Douglas B. Muchmore

Ultrafast-Acting Insulins: State of the Art:

Optimal coverage of prandial insulin requirements remains an elusive goal. The invention of rapid-acting insulin analogs (RAIAs) was a big step forward in reducing postprandial glycemic excursions in patients with diabetes in comparison with using regular human insulin; however, even with these, the physiological situation cannot be adequately mimicked. Developing ultrafast-acting insulins (UFIs)—showing an even more rapid onset of action and a shorter duration of action after subcutaneous (SC) administration—is another step forward in achieving this goal. The need for UFIs has been gradually recognized over the years, and subsequently, a number of different approaches to cover this need are in clinical development. A rapid increase in circulating insulin levels can be achieved by different measures: Modification of the primary structure of insulin molecule (as we know from RAIAs), addition of excipients that enhance the appearance in the monomeric state post-injection, or addition of enzymes that enable more free spreading of the insulin molecules in the SC tissue. Other measures to increase the insulin absorption rate increase the local blood flow nearby the insulin depot in the SC tissue, injecting the insulin intradermally or applying via another route, e.g., the lung. The development of these approaches is in different stages, from quite early stages to nearing market authorization. In time, daily practice will show if the introduction of UFIs will fulfill their clinical promise. In this review, the basic idea for UFIs will be presented and the different approaches will be briefly characterized.

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

For 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.

Comparative Pharmacokinetics and Insulin Action for Three Rapid-Acting Insulin Analogs Injected Subcutaneously With and Without Hyaluronidase

OBJECTIVE To compare the pharmacokinetics and glucodynamics of three rapid-acting insulin analogs (aspart, glulisine, and lispro) injected subcutaneously with or without recombinant human hyaluronidase (rHuPH20). RESEARCH DESIGN AND METHODS This double-blind six-way crossover euglycemic glucose clamp study was conducted in 14 healthy volunteers. Each analog was injected subcutaneously (0.15 units/kg) with or without rHuPH20. RESULTS The commercial formulations had comparable insulin time-exposure and time-action profiles as follows: 50% exposure at 123–131 min and 50% total glucose infused at 183–186 min. With rHuPH20, the analogs had faster yet still comparable profiles: 50% exposure at 71–79 min and 50% glucose infused at 127–140 min. The accelerated absorption with rHuPH20 led to twice the exposure in the first hour and half the exposure beyond 2 h, which resulted in 13- to 25-min faster onset and 40- to 49-min shorter mean duration of insulin action. CONCLUSIONS Coinjection of rHuPH20 with rapid-acting analogs accelerated insulin exposure, producing an ultra-rapid time-action profile with a faster onset and shorter duration of insulin action.

Accelerating and improving the consistency of rapid-acting analog insulin absorption and action for both subcutaneous injection and continuous subcutaneous infusion using recombinant human hyaluronidase.

Rapid-acting insulin analogs were introduced to the market in the 1990s, and these products have improved treatment of diabetes by shortening the optimum delay time between injections and meals. Compared with regular human insulin, rapid-acting insulin formulations also reduce postprandial glycemic excursions while decreasing risk of hypoglycemia. However, the current prandial products are not fast enough for optimum convenience or control. Recombinant human hyaluronidase (rHuPH20) has been used to increase the dispersion and absorption of other injected drugs, and in the case of prandial insulin analogs, it confers both ultrafast absorption and action profiles. Animal toxicology studies have demonstrated excellent tolerability of rHuPH20, and human studies, involving over 60,000 injections of prandial insulin + rHuPH20 to date, have similarly shown excellent safety and tolerability. Studies using rapid-acting analog insulin with rHuPH20 have included clinic-based pharmacokinetic and glucodynamic euglycemic glucose clamp studies, test meal studies, and take-home treatment studies. Administration methods have included subcutaneous injection of coformulations of rapid-acting insulin + rHuPH20 as well as continuous subcutaneous infusion of coformulations or use of pretreatment of newly inserted infusion sets with rHuPH20 followed by standard continuous subcutaneous insulin infusion therapy. These studies have demonstrated acceleration of insulin absorption and action along with improvement in postprandial glycemic excursions and reduction in hypoglycemia risks. Further, rHuPH20 reduces intrasubject variability of insulin absorption and action and provides greater consistency in absorption and action profiles over wear time of an infusion set. Further studies of rHuPH20 in the take-home treatment setting are underway.

Clinical Immunogenicity of rHuPH20, a Hyaluronidase Enabling Subcutaneous Drug Administration.

Recombinant human PH20 hyaluronidase (rHuPH20) is used to facilitate dispersion of subcutaneously delivered fluids and drugs. This report summarizes rHuPH20 immunogenicity findings from clinical trials where rHuPH20 was co-administered with SC human immunoglobulin, trastuzumab, rituximab, or insulin. Plasma samples were obtained from evaluable subjects participating in ten different clinical trials as well as from healthy plasma donors. A bridging immunoassay and a modified hyaluronidase activity assay were used to determine rHuPH20-reactive antibody titers and neutralizing antibodies, respectively. rHuPH20-binding antibody populations from selected subjects with positive titers were affinity-purified and subjected to further characterization such as cross-reactivity with endogenous PH20. Among individual trials, the prevalence of pre-existing rHuPH20-reactive antibodies varied between 3 and 12%, excepting the primary immunodeficiency (PID) studies. Incidence of treatment-induced rHuPH20 antibodies was 2 to 18%, with the highest titers (81,920) observed in PID. No neutralizing antibodies were observed. Within most trials, the kinetics of antibody responses were comparable between pre-existing and treatment-induced antibody responses, although responses classified as persistent were more common in subjects with pre-existing titers. There was no association between antibody positivity and either local or systemic adverse events. Pre-existing and treatment-induced antibody populations were of similar immunoglobulin isotypes and cross-reacted to endogenous PH20 to similar extents. No cross-reactivity to PH20 paralogs was detected. rHuPH20 induces only modest immunogenicity which has no association with adverse events. In addition, antibodies purified from baseline-positive individuals are qualitatively similar to those purified from individuals developing rHuPH20-reactive antibodies following exposure to the enzyme.

The End Point is Just the Beginning

Clinical trials to support registration of new drugs are arduous, lengthy, and expensive. Diabetes treatment trials intended to seek indications for glycemic control are facilitated by the regulatory acceptance of glycosylated hemoglobin (A1C) as a validated intermediate efficacy end point. However, A1C outcomes are not meaningful when taken outside of the context of hypoglycemia risks. Current regulatory guidance indicates that A1C efficacy end points and hypoglycemia safety end points be considered separately. A composite end point for diabetes treatment trials that integrates A1C and hypoglycemia risk into a single measure is proposed. An example would be “percentage of patients achieving A1C <7% without unacceptable hypoglycemia.” The benefits and limitations of such an approach are discussed.

Benefits of Blinded Continuous Glucose Monitoring during a Randomized Clinical Trial

Background: Real-time, personal continuous glucose monitoring (CGM) is a validated technology that can help patients improve glycemic control. Blinded CGM is a promising technology for obtaining retrospective data in clinical research where the quantity and quality of blood glucose information is important. This study was designed to investigate the use of novel procedures to enhance data capture from blinded CGM. Methods: Following a 4-week run-in, 46 patients with type 1 diabetes were randomized to one of two prandial insulins for a 12-week treatment period, after which they were crossed over to the alternate treatment for 12 weeks. Continuous glucose monitoring was implemented at the end of run-in (practice only) and during the last 2 weeks of each treatment period. Eighty percent of 288 possible daily glucose values were required for at least three days. Continuous glucose monitoring was extended for an additional week if these criteria were not met, and patients were allowed to insert sensors at home when necessary. Continuous glucose monitoring results were compared to reference eight-point self-monitoring of blood glucose (SMBG). Results: Higher than expected sensor failure rate was approximately 25%. During run-in, 12 of 45 attempted profiles failed adequacy criteria. However, treatment periods had only 1 of 82 attempted profiles considered inadequate (6 cases required an additional week of CGM). Using SMBG as reference, 93.7% of 777 CGM values were in Clarke error grid zones A+B. Conclusions: With appropriate training, adequate practice, and opportunity to repeat blinded CGM as needed, nearly 100% of attempted profiles can be obtained successfully.

The Need for Faster Insulin: Problem Solved?

Considerable progress in treatment of diabetes has been made in the nearly 100 years following the discovery of insulin, and advances in insulin therapy have improved convenience, quality of life, overall glycemic control (A1C), and risk of hypoglycemia. An unmet need remains for a mealtime insulin that can faithfully reproduce the metabolic profile that ensues following meal ingestion in healthy persons. A number of “ultra-fast” insulin programs have been initiated, and Afrezza® (insulin human; Inhalation Powder, MannKind Corporation, Danbury, CT) stands as the first such product to be approved by the US FDA. Afrezza is unique as an “ultra-ultra” fast insulin, faster than any other entrant except IV insulin. The benefits and limitations of the Afrezza profile are discussed in this analysis.

Pump Users Clamor for Faster Insulin: Is Fast-Acting Insulin Aspart Ready for Them?:

Recently approved in Europe, Canada, and the United States, fast-acting insulin aspart (FIASP®) is a new rapid acting insulin. Approved for subcutaneous or IV injection use, there is little data available regarding the clinical utility of FIASP in insulin pumps. The article by Zijlstra and colleagues in this issue begins to close this gap by testing pump compatibility of FIASP in the clinic. Reporting on a small (37 subjects) and short (6 weeks) study looking at aspects of infusion set propensity for clogging and malfunction, no cases of infusion set plugging in either FIASP (25 subjects) or insulin aspart (12 subjects) were seen. Unexplained hyperglycemia and premature infusion set changes were more common with FIASP than with insulin aspart. This study demonstrated sufficient safety and efficacy of FIASP in the pump setting to pave the way for longer, larger and more definitive clinical trials.