Miriam E Tucker

October 03, 2016

MUNICH — Investigational technology (BioChaperone, Adocia) that enhances the action of already-approved off-patent insulins could improve glycemic control in patients with type 1 and type 2 diabetes, the results of two small trials suggest.

Findings from two studies — one for Ultra-Rapid BioChaperone Lispro in type 1 diabetes, the other for BioChaperone Combo (a fixed-dose 25/75 coformulation of lispro plus glargine) in type 2 diabetes — were both presented recently at the European Association for the Study of Diabetes (EASD) 2016 Annual Meeting by Dr Tim Heise, chair of Profil Germany, a clinical research organization, and Adocia chief medical officer Dr Simon Bruce, respectively.

Adocia's website describes the BioChaperone technology as a "molecular delivery system for therapeutic proteins," based on polymers, oligomers, and small organic compounds that form a physical complex with proteins, thereby protecting them from enzymatic degradation and ultimately altering their effects.

Use of BioChaperone Lispro, the company's reformulated version of the standard lispro insulin, resulted in faster absorption and reduced postprandial glucose excursions compared with standard premeal lispro (Humalog, Lilly) in type 1 patients, Dr Heise reported.

And the Combo, Dr Bruce said, would be the first ever to combine two "gold-standard" (and off-patent) insulins, since current lispro and glargine formulations traditionally can't be mixed in the same syringe due to pH differences.

Asked to comment, William H Herman, MD, professor of internal medicine in the division of metabolism, endocrinology, and diabetes at the University of Michigan Ann Arbor, said: "I thought the studies were very well done and the results were impressive," adding, "People now think of lispro as being fast on–fast off, but it really isn't."

Regarding the combination product, Dr Herman commented, "I thought it was fascinating that you could actually put them together."

Addressing a concern from an audience member — that fixed-dose insulin combinations don't allow for sufficient flexibility in dosing — Dr Herman remarked, "I think most endocrinologists think they're nonphysiologic…but I think the data actually show utility, so I will be curious to see whether it actually comes to market."

However, he said cost will be key, particularly in the United States: "I'm terribly concerned by the price of insulin. I can't see these things coming to market at a lower price than the existing insulins, and I think the current price of insulins in the US is oftentimes unaffordable."

Asked about the products' potential cost, an Adocia spokesperson responded by email: "The aim of the BioChaperone technology is to enable drug performance improvement without necessarily increasing the drug's price since BioChaperone has a marginal cost compared with the one of protein."

"Faster in, Faster Out"

In the BioChaperone Lispro trial, a single-center, double-blind, randomized, single-dose, two-period crossover study, 38 patients with type 1 diabetes (mean age 44 years, diabetes duration 23 years, HbA1c 7.4%) participated in two meal tests using a standardized liquid meal (400-mL Ensure Plus, Abbott) containing 600 kcal, comprising 80 g carbohydrates, 25 g protein, and 20 g fat.

Their premeal blood glucose levels were stabilized at 100 mg/dL and no basal insulin was given during the tests. Treatments were either BioChaperone Lispro U100 at 0.2 U/kg or Humalog U100 at 0.2 U/kg, both given immediately before meals.

Maximum insulin concentrations were reached about 15 minutes earlier with the BioChaperone Lispro compared with Humalog (47 vs 62 minutes) and were also 13% higher.

While total area under the curve (AUC) for 8 hours postinjection was similar between the two insulins, AUC was 2.7-fold higher in the first 30 minutes and 1.5-fold higher in the first hour with BioChaperone Lispro compared with Humalog.

From 2 to 8 hours, an earlier decline was seen with BioChaperone Lispro, such that maximum concentrations were reached about 25 minutes earlier (135 vs 160 minutes), and the area under the curve was 21% lower.

"The pharmacokinetic data indicated that BioChaperone Lispro is faster in and faster out compared with Humalog," Dr Heise said.

Postprandial blood glucose excursions were reduced by 61% at 2 hours with the BioChaperone Lispro, with values of 7.0 mmol/L (126 mg/dL) vs 8.5 mmol/L (153 mg/dL) at 2 hours with Humalog, representing "quite a significant reduction in the blood glucose excursions," he commented.

There were no serious adverse events, no local tolerability problems, and hypoglycemia (< 50 mg/dL) rates were low and roughly equal for both insulins (18 events for BioChaperone vs 19 for Humalog).

Dr Heise added that a concentrated U200 formulation of BioChaperone Lispro is also being developed.

A Better Fixed-Dose Combination?

During his presentation, Dr Bruce said there is a need for simplified combination insulin products: "Premixes twice daily afford an opportunity for the nonspecialist, who may not have the dedicated resources of an integrated diabetes team to initiate or intensify insulin therapy."

He acknowledged that many endocrinologists don't use fixed-dose insulin combinations but also suggested that the BioChaperone Combo might offer a superior alternative.

"Most diabetes specialists have concerns about premixes because they represent a significant therapeutic compromise. While I don't think anyone would deny that there's a need for pragmatic therapies, part of the concern with conventional premixes is that they have a fairly anachronistic time-action profile. This is largely because it has been impossible to coformulate the two gold standard components, glargine and lispro, due to glargine's design to be insoluble at neutral pH."

In contrast, BioChaperone forms a reversible complex with glargine and solubilizes it at neutral pH, allowing it to be coformulated with the fast-acting lispro, thereby allowing for both the prandial and basal insulin to be delivered in a single injection, he explained.

He described the single-center, double-blind, randomized, double-dummy, single-dose, three-treatment, three-period crossover euglycemic clamp study, which had three arms: 0.8 U/kg of BioChaperone Combo, 0.8 U/kg of LisproMix 25/75 (25/75 lispro/protamine-retarded lispro), or simultaneous subcutaneous injections of 0.2 U/kg lispro and 0.6 U/kg glargine.

Subjects included 24 patients with type 2 diabetes (all white males, mean age 57, HbA1c 7.4%) on stable multiple daily injection regimens.

Time to peak insulin action was 1.3 hours with BioChaperone Combo vs 2.9 hours with separate lispro plus glargine and 3.8 hours with LisproMix (P = .006 and 0.0001, respectively).

Late insulin action — assessed by the AUC glucose infusion rates — was similar for the BioChaperone Combo and lispro plus glargine, 186 mg/kg vs 174 (P = .67) and less than Lispro Mix (99 mg/kg, P = .01).

Thus, the BioChaperone Combo provided a faster early effect and lower late postprandial effect, which could reduce the risk of delayed postprandial hypoglycemia, Dr Bruce said.

There were no significant differences in safety profiles among the study arms, with good local tolerability without any injection-site reactions.

During the question-and-answer period, a doctor from Italy expressed concern that the premix wouldn't allow adjustment for the carbohydrates consumed and that giving it just once a day would be providing prandial insulin only at one of three daily meals, but giving it twice might increase the risk for hypoglycemia.

"The technology is wonderful, but I don't think clinicians and patients need such an approach," the commenter said.

Dr Bruce responded: "I think there's a bit of a discrepancy between what you know about premixes as they exist today, which have all those problems, and what may be possible with this product.

"We will not be able to get around the inability to exquisitely titrate the prandial dose. However, if the profiles are clean and differentiated, I think this is something you could recommend with a great deal more comfort to your nondiabetes specialist colleagues, who may be in desperate need and still using conventional premixes."

Will These Newer Formulations Be Affordable?

Dr Herman, who earlier this year coauthored a research letter in the Journal of the American Medical Association about the escalating costs of insulin, told Medscape Medical News, "In the US, because of the cost of insulin, we're seeing people actually going back to the human regular [insulin] as opposed to the analogs. So at one level we're pushing better, faster, more expensive analogs, and yet, to the extent that they're unaffordable, I don't know how it's going to shake out."

He added, "I think it sort of sneaked up on clinicians and they haven't really thought about it. There needs to be pushback. I think it's great that they're doing this work, but the question is what the value is for the money. If it's a premium price, how important will it be?"

Dr Heise is on the advisory board for Novo Nordisk, speaker's bureau for Eli Lilly, Mylan, and Novo Nordisk, and receives grant/research support from Adocia, AstraZeneca, BD, Biocon, Boehringer Ingelheim, Dance Pharmaceuticals, Eli Lilly, Grünenthal, Medtronic, Novo Nordisk, Novartis, Sanofi, and Senseonics. Dr Bruce is an employee and shareholder of Adocia. Dr Herman is on data safety monitoring boards for Merck and Lexicon.

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European Association for the Study of Diabetes (EASD) 2016 Annual Meeting; September 13, 2016; Munich, Germany. Abstracts 7 and 8.

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