Adverse Effects, Drugs
April 13, 2015
Portola Pharmaceuticals reported results
from the second part of the phase III study of
andexanet alfa with the Factor Xa inhibitor
Eliquis (apixaban) in healthy volunteers. Andexanet
alfa, a FDA-designated Breakthrough
Therapy, was administered as an intravenous
(IV) bolus followed by a continuous two-hour
infusion to sustain the reversal of anti-coagulation
activity. The randomized, double-blind,
placebo-controlled study enrolled 31 healthy
volunteers given apixaban 5mg twice daily for
four days and then randomized in a 3:1 ratio
to andexanet alfa administered as a 400mg
IV bolus followed by a continuous infusion of
4mg/min for 120 minutes (n=23) or to placebo
(n=8). Two to five minutes after completion of
a bolus dose of andexanet alfa, the anticoagulant
activity of apixaban was reversed by
approximately 94% (p<0.0001) compared
with placebo as measured by anti-Factor Xa
activity. Every subject treated with andexanet
alfa had between 90% and 96% reversal of the
anticoagulant activity of apixaban. No serious
adverse events, thrombotic events or antibodies
to Factor X or Xa were reported. Portola
plans to submit data from the study, and initial
data from a phase IV study, as part of its BLA
to the FDA under an Accelerated Approval
pathway by the end of 2015.
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).
March 16, 2015
Portola Pharmaceuticals issued results
of a phase III study of andexanet alfa in
healthy volunteers. The randomized, doubleblind,
placebo-controlled study evaluated
andexanet alfa in reversing XARELTO-induced
anticoagulation in healthy volunteers ages
50 to 75. 41 healthy volunteers were given
XARELTO 20mg once daily for four days
to steady state. They were then randomized
in a 2:1 ratio to receive at Cmax either
andexanet alfa administered as an 800mg
IV bolus (n=27) or placebo (n=14). Results
showed, for the primary endpoint, andexanet
alfa reduced the anti-Factor Xa activity of
rivaroxaban from baseline to nadir by >90%,
a highly significant difference (p<0.0001).
Significantly more andexanet alfa subjects
(26 of 27) than placebo subjects (zero) had a
90% or greater reduction in anti-Factor Xa activity
from baseline to nadir (p<0.0001). The
free (unbound) XARELTO concentration from
baseline to nadir was reduced significantly
by andexanet alfa compared with placebo
(p<0.0001). ETP significantly increased from
baseline to peak in andexanet alfa subjects
compared with placebo subjects (p<0.0001).
26 of 27 andexanet alfa subjects returned to
the normal range of thrombin generation
within 10 minutes of the end of the bolus
administration. In the study, andexanet alfa
was well-tolerated. There were no serious
or severe adverse events, no thrombotic
events and no antibodies to Factor X or Xa
were observed. The company plans to submit
these data as part of a BLA to the FDA by the
end of 2015.
April 14, 2014
Collegium Pharmaceutical reported results
of a phase II study evaluating the effect of
physical manipulation by crushing Oxycodone
DETERx compared with reformulated Oxy-
Contin. The objective was to assess pharmacokinetics
of Oxycodone DETERx when the
capsule was taken intact after oral administration
compared with opening the capsule and
crushing the capsule contents (microspheres)
prior to oral administration. These treatments
were compared with OxyContin intact,
OxyContin crushed and an immediate-release
(IR) oxycodone tablet formulation crushed in
naltrexone-blocked, healthy subjects (n=42).
The study was an open label, randomized,
active-controlled, five-treatment, five-period,
cross-over comparison design. Crushed Oxycodone
DETERx capsule contents (microspheres)
(Cmax = 62.9ng/mL) were bioequivalent based
upon Cmax and AUC to intact Oxycodone
DETERx capsules) (Cmax = 67.5ng/mL) with
similar Tmax demonstrating that crushing
the contents of Oxycodone DETERx capsules
did not alter the pharmacokinetics. Crushed
OxyContin tablets (Cmax = 78.4ng/mL) were
bioequivalent based upon Cmax and AUC to
crushed IR tablets (Cmax = 79.4ng/mL), demonstrating
that crushing OxyContin compromised
the integrity of the time-release formulation,
transforming the drug-release profile from
an ER profile to an IR profile. The mean Abuse
Quotient (“AQ” = Cmax/Tmax) value for crushed
Oxycodone DETERx was lower than that of
Oxycodone DETERx intact. The AQ for crushed
OxyContin was approximately four times
higher than the AQ value for OxyContin intact
and similar to the crushed oxycodone IR tablets.
The product’s abuse-deterrent characteristics
are being evaluated in phase III trials, which
have completed enrollment. The company is on
track to file an NDA in Q4 of this year.
April 9, 2012
Ventria Bioscience issued results from a phase II trial of VEN100, human recombinant lactoferrin, for the treatment of antibiotic-associated diarrhea. This randomized, double-blind, placebo-controlled study enrolled 30 high-risk subjects taking antibiotics. The subjects received VEN100 or placebo for eight weeks. The results showed a 52% relative risk reduction and a 47.9% absolute risk reduction in the incidence of diarrhea in the placebo versus VEN100 treatment groups (92.3% versus 44.4%, respectively; P≡0.023). VEN100 was safe and well tolerated, with no observed adverse events in the study.
August 22, 2011
Adolor reported results from two phase II trials of ADL5945 for chronic non-cancer opioid-induced constipation. The primary endpoint for both studies was the change from baseline in the weekly average of spontaneous bowel movements (SBMs) during treatment. The key secondary endpoint was responder analysis, with responders defined as the subjects who achieved an average weekly frequency of at least three SBMs and an increase of at least one SBM above baseline. Study 242 enrolled approximately 120 subjects who received ADL5945 (0.10mg or 0.25mg) given twice daily (BID) or placebo over a four week period. Statistical significance (p≡0.0003) was achieved for the primary endpoint in the 0.25 mg BID dose group. Statistical significance (p≡ 0.005) also was achieved in the 0.25 mg BID dose group for the secondary endpoint, with a 56% response rate for the active arm and a 26% response rate for the placebo arm. Study 243 enrolled approximately 80 subjects who received a single dose of 0.25 mg once daily or placebo over four weeks. Statistical significance (p≡0.01) was achieved for the primary endpoint. For the secondary endpoint: while the proportion of responders was higher in the 0.25 mg treatment group (42.5% vs. 29.3% in placebo), statistical significance was not achieved.
February 21, 2011
Alkermes reported preliminary results from a phase II trial of ALKS-37 for the treatment of opioid-induced bowel dysfunction (OBD). This randomized, double-blind, placebo-controlled, multi-dose study enrolled 87 subjects experiencing OBD during treatment with opioids for chronic, non-cancer pain. The subjects received placebo or escalating doses of oral ALKS 37 once daily (1-100 mg) for two weeks. The primary efficacy endpoints were the change in average number of spontaneous bowel movements (SBMs) per week from baseline and the change in average number of complete SBMs per week from baseline. The two highest doses tested (30 mg and 100 mg once daily) demonstrated a statistically significant increase in the number of SBMs compared to placebo. Subjects in the 100 mg arm the mean change from baseline in the average number of SBMs per week of 4.6 versus 0.7 in the placebo group (p≡0.003), or a net increase of 3.9 SBMs over placebo. The 100 mg dose also showed a statistically significant increase in the average number of CSBMs per week from compared to placebo. The mean change from baseline in the average number of CSBMs per week was 3.6 versus 0.8 in the placebo group (p≡0.006), or a net increase of 2.8 CSBMs over placebo. There was no reversal of analgesia.
November 1, 2010
Theravance released positive results from a phase II trial of TD-1211 for opioid-induced constipation. This U.S.-based, randomized, double-blind, placebo-controlled, dose-escalation study enrolled 70 subjects experiencing constipation while receiving chronic opioid therapy. The subjects received TD-1211 (0.25 mg, 0.75 mg, 2 mg, 5 mg, and 10 mg) or placebo administered orally once-daily in addition to their opioid treatment for a two-week treatment period. The primary efficacy endpoint was the change from baseline in average number of spontaneous bowel movements (SBMs) per week over the treatment period. The two highest doses of TD-1211 demonstrated a statistically significant increase in average SBMs per week of 3.2 SBMs per week and 4.9 SBMs per week, respectively. Median time to first SBM was 28.7 hours for placebo compared with 8.6 hours for 5 mg and 3.6 hours for 10 mg of TD-1211. TD-1211 was generally well tolerated.
April 12, 2010
SciClone reported positive results from a phase II trial of SCV-07 for the prevention of severe oral mucositis (OM). This U.S.-based, randomized, double-blind, placebo-controlled study enrolled 59 subjects receiving radio-chemotherapy for the treatment of head and neck cancer. The subjects received either placebo, SCV-07 at a dose of 0.02 mg/kg, or SCV-07 at a dose of 0.1 mg/kg. The treatment period was approximately seven weeks, with a follow-up visit approximately 30 days following the last day of radiation therapy. The primary efficacy endpoint was delay of onset of severe OM. The subjects who received the higher dose (0.1 mg/kg) of SCV-07 showed a trend towards delay to onset. Those in the low dose treatment arm appeared to do worse than placebo, suggesting a dose-related treatment effect. SCV-07 was safe and well tolerated with no drug-related serious adverse events reported.
November 2, 2009
Nektar issued positive results from a phase II trial of NKTR-118 for the treatment of opioid induced constipation. This multi-center, randomized, placebo-controlled, dose-escalation trial enrolled 208 subjects who were being treated with opiates for moderate to severe pain. The subjects received placebo or one of three different doses of NKTR-118 (5, 25 or 50 mg) given as a single daily oral dose for a treatment period of four weeks, in addition to their opioid therapy. The primary endpoint was increase from baseline in spontaneous bowel movements (SBMs) per week. Both the 25 and 50mg dose cohorts reached the endpoints with statistical significance. The mean change from baseline in SBMs per week for the 25 mg NKTR-118 cohort was 3.6 versus 1.9 in the placebo group (p≡0.002). Subjects receiving 50 mg NKTR-118 had a mean change from baseline in SBMs per week of 4.4 versus 1.9 in the placebo group (p≡0.0001). The increase from baseline in SBMs versus placebo averaged over the four-week treatment period was significant for both the 25 mg (p≡0.002) and 50 mg (p<0.0001) dose groups. There was also a statistically significant difference in median time to first SBM for subjects the 25 mg and 50 mg dose cohorts as compared to placebo. Median time to first SBM for the 25 mg dose cohort was 6.6 hours as compared to placebo which was 48.6 hours (p≡0.001), and for the 50 mg dose cohort, median time to first SBM was 2.9 hours as compared to placebo, which was 44.9 hours (p<0.002). There was no apparent reversal of opioid-mediated analgesia with any of the NKTR-118 dose groups.
July 27, 2009
Sucampo and Takeda reported positive results from two phase III trials of lubiprostone for the management of opioid-induced bowel dysfunction (OBD) in subjects with chronic, non-cancer pain. These identical 12-week, double-blind, placebo-controlled studies, OBD0631 and OBD0632, enrolled 875 subjects in the US and Canada. The subjects received placebo or one 24-mcg gel capsule of lubiprostone twice a day for 12 weeks, along with different opioid pain medications. All subjects had fewer than three spontaneous bowel movements (SBMs) per week at baseline. In study OBD0631, the primary endpoint of a statistically significant change from baseline in the frequency of SBMs at Week 8 of treatment was met when lubiprostone was compared to placebo. The increase in the frequency of SBMs in the lubiprostone arm went from a baseline of 1.42 to 4.54 SBMs at Week 8. Statistical significance was also achieved for eight of the twelve secondary endpoints, including key symptoms associated with OBD. Study OBD0632 did not achieve statistical significance for the same primary endpoint. Statistically significant improvements with lubiprostone were achieved for two of the secondary endpoints and positive trends were observed in four of the other secondary endpoints. There was a high rate of response in the placebo arm of the 632 trial. Approximately 58% of subjects treated with placebo experienced more than three SBMs per week during each week of the trial. Treatment was well tolerated and the adverse event profile was similar between the active and placebo arms.
July 13, 2009
Sucampo issued positive results from a phase II trial of cobiprostone for the prevention of gastric ulcers and other gastrointestinal injuries associated with non-steroidal anti-inflammatory drugs (NSAIDs). This 12-week, double-blinded, randomized, dose-ranging and placebo-controlled study enrolled 124 subjects in the US. All the subjects received 500 mg of naproxen twice a day. There were four treatment cohorts: one cohort received placebo while the other three cohorts received 18 mcg of cobiprostone either once, twice or three times a day (daily totals of 18, 36 or 54 mcg, respectively). The primary endpoint was a reduction in the incidence of ulcers at week 12. The subjects receiving the 54 mcg dose experienced a 50.0% reduction in the overall incidence of gastric ulcers when compared to the placebo arm. Cobiprostone also resulted in an overall statistically significant reduction in the number of gastric erosions through the treatment period of twelve weeks compared to placebo. The reduction of gastric erosions through Week 12 was dose dependent, with 36 mcg and 54 mcg demonstrating statistical significance. The time-to-onset of all ulcer or erosion development was delayed in the cobiprostone cohorts with overall statistical significance across the 12 week treatment period. Treatment was well tolerated.
May 18, 2009
Progenics released positive results from a phase III trial of Relistor (methylnaltrexone) for the treatment of opioid-induced constipation in patients with chronic, non-cancer pain. This doubled blind, randomized, placebo controlled study enrolled 468 subjects on stable doses of opioids and experiencing less than three bowel movements per week. The subjects received subcutaneous methylnaltrexone 12 mg either once daily (QD) or once every other day (QOD) or placebo for four weeks. The co-primary endpoints were reached. Subjects taking methylnaltrexone experienced rescue-free bowel movements within four hours of the first dose significantly more frequently than those taking placebo (34.2% versus 9.9%, P<0.001). In addition, the percentage of all active doses resulting in laxation within four hours was significantly greater than placebo for each of the methylnaltrexone treatment groups (30.2% versus 9.3% for methylnaltrexone versus placebo, QOD, and 28.9% versus 9.4% for methylnaltrexone versus placebo, QD, respectively, P<0.001). Key secondary end points of the study, time to first rescue free bowel movements (RFBM) after the first injection and the average increase in weekly number of RFBMs from baseline, were both statistically significant relative to placebo. Treatment was generally well tolerated.
March 9, 2009
Nektar Therapeutics released positive results from a phase II trial of NKTR-118 for the treatment of opioid-induced constipation (OIC). This international, multi-center, randomized, double-blind, dose-escalation, placebo-controlled trial enrolled 208 subjects who were being treated with opiates for moderate to severe pain. The subjects received placebo or one of three different dose cohorts (5 mg, 25 mg, and 50 mg given as a single daily oral dose) for a treatment period of four weeks. The primary endpoint was a change in spontaneous bowel movements (SBMs) from baseline to after the first week of NKTR-118 treatment. The primary endpoint was reached with statistical significance in both the 25 mg and 50 mg cohorts versus placebo. In the 25 mg dose cohort, subjects had an average of 5.1 SBMs during the first week of treatment as compared to 1.5 SBMs per week during the baseline period. Subjects in the 50 mg dose cohort had an average of 5.7 SBMs during the first week of treatment versus 1.6 SBMs per week during the baseline period. The increase in SBMs versus placebo was maintained over the 28-day treatment period (p<0.01). Secondary endpoints were also reached; there was no reversal of analgesia as measured by a change in pain Numerical Rating Scale and no increase in opiate use. NKTR-118 was well tolerated. Based on the results, Nektar plans to development into phase III trials.