The goal of insulin therapy for diabetic patients is to mimic closely the physiologic pattern of insulin release by the pancreas in order to maintain normoglycaemia.
Available as the beef/pig pancreas derived hormone since 1922, the first human recombinant insulin was developed by Genentech and marketed by Eli Lilly in 1982.
Standard 2 Zinc-insulin (which is hexameric) must be injected ~30 minutes before a meal to allow for disassembly in the subcutaneous depot into dimers and monomers (the active species).
At the turn of the millenium, to facilitate more accurate dosing, the principles of protein engineering were applied to destabilize the dimer and hexamer interfaces and produce rapid-acting insulin analogs (Fig. 1).
Figure 1. Amino acid compositions of the rapid-acting insulin analogues (1).
Lispro/Humalog (Eli Lilly), Aspart/Novalog (Novo Nordisk) and Glulisine/Apidra (Sanofi-Aventis) can all be injected 5 to 15 minutes before a meal (Fig. 2).
Figure 2. 4 hour physiological plasma insulin profiles plotted together with pharmacokinetic profiles for insulin lispro and human insulin in type 1 diabetes (2).
Attention has more recently focused on the development of ultra-rapid insulins for dosing at (or even after) the time of the meal, for the benefit of children, insulin pump users and for highly insulin-resistant type 2 diabetics. Current approaches to speeding up the onset of absorption include modification of excipients and enabling of tissue diffusion.
Powdered insulin delivered by a nebulizer into the lungs is absorbed more rapidly than subcutaneous insulin and absorption is of short duration. Exubera, developed by Inhale Therapeutics (then Nektar) was the first hexameric inhaled insulin product to be marketed by Pfizer in 2006. Unfortunately a 2007 study concluded that Exubera “appears to be as effective, but no better than injected short-acting insulin”. Exubera was dispensed using a bulky device (Fig. 3) with little dosing flexibility and poor sales led to its withdrawal in 2007. More recently, Afrezza, a monomeric inhaled insulin developed by Mannkind was approved by the FDA in 2014. Afrezza is delivered using a small device about the size of an asthma inhaler (Fig. 3), peaks at ~15-20 minutes and is eliminated from the body within ~2-3 hours.
The rapid absorption and decreased duration of Afrezza closely resembles physiological insulin release (Figs. 2 & 4).
Figure 4. Pharmacokinetic profiles for inhaled Afrezza and SC insulin lispro (in type 1 DM patients) and for inhaled Exubera and SC human insulin (in type 2 DM patients)(4).
An alternative to engineering the insulin aggregation interfaces is to introduce biotechnological enhancers. Eli Lilly has complexed Lispro insulin with French biotech company Adocia’s proprietary BioChaperone (BC) to accelerate absorption (licensed in 2014) (Fig. 5).
Figure 5. Adocia’s BioChaperone technology is based on polymers, oligomers and organic compounds. The BC-insulin complex forms spontaneously in water, protecting it from enzymatic degradation and enhancing absorption after injection (5).
BC Lispro promoted a statistically significant 63% increase in metabolic effect over the first hour in comparison with Novolog, having previously been demonstrated to outperform Eli Lilly’s Humalog (Fig. 6).
Figure 6. Comparison of mean blood glucose profiles after subcutaneous injection of lispro and BC lispro (6).
Despite results from 6 clinical studies indicating that BC Lispro performs better than Humalog, Eli Lilly decided to terminate its collaboration with Adocia in 2017 (possibly because of the costly failure of its Alzheimer’s drug solanezumab). Lilly is now developing its own ultra-rapid Lispro in house (LY900014 currently in phase 3), formulated with two new excipients, treprostinil (a vasodilator) and citrate (a vascular permeabilizer). The rights to BC Lispro reverted back to Adocia from Eli Lilly at no cost and the company is currently seeking a new partner to shoulder the costs of phase 3 clinical trials, regulatory and marketing hurdles.
Novo’s Faster-acting insulin aspart (FIASP), the first ultra-rapid insulin to be approved and marketed (Fig. 7), is an innovative formulation containing Vitamin B3 (niacinamide) to increase the speed of absorption, and the naturally occurring amino acid (L-Arginine) for stability.
FIASP was sidelined by the FDA in October 2016 but approved in September 2017 following clarification of immunogenicity and clinical pharmacology data.
Figure 7. Fiasp FlexTouch Prefilled Pens -100 units/mL (7).
FIASP can be injected from 2 minutes before to up to 20 minutes into a meal and acts twice as fast as Novolog/Aspart (Fig. 8).
Figure 8. Blood insulin Aspart concentration after subcutaneous injection of Fiasp and Novolog in patients with type 1 diabetes (8).
This was achieved without a significant difference in the overall rate of severe or confirmed hypoglycemia. Clinical trial data showed that FIASP gave a lower post-meal spike and that patients also lowered their A1C levels.
Novo Nordisk is very keen to expand the use of ultra-rapid acting FIASP in an artificial pancreas setting and it is already approved for use in insulin pumps in Europe.
Given that Novolog was the third best selling diabetes medication in 2015 with $3.03 billion in global sales (9), Fiasp is well poised to become the leader in this enormous market segment.
- Home, P.D. (2015) Plasma insulin profiles after subcutaneous injection: how close can we get to physiology in people with diabetes? Diabet. Obes. Metab. 17, 1011-1020.
- http://pharmamkting.blogspot.co.uk/2015/02/look-ma-no-bong-afrezza-inhaled-insulin.htmlAl-Tabakha, M.M. (2015) Future prospect of insulin inhalation for diabetic patients: The case of Afrezza versus Exubera. J. Control. Release 215, 25-38.
Blog written by Raj Gill