November 20, 2017
Boehringer Ingelheim issued results from two new analyses of the phase III RE-VERSE AD study, which evaluated the safety and efficacy of idarucizumab, marketed in the U.S. as Praxbind, in reversing the anticoagulant effect of Pradaxa (dabigatran etexilate mesylate) in patients in diverse emergency situations, including those with acute bleeding or requiring an urgent surgery or procedure, such as an orthopedic, vascular or abdominal procedure. Mortality and thromboembolic event rates for patients with a GI bleed were consistent with the overall findings of RE-VERSE AD. One of the subanalyses focused on patients with GI bleeding, the most common type of bleeding event among patients who were enrolled in the study due to acute bleeding. Of the 137 patients enrolled with a GI bleed, complete reversal of the anticoagulant effect of Pradaxa was observed in more than 95% of patients. The median time to cessation of bleeding post-idarucizumab administration was less than three hours when the location of the GI bleed was known and 6.4 hours when the location was unknown. In the subanalysis, as presented in the abstract, at 90 days, there were low thromboembolic event rates of 5.1% in patients with a GI bleed, compared to 6.3% in non-GI bleed patients. Mortality in the first five days following administration was 6% in patients with a GI bleed, compared to 9% in non-GI bleed patients. At 90 days, mortality rates were 16% and 23%, respectively.
November 28, 2016
Ocular Therapeutix reported results of a phase III trial of Dextenza (dexamethasone insert) 0.4mg for the treatment of post-surgical ocular inflammation and pain. This prospective, multicenter, 1:1 randomized, parallel-arm, double-masked, vehicle-controlled study enrolled 438 patients who were undergoing clear corneal cataract surgery at 21 sites throughout the U.S. The trial successfully met its two primary efficacy endpoints for inflammation and pain, achieving statistically significant differences between the treatment group and the placebo group for the absence of inflammatory cells on day 14 and the absence of pain on day eight, respectively. Fifty-two point three percent of patients treated with Dextenza showed an absence of inflammatory cells in the anterior chamber of the study eye on day 14, compared to 31.1% of those receiving the placebo vehicle control punctum plug (p<0.0001). Seventy-nine point six percent of patients treated with Dextenza reported absence of pain in the study eye on day eight, compared to 61.3% of those receiving the placebo vehicle control punctum plug (p<0.0001). Ocular Therapeutix has submitted an NDA to the FDA.
April 27, 2015
Icon Bioscience issued results from a phase
III trial of IBI-10090 for treatment of inflammation
post cataract surgery. The study was
a prospective, randomized, double-masked,
placebo-controlled, multicenter clinical trial
involving 394 patients consisting of both
men and women aged 40 years and older,
undergoing unilateral cataract surgery by
phacoemulsification with posterior chamber
intraocular lens implantation. Three treatment
arms included placebo and IBI-10090 at 342μg
or 517μg placed into the anterior chamber of
the eye at the conclusion of cataract surgery.
Patients were followed for 90 days postoperatively.
The primary endpoint in the clinical
trial was the percentage of patients achieving
anterior chamber cell (ACC) clearing at day
8, i.e., ACC=0. Secondary outcome measures
included anterior chamber flare (ACF) and
anterior chamber cell + flare (ACCF) clearing in
the study eye. Ocular and non-ocular adverse
events were assessed. In both drug treatment
arms, the percentage of patients with
an ACC=0 grade at day eight was statistically
significant compared to placebo. Specifically,
the percentage of patients with ACC clearing
at day eight was 63.1% and 66% in the 342μg
and 517μg treatment groups, respectively, (P<0.001) compared to 25% in the placebo group.
The percentage of patients with ACF clearing
at day eight was 92.4%, and 89.1%, respectively,
in the 342μg and 517μg treatment groups
(P<0.001) compared to 63.8% in the placebo
group. The percentage of patients with ACCF
clearing at day eight was 63.1% and 67.3%
in the 342μg and 517μg treatment groups,
respectively, (P<0.001) compared to 33.8% in
the placebo group. Additionally, no ocular serious
adverse events were reported up to day 90
and adverse events among the three groups
April 20, 2015
Kala Pharmaceuticals reported results of
a phase III study of KPI-121 for the treatment
of inflammation and pain in patients
who had undergone cataract surgery. The
multicenter, randomized, double-masked,
vehicle-controlled, parallel-group trial in
380 patients was designed to evaluate two
dosing regimens of KPI-121 ophthalmic suspension
v. vehicle. Patients were randomized
to receive either 0.25% KPI-121 four times
daily, 1% KPI-121 two times daily or their
corresponding vehicles administered for two
weeks. At day eight, statistically significant
differences favoring KPI-121 were achieved
for the primary endpoint of complete resolution
of inflammation with both 1% KPI-121
dosed twice a day (p=0.0024) and 0.25%
KPI-121 dosed four times a day (p<0.0001).
Complete resolution of ocular pain by day
eight (also a primary endpoint) was achieved
for 1% KPI-121 dosed twice a day (p=0.0019)
and 0.25% KPI-121 dosed four times a day
(p=0.0003). KPI-121 achieved all primary efficacy
endpoints and was generally well-tolerated,
with no significant treatment-related
safety findings observed during the course
of the trial.
Ocular Therapeutix issued results from
the second of two phase III trials of OTX-DP
(Sustained Release Dexamethasone, 0.4mg),
for the treatment of ocular inflammation
and pain following cataract surgery. The
randomized, parallel-arm, double-masked,
vehicle-controlled trials were completed
with a total of 487 patients (247 patients in
the first phase III trial and 240 patients in the
second phase III trial) undergoing unilateral
clear corneal cataract surgery. Patients were
randomized 2:1 to receive either OTX-DP
or a placebo vehicle control punctum plug
without active drug. 77.5% of patients
receiving OTX-DP reported an absence of
pain in the study eye on day eight following
insertion of the drug product, compared to
58.8% of those receiving placebo vehicle
control punctum plug, a difference which
was statistically significant (p=0.0025).
39.4% of OTX-DP-treated patients showed
an absence of inflammatory cells in the
anterior chamber of the study eye on day 14
following drug product insertion, compared
to 31.3% of those receiving placebo vehicle
control punctum plug, a difference which
was not statistically significant (p=0.2182).
The company examined the aggregate result
on a post-hoc basis of the absence and very
minimal presence of inflammatory cells
(defined as zero and 0.5 on a scale of zero to
4) and the difference between the treatment
and placebo groups was found to be highly
significant (66.3% in the treatment group
and 42.5% in the placebo group, p=0.0004).
There were no ocular or treatment-related
serious adverse events in the OTX-DP treatment
group in either trials.
March 23, 2015
CSL Behring issued results of a phase
III study of Kcentra for the urgent reversal
of acquired coagulation factor deficiency
induced by vitamin K antagonist (VKA) therapy
in adult patients needing an urgent surgery or
invasive procedure. Results of the multicenter,
open-label, phase IIIb randomized trial showed
in 168 evaluable patients, 90% of patients
treated with Kcentra achieved effective hemostasis,
compared to 75% of patients treated
with plasma. Additionally, INR reduction to
<=1.3 at 30 minutes after the end of infusion
was achieved in 55% of patients treated with
Kcentra v. 10% of patients treated with plasma.
Incidences of adverse events, serious adverse
events, thromboembolic events and deaths
were similar between the Kcentra and plasma
groups. In post-hoc analysis, the median time
from start of infusion to start of urgent surgical
procedure was shorter in the Kcentra group
(3.6 hours [IQR 1.9-10.8]) than in the plasma
group (8.5 hours [IQR 2.8-18.7]); (p=0.0098).
Ocular Therapeutix reported results
of a phase III study of OTX-DP (Sustained
Release Dexamethasone) for ocular inflammation
and pain following cataract surgery.
The multicenter, randomized, parallel-arm,
double-masked, vehicle-controlled study
enrolled 247 patients randomized 2:1 to
receive either OTX-DP or a placebo vehicle
control punctum plug without active drug.
33.7% of OTX-DP-treated patients showed
an absence of inflammatory cells in the
anterior chamber of the study eye on day 14
following drug product insertion, compared
to 14.6% of those receiving placebo
vehicle control punctum plug (p=0.0015).
In addition, 76.1% of patients receiving
OTX-DP reported absence of pain in the
study eye on day 8 following insertion of the
drug product, compared to 36.1% of those
receiving placebo vehicle control punctum
plug (p<0.0001). Ocular is continuing to
analyze the safety findings from the clinical
trial. The company is on track to submit an
NDA to the FDA for OTX-DP for post-surgical
ocular inflammation and pain in the second
quarter of 2015.
December 22, 2014
Trevena released results from its randomized,
double-blind, placebo- and active-controlled
phase II trial of TRV130 in
moderate-to-severe postoperative acute
pain. Doses of 2mg and 3mg of TRV130 at
three-hour intervals achieved a statistically
significant reduction in pain intensity difference
from placebo over 48 hours, measured
as the time-weighted average change in
pain score (TWA0-48). At 2mg, TRV130 reduced
average pain score (LS mean change
in TWA0-48) by 1.4 points (p=0.0024 v. placebo;
all p-values 1-sided). At 3mg, TRV130
reduced LS mean TWA0-48 by 2.4 points
(p<0.0001 v. placebo). TRV130 achieved a
reduction in mean pain intensity of up to
approximately six points, with notable efficacy
at five minutes, the first pain intensity
assessment after dosing. Over 48 hours, 3mg
of TRV130 at three-hour intervals achieved
a statistically significant reduction in pain
intensity difference from 4mg morphine
at four-hour intervals, reducing average
pain score (LS mean change in TWA0-48)
by one point v. morphine (p=0.014). When
study pain was most severe, during the first
three hours after the initial dose, TRV130
at 1mg, 2mg and 3mg showed a statistically
significant reduction in pain (TWA0-3)
v. placebo (LS mean change -1.0, -2.4, and
-3 respectively; p=0.021, p<0.0001 and
p<0.0001, respectively). More patients
reported statistically greater peak pain relief
during the first dosing period for 2mg and
3mg TRV130 compared to 4mg morphine
(p=0.005 and p<0.0001 for TRV130 2mg and
3mg v. morphine, respectively). A phase III
study is planned.
December 8, 2014
Portola Pharmaceuticals, Bristol-Myers
Squibb and Pfizer issued results of a phase
III study of andexanet alfa. The randomized,
study is evaluating the safety and efficacy of
andexanet alfa in reversing Eliquis-induced
anticoagulation in older healthy volunteers
ages 50-75. Thirty-three healthy volunteers
(ages 50-73) were given Eliquis 5mg twice
daily for four days and then randomized in a
3:1 ratio to andexanet alfa administered as a
400mg IV bolus (n=24) or to placebo (n=9).
Andexanet alfa produced rapid and nearly
complete reversal (by approximately 94%, p
value < 0.0001) of the anticoagulant effect of
Eliquis. Every subject treated with andexanet
alfa had between 90% and 96% reversal of
the anticoagulant activity of Eliquis. In this
study, no serious adverse events, thrombotic
events or antibodies to Factor X or Xa were
reported following andexanet alfa administration.
Mild infusion reaction was reported in
November 11, 2013
Cara Therapeutics issued results of a phase II trial of I.V. CR845 for the treatment of acute pain. The randomized, doubleblind, placebo-controlled trial of I.V. CR845 (0.005mg/kg/dose) enrolled 51 women and men undergoing a primary unilateral first-metatarsal bunionectomy surgery in the U.S. Repeat dosing of I.V. CR845 over 48 hours post-surgery provided statistically greater pain reduction than placebo at both the 24- and 48-hour time points following initiation of treatment, as assessed using the FDA recommended endpoint, the Summed Pain Intensity Difference (SPID). The I.V. CR845 treatment arm met the trial’s primary endpoint of a statistically significant reduction in pain intensity, as measured by the SPID score, over the initial 24-hour time period (SPID0-24; p<0.05) compared to placebo. The I.V. CR845 treatment arm also met the secondary endpoint of a statistical reduction in pain intensity over the entire 48-hour dosing period (SPID0-48; p<0.025). In addition, I.V. CR845 treatment resulted in a statistically significant reduction in the incidence of opioid-related adverse events of nausea and vomiting (by 60% and 80%, respectively; p<0.05) compared to placebo during the 48-hour treatment period.
October 13, 2008
OMRIX reported positive interim results from a phase II trial of Evicel, a Patch for the treatment of mild to moderate bleeding during surgery. This randomized, controlled study planned to enroll up to 210 subjects in the United States who were treated with Evicel or Surgicel, the current standard of care. To date 90 subjects have been enrolled and treated. Evicel was superior to Surgicel in the primary efficacy endpoint, which measured the proportion of subjects achieving hemostatic success at 4 minutes after randomization with no re-bleeding requiring treatment during a subsequent 6-minute observation period. In accordance with the study protocol, since superiority was established, randomization has been stopped and additional non-randomized subjects are undergoing enrollment and treatment with Evicel.
August 18, 2008
Nuvelo issued positive results from a phase Ib trial of NU172 as a potential short-acting anticoagulant during medical procedures. This single center study enrolled 24 healthy male subjects who were placed into four dosing cohorts. Each cohort received a 2 mg/kg bolus dose followed by escalating infusion doses of NU172 for four hours. In all four cohorts, NU172 produced dose-dependent increases in anticoagulation, measured by activated clotting time (ACT), prothrombin time (PT) and activated partial thromboplastin time (aPTT). The highest infusion dose rate tested, 6.0 mg/kg/hr, resulted in an average ACT per subject ranging from 373 to 414 seconds and an increase of approximately three times baseline. Average PT values per subject ranged from 56 to 92 seconds and had an increase of approximately five times baseline. Average aPTT values per subject ranged from 130 to 178 seconds and had an increase of approximately five times baseline. These measurements remained stable throughout the four-hour infusion. Once the infusion ended, the coagulation parameters showed a rapid return toward baseline. NU172 was well-tolerated with no serious adverse events. Based on the results, Nuvelo plans to commence phase II studies in the fourth quarter of 2008 or the first quarter of 2009.
September 11, 2006
Zymogenetics issued positive results from a phase III trial of rhThrombin for the treatment of blood loss during surgery. This multiple site, randomized, double-blind, controlled trial enrolled 400 subjects undergoing surgery. Subjects were randomized in a 1:1 ratio to receive rhThrombin (1000 U/mL) or bovine thrombin (1000 U/mL). During the surgical procedure subjects were treated with one of the two study drugs, in combination with an absorbable gelatin sponge, at appropriate bleeding evaluation sites. The primary outcome was time to hemostasis when compared to currently approved bovine-derived thrombin, measured by incidence of hemostasis within 10 minutes. The trial met the primary endpoints, with hemostasis occurring within 10 minutes in both treatment groups. Secondary endpoints were met as well with adverse effects comparable between the two groups and the rate of antibody formation at 1.5% in the rhThrombin group, versus 22% for those treated with the bovine thrombin product (p < 0.0001). ZymoGenetics plans to submit a Biologics Licensing Application for rhThrombin to the FDA in late 2006.
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.
December 12, 2005
Medicure has announced positive results of a phase II trial, dubbed MEND-CABG, of MC-1, for the treatment of acute cardiovascular events following coronary artery bypass graft (CABG) surgery. The drug produced significant efficacy in the primary composite efficacy endpoint, significantly reducing incidence of death, non-fatal myocardial infarction (peak CK-MB >/= 100ng/ml) and non-fatal stroke, at a dose of 250 mg, vs. placebo (-37.2%; p=0.028). Additional efficacy was noted in reduction of myocardial infarction (peak CK-MB >/= 100ng/ml) alone, vs. placebo (-46.9%; p=0.008); and in the rate of physician diagnosed myocardial infarction (-78.7%; p=0.0065). The 250 mg dose produced superior efficacy to the 750 mg dose, and neither dose group yielded significant efficacy in the composite endpoint when it included myocardial infarctions with peak CK-MB >/= 50ng/ml. This double blind, parallel group, randomized, placebo-controlled study enrolled 901 CABG patients across 42 sites in Canada and the US, who received one of two daily doses of MC-1 (250 mg or 750 mg) or placebo for 30 days. Based on these results, the company announced plans to move forward with phase III studies of the drug.
December 5, 2005
Alexion and Procter & Gamble announced negative preliminary results of a phase III study, dubbed PRIMO-CABG2, of pexelizumab, for the prevention of myocardial infarction following coronary artery bypass graft (CABG) surgery. Trial data demonstrated a positive trend, but failed to reach statistical significance, in the primary endpoint of reducing the combined incidence of nonfatal myocardial infarction or death through 30 days in moderate-to-high risk patients, compared to placebo. This randomized, double-blind, placebo controlled, parallel assignment study enrolled 4,250 subjects across 250 sites worldwide. The company announced that they were assessing the impact of these results on their other ongoing phase III studies, and full results of PRIMO-CABG2 were to be released in the near future at a major medical conference.
November 28, 2005
AstraZeneca reported positive results of their phase IIb DISPERSE2 trial of AZD6140, their investigational platelet-aggregation inhibitor for the treatment of acute coronary syndromes (ACS). Primary safety data indicated comparable rates of bleeding events for low- and high-dose treatment groups and a control group receiving the approved drug clopidogrel at the end of the treatment period: 10.2% of subjects in each of the two treatment groups experienced bleeds of any severity, vs. 9.2% for the approved drug. Incidence of major bleed events were 7.8% and 6.2% for low- and high-dose AZD6140 groups respectively, vs. 8.0% for the approved drug. Finally, data from an interim 4-week analysis indicated all-severity bleed rates of 9.6%, 7.7% and 8.0%, respectively. This double-blind, parallel group, randomized, dose-ranging study enrolled 990 ACS patients, who received one of two doses of AZD6140 (90 or 180 mg, twice daily) or a standard dose of clopidogrel (75 mg once daily) for 12 weeks.
Corgentech announced negative results of a phase III trial, dubbed PREVENT IV, of edifoligide for the prevention of graft failure in coronary artery bypass graft (CABG) surgery. Trial data failed to significantly reduce the number of patients with one or more grafts at least 75% blocked at 1 year, the trial’s primary endpoint: 45.2% of patients who received the drug had 75% blockage, compared to 46.3% for the control group. Further, no difference was noted in the total number of 75%-occluded graft veins between edifoligide (28.5% of grafts) and control. (29.7% of grafts) groups. This randomized, double-blind, placebo-controlled trial enrolled 3,014 CABG patients across 107 US sites, each of whom had received at least two venous grafts. Further development of edifoligide for this indication was not planned.
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.
August 29, 2005
ZymoGenetics reported aggregate results of four-phase II trials of their recombinant human Thrombin (rhThrombin) being investigated to control bleeding during surgery. Combined results showed product appeared to be safe and well tolerated, with a favorable immunogenicity profile. The trial enrolled 130 subjects undergoing various procedures including spinal surgery, liver section, peripheral artery bypass, or arteriovenous graft construction. The results were presented at The International Society on Thrombosis and Haemostasis annual meeting in Sydney, Australia. The company also announced it is finalizing its plans for a phase III pivotal trial for late 2005.
June 27, 2005
ZymoGenetics reported positive results of a pair of phase II trials of rhThrombin (recombinant human thrombin) for use as a surgical homeostat. The drug was shown to be efficacious in promoting homeostasis, with 90% of bleeding sites treated with rhThrombin achieving homeostasis within 10 minutes, vs. 74% for placebo. Average time to homeostasis was 27% lower for rhThrombin treated subjects. Furthermore, only 2.7% of treated subjects (n=1) demonstrated antibody response against the drug, vs. over 40% for bovine thrombin. These randomized, double-blinded trials enrolled a total of 60 patients undergoing either arteriovenous grafting surgery or peripheral artery bypass surgery, who were treated with either rhThrombin- or placebo-soaked sponges at bleeding sites during the surgery. ZymoGenetics announced plans initiate pivotal trials of rhThrombin during the second half of 2005.