Status - approved; marketed

Organizations involved:

Lilly, Eli & Co. – R&D; Manuf. other; World mark.; Parent

Hoffmann-La Roche Ltd. – World mark.

Dista Products Ltd. – Manuf.

Lilly France S.A. – Manuf. other

Genentech, Inc. – Tech.

City of Hope National Medical Center – Tech.; Patent dispute.

Cross ref.: See the Insulin Products entry (#630). See also Humulin (#192) also from Lilly.

Description: Insulin Lispro Injection (rDNA origin) or Humalog refers to aqueous formulations of recombinant insulin lispro, a mutein (mutant or modified form) of human insulin with a slightly different amino acid sequence, expressed by transformed Escherichia coli (E. coli) bacteria, and purified as crystals of insulin lispro complexed with zinc (zinc-insulin lispro). Insulin lispro or Lys(B28), Pro(B29) human insulin is human insulin with the lysine and proline amino acids, at positions 29 and 28, respectively, of the human insulin B-chain reversed. Insulin lispro has the molecular formula C257-H383-N65-O77-S6, and a molecular weight of 5,808 (5.808 kDa), both identical to that of human insulin.

Two formulations are available – regular insulin lispro (zinc-insulin lispro crystals; Humalog R) with a fast onset, earlier peak, and shorter duration for glucose lowering activity than regular human insulin; and a fast onset, longer-acting formulation (Humalog Mix75/25) composed of a mixture of Humalog R plus insulin lispro neutral protamine (NPL) complex. Humalog R is zinc-insulin lispro crystals dissolved in a clear aqueous fluid. Humalog NPL is a suspension of crystals formed from combination of insulin lispro and protamine sulfate.

Insulin lispro has an A-chain (21 residues) with the amino acid sequence Gly-Ile-Val-Glu-Gln-Cys-Cys-Thr-Ser-Ile-Cys-Ser-Leu-Tyr-Gln-Leu-Asn-Tyr-Cys-Asn; and a B-chain (30 residues) with sequence Phe-Val-Asn-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly-Glu-Arg-Gly-Phe-Tyr-Thr-Lys-Pro-Thr. Like native human insulin, the A and B chains are linked by disulfide -S-S- bridges between the cysteine residues at A chain residue 7 and B chain residue 7, and at A chain residue 20 and B chair residue 19. An intrachain disulfide (-S-S-) link connects the cysteines at A chain residues 6 and 11. Insulin lispro was designed for its rapid onset of action, monomeric properties (i.e., it does not polymerize), and weak self-association in solution.

Pharmacokinetic and pharmacodynamic studies have shown Humalog R to be equipotent to human regular insulin (i.e., one unit has the same glucose-lowering capability as one unit of regular insulin), but with more rapid onset of activity. The quicker glucose-lowering effect of insulin lispro is related to its more rapid absorption rate from subcutaneous tissue (due to its structural modifications).

Humalog R, regular or uncomplexed insulin lispro, is supplied in packages of 10 vials, each containing 10 mL (1,000 Units), and in packages of five 1.5 mL (150 Units) cartridges for use in approved delivery devices – the B-D Pen from Becton Dickinson and Co. and in the NovoPen and NovolinPen from Novo Nordisk A/S. Each mL of Humalog contains 100 Units insulin lispro, 16 mg glycerin (tonicity modifier), 1.88 mg dibasic sodium phosphate (buffer), 3.15 mg m-cresol (1,3-dihydroxybenzene, as preservative), zinc oxide content adjusted to provide 0.0197 mg zinc ion, trace amounts of phenol, and Water for Injection. Hydrochloric acid 10% and/or sodium hydroxide 10% may be added to adjust pH to 7.0-7.8.

Humalog R has a rapid onset of action (about 15 minutes), allowing it to be administered shortly before eating a meal, compared to normal human insulin which must be administered 30-45 minutes before a meal. Humalog R’s duration of activity is shorter (2-5 hours) than normal human insulin, and Humalog R is generally used in conjunction with a longer-acting insulin product. The short duration of action of Humalog R means that patients, such as those with type 1 diabetes whose basal insulin levels are inadequate, will also require a longer-acting insulin to attain optimal glucose control.

Humalog Mix75/25 (a quick onset, longer-acting formulation) is supplied in packages of five 3 mL (300 Units) self-contained delivery devices (prefilled injectors). Humalog Mix75/25 is a mixture of 75% Humalog R; and 25% Humalog NPL or insulin lispro protamine suspension, a longer-acting neutral protamine formulation, similar to NPH. Insulin lispro NPL is a suspension of crystals formed from combination of insulin lispro and protamine sulfate under conditions to optimize crystal formation. This NPL component was specially developed to be mixed with Humalog R and is not marketed separately. Each mL of Humalog Mix75/25 contains 100 Units of insulin lispro, 0.28 mg protamine sulfate, 16 mg glycerin, 3.78 mg dibasic sodium phosphate, 1.76 mg m-cresol (1,3-dihydroxybenzene, as preservative), zinc oxide content adjusted to provide 0.025 mg zinc ion, 0.715 mg phenol, and Water for Injection. Hydrochloric acid 10% and/or sodium hydroxide 10% may be added to adjust pH to 7.0-7.8. Humalog Mix75/25 is used in Lilly’s prefilled Humalog Mix75/25 Pen delivery device (injector). Humalog R and the 75/25 mix should be stored at 2-8˚C (refrigerated). Shelf life is two years.

Launched in 1996, Humalog was the first rapid-acting insulin in the U.S. market. The rapid action of Humalog eliminated the waiting period between injection and eating, making it easier to deal with insulin regimens amidst busy schedules. Before Humalog’s introduction, people with diabetes were required to inject their regular insulin 30 to 45 minutes before a meal to give it a chance to begin working before eating. This need to wait before eating often resulted in blood sugar levels that were not well controlled.

Lilly launched the Humalog Mix75/25 Pen in March 2000. This is the Humalog Mix75/25 formulation packaged in the Lilly prefilled insulin pen, a pen-like subcutaneous injection device. The rapid-acting insulin, Humalog, is absorbed quickly by the body, within 15 minutes of eating. The insulin lispro protamine suspension or Humalog NPL component, the intermediate-acting insulin, helps to control blood-glucose levels throughout the day. By combining the benefits of a rapid-acting, mealtime insulin (Humalog R) and an intermediate-acting insulin (Humalog NPL), Humalog Mix75/25 provides blood-glucose control throughout the day – at mealtime, between meals, and at nighttime. Humalog Mix 75/25 has a duration of action similar to Humulin 70/30 (70% recombinant human insulin isophane suspension, 30% recombinant regular insulin injection).

Lilly launched the HumaPen Memoir, the first insulin pen with memory, in the U.S. in March 2007. The device has a “push-to-know” digital display that allows patients to record and review their last 16 Humalog doses, including priming doses.

Lilly launched HumaPen Luxura HD, a reusable pen that can deliver one to 30 units of Humalog in half-unit increments, in April 2007. This type of pen may be useful for people with diabetes who do not need large amounts of insulin, or for children with diabetes.

Lilly launced KwikPen, a third new insulin pen prefilled with Humalog insulins, in Feb. 2008.

In Jan 2007, Lilly halted ongoing construction of a new plant in Prince William County, Virginia, slated for recombinant insulin, including Humalog, manufacture.

Nomenclature: Insulin Lispro, rDNA [BIO]; Humalog [TR]; Liprolog [TR former in Europe]; Humalog Mix75/25 [TR]; Insulin Lispro Injection (rDNA origin) [FDA]; Insulin Lispro Protamine [FDA for Humalog Mix]; insulin (human), 28b-L-lysine-29b-L-proline- [CAS]; 28b-L-Lysine-29b-L-proline insulin (human) [CAS]; 133107-64-9 [CAS RN]; LY 275585 [SY]; Lys(B28), Pro(B29) human insulin [SY]; insulin lispro protamine suspension [SY for NPL-component of Humalog Mix75/30]; NDC 0002-7510-01; NDC 0002-7515-59 [NDC]

Note, many sources, including Lilly, sometimes use the terms ‘Humalog’ and ‘insulin lispro’ to varyingly refer to zinc-insulin lispro, the final zinc-insulin lispro crystal formulation, and/or the uncomplexed insulin lispro protein.

Companies.: The U.S. product insert/labeling cites manufacture by Lilly France S.A. (Fegersheim, France) for Eli Lilly and Co. (Indianapolis, IN). The European Public Assessment Report (EPAR) issued by EMEA, European Union is more informative, and reports that recombinant E. coli fermentation and isolation of granules (inclusion bodies containing expressed protein) are performed by Dista Products Ltd. (Speke, Liverpool, U.K.), a Lilly affiliate; the product is purified by Eli Lilly & Co. (Indianapolis, IN); final formulation and filling into unlabeled vials are performed by Lilly France S.A. (Fegersheim, France); and final labeling (including cartridges), packaging and batch release are handled by Lilly France S.A. or Lilly Deutschland GmbH (Geissen, Germany).

Humalog, like Humulin, is jointly marketed worldwide by Eli Lilly & Co. and Hoffmann-La Roche Ltd.

Lilly has built a facility in Puerto Rico (PR), which will be one of the largest biopharmaceutical facilities in the world, for large-scale manufacture of insulin lispro. This was expected to be fully operational in 2005.

Manufacture: Insulin lispro, differing from insulin only by switching position of two adjacent amino acid residues, is presumably manufactured much the same as Humulin (Lilly’s regular recombinant insulin).

FDA class: Drug NDA

Approvals: Date = 19960614; NDA supplement (to prior porcine insulin NDA); for Humalog R injection

Date = 19980806; NDA supplement; for prefilled Humalog R Pen

Date = 19991222; NDA supplements 21-018 and 21-017; for Humalog Mix 75/25 and Humalog Mix 50/50

Date = 20000404; NDA supplement; Indication = for treatment of high blood-sugar in children over age three and adults over age 65, for use in combination with sulfonylureas, as well as allowing patients to inject the insulin immediately after a meal

Date = 20000602; NDA supplement; Indication = for treatment of high blood-sugar in children over age three and adults over age 65; for use in combination with sulfonylureas; and injection of immediately after a meal

Date = 20030923; NDA supplement; Indication = approval of Abbott Labs. (McPherson, KS) as an alternate site for manufacture of Humalog vials

Date =20040602; NDA supplement; Indication = approval for use with external insulin pumps (several models from MiniMed and Disertronic)

Date = 20101200; NDA supplement; Indication = 510K clearance of V-Go, a fully disposable, non-electronic basal-bolus injector device, for the delivery of Humalog. V-Go is a once-daily, disposable, waterproof device that provides a continuous set basal rate and on-demand bolus dosing for meal-time coverage, via a rapid acting insulin analogue.

Date = 20110606; NDA supplement: Indication = approval of continuous insulin infusion pump therapy in children 4 years of age and over with type 1 diabetes extension of the time-in-use in the external pump reservoir to a maximum of seven days; and extension of the time-in-use of the infusion set and of the infusion set subcutaneous insertion site to a maximum of three days.

Indications: [full text of the "INDICATIONS AND USAGE” section from Humalog insert/labeling]:

Humalog is an insulin analog that is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Humalog has a more rapid onset and a shorter duration of action than human regular insulin. Therefore, Humalog should be used in regimens including a longer-acting insulin.

[full text of the "INDICATIONS AND USAGE” section from Humalog insert/labeling, 6/2012]:

HUMALOG® is a rapid acting human insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus.

Status: The European Union (EU) first approved Humalog R for the treatment of diabetes in adults on April 30, 1996. Humalog has been approved for use in subcutaneous infusion pumps in the EU since April 1998. In April 2000, Humalog R received supplemental EU approval for the treatment of diabetes in children and adolescents; and the EU also approved the claim that use of Humalog in subcutaneous pumps (pumps that inject insulin beneath the skin) reduces HbA1c better compared with prior human insulin formulations. Hemoglobin A1c (HbA1c) is an indirect measure of long-term diabetes control. Improvement in HbA1c has been shown to reduce the occurrence of diabetes complications.

Humalog Mix 50/50 in a premixed, prefilled pen injector device was launched in the U.S. in Feb. 2006.

LiproLog (former European trade name for a formulation from Lilly also containing insulin lispro) received European Union approval (MAA) on May 7, 1997. However, at the request of Lilly, this approval was withdrawn on Feb. 19, 2001.

In Jan. 2010, Calibra Medical announced receiving 510(k) clearance from FDA for its Finesse insulin patch-pen for up to three-day use with Humalog rapid acting insulin. Combining the mealtime therapy-adherence benefits of insulin pumps with the simplicity and affordability of syringes and pens, Calibra's novel bolus-only patch-pen is a small, adhesively attached, flat device that can be operated discretely through clothing to deliver mealtime, snack time, and correction bolus insulin in seconds..

Tech. transfer: U.S. 5,514,646, “ Insulin analogs modified at position 29 of the B chain,” assigned to individuals (Lilly staff; presumably, reassigned to Lilly) upon issuance, claims analogs of human insulin modified at position 29 of the B chain, including insulin lispro; and expires on May 7, 2013 according to the FDA Orange Book. U.S. 5,474,978, “ Insulin analog formulations,” assigned to Lilly, includes claims for insulin lispro formulations, and expires on June 14, 2014, according to the FDA Orange Book. U.S. 5,514,646 and 5,474,978 also provide coverage for Humalog Pen, according to the FDA Orange Book. U.S. patents covering Humalog Mix 75/25 and Humalog Mix 50/50 are 5,461,031, expiring on June 16, 2014; 5,747,642, expiring on June 16, 2014 ; 5,474,978, expiring on June 16, 2014; and 5,514,646, expiring on May 7, 2013, according to the FDA Orange Book.

See the Tech. transfer sections in the Humulin (#192) and the Insulin Products (#630) entries.

Trials: In open-label, crossover studies of 1,008 patients with type I diabetes and 722 patients with type II (non-insulin-dependent) diabetes, Humalog R provided comparable efficacy and reductions in postprandial glucose compared with human regular insulin. The clinical significance of improvement in postprandial hyperglycemia has not been established. In 12-month parallel studies in type I and type II patients, hemoglobin A1c did not differ between patients treated with regular insulin and Humalog. While the overall rate of hypoglycemia did not differ between patients with type I and type II diabetes treated with Humalog, compared with human regular insulin, patients with type I diabetes treated with Humalog had fewer hypoglycemic episodes between midnight and 6 A.M. The lower rate of hypoglycemia in the Humalog-treated group may have been related to higher nocturnal blood glucose levels, as reflected by a small increase in mean fasting blood glucose levels.

Medical: Humalog is intended for subcutaneous administration. Dosage regimens are individualized based on factors including the patient’s metabolic needs, eating habits, and other lifestyle variables.

Market: Total worldwide Humalog sales were about $2.37 billion in 2011; $2.054 billion in 2010; $1.96 billion in 2009; $1.73 billion in 2008; $1.475 billion in 2007; ~$1.2 billion in 2006; $1.2 billion in 2005; $1.102 billion in 2004 (also reported as $998 million); $1.021 billion in 2003 (achieving blockbuster status); $834 million in 2002; and $628 million in 2001.

The 2007 Average Wholesale Price (AWP) for Humalog is $156.18/five 3 mL (100 U/mL) cartridges, with a Direct Price (discount priice) of $130.15; and $84.37/10 mL (100 U/mL) vials, with a Direct Price of $70.31.