Post by spiro on Sept 9, 2013 14:59:01 GMT -5
Wow, talk about weak results and this was only a Phase 2 study only involving type 1's.
Highlights
Compared to Humalog(R), BIOD-123 demonstrated:
Achievement of primary efficacy endpoint; demonstration of non-inferiority in change from baseline HbA1c
Comparable weight gain, mean hypoglycemia event rates and postprandial glucose excursions over the entire treatment period with some notable trends in favor of BIOD-123 in weight gain during the stable dosing period, median hypoglycemia event rates and postprandial glucose excursions to a liquid meal challenge test
Comparable safety and adverse event profiles with the exception of an increased frequency of injection site pain associated with BIOD-123 which appears to be clinically minor, was short-lived and did not result in patient dropouts
Dr. Alan Krasner, chief medical officer of Biodel, stated: "BIOD-123 has passed the first and most critical test—showing that HbA1c non-inferiority can be achieved in a multi-dose outpatient setting. This study provides a rich database which will be used to explore how two insulins with distinct pharmacodynamic profiles can influence a number of important clinical outcomes. Continued analysis of this database will be invaluable in our development of BIOD-123 and other meal-time insulin candidates."
Dr. Errol De Souza, president and chief executive officer of Biodel, stated: "The establishment of non-inferiority in HbA1c of BIOD-123 versus Humalog(R) in this study gives us a high level of confidence that BIOD-123 could achieve this primary endpoint for FDA approval in larger pivotal studies. We look forward to completing the full analysis of the results, sharing the data with experts and potential partners to obtain feedback and preparing for an end of Phase 2 meeting with the FDA to define the path forward."
About Study 3-201
Design
Study 3-201 is a Phase 2, open-label, parallel group study conducted at 32 centers in the U.S. In the trial, 132 patients with type 1 diabetes and HbA1c levels between 6.5-8.5% were randomized to receive either BIOD-123 or Humalog(R) to use as their mealtime insulin during an 18-week treatment period. Both arms of the study used insulin glargine, sold as Lantus(R), as the basal insulin. Following randomization, subjects entered a 6-week dose titration period during which basal insulin and then prandial insulin doses were to be titrated in order to reach standard American Diabetes Association (ADA) recommended pre-prandial glucose targets. Upon completion of the titration period, subjects entered a "relative stable dosing period" for an additional 12 weeks.
Secondary endpoints include hypoglycemic events measured and analyzed according to ADA Workshop recommendations, weight recorded at multiple time points and postprandial glucose excursions measured in multiple ways including a liquid meal challenge test, 10-point glucose profiles, continuous glucose monitoring profiles and routine self-monitoring of blood glucose (SMBG) levels throughout the study. The study was powered to demonstrate non-inferiority of HbA1c. As is typical with a Phase 2 Study, the goal with respect to the secondary measures was to look for initial trends that would assist in the design of future studies. Endpoints were analyzed primarily using the day of randomization as baseline. These analyses involve data from the entire 18-week treatment period, including the initial 6-week titration phase. Secondary analyses were also performed using Week 6 (the end of the dose titration period) values as baseline. These results assess changes during the 3 month stable dosing period.
Demographics
Sixty six (66) subjects were randomized into each arm of the study. A central randomization process was utilized. At baseline, mean HbA1c was balanced between treatment groups: 7.36% in the BIOD-123 group and 7.33% in the Humalog(R) group. Several between-group imbalances were noted in the baseline characteristics of the randomized subjects. The mean age in the BIOD-123 group was 48.8 years compared to 41.3 years in the Humalog(R) group. The mean duration of diabetes was 25.8 years in the BIOD-123 group compared to 20.5 years in the Humalog(R) group. 50.8% of the subjects in the BIOD-123 group were female compared to 28.8% in the Humalog(R) group. The mean weight in the BIOD-123 group was 78.6 kg compared to 84.3 kg in the Humalog(R) group, likely related to the difference in gender make-up between the two groups. Body mass index (BMI), however, was more closely balanced at baseline: 26.8 kg/m2 in the BIOD-123 group and 27.0 kg/m2 in the Humalog(R) group. Subjects randomized to the BIOD-123 arm were treated at the beginning of the study with an average of 52.4 units (0.64 units/kg) of insulin, and those randomized to Humalog(R) were treated with 60.2 units (0.71 units/kg) of insulin.
The randomization was performed properly and the observed baseline imbalances occurred by chance in this Phase 2 study with limited sample size. The baseline imbalances do not affect the conclusion of non-inferiority of HbA1c. Some gender-based differences in weight change were observed. The effect of gender and possible dose imbalances on other secondary variables are under investigation.
Results
The primary objective of the study was to demonstrate non-inferiority in change from baseline HbA1c, defined as the upper bound of the 95% confidence interval around change from baseline HbA1c (R) group. The 95% confidence interval (-0.01, 0.35) of the between group difference in change from baseline HbA1c did not exceed the pre-determined threshold of 0.40%, thereby establishing non-inferiority. HbA1c change during the stable dosing period was similar in both treatment arms. During this period, the mean change in HbA1c in the BIOD-123 group was -0.01% and in the Humalog(R) group was +0.02%.
Hypoglycemia frequencies and mean event rates were not statistically significantly different between groups. However, in the most frequent forms of hypoglycemia reported, median event rates appear to be lower in the BIOD-123 group compared to Humalog(R). This observation requires further investigation.
Baseline weights were substantially different between groups, however, the change from baseline in weight was not significantly different; both groups gained on average 1.0 kg over the course of the study. During the 6-week titration period, patients in the BIOD-123 group gained an average of 0.94 +/- 0.31 kg, and patients in the Humalog(R) group gained an average of 0.43 +/- 0.35 kg. In contrast, during the subsequent stable dosing period of 12 weeks, patients in the BIOD-123 group gained an average of 0.10 kg compared to 0.60 kg in the Humalog(R) group. This beneficial weight trend in favor of BIOD-123 during the stable dosing period was observed in both genders, yet was more pronounced in females in which a small weight loss was observed.
Postprandial glucose was measured using multiple methods, generating a dataset of more than 1.5 million data points, many of which are still being analyzed. Postprandial glucose excursions are defined as the change in glucose concentration from before to after a meal. In the liquid meal challenge test, the average baseline glucose values of 177.3 mg/dl were higher in the BIOD-123 group compared to 148.3 mg/dl in the Humalog(R) group. The maximal postprandial glucose excursion of 71.8 mg/dl was significantly lower in the BIOD-123 group compared the 92.6 mg/dl maximal glucose excursion in the Humalog(R) group; this difference was significant at p=0.034. Additional statistical analysis indicates that this significant difference in excursion is not due to the differences in baseline glucose or gender.
Initial overall analyses show mostly no differences in 10-point SMBG or continuous glucose monitoring profiles. Some time points show lower postprandial glucose values in the Humalog(R) arm. Additional analyses of within-patient glucose excursions are pending.
Overall, the adverse event profile between treatment groups appears to be balanced with the exception of injection site pain. Drop-out rates in the two arms of the study were similar. No patients in either the BIOD-123 or Humalog(R) arm reported an incidence of severe pain or dropped out of the study because of injection site pain. One patient (1.5%) in the BIOD-123 arm reported a single incidence of moderate pain, compared to none in the Humalog(R) arm. Nine patients (13.8%) in the BIOD-123 group reported at least one episode of mild injection site pain during the study compared to 1 patient (1.5%) in the Humalog(R) group. Six out of 10 patients reporting discomfort with BIOD-123 had complete resolution during the course of the study while continuing study drug. It was noted that about half of the patients in the study reporting injection site pain were from 2 out of 32 investigative sites, with patients from 25 out of 32 sites reporting no injection site pain. Injection site pain associated with BIOD-123 was not a medically important safety issue and was greatly improved relative to that associated with VIAject(TM).
Highlights
Compared to Humalog(R), BIOD-123 demonstrated:
Achievement of primary efficacy endpoint; demonstration of non-inferiority in change from baseline HbA1c
Comparable weight gain, mean hypoglycemia event rates and postprandial glucose excursions over the entire treatment period with some notable trends in favor of BIOD-123 in weight gain during the stable dosing period, median hypoglycemia event rates and postprandial glucose excursions to a liquid meal challenge test
Comparable safety and adverse event profiles with the exception of an increased frequency of injection site pain associated with BIOD-123 which appears to be clinically minor, was short-lived and did not result in patient dropouts
Dr. Alan Krasner, chief medical officer of Biodel, stated: "BIOD-123 has passed the first and most critical test—showing that HbA1c non-inferiority can be achieved in a multi-dose outpatient setting. This study provides a rich database which will be used to explore how two insulins with distinct pharmacodynamic profiles can influence a number of important clinical outcomes. Continued analysis of this database will be invaluable in our development of BIOD-123 and other meal-time insulin candidates."
Dr. Errol De Souza, president and chief executive officer of Biodel, stated: "The establishment of non-inferiority in HbA1c of BIOD-123 versus Humalog(R) in this study gives us a high level of confidence that BIOD-123 could achieve this primary endpoint for FDA approval in larger pivotal studies. We look forward to completing the full analysis of the results, sharing the data with experts and potential partners to obtain feedback and preparing for an end of Phase 2 meeting with the FDA to define the path forward."
About Study 3-201
Design
Study 3-201 is a Phase 2, open-label, parallel group study conducted at 32 centers in the U.S. In the trial, 132 patients with type 1 diabetes and HbA1c levels between 6.5-8.5% were randomized to receive either BIOD-123 or Humalog(R) to use as their mealtime insulin during an 18-week treatment period. Both arms of the study used insulin glargine, sold as Lantus(R), as the basal insulin. Following randomization, subjects entered a 6-week dose titration period during which basal insulin and then prandial insulin doses were to be titrated in order to reach standard American Diabetes Association (ADA) recommended pre-prandial glucose targets. Upon completion of the titration period, subjects entered a "relative stable dosing period" for an additional 12 weeks.
Secondary endpoints include hypoglycemic events measured and analyzed according to ADA Workshop recommendations, weight recorded at multiple time points and postprandial glucose excursions measured in multiple ways including a liquid meal challenge test, 10-point glucose profiles, continuous glucose monitoring profiles and routine self-monitoring of blood glucose (SMBG) levels throughout the study. The study was powered to demonstrate non-inferiority of HbA1c. As is typical with a Phase 2 Study, the goal with respect to the secondary measures was to look for initial trends that would assist in the design of future studies. Endpoints were analyzed primarily using the day of randomization as baseline. These analyses involve data from the entire 18-week treatment period, including the initial 6-week titration phase. Secondary analyses were also performed using Week 6 (the end of the dose titration period) values as baseline. These results assess changes during the 3 month stable dosing period.
Demographics
Sixty six (66) subjects were randomized into each arm of the study. A central randomization process was utilized. At baseline, mean HbA1c was balanced between treatment groups: 7.36% in the BIOD-123 group and 7.33% in the Humalog(R) group. Several between-group imbalances were noted in the baseline characteristics of the randomized subjects. The mean age in the BIOD-123 group was 48.8 years compared to 41.3 years in the Humalog(R) group. The mean duration of diabetes was 25.8 years in the BIOD-123 group compared to 20.5 years in the Humalog(R) group. 50.8% of the subjects in the BIOD-123 group were female compared to 28.8% in the Humalog(R) group. The mean weight in the BIOD-123 group was 78.6 kg compared to 84.3 kg in the Humalog(R) group, likely related to the difference in gender make-up between the two groups. Body mass index (BMI), however, was more closely balanced at baseline: 26.8 kg/m2 in the BIOD-123 group and 27.0 kg/m2 in the Humalog(R) group. Subjects randomized to the BIOD-123 arm were treated at the beginning of the study with an average of 52.4 units (0.64 units/kg) of insulin, and those randomized to Humalog(R) were treated with 60.2 units (0.71 units/kg) of insulin.
The randomization was performed properly and the observed baseline imbalances occurred by chance in this Phase 2 study with limited sample size. The baseline imbalances do not affect the conclusion of non-inferiority of HbA1c. Some gender-based differences in weight change were observed. The effect of gender and possible dose imbalances on other secondary variables are under investigation.
Results
The primary objective of the study was to demonstrate non-inferiority in change from baseline HbA1c, defined as the upper bound of the 95% confidence interval around change from baseline HbA1c (R) group. The 95% confidence interval (-0.01, 0.35) of the between group difference in change from baseline HbA1c did not exceed the pre-determined threshold of 0.40%, thereby establishing non-inferiority. HbA1c change during the stable dosing period was similar in both treatment arms. During this period, the mean change in HbA1c in the BIOD-123 group was -0.01% and in the Humalog(R) group was +0.02%.
Hypoglycemia frequencies and mean event rates were not statistically significantly different between groups. However, in the most frequent forms of hypoglycemia reported, median event rates appear to be lower in the BIOD-123 group compared to Humalog(R). This observation requires further investigation.
Baseline weights were substantially different between groups, however, the change from baseline in weight was not significantly different; both groups gained on average 1.0 kg over the course of the study. During the 6-week titration period, patients in the BIOD-123 group gained an average of 0.94 +/- 0.31 kg, and patients in the Humalog(R) group gained an average of 0.43 +/- 0.35 kg. In contrast, during the subsequent stable dosing period of 12 weeks, patients in the BIOD-123 group gained an average of 0.10 kg compared to 0.60 kg in the Humalog(R) group. This beneficial weight trend in favor of BIOD-123 during the stable dosing period was observed in both genders, yet was more pronounced in females in which a small weight loss was observed.
Postprandial glucose was measured using multiple methods, generating a dataset of more than 1.5 million data points, many of which are still being analyzed. Postprandial glucose excursions are defined as the change in glucose concentration from before to after a meal. In the liquid meal challenge test, the average baseline glucose values of 177.3 mg/dl were higher in the BIOD-123 group compared to 148.3 mg/dl in the Humalog(R) group. The maximal postprandial glucose excursion of 71.8 mg/dl was significantly lower in the BIOD-123 group compared the 92.6 mg/dl maximal glucose excursion in the Humalog(R) group; this difference was significant at p=0.034. Additional statistical analysis indicates that this significant difference in excursion is not due to the differences in baseline glucose or gender.
Initial overall analyses show mostly no differences in 10-point SMBG or continuous glucose monitoring profiles. Some time points show lower postprandial glucose values in the Humalog(R) arm. Additional analyses of within-patient glucose excursions are pending.
Overall, the adverse event profile between treatment groups appears to be balanced with the exception of injection site pain. Drop-out rates in the two arms of the study were similar. No patients in either the BIOD-123 or Humalog(R) arm reported an incidence of severe pain or dropped out of the study because of injection site pain. One patient (1.5%) in the BIOD-123 arm reported a single incidence of moderate pain, compared to none in the Humalog(R) arm. Nine patients (13.8%) in the BIOD-123 group reported at least one episode of mild injection site pain during the study compared to 1 patient (1.5%) in the Humalog(R) group. Six out of 10 patients reporting discomfort with BIOD-123 had complete resolution during the course of the study while continuing study drug. It was noted that about half of the patients in the study reporting injection site pain were from 2 out of 32 investigative sites, with patients from 25 out of 32 sites reporting no injection site pain. Injection site pain associated with BIOD-123 was not a medically important safety issue and was greatly improved relative to that associated with VIAject(TM).
