An insulin analog formulated with recombinant human hyaluronidase (rHuPH20) was noninferior to lispro in a comparator crossover study and had a similar safety and tolerability profile, said Irl B. Hirsch, MD, University of Washington, Seattle. He presented the study results at the 2012 ADA meeting.
rHuPH20 is a genetically engineered soluble version of the naturally occurring human hyaluronidase enzyme, and there are more than 60 years of clinical use to support the safety of hyaluronidase, Dr Hirsch said. rHuPH20 is the first and only US Food and Drug Administration–approved recombinant human hyaluronidase enzyme.
“Current rapid-acting analog insulin products are too slow to mimic the physiologic insulin mean response,” said Dr Hirsch. Postprandial glucose control is improved with rHuPH20, because it accelerates the absorption and action of insulin.
Dr Hirsch and colleagues compared a rapid-acting insulin plus rHuPH20 with insulin lispro alone to determine the effects on glycemic control parameters, safety, and tolerability in an intensive basal-bolus insulin therapy regimen in patients with type 1 diabetes.
In this randomized, double-blind trial, after a 4- to 6-week run-in period when all patients received insulin glulisine for their prandial insulin and twice-daily insulin glargine, patients were randomized to 1 of 2 cohorts. In one cohort, patients were randomized to initiate a regimen of insulin aspart (100 U/mL) plus rHuPH20 (5 mcg) or insulin lispro alone (100 U/mL). In the other cohort, the patients were randomized to start insulin lispro (100 U/mL) plus rHuPH20 (5 mcg) or insulin lispro alone (100 U/mL).
The study involved two 12-week intensive management periods; the patients were crossed over to the other regimen in their cohort for the second management period. Prandial doses were taken immediately before meals.
Dr Hirsch noted that only patients who met the aggressive fasting blood glucose targets of 80 to 120 mg/dL were included in the trial. Of the 117 randomized patients, 113 completed the trial. They were aged 42 years on average, 61 were women, and most were white. The mean body mass index was 27.3 kg/m2.
“The prespecified noninferiority margin of 0.4% was met, with a difference in the change of A1c from baseline of 0.05% with rHuPH20,” said Dr Hirsch. In both the lispro and analog-rHuPH20 groups, the 7.43% hemoglobin A1c at screening was reduced to 7.02% at randomization, and was reduced further to 6.83% with lispro and 6.88% with analog-rHuPH20.
Prandial control was better with analog-rHuPH20 compared with lispro throughout the study. The glycemic excursion was reduced by 73% at breakfast, 34% at lunch, and by 219% at dinner. The overall reduction in the glycemic excursion was a significant 82%.
“The glucose profile was flatter in the analog-rHuPH20 group,” compared with lispro, as measured by a 10-point glucose profile at the end of the study, said Dr Hirsch.
Overall hypoglycemia rates were significantly reduced with analog-rHuPH20 compared with lispro. The prespecified hypoglycemia criterion for overall hypoglycemic events, ≤70 mg/dL, was reduced by 5%, and the criterion of <56 mg/dL by 7% with analog-rHuPH20.
One severe hypoglycemic episode occurred in 1 patient in the analog-rHuPH20 group, and 5 episodes occurred in 5 patients in the lispro group.
Two favorable trends were seen with analog-rHuPH20. Compared with lispro, there was a small reduction of 2.5 U/mL in the total daily insulin dose and a small difference in weight (a slight reduction of 0.25 lb with analog-rHuPH20 and a gain of 0.10 lb with lispro alone).
Adverse events were similar between the groups for all system-organ classes. Treatment-phase severe adverse events were limited to severe hypoglycemia, which occurred in 2 patients treated with lispro alone. No difference was seen for injection-site pain between groups, with approximately 70% of patients reporting none and 30% minimal injection-site pain.
Immunogenicity profiles were not changed, regardless of the sequence in which the patient received analog-rHuPH20 or lispro. The anti-insulin antibodies were at 86% at baseline and at 81% at the end of the second treatment period for patients receiving analog-rHuPH20 first and then lispro, and were 76% at baseline and 71% at the end of the second treatment period in the patients receiving lispro and then analog-rHuPH20.
Positive anti-rHuPH20 antibodies were found in 13 patients at baseline and in 12 patients at the end of the second treatment period.