Affymax (AFFY) and Takeda Pharma Announce Hematide/Peginesatide Phase 3 Results
Up)
Affymax, Inc. (Nasdaq: AFFY) and Takeda Global Research & Development Center, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, today announced preliminary top-line results from the Phase 3 clinical program for the investigational drug, Hematide™/peginesatide, for the treatment of anemia in chronic renal failure patients. The primary efficacy endpoint, the mean change in hemoglobin (Hb) from baseline, in each of the four Phase 3 studies (EMERALD 1, EMERALD 2, PEARL 1 and PEARL 2) met the statistical criteria for non-inferiority, when Hematide was compared to epoetin and darbepoetin, in correcting and/or maintaining Hb in the target range. Hematide also met the statistical criterion for non-inferiority in the combined four studies for the adjudicated cardiovascular composite safety endpoint (CSE), which was composed of death, stroke, myocardial infarction, congestive heart failure, unstable angina, and arrhythmia (hazard ratio (HR) 1.06, 90 percent confidence interval (CI) 0.91 – 1.22). The median duration of follow-up for patients on study drug in the four trials was 1.3 years.
In a subgroup analysis of CSE events in the EMERALD studies in maintenance treatment of anemia in dialysis patients, the frequency of CSE events was balanced between Hematide and the comparator (HR 0.95, 90 percent CI 0.79 – 1.13).
A difference in CSE events was noted, however, when a subgroup analysis was conducted in non-dialysis patients. In the PEARL trials, which evaluated correction and maintenance treatment of anemia in non-dialysis patients, the frequency of CSE events was higher in the Hematide group (21.6 percent) versus the comparator (17.1 percent) (HR 1.34, 90 percent CI 1.03 – 1.73).
The Hematide Phase 3 program, which involved 2,609 randomized patients, consisted of four open-label, randomized active-controlled clinical trials in the U.S. and Europe, including two studies in non-dialysis patients (PEARL 1 and 2) and two others in dialysis patients (EMERALD 1 and 2). In all studies, Hematide was dosed once every four weeks while comparator drugs were dosed more frequently according to their product labels. In these studies, epoetin was dosed one-to three-times per week and darbepoetin was dosed every two weeks. The Hb target range was 11-12 g/dL for non-dialysis patients and 10-12 g/dL for those on dialysis.
“Completion of these four Phase 3 studies is a key milestone and we look forward to pre-NDA discussions with the FDA,” said Arlene M. Morris, chief executive officer of Affymax, Inc. “We are continuing to evaluate the data, in particular the non-dialysis studies, and the impact on the timing of an NDA submission.”
“The focus of Takeda and Affymax is patients’ needs, which are paramount in drug development. Together, we are working to bring this treatment option to patients with chronic renal failure and to physicians who treat them,” said Azmi Nabulsi, M.D., M.P.H, president of Takeda Global Research & Development Center.
EMERALD 1 & 2 (Dialysis)
In the EMERALD studies, patients were randomized two to one to receive Hematide or epoetin. The starting dose of Hematide was based on a conversion from the prior epoetin dose.
The primary efficacy endpoint of these two studies was a mean change in Hb between baseline and the evaluation period, which was between weeks 29 and 36 following entry into the study. This endpoint was met in both studies. The secondary endpoints of the two studies were the proportion of patients who received red blood cell (RBC) transfusions and the proportion of patients who maintained Hb within the target range during the evaluation period.
EMERALD 1
Primary Endpoint HematideQ4W Epoetin1-3x/week
Number of patients 524 269
Mean change from baseline in Hb (g/dL) -0.24 -0.09
Treatment difference (CI)* -0.15 (-0.29, -0.01)
* Lower limit of the 95 percent two-sided confidence interval for the difference from epoetin (Hematide – epoetin) met the pre-specified criterion for non-inferiority (lower bound of confidence interval > - 1.0 g/dL)
Regarding the secondary endpoints, the proportion of patients who received RBC transfusions was similar between groups (10.3 percent in the Hematide group and 8.6 percent in the epoetin group). The proportion of patients with a mean Hb within the target range during the evaluation period was statistically significantly lower in the Hematide group (63.0 percent) compared to the epoetin group (71.7 percent).
The mean Hb level during the evaluation period was 11.1 g/dL for Hematide and 11.3 g/dL for epoetin. Serious adverse events (SAEs) occurred in 58 percent of Hematide patients and in 63 percent of epoetin patients.
EMERALD 2
Primary Endpoint HematideQ4W Epoetin1-3x/week
Number of patients 542 273
Mean change from baseline in Hb (g/dL) -0.07 -0.17
Treatment difference (CI)* 0.10 (-0.05, 0.26)
* Lower limit of the 95 percent two-sided confidence interval for the difference from epoetin (Hematide – epoetin) met the pre-specified criterion for non-inferiority (lower bound of confidence interval > - 1.0 g/dL)
Regarding the secondary endpoints, the proportion of patients who received RBC transfusions was similar (7.6 percent in the Hematide group and 9.9 percent in the epoetin group). The proportion of patients with a mean Hb within the target range during the evaluation period was also similar (63.5 percent in the Hematide group vs 65.9 percent in the epoetin group).
The mean Hb level during the evaluation period was 11.1 g/dL for Hematide and 11.1 g/dL for epoetin. SAEs occurred in 49 percent of Hematide patients and in 52 percent of epoetin patients.
PEARL 1 & 2 (Non-dialysis)
In the PEARL studies, patients were randomized into one of three treatment groups: Hematide starting dose of 0.025 mg/kg administered once every four weeks, Hematide starting dose of 0.04 mg/kg administered once every four weeks and darbepoetin starting dose of 0.75 mcg/kg administered every two weeks.
The primary endpoint for these two studies was a mean change in Hb between baseline and the evaluation period, which was between weeks 25 and 36 following entry into the study. This endpoint was met in both studies. The secondary endpoints of the two studies were the proportion of patients who received RBC transfusions and the proportion of patients who responded during the correction and evaluation periods.
Analysis of Cardiovascular Composite Endpoint
The CSE was evaluated in a pooled analysis of all four Phase 3 pivotal trials. The CSE was defined as time to first event, consisting of death from any cause or a cardiovascular event (myocardial infarction, stroke, or a serious adverse event of congestive heart failure, unstable angina, or arrhythmia). The criterion for non-inferiority required the upper limit of the two-sided 90% confidence interval for the estimated HR to be less than 1.3. CSE events were adjudicated by a prospectively-established, independent, blinded Event Review Committee.
For the CSE from the pooled EMERALD and PEARL studies, 22.4 percent of patients in the Hematide group and 21.6 percent of patients in the control group (epoetin or darbepoetin) experienced at least one CSE event. The pre-specified criterion for non-inferiority was met with a HR of 1.06, 90 percent CI (0.91, 1.22).
In a subgroup analysis of dialysis patients (EMERALD studies), 22.8 percent of patients in the Hematide group and 24.4 percent in the epoetin group experienced at least one CSE event, HR 0.95, 90 percent CI (0.79, 1.13).
Of note, in a subgroup analysis of non-dialysis patients (PEARL studies), 21.6 percent of patients receiving Hematide and 17.1 percent of patients receiving darbepoetin experienced at least one CSE event, HR 1.34, 90 percent CI (1.03, 1.73). The HR in the non-dialysis patients was primarily driven by higher rates of death, unstable angina, and arrhythmia events in the Hematide treated patients. The percentages of patients experiencing stroke, myocardial infarction, and congestive heart failure were similar between treatment groups.
Further investigation into these data is ongoing.
In a subgroup analysis of CSE events in the EMERALD studies in maintenance treatment of anemia in dialysis patients, the frequency of CSE events was balanced between Hematide and the comparator (HR 0.95, 90 percent CI 0.79 – 1.13).
A difference in CSE events was noted, however, when a subgroup analysis was conducted in non-dialysis patients. In the PEARL trials, which evaluated correction and maintenance treatment of anemia in non-dialysis patients, the frequency of CSE events was higher in the Hematide group (21.6 percent) versus the comparator (17.1 percent) (HR 1.34, 90 percent CI 1.03 – 1.73).
The Hematide Phase 3 program, which involved 2,609 randomized patients, consisted of four open-label, randomized active-controlled clinical trials in the U.S. and Europe, including two studies in non-dialysis patients (PEARL 1 and 2) and two others in dialysis patients (EMERALD 1 and 2). In all studies, Hematide was dosed once every four weeks while comparator drugs were dosed more frequently according to their product labels. In these studies, epoetin was dosed one-to three-times per week and darbepoetin was dosed every two weeks. The Hb target range was 11-12 g/dL for non-dialysis patients and 10-12 g/dL for those on dialysis.
“Completion of these four Phase 3 studies is a key milestone and we look forward to pre-NDA discussions with the FDA,” said Arlene M. Morris, chief executive officer of Affymax, Inc. “We are continuing to evaluate the data, in particular the non-dialysis studies, and the impact on the timing of an NDA submission.”
“The focus of Takeda and Affymax is patients’ needs, which are paramount in drug development. Together, we are working to bring this treatment option to patients with chronic renal failure and to physicians who treat them,” said Azmi Nabulsi, M.D., M.P.H, president of Takeda Global Research & Development Center.
EMERALD 1 & 2 (Dialysis)
In the EMERALD studies, patients were randomized two to one to receive Hematide or epoetin. The starting dose of Hematide was based on a conversion from the prior epoetin dose.
The primary efficacy endpoint of these two studies was a mean change in Hb between baseline and the evaluation period, which was between weeks 29 and 36 following entry into the study. This endpoint was met in both studies. The secondary endpoints of the two studies were the proportion of patients who received red blood cell (RBC) transfusions and the proportion of patients who maintained Hb within the target range during the evaluation period.
EMERALD 1
Primary Endpoint HematideQ4W Epoetin1-3x/week
Number of patients 524 269
Mean change from baseline in Hb (g/dL) -0.24 -0.09
Treatment difference (CI)* -0.15 (-0.29, -0.01)
* Lower limit of the 95 percent two-sided confidence interval for the difference from epoetin (Hematide – epoetin) met the pre-specified criterion for non-inferiority (lower bound of confidence interval > - 1.0 g/dL)
Regarding the secondary endpoints, the proportion of patients who received RBC transfusions was similar between groups (10.3 percent in the Hematide group and 8.6 percent in the epoetin group). The proportion of patients with a mean Hb within the target range during the evaluation period was statistically significantly lower in the Hematide group (63.0 percent) compared to the epoetin group (71.7 percent).
The mean Hb level during the evaluation period was 11.1 g/dL for Hematide and 11.3 g/dL for epoetin. Serious adverse events (SAEs) occurred in 58 percent of Hematide patients and in 63 percent of epoetin patients.
EMERALD 2
Primary Endpoint HematideQ4W Epoetin1-3x/week
Number of patients 542 273
Mean change from baseline in Hb (g/dL) -0.07 -0.17
Treatment difference (CI)* 0.10 (-0.05, 0.26)
* Lower limit of the 95 percent two-sided confidence interval for the difference from epoetin (Hematide – epoetin) met the pre-specified criterion for non-inferiority (lower bound of confidence interval > - 1.0 g/dL)
Regarding the secondary endpoints, the proportion of patients who received RBC transfusions was similar (7.6 percent in the Hematide group and 9.9 percent in the epoetin group). The proportion of patients with a mean Hb within the target range during the evaluation period was also similar (63.5 percent in the Hematide group vs 65.9 percent in the epoetin group).
The mean Hb level during the evaluation period was 11.1 g/dL for Hematide and 11.1 g/dL for epoetin. SAEs occurred in 49 percent of Hematide patients and in 52 percent of epoetin patients.
PEARL 1 & 2 (Non-dialysis)
In the PEARL studies, patients were randomized into one of three treatment groups: Hematide starting dose of 0.025 mg/kg administered once every four weeks, Hematide starting dose of 0.04 mg/kg administered once every four weeks and darbepoetin starting dose of 0.75 mcg/kg administered every two weeks.
The primary endpoint for these two studies was a mean change in Hb between baseline and the evaluation period, which was between weeks 25 and 36 following entry into the study. This endpoint was met in both studies. The secondary endpoints of the two studies were the proportion of patients who received RBC transfusions and the proportion of patients who responded during the correction and evaluation periods.
Analysis of Cardiovascular Composite Endpoint
The CSE was evaluated in a pooled analysis of all four Phase 3 pivotal trials. The CSE was defined as time to first event, consisting of death from any cause or a cardiovascular event (myocardial infarction, stroke, or a serious adverse event of congestive heart failure, unstable angina, or arrhythmia). The criterion for non-inferiority required the upper limit of the two-sided 90% confidence interval for the estimated HR to be less than 1.3. CSE events were adjudicated by a prospectively-established, independent, blinded Event Review Committee.
For the CSE from the pooled EMERALD and PEARL studies, 22.4 percent of patients in the Hematide group and 21.6 percent of patients in the control group (epoetin or darbepoetin) experienced at least one CSE event. The pre-specified criterion for non-inferiority was met with a HR of 1.06, 90 percent CI (0.91, 1.22).
In a subgroup analysis of dialysis patients (EMERALD studies), 22.8 percent of patients in the Hematide group and 24.4 percent in the epoetin group experienced at least one CSE event, HR 0.95, 90 percent CI (0.79, 1.13).
Of note, in a subgroup analysis of non-dialysis patients (PEARL studies), 21.6 percent of patients receiving Hematide and 17.1 percent of patients receiving darbepoetin experienced at least one CSE event, HR 1.34, 90 percent CI (1.03, 1.73). The HR in the non-dialysis patients was primarily driven by higher rates of death, unstable angina, and arrhythmia events in the Hematide treated patients. The percentages of patients experiencing stroke, myocardial infarction, and congestive heart failure were similar between treatment groups.
Further investigation into these data is ongoing.
You May Also Be Interested In
- Auxilium (AUXL) Files Suit Against Watson (WPI) Over Testim 1% Gel
- Canaccord Genuity Reiterates a 'Buy' on InterMune Inc. (ITMN); Esbriet (pirfenidone) Positive GBA Assessment
- Medivation (MDVN) Submits NDA for Enzalutamide to U.S. FDA
Create E-mail Alert Related Categories
Corporate News, FDASign up for StreetInsider Free!
Receive full access to all new and archived articles, unlimited portfolio tracking, e-mail alerts, custom newswires and RSS feeds - and more!
