the current high dose group of 0.250 mg/kg (p<0.001). ALN-PCS also resulted in dose-dependent reductions in LDL-C of up to 50% relative to baseline, with a statistically significant mean reduction of 39% at day four (p<0.05) at the 0.250 mg/kg dose level. There was also a dose-dependent increase in the proportion of subjects who achieved target levels of LDL-C of less than 100 mg/dL (p<0.05), with 100% of subjects in the two highest dose groups achieving target and a mean LDL-C of 84.0 mg/dL, as compared with 21.4% of subjects achieving target in any other group. There was no significant decrease in HDL-C.
August 9, 2010
Genzyme and Isis reported positive results from two phase III studies of mipomersen for the treatment of hypercholesterolemia. In both trials, the subjects received 200 mg of mipomersen or placebo weekly for 26 weeks. The first trial enrolled 58 subjects with severe hypercholesterolemia who were on a maximally tolerated lipid-lowering regimen. The average LDL-C at baseline was 276 mg/dL. At the end of the treatment period, the average LDL-C level was 175 mg/dL, representing an average LDL-C reduction of 101 mg/dL (36%). The second trial enrolled 158 subjects with hypercholesterolemia on maximally tolerated dosages of statins who were at high risk for coronary heart disease. Enrollment included those with type II diabetes. The average LDL-C at baseline was 123 mg/dL. At the end of the study, the average LDL-C level was 75 mg/dL, representing an average LDL-C reduction of 48 mg/dL (37%). Half of the mipomersen-treated group achieved LDL-C levels of less than 70 mg/dL. Both trials also reached each of three secondary endpoints, statistically significant reductions in apo-B, non-HDL-cholesterol and total cholesterol.
February 15, 2010
Genzyme and ISIS reported positive results from a phase III study of mipomersen for the treatment of heterozygous familial hypercholesterolemia (heFH). This North American, randomized, double-blind, placebo-controlled study enrolled 124 subjects with heFH, pre-existing coronary artery disease and LDL-C levels greater than 100 mg/dL. The subjects received a 200 mg dose of mipomersen or placebo weekly for 26 weeks. The primary endpoint was reached, with a highly statistically significant 28% reduction in LDL-cholesterol after 26 weeks of treatment, compared with an increase of 5% for placebo. Forty-five percent of the mipomersen-treated group achieved LDL-C levels of less than 100 mg/dL. The trial also met each of its three secondary endpoints with statistically significant reductions in apo-B, total cholesterol, and non-HDL-cholesterol. Mipomersen was well tolerated.
November 24, 2008
Daiichi Sankyo issued positive results from a clinical trial of colesevelam HCl for the treatment of pediatrics with heterozygous familial hypercholesterolemia. This 32 week, multi-center, controlled study enrolled 194 pediatric subjects, 10-17 years of age, who were either treatment nave or on stable background statin therapy. The study consisted of an initial four-week, single-blind, placebo run-in, to measure compliance, followed by an eight-week, double-blind period in which subjects were randomized to either placebo, colesevelam HCl 1.875 g/day or colesevelam HCl 3.75 g/day. The eight-week, double-blind period was followed by an 18-week open-label treatment to goal (LDL cholesterol <110 mg/dL) in which all subjects received colesevelam HCl 3.75 g/day. At week eight, subjects who received colesevelam HCl 3.75 g/day showed a significant, placebo-adjusted mean reduction of 13% in LDL cholesterol (p≤0.0001). These were maintained through the 18-week open-label treatment period. The eight-week study period also showed that subjects in the colesevelam HCl 3.75 g/day group demonstrated a clinically and statistically significant, placebo-adjusted mean 6% increase in high density lipoprotein (HDL) (p<0.01). Statistically significant placebo-corrected reductions from baseline in total cholesterol (7%; p<0.01), apolipoprotein B (8%; p<0.01) and non-HDL cholesterol (11%; p≤0.0001), as well as an increase in apolipoprotein A-I (7%; p<0.01) were also observed. Treatment was generally well tolerated.
February 4, 2008
QuatRx issued positive results from two phase I trials of sobetirome for the treatment of elevated low-density lipoprotein (LDL). Both the single and multiple dose studies were of a randomized, double-blind, placebo-controlled design. In the single dose study, thirty two subjects received up to 450 micrograms of sobetirome or placebo. Sobetirome decreased LDL cholesterol levels by up to 22% compared to 2% for the placebo group. The greatest reductions were observed seventy two hours after dosing. In the multiple dose study, twenty four subjects received sobetirome up to 100 micrograms or placebo once a day for two weeks. Sobetirome decreased LDL levels by up to 41% compared to 5% for the placebo group. Based on the results QuatRx plans to move forward with the development of sobetirome.
January 21, 2008
Merck and Schering-Plough reported negative results from a clinical trial of Vytorin for the treatment of Heterozygous Familial Hypercholesterolemia (HeFH). This multinational, randomized, double-blind, active comparator trial, dubbed ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia), enrolled seven hundred and twenty subjects with HeFH. The subjects were randomized to Vytorin (10 mg ezetimibe + 80 mg simvastatin) or simvastatin alone (80 mg) for two years. There was no statistically significant difference between the treatment groups on the primary endpoint, the mean change in the intima-media thickness (IMT), measured at three sites in the carotid arteries. The change from baseline in the mean carotid IMT was 0.0111 mm for the ezetimibe/simvastatin 10/80 mg group versus 0.0058 mm for the simvastatin 80 mg group (p =0.29). In addition, no statistically significant differences were observed in the key secondary imaging endpoints. There was a significant difference in low-density lipoprotein (LDL) cholesterol lowering seen between the treatment groups -- 58% LDL cholesterol lowering at twenty four months on ezetimibe/simvastatin 10/80 mg as compared to 41% at twenty four months on simvastatin 80mg alone, (p<0.01). The overall adverse events profile was similar between the two treatment groups. Additional post-marketing trials are currently underway.
February 13, 2006
Isis Pharmaceuticals has announced positive results of a phase I trial of an oral formulation of ISIS 301012, for the treatment of familial hypercholesterolemia. Pharmacokinetic results yielded 6% oral bioavailability. Preliminary evidence of efficacy was also noted with an average reduction of apoB-100 (the drugs target protein) of 13% at one month compared to placebo (p=0.005), with resultant reductions in low density lipoprotein (LDL) cholesterol (p=0.001). Peak pharmacological efficacy was seen to correlate to maximum drug plasma concentration. Treatment was generally well tolerated, with no drug-related withdrawals; the most common adverse event was mild intermittent gastrointestinal symptoms. This placebo-controlled study enrolled healthy volunteers, who received oral doses of ISIS 301012 or placebo for 1 month.
June 13, 2005
Isis Pharmaceuticals has issued positive results of a phase I trial of ISIS 301012, for the treatment of hypercholesterolemia. Trial data yielded efficacy in treating a number of disease measures, including dose dependent reductions in ApoB-100 (ranging from 30% with the 50 mg dose to 52% for the 400 mg dose), LDL (17% at 50 mg to 48% at 400 mg), and total cholesterol levels (16% at 50 mg to 40% at 400 mg). The 200 mg trial dose achieved statistical significance in all three endpoints, vs. placebo: for ApoB-100, p=0.006; for LDL, p=0.002; and for total cholesterol, p= 0.0006. Reductions in these measures were long-lasting, and maintained through 100 days for some subjects in the 100 mg and 200 mg dosing groups. This placebo-controlled, dose-escalation study enrolled 36 subjects with elevated cholesterol levels, who received a single safety evaluation dose of the drug, a three dose loading regimen, then once-weekly subcutaneous injections of one of four doses of ISIS 301012 (50 mg, 100 mg, 200 mg or 400 mg) for three weeks. These data serve to support initiation of phase II trials in the second half of 2005.
October 25, 2004
deCODE genetics issued positive preliminary results of a phase IIa trial of DG031, their investigational cardioprotective for the prevention of heart attack. Trial data met their primary efficacy endpoint, demonstrating a significant reduction in one or more biomarkers of heart attack, in at-risk patients. This included a significant reduction of leukotriene B4 at all investigational doses, and significant reductions of MPO and sICAM-I at the highest investigational dose, compared with placebo. No serious tolerability concerns were raised, though one myocardial infarction occurred in the active drug group and one sudden death occurred in a subject receiving placebo. This double-blind, placebo-controlled, dose-escalating crossover study enrolled 172 subjects with a history or a genetic predisposition to heart attack.
Liponex has issued preliminary results from a phase I trial of CRD5, for the treatment hypercholesterolemia and atherosclerosis. Data from the trial showed that drug was safe and well tolerated with no adverse reactions reported, meeting their primary endpoint. In addition, secondary efficacy data indicated that the drug showed significant efficacy in both increasing HDL (good) cholesterol (18% over baseline) and reducing LDL (bad) cholesterol (15%-60% from baseline). This open-label study enrolled 56 healthy volunteers, who received CRD5 for two weeks. Based upon these results, Liponex announced plans to initiate phase II trials of CRD5 in 2005.
Vertex Pharmaceuticals reported preliminary results from a phase IIa trial of VX-702, their investigational p38 MAP kinase inhibitor, for the treatment of acute coronary syndrome in patients undergoing percutaneous coronary intervention. Study results indicate that the drug met its primary safety and pharmacokinetic endpoints, with no significant increase in adverse events compared with placebo, and no significant difference in incidence of liver enzyme abnormalities. The drug also met its secondary efficacy endpoints, significantly reducing serum C-reactive protein (CRP) levels up to 48 hours after treatment in all dosing cohorts compared with placebo. This double-blind, placebo-controlled dose escalation study enrolled a total of 45 patients with unstable angina and acute coronary syndrome. Subjects were randomized to receive one of four doses of the drug or placebo once daily for five days, prior to PCI intervention.
September 13, 2004
CEL-SCI announced positive results from a clinical trial investigating Multikine, an immunotherapeutic agent for the treatment of elevated cholesterol. Multikine is a mixture of naturally occurring cytokines including interleukins, interferons, chemokines and colony-stimulating factors. Results showed that treatment with Multikine showed no liver toxicity while achieving reduction in total cholesterol levels. A meta-analysis showed the reduction of total cholesterol following treatment with Multikine to be highly statistically significant (p<0.0001). The drug did not affect the levels of AST/ALT (liver enzymes) nor did it produce any severe adverse effects. Subjects were treated with Multikine for 2 to 24 weeks. The study enrolled 120 subjects and was designed to evaluate multiple doses and different treatment regimens in head and neck cancer. Multikine is also under investigation for the treatment of several types of cancer, including head & neck; this is these are the first data reported for the drug for a cardiological indication. The company is now planning to initiate phase III trials for head and neck cancer.
Lilly and Sankyo have reported positive results of a phase II comparative safety study of CS-747, their investigational anti-platelet agent. Trial data met the study’s primary safety endpoint, and demonstrated CS-747 has a comparable safety profile to the current approved therapy clopidogrel: CS-747 produced significant differences in 30-day-post-treatment bleeding in patients who had undergone coronary artery stent implantation. In addition, the trial found non-significant reductions in the incidence of 30-day-post-treatment major coronary events (including death, re-ischemia, target vessel thrombosis, heart attack or stroke; this was the secondary endpoint). The trial enrolled a total of 904 subjects in the US and Canada, who were randomized to receive one of three regimens of CS-747 or a standard regimen of clopidogrel, all of whom had undergone implantation of a coronary stent to open a blocked artery; following the initial dose, all subjects were followed for 30 days for safety and efficacy observations. Based on these results, the companies announced plans to move forward into phase III testing.
August 16, 2004
Isis Pharmaceuticals reported positive results from a phase I trial investigating ISIS 301012 for the treatment of elevated cholesterol. Results showed that ISIS 301012 produced dose-dependent, rapid and prolonged reductions of apoB-100, a molecular carrier of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) cholesterol, by up to 55%. Data also demonstrated reductions in LDL, VLDL and total cholesterol levels in normal subjects with borderline elevated cholesterol. The placebo-controlled, dose-escalation study will enroll 40 subjects with serum cholesterol levels from 200 to 300 mg/dL. The study is designed to measure the safety and pharmacokinetic profile of ISIS 301012, and its ability to reduce several components of cholesterol. Subjects received a single dose of ISIS 301012 (50 mg to 400mg) then six doses of ISIS 301012 (over 21 days) four weeks later. Results were presented at the 9th Drug Discovery Technology World Congress in Boston.
April 26, 2004
CV Therapeutics reported results from a phase III trial investigating Ranexa (ranolazine), a pFOX inhibitor for the treatment of angina. Results demonstrated a statistically significant increase in symptom-limited exercise duration at trough drug concentrations, the studies primary endpoint. Data showed a statistically significant increase in the time to onset of angina pain during exercise testing and exercise time in subjects receiving Ranexa. Specific dose-related adverse events included dizziness, nausea, asthenia and constipation. The double-blind, placebo-controlled, randomized study, called MARISA, enrolled 191 subjects with angina not receiving any other anti-anginal medications. Subjects receive Ranexa (500, 1000 and 1500 mg) or placebo twice a day. Results were reported in an April issue of the Journal of the American College of Cardiology.
Forbes Medi-Tech reported additional data from a European phase II trial investigating FM-VP4, an analogue of phytostanols for the treatment of high cholesterol. Results showed that FM-VP4 demonstrated a statistically significant dose-response, suggesting that 400 mg/day may be the optimal dose. Data revealed that LDL cholesterol levels might continue to decrease if FM-VP4 was administered for longer than 4 weeks. Analysis also showed a need to examine the effects of timing of FM-VP4 with respect to food intake and efficacy. Complete results are anticipated in June of 2004.
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.
March 8, 2004
Pfizer and The Cleveland Clinic reported positive results from a head-to-head trial comparing atorvastatin with pravastatin, two marketed anti-cholesterol medications. Results showed that he pravastatin-treated subjects demonstrated a 2.7% increase in atherosclerotic plaque, compared to a .4% decrease in atorvastatin-treated subjects. Data showed that subjects intensively treated with atorvastatin reached an LDL-C level of 79 mg/dL, compared with 110 mg/dL in moderately treated pravastatin subjects. The randomized, head-to-head study, called REVERSAL, enrolled 502 subjects with heart disease at 34 sites in the U.S. Subjects received either 40-mg doses of pravastatin or 80-mg doses of atorvastatin for 18 months. The progression of heart disease was measured using intravascular ultrasound. Complete trial results will be published in the March 3rd 2004 issue of the Journal of the American Medical Association.
December 8, 2003
Esperion Therapeutics reported positive results from a phase I trial investigating ETC-1001, a lipid-regulating agent for the treatment of hyperlipidemia. Results showed that the therapy was safe and well tolerated among all subjects. No serious adverse events occurred. The double-blind, placebo-controlled study enrolled 36 healthy subjects and was designed to determine the safety and tolerability of escalating doses of ETC-1001. Subjects took single doses of ETC-1001 over a range of dose levels and were monitored for 72 hours. ETC-1001 was also shown to inhibit the progression of atherosclerosis in pre-clinical studies.
November 10, 2003
Hollis-Eden Pharmaceuticals reported negative preliminary results from a phase II trial investigating HE2200, an immune-regulating hormone for the treatment of dyslipidemia. Results of the study indicated that although HE2200 was well tolerated, it did not have a statistically significant effect on lipids when compared with placebo. Earlier studies had shown that HE2200 reduced cholesterol levels after 3 days of subcutaneous or 5 days of buccal dosing in healthy subjects. The study enrolled 66 subjects with significant dyslipidemia that could not be corrected by strict dietary control. It was designed to evaluate the safety of HE2200 as well as the effect of the compound when given buccally once daily for 28 days.
October 27, 2003
Avant Immunotherapeutics mixed preliminary results from a phase II trial investigating CETi-1, a cholesteryl ester transfer antigen for the treatment of high cholesterol. Results showed that the vaccine was well-tolerated, immunogenic and produced an increase in HDL-cholesterol from baseline in all groups. In addition, the increase in HDL-cholesterol from baseline was statistically significant (8.4%) in the high dose group. Subjects taking statins, however, did not show significant changes in HDL-cholesterol. The placebo controlled, six-month study enrolled 203 subjects who received either placebo or vaccine. The study was designed to investigate the ability of CETi-1 to increase HDL-cholesterol in two groups with and without taking statin treatment.
February 3, 2003
Forbes Medi-Tech reported positive results from a phase I trial investigating FM-VP4, an amphipathic synthetic phytostanols analogue for the treatment of hypercholesterolemia. No serious adverse events were reported. The study consisted of six dosing groups of five healthy males (4 active and 1 placebo) with mild or moderate hypercholesterolemia. Subjects were administered single doses of FM-VP4 ranging from 100 mg to 2000 mg. After receiving treatment, each subject was monitored over a 24-hour period over seven days. FM-VP4 was discovered by extracting plant sterols from wood pulping by-products.
Theratechnologies reported positive results from a phase II trial investigating ThGRF, a growth hormone releasing factor analogue for the treatment of type II diabetes. The results showed the drug was safe and well tolerated with no glycemic control interference reported. The primary endpoint, relative insulin response through glucose tolerance, showed no clinically or statistically significant differences among the treatment groups compared to placebo. Data also showed a dose-dependent increase in the blood levels of IGF-1, a marker of the anabolic effects of ThGRF and a decrease in atherogenic cholesterol levels. At the end of the treatment period, IGF-1 levels increased on average by 32 % (1 mg group) and 67 % (2 mg group). The double blind, randomized, placebo-controlled study enrolled a total of 53 subjects over age 50 with type II diabetes.
March 25, 2002
Phase III trial results indicate that Zetia (ezetimibe) provides additional reductions in LDL-C when co-administered with a statin. All subjects in the "Add-On" trial were diagnosed with hypercholesterolemia, coronary heart disease, and/or multiple risk factors and had not reached their LDL-C goal. Subjects were randomized to receive 10 mg of Zetia or placebo in addition to their current statin dose. Results showed that Zetia reduced LDL-C by an additional 25% when added to the ongoing statin therapy, compared to a 4% reduction with the statin plus placebo. Additionally, Zetia treatment increased HDL-C by an additional 3%, compared to 1% for statin plus placebo, and triglycerides were lowered by an additional 14%, versus 3% for statin plus placebo. Zetia is being developed by Merck and Schering-Plough.