Review of the Mechanism of Action and Clinical Efficacy of Recombinant Human Hyaluronidase Coadministration with Current Prandial Insulin Formulations

Abstract

Abbreviations: (A1C) derived average glucose, (C max ) peak plasma concentration, (PK) pharmacokinetics, (PPG) postprandial plasma glucose, (rHuPH20) recombinant human hyaluronidase, (SC) subcutaneous, (t max ) time to peak plasma concentration Keywords: diabetes, glycemic control, hyaluronidase, rHuPH20, ultrafast insulin AbstractFor patients with type 1 or type 2 diabetes, achieving good glycemic control is critical for successful treatment outcomes. As many patients remain unable to reach glycemic goals with currently available rapid-acting analog insulins, ultrafast insulin products are being developed that provide an even faster pharmacokinetic profile compared with current rapid prandial insulin products. The overall strategy of these ultrafast insulin products is to better mimic the normal physiologic response to insulin that occurs in healthy individuals to further improve glycemic control. Recombinant human hyaluronidase (rHuPH20) is a genetically engineered soluble hyaluronidase approved by the U.S. Food and Drug Administration as an adjuvant to increase the absorption and dispersion of other injected drugs; mammalian hyaluronidases as a class have over 6 decades of clinical use supporting the safety and/or efficacy of hyaluronidase coadministration. Clinical findings have demonstrated that coadministration of rHuPH20 with insulin or an insulin analog achieved faster systemic absorption, reduced inter-and intrapatient variability of insulin absorption, and achieved faster metabolic effects compared with injection of either insulin formulation alone. The magnitude of this acceleration is similar to the incrementally faster absorption of prandial insulin analogs as compared with regular insulin. In addition, coadministration of rHuPH20 with regular insulin or insulin analog also improved the achievement of prandial glycemic targets. Thus, rHuPH20 coadministration shows promise as a method of establishing a more rapid insulin profile to prandial insulin in patients with diabetes and has the potential to yield substantial improvements in postprandial glycemic excursion.

Insulin Therapy and Hypoglycemia - Present and Future

“…A second study in healthy subjects also reported a lower intra-subject variability with rHuPH20 coadministration (94). A phase 2 standardized meal-test study in patients with type 1 diabetes examined whether the accelerated insulin absorption has favorable consequences on the control of postprandial glycemic excursions (94). As in the phase 1 studies, the coadministration of rHuPH20 with regular insulin or lispro yielded an accelerated insulin concentration profile that was accompanied by a significant reduction in both mean peak and total post-meal glucose concentrations compared to either insulin alone.…”

“…As in the phase 1 studies, the coadministration of rHuPH20 with regular insulin or lispro yielded an accelerated insulin concentration profile that was accompanied by a significant reduction in both mean peak and total post-meal glucose concentrations compared to either insulin alone. Post-meal hypoglycemia was reported to be generally mild and the overall hypoglycemic risk comparable for lispro with or without rHuPH20 and reduced for regular insulin with rHuPH20 compared with regular insulin alone (94). Clinical studies reported a good tolerability profile without severe adverse effects, but there is no safety data so far regarding the repeated or long term exposure to recombinant hyaluronidase.…”

“…A rise in insulin concentration was observed within 3 minutes following the injection and the enhanced pharmacokinetic and glucodynamic effects early after injection were accompanied by reduced late effects. A second study in healthy subjects also reported a lower intra-subject variability with rHuPH20 coadministration (94). A phase 2 standardized meal-test study in patients with type 1 diabetes examined whether the accelerated insulin absorption has favorable consequences on the control of postprandial glycemic excursions (94).…”

“…Following this, concomitant injection with proteins / drugs such as insulin, is expected to lead to an enhanced absorption and improved bioavailability. Recombinant human hyaluronidase (rHuPH20) is a genetically engineered soluble hyaluronidase approved by the Food and Drug Administration as an adjuvant to enhance permeation of other injected drugs (94). Since rHuPH20 is rapidly metabolized locally, without systemic exposure and because hyaluronan has a fast turn-over, the permeation effects are transient (94).…”

“…Recombinant human hyaluronidase (rHuPH20) is a genetically engineered soluble hyaluronidase approved by the Food and Drug Administration as an adjuvant to enhance permeation of other injected drugs (94). Since rHuPH20 is rapidly metabolized locally, without systemic exposure and because hyaluronan has a fast turn-over, the permeation effects are transient (94). A phase 1 glucose clamp study in healthy volunteers evaluated the insulin timeconcentration curve and pharmacodynamic profiles of insulin analogue (lispro) and of regular human insulin combined with rHuPH20 and reported significantly faster systemic absorption, enhanced insulin plasma concentrations and faster metabolic effects compared with either insulin formulation alone (95).…”