Status - approved; marketed

Organizations involved:

Sanofi Aventis S.A. – Manuf.; R&D; Tech.; Intl. mark.

Sanofi Aventis Pharmaceuticals, Inc. – USA mark.

Hoechst AG – Former

Novo Nordisk A/S – Tech.; Patent dispute

Novo Nordisk Pharm., Inc. – Patent dispute

Cross ref.: See the Insulin Products entry (#630).

Description: Lantus is an aqueous formulation of recombinant insulin glargine, a mutein (mutant or modified form) of human insulin with three amino acid alterations to extend its duration of action, expressed by Escherichia coli (E. coli K12). Insulin glargine [Gly(A21)-human Insulin Arg(B31)-Arg(B32)-OH] has the same primary amino acid sequence as human insulin, except that the amino acid asparagine at position A21 (position 21 on the A chain of the insulin dimer molecule) is replaced by glycine, and two arginines are added to the C-terminus of the B-chain. Insulin glargine is a long-acting (basal) insulin, with duration of activity up to 24 hours. It was designed to have low aqueous solubility at neutral pH, while being completely soluble at lower (acidic) pH. The potency of insulin glargine is approximately the same as human insulin. Insulin glargine has the formula 21A-Gly-30BA-L-13-Arg-30Bb-L-Arg-human insulin, molecular formula of C267-H404-N72-O78-S6, and a molecular weight of 6,063 Dalton (6.063 kDa).

The three amino acid substitutions alter the physical properties of the molecule, resulting in slower release from subcutaneous tissues into the bloodstream, providing continuous delivery throughout 24 hours. Patients may need only one injection of insulin glargine daily to manage their diabetes. After injection into the subcutaneous tissue, the acidic (pH = 4) solution is neutralized, leading to formation of microprecipitates from which small amounts of insulin glargine are slowly released, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peak. This allows once-daily dosing as a patient’s basal insulin. Insulin glargine differs from other insulins in isoelectric point, and it cannot be mixed or diluted with other insulins or solutions (with mixing possibly delaying its onset of action).

Lantus consists of insulin glargine dissolved in clear aqueous fluid. Lantus is supplied in 10 mL vials ((1000 Units/10 mL); 3 mL vials for use with the SoloSTAR pen device (300 Units/3 mL); and 3 mL vials (300 Units/3 mL) for use with the OptiClik pen device (discontinued in early 2011). Each milliliter contains 100 IU (3.6378 mg) insulin glargine. Lantus was formerly also available in 3 and 5 mL vials. Excipients in the 10 mL vial are 30 µg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, 20 µg polysorbate 20, and water for injection. Excipients in the 3 mL cartridges are 30 µg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, and water for injection. pH is adjusted to 4 by addition of aqueous solutions of hydrochloric acid and sodium hydroxide. Lantus is stored at 36-46°F (2-8°C; refrigerated). A new reusable pen injector device, OptiClik, was approved in Aug. 2004. Excipients in the 10 mL vial are 30 µg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, 20 µg polysorbate 20, and water for injection. Excipients in the 3 mL cartridge, used with both OptiClik and SoloSTAR pens, are 30 µg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, and water for injection.

A new “disposable” pen injector device, the SoloSTAR pen, was approved by FDA in May 2007 and will be launched later in 2007. The pen can administer doses from 1-80 units in one injection.     

Nomenclature: Insulin glargine, rDNA [BIO]; Lantus [TR]; insulin glargine [rDNA origin] [FDA]; insulin (human), 21A-Glycine-30Ba-L-arginine-30Bb-L-arginine- [CAS]; 160337-95-1 [CAS RN]; Insuman [SY]; Insulin Human Winthrop Rapid [SY]; HOE1 [SY]; 21A-Gly-30Ba-L-13-Arg-30Bb-L-Arg-human insulin [SY]; insulin, recombinant long-acting [SY]; HOE-901 [SY]; Optisulin [TR EU]; Gly(A21)-human Insulin Arg(B31)-Arg(B32)-OH, recombinant [SY]; NDC 0088-2220-33, NDC 0088-2220-52, NDC 0088-2219-05 [NDC]

Companies.: Lantus was originally developed by Hoechst Marion Roussel Deutschland GmbH (Hoechst AG; Frankfurt am Main, Germany), later Aventis Hoechst AG, a subsidiary of Aventis Pharma, which is merged into Sanofi Aventis S.A. in late 2004. Lantus is manufactured by Sanofi Aventis Pharma at facilities in Frankfurt, Germany, and distributed from there all over the world. In Dec. 2005, Sanofi Aventis announced initiation of pre-planning studies for a EUR30 million expansion of its Frankfurt manufacturing facilities for Lantus.

Lantus is marketed in the U.S. by Sanofi Aventis Pharmaceuticals Inc., formerly Hoechst Marion Roussel Inc., and internationally by Sanofi Aventis S.A. affiliates.

In early 2009, Sanofi-Aventis reported a 100 million euro investment in one of its plants in Beijing, China, to ramp up production capacity for Lantus.

In June 2009, Sanofi Aventis purchased from Pfizer the Diabel manufacturing plant in Frankfurt-Höchst, Germany, one of the largest state-of-the-art insulin manufacturing plants in the world.. Sanofi-aventis exercised its step-in rights from a purchase contract signed between Pfizer and Mannkind in March 2009 (see the entry for the failed Exubera inhaled insulin product). The acquisition included buildings, equipment, machinery and some existing contracts, and was valued at 30 million euros. With this, "Sanofi-aventis will operate the largest insulin capacity in the world in Frankfurt."

Manufacture: Manufacture involves fermentation of the transformed E. coli; isolation of cells; cell disruption/homogenization; collection of inclusion bodies; isolation and purification of fusion proteins (with preproinsulin glargine apparently expressed as a fusion with a polyhistidine (His-Tag) or other fusion protein purification tag used to facilitate specific affinity chromatography purification); (re)folding of the molecule; enzymatic cleavage of the purification tag and other unneeded terminal sequences; prepurification and concentration by adsorption chromatography; ion-exchange chromatography; reversed-phase chromatography; crystallization and lyophilization; and blending/filling.

FDA class: Drug NDA

Approvals: Date = 20000420; NDA 21-081

Date = 20030508; NDA supplement; Indication = change in dosing schedule from once daily at bedtime to flexible (anytime) daily dosing

Date = 20040812; NDA supplement; Indication = approval of OptiClik, a new reusable pen delivery device

Date = 20041116; NDA supplement; Indication = approval of packaging in 10 mL vials and 3 mL cartridges.

Date = 20050315; NDA supplement; Indication = approval of an additional stabilizing agent, 20 ppm of polysorbate 20 (Tween 20), in the 10 mL vial presentation

Date = 20070502; NDA supplement’ Indication = approval of SoloSTAR, a new prefilled disposable for once-daily 24-hour Lantus injection for the treatment of hyperglycemia in people with type 1 or type 2 diabetes..

Indications: [full text of "INDICATIONS AND USAGE” section of product insert/labeling, 4/2005]:

LANTUS is indicated for once-daily subcutaneous administration for the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.

Status: Aventis filed its NDA on April 23, 1999, and approval was granted on April 20, 2000 (approval time = ~1 year). Lantus was launched in the U.S. on May 22, 2001. In Feb. 2004, Aventis filed for approval of OptiClik, a reusable pen for administering Lantus, in both the U.S. and European Union.

European Union (EU) approval was granted in June 2000. On Dec. 12, 2002, Lantus received EU approval for flexible (anytime) daily dosing. On March 17, 2003, Lantus received EU approval for pediatric use (6 years and older) for diabetes mellitus. Lantus was first launched in Germany in June 2000, and was launched in the U.K. in May 2002. Lantus was approved in Japan on Oct. 16, 2003.

The “disposable” Lantus SoloSTAR pen injector was approved by FDA in May 2007, and was expected to be available in pharmacies later in 2007.. Lantus in the SoloSTAR pen provides diabetes patients with an alternative to the traditional needle and syringe for insulin therapy. Sanofi-Aventis asserts that its Lantus SoloSTAR is the only disposable insulin pen that allows patients to administer doses from 1 up to 80 units in one injection.

In July 2009, FDA notified healthcare professionals and patients that it was aware of four recently-published observational studies that looked at the use of Lantus and possible risk for cancer in patients with diabetes. Three of the four studies suggested an increased risk for cancer associated with use of Lantus. Based on the currently available data, the FDA recommended that patients should not stop taking their insulin therapy without consulting a physician. Sanofi defended Lantus, saying that data from studies of 70,000 patients and post-marketing surveillance data "confirms the safety profile of Lantus."

In June 2012, a results from the 12,000-patient randomized ORIGIN trial found no association between Lantus and cancer after 6 years of follow-up. Three other studies have backed up the no-cancer-link conclusion. This has essentially laid to rest concerns about Lantus inducing cancer.

Tech. transfer: The product insert cites U.S. patents 5,656,722; 5,370,629; and 5,509,905. More recent U.S. patents, 6,100,376 (expired May 6, 2010) and 6,221,837, also describe aspects of recombinant insulin glargine.

According to the FDA Orange Book, U.S. 5,656,722, “A21-B30-modified insulin derivatives having an altered action profile,” assigned to Hoechst AG, covers insulin glargine, has an expiration date of Sept. 12, 2014, and also provides pediatric exclusivity expiring on March 12, 2015. Otherwise, FDA pediatric exclusivity expires Oct. 20, 2005; new chemical entity exclusivity expires on April, 20, 2005; and exclusivity related to approval for change in dosing from once daily at bedtime to flexible use expires on May 1, 2006.

U.S. 6,100,376, “A21, B30, modified insulin derivatives having an altered action profile,” August 8, 2000, assigned to Hoechst AG, describes recombinant Gly(A21)-human Insulin Arg(B31)-Arg(B32)-OH (insulin glargine). Example 6 describes construction of a plasmid for the preparation of insulin glargine. The DNA plasmid pSW2 encoding monkey proinsulin is used as starting material for the construction of the expression plasmid. Monkey proinsulin differs from human proinsulin merely by replacement of a single amino acid in the C peptide (B37-Pro in place of Leu at this position of human proinsulin). pSW2 is cleaved with PvuII and SalI and ligated with a synthetic DNA plasmid (pIK100) which encodes the modified A chain, resulting in plasmid pSW21 for expression of insulin glargine or Gly(A21)-human Insulin Arg(B31)-Arg(B32)-OH.

Novo Nordisk A/S filed suit in Germany in April 2000 against Aventis Pharma (now Sanofi Aventis S.A.) alleging that production and sale of Lantus infringes two of its German patents. This suit was settled in Jan. 2001 with Novo Nordisk granting Aventis an exclusive license to the contested patents. Aventis paid an up-front fee “expected to increase Novo Nordisk’s profits by close to $31 million” in 2001, with unspecified payments in 2003 and 2004.

On Sept. 2, 2005, Novo Nordisk filed a U.S. patent infringement lawsuit against Sanofi-Aventis claiming that the OptiClik pen system used with Lantus infringes a Novo Nordisk U.S. Patent. The OptiClik pen system is sanofi-aventis’s only FDA-approved insulin delivery device and is used with all its U.S. insulin products (Apidra and Lantus). The OptiClik device, which is produced for Sanofi Aventis by Ypsomed Holding AG (Switzerland). The case is expected to go to trial in 2007.

In May 2006, Novo Nordisk filed a complaint against Sanofi-Aventis with the U.S. International Trade Commission (ITC), alleging patent infringement by OptiClik and its cartridges and seeking to restrict the U.S. importation and sale of the infringing device.

In July 2007, Novo Nordisk initiated an infringment suit alleging that the Solo-Star injection pen with Lantus insulin, then recently approved, infringes its patents on its NovoPen 4.

Trials: Controlled clinical trials have shown that Lantus has similar levels of efficacy, in regards to metabolic control, as insulin NPH formulations. Lantus showed a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak, in comparison to NPH human insulin. Lantus injection once-daily at bedtime was studied in more than 4,000 patients in six open-label, randomized, parallel studies comparing its safety and efficacy to NPH human insulin. Lantus, in combination with oral hypoglycemic agents, was as effective as once-daily NPH in combination with oral hypoglycemic agents (including sulfonylureas, metformin, and acarbose).

In the Nov. 2003 issue of Diabetes Care, the 756-patient Treat-to-Target study was published. Nearly 25% more type 2 diabetes patients treated with Lantus achieved greater complete treatment success, rigorously defined as reaching target A1C (glycated hemoglobin or HbA1c) <7%, without an episode of documented nocturnal hypoglycemia, compared to those treated with NPH insulin. Rates of other categories of symptomatic hypoglycemia were 21-48% lower with Lantus. Insulin use, which can improve glycemic control, is often delayed or not used aggressively enough due, in part, to fear of hypoglycemia.

In July 2007, Novo Nordisk filed suit in U.S. federal court asserting that the SoloSTAR pen injector violates patents that cover its NovoPen 4 injectors.

In Sept. 2009, results were reported from a head-to-head study of once-daily, 24-hour basal Lantus compared to twice-daily insulin detemir (Levemir). The 964 patients taking Lantus required an average daily dose of 43.5 units to achieve the primary endpoint of HbA1c below 7% without symptomatic hypoglycaemia compared to patients on insulin detemir, who received 76.5 units - an increase of 76% (p<0.001). Despite lower doses of insulin in the glargine group, Lantus once-daily and Levemir twice-daily resulted in similar improvements in glycemic control (HbA1c) and a similar risk of hypoglycaemia (primary endpoint: 27.5% vs 25.6%, p=0.52). Patients in the Lantus arm of the study also achieved significantly lower fasting blood glucose (-63.1mg/dl Lantus vs -57.7mg/dl, p<0.001). Patients taking Lantus once-daily reported a significantly greater treatment satisfaction over insulin Detemir twice-daily, with over 50% less drop-outs (4.6% vs 10.1%, p=0.001). Discontinuations in patients taking insulin Detemir were primarily due to adverse events, including skin reactions. A similar rate of overall hypoglycaemia and nocturnal hypoglycaemia was observed in both arms, but patients on Lantus once-daily experienced less daytime hypoglycaemia as compared to insulin Detemir (1.06 vs 1.64 events per patient year, p=0.046). Patients on insulin Detemir experienced less weight gain (0.6 vs 1.4kg, difference 0.77 kg, p<0.001). This study demonstrated that for insulin-naive patients with type 2 diabetes, initiating insulin therapy with once-daily Lantus achieved the same glycemic control as twice-daily Levemir, with somewhat more weight gain, but lower insulin dose."

In Sept. 2009, Sanofi-Aventis announced plans to provide methodologically robust studies to resolve the debate over insulin safety, including insulin analogs and Lantus (insulin glargine) association with increased risk for cancer. The research program is designed to generate more information on whether there is any association between cancer and insulin use and to assess if there is any difference in risk between insulin glargine and other insulins. "Sanofi-aventis' scientific plan will encompass state-of-the-art pre-clinical and clinical programs involving human insulin and insulin glargine. Pre-clinical studies will assess the differential effects of insulin glargine, its metabolites and other insulins in various models. The clinical development plan is based on several rigorous epidemiological studies, designed and implemented with the support of international experts and institutions, that will be conducted across Europe and North America. T he plan is structured to yield short-term and longer-term results"

In June 2010, results from a study of 1,500 patients were published in Diabetes Care linking Lantus to a higher cancer risk. The study was “methodologically challenged,” according to Sanofi-Aventis, with 1,500 patient insufficient to support conclusions and such such observational studies carrying little scientific weight. A potential link to increased cancer had been reported by investigators in Diabetologia in June 2009. As demonstrated by its approval, FDA did not have problems with Lantus causing cancer.

In Feb. 2011, FDA reported, "FDA has reviewed the four studies and has determined that the evidence presented in the studies is inconclusive, due to limitations in how the studies were designed and carried out and in the data available for analysis."

Medical: Insulin glargine is administered subcutaneously once daily at bedtime. The average starting dose is 10 IU daily. The dose range is 2-100 IU. This regimen is individually adjusted according to need.

Lantus is unique in that it has no pronounced peak concentration in vivo, and is indicated for once-daily administration at bedtime in the treatment of adult and pediatric patients (6 years of age and older) with type 1 diabetes or adult patients with type 2 diabetes who require basal (long-acting) insulin for the control of hyperglycemia. Lantus works almost twice as long as insulin neutral protamine Hagedorn (NPH), then the most commonly used intermediate-acting insulin available. Lantus’ duration of action is 24 hours versus 14.5 hours with NPH insulin. Lantus has slower and more prolonged absorption and a relatively constant concentration/time profile over 24 hours. In contrast, two NPH injections are required to provide full basal insulin coverage. Lantus is not meant to replace short-acting insulins, such as Regular insulin or faster-acting types, which provide a “bolus” at meal time. Lantus can be used with oral diabetes medications and/or short-acting insulin to help control diabetes.

Market: Worldwide sales were about $6.4 b billion in 2012 (based on reported nearly €5 billion revenue); $5.19 billion in 2011; $4.83 billion in 2010; $3.1 billion euros ($3.8 billion) in 2009 (according to press reports). However, La Merie reports worldwide sales were $4.185 billion in 2009, $3.130 billion in 2008 and $3.167 billion in 2008. Worldwide 2006 sales were $2.188 billion; 2005 sales were € 1.214 billion ($1.47 billion on 4/15/06); $1.053 billion in 2004, achieving blockbuster status; € 487 million (~$550 million) in 2003, and € 299 million (then ~$329 million).

In mid-2012, Lantus held 80% of the long-acting insulin market.

2012 worldwide sales break down to about $4 billion in U.S., $1 billion in Europe, ROW/emerging markets, $1.4 billion. Sales in Western Europe amounted to €778 million ($1.04 billion) in 2012, while Lantus brought in more in emerging markets. Following 2012 EU approval, Tresiba will be launched market-by-market in the EU as pricing and reimbursement negotiations allow.

In Feb. 2013, FDA's rejection of approval of Tresiba, a competing long-acting insulin, from Novo Nordisk delayed a major potential competitor for Lantus from the market for likely several years. With this, Leerink Swann, increased their sales forecast for Lantus to $8.83 billion in 2020. With Sanofi testing a once-daily formulation of Lantus in clinical trials, this might further increase Lantus use.

In Aug. 2013, Sanofi increased the U.S. list price for Lantus vials by 14.9% to $16.64 per ml and Lantus SoloSTAR increased 9.9% to $18.38 per mL.

U.S. 2005 sales were € 717 million ($868 million, 4/15/06), and € 495 million ($599 million, 4/15/06) in 2004. European 2005 sales were € 413 million ($500 million, 4/15/06), and € 296 million ($358 million, 4/15/06) in 2004.

The 2007 Average Wholesale Price (AWP) is $161.71/five 3 mL vials, and $80.83/10 mL vial (Red Book, 2007).

In May 2004, among the major insulin products in the U.S. market (Lantus, Humalog, Humulin, Novolog and Novolin ), Lantus held 24.8% of the U.S. insulin market with 124,468 total prescriptions filled in the prior four weeks, including 43,643 new prescriptions.

In the U.S., Lantus is the most frequently prescribed long-acting insulin; and Lantus is the most frequently prescribed insulin for newly-diagnosed type I diabetes patients and in newly insulinized type II patients. Over half of new patients with Type 1 diabetes started on insulin are prescribed Lantus.

In Dec. 2002, it was reported that the worldwide advertising/promotional budget for Lantus would be about $100 million, with Euro RSCG Worldwide handling worldwide advertising.

In Jan. 2013, In Denmark, in a reassessment of reimbursement grant to diabetes drugs, the Reimbursement Committee moved the analog insulins Lantus and Levemir from general to limited reimbursement. In addition, the Board made a distinction between products, and recommended that patients must first be treated with Sanofi's Lantus, and only if that does not work, they can be treated with Novo Nordisk's Levemir. Overall, this does not bode well for the next generation insulins from Novo Nordisk , Lilly and Sanofi which are expected to reach the market over the next few years. This new differentiation was made solely on the basis of the price differential between the two products. Both Lantus and Levemir are considered to have the same efficacy and safety profile, but there is a significant price difference.

Competition: Levemir is Lantus' primary competitor in most major markets.

In June 2009, Biocon launched its long-acting insulin glargine (marketed as Basalog) biosimilar/biogeneric version of Sanofi Aventis' Lantus, on the domestic Indian market. Basalog is available in 10ml and 3 ml vials.