liraglutide - Victoza; Arg34-GLP-1[7-37]; GLP-1 [recombinant]
Status - approved in the European Union; NDA approved in Jan. 2010
Organizations involved:
Novo Nordisk A/S – Manuf.; R&D; Tech.; World mark.
Cross ref.: See the Glucagon Products entry and specific Glucagon products.
Description: Victoza is an aqueous formulation of liraglutide, a long acting analog (fragment) of the naturally occurring recombinant human glucagonlike peptide-1 [GLP-1(7-37)] with one amino acid substitution (arginine at position 34) expressed by transformed Saccharomyces cerevisiae (yeast) cells, strain z, with a chemically attached lipophilic fatty acid chain substituent for prologation of in vivo half-life. Liraglutide has 97% homology with human GLP-1(7-37), substituting arginine for lysine at position 34. Liraglutide is manufactured by chemcially linking (acylaing) a C-16 fatty acid (palmitic acid) with a glutamic acid spacer on the remaining lysine residue at position 26 of the recombinant expressed peptide precursor during down-stream processing. The calculated molecular formulat is C172H265N43O51, and calculated molecular weight of liraglutide is 3.75120 kDa.
Victoza is is packaged as a solution for subcutaneous injection containing 6.0 mg/ml of liraglutide in a 3 mL cartridge presented in a pre-filled, multi-dose pen-injector for subcutaneous injection. Each individual pen delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL).
The formulation is a phosphate–buffered solution with polypropylene glycol as isotonic agent. Excipients include disodium phosphate dihydrate, phenol, propylene glycol, sodium hydroxide, hydrochloric acid, water for injections. The pH of the isotonic solution is 8.15.
Victoza may contain residues from leachables from the packaging of the product, consisting of xylenes and brominated phenols. The amount of xylenes that can maximally be taken in by users of Victoza is far below the EU Permitted Daily Exposure of 21.7 mg/day and the amount of Br-phenols that can maximally be taken in is below the threshold for toxicological concern (TTC) of 1.5 µg/day. Therefore, according to EMEA/EU, "no relevant risk is expected of these leachables."
Biological activity of liraglutide is measured with a cell based bioassay reflecting the expected physiological mechanism in the clinic. Liraglutide stimulates a continuous mammalian cell line transfected with human GLP-1 receptors to produce intracellular cAMP in a dose dependent manner. The bioactivity of the sample is calculated relative to the SRM (secondary reference material).
Liraglutide is the first once-daily human glucagon-Like Peptide-1 (GLP-1) analogue developed for the treatment of type 2 diabetes.
Nomenclature: Liraglutide [USAN; INN]; Liraglutide (genetical recombination) [JAN]; Glycine, L-histidyl-L-alanyl-L-alpha-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-alpha-glutamylglycyl-L-glutaminyl-L-alanyl-L-alanyl-N6-(N-(1-oxohexadecyl)-L-gamma-glutamyl)-L-lysyl-L-alpha-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L-arginylglycyl-L-arginyl- [CAS]; Glycine, L-histidyl-L-alanyl-L-alpha-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-alpha-glutamylglycyl-L-glutaminyl-L-alanyl-L-alanyl-N6-(N-(1-oxohexadecyl)-L-gamma-glutamyl)-L-l [CAS]; 204656-20-2 [CAS RN]; Arg34-GLP-1[7-37] [SY]; Arg34Lys26-(N--(-Glu(N--hexadecanoyl)))-GLP-1[7-37] [SY]; D06404 [SY]; N26-(Hexadecanoyl-gamma-glutamyle)-(34-arginine)GLP-1-(7-37)-peptide [SY]; N26-(Hexadecanoyl-gamma-glutamyle)-(34-arginine)glucagon-like-peptide-1-(7-37)-peptide [SY]; NN 2211 [SY]; NN2211 [SY]; NNC 90-1170 [SY]; Arg34-GLP-1[7-37] [SY]; NDC 0169-4060-12 and NDC 0169-4060-13 [NDC]
Biological.: GLP-1 is an important gut hormone with regulatory function in glucose metabolism and gastrointestinal secretion and metabolism. Human GLP-1 is a 30 amino acid peptide originating from preproglucagon, which is synthesized in the L-cells in the distal ileum and in the brain. Processing of preproglucagon to yield GLP-1 (7-36)amide and GLP-2 occurs mainly in the L-cells. GLP-1 is normally secreted in response to food intake, in particular carbohydrates and lipids stimulate GLP-1 secretion. GLP-1 has been identified as a very potent and efficacious stimulator for insulin release. GLP-1 lowers plasma glucagon concentrations, slows gastric emptying, stimulates insulin biosynthesis and enhances insulin sensitivity.
The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells. The effects of liraglutide are mediated exclusively by activation of the GLP-1 receptor. Unlike GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in humans suitable for once daily administration. Following subcutaneous administration, this protracted action profile is based on self-association, which results in slow absorption, and binding to albumin and enzymatic stability towards the DPP-IV enzyme, both resulting in a prolonged plasma half-life.
Liraglutide is a long-acting GLP-1 analog. It has been designed to bind to albumin as the main molecular mechanism of protraction (slowing its breakdown in vivo). In vitro, this was shown in the receptor cAMP as well as binding assays where addition of albumin right-shifted the dose-response and/or binding curve. The apparent reduced potency of liraglutide shows that only the free fraction of liraglutide is responsible for its pharmacological effect in vitro as well as in vivo. Also, liraglutide in a pharmaceutical solution forms a micell-like heptamer which may contribute to the slowing of absorption from the subcutis.
Liraglutide works by stimulating the release of insulin only when glucose levels become too high and by inhibiting appetite.
Liraglutide is a potent, selective and efficacious agonist on the human as well as mouse, rat, rabbit, pig and Cynomolgus monkey GLP-1 receptors. Liraglutide has been shown to exert a number of actions in vitro that are known to be specific GLP-1 effects. Liraglutide has also been shown to glucose-dependently stimulate insulin secretion from isolated -cell islets in vitro. Liraglutide attenuated -cell apoptosis in vitro under adverse conditions with high concentrations of free fatty acids and proinflammatory cytokines. A proliferative effect on primary rat -cells could be shown for liraglutide in vitro, but no consistent effect was observed under hyperglycaemic conditions in vivo.
In vivo, liraglutide lowers blood glucose and body weight in a number of diabetic and obese animal models using rodents, pigs and monkeys. The mechanism of action in vivo involves glucose-dependent increase in insulin secretion, lowered glucagon secretion, decreased gastric emptying, loss of body fat, lowered food intake, altered food preference, and maintained energy expenditure. The mechanisms of action are consistent with a specific GLP-1 effect.
Liraglutide's primary mechanisms of action are 1) to stimulate insulin secretion and decrease glucagon secretion in a glucose-dependent manner, 2) delay gastric emptying, and 3) reduce appetite. In addition, GLP-1 might be involved in preserving beta-cell mass and function.
An important and possibly primary defect in type 2 diabetes may be an impaired incretin function. Treatment with glucagon like peptide-1 (GLP-1) may help to compensate for this defect, as GLP-1 has been shown to reduce hyperglycemia in subjects with type 2 diabetes.
Liraglutide has been evaluated by EMEA/EU "to be safe with regard to both TSE and viral agents, since no animal derived raw materials are used in the production process." Yeast is not a natural host for mammalian viruses, so no virus testing had been performed on either the cell banks or the drug substance.
Victoza is not a substitute for insulin and should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
Companies.: Victoza was developed and is manufactured and marketed by Novo Nordisk A/S.
In April 2005 Novo Nordisk broke ground for a new facility in Kalundborg, Denmark, to produce liraglutide. The new 7,000m² plant represented an estimated investment of €100m. The Greenfield facility was constructed according to Novo Nordisk Engineering ’s well-proven concept for modular engineering.
Manufacture: manufacture involves the following main steps: fermentation of yeast cells, recovery and purification of liraglutide precursor, acylation of the precursor and further purification of liraglutide to drug substance. No animal derived raw materials or excipients are used in the manufacture of liraglutide.
The DNA encoding Arg34-GLP-1[7-37] was obtained using synthetic DNA oligonucleotides and standard PCR techniques. This was used to construct the expression plasmid pKV308, used to transform Saccharomyces cerevisiae strain ME1719, resulting in the generation of S. cerevisiae strain YES2085 expressing liraglutide precursor.
For EU approval, consistency in production had been shown on three full scale commercial batches. Although a number of changes had been introduced in manufacturing during development, EMEA/EU reported "a good comparability study has been presented in the dossier showing that batches of drug substances derived from the different manufacturing processes and locations are indeed comparable as far as the purity profile is concerned."
FDA class: Drug NDA
Approvals: Date = 20100129, BLA
Date = 20120406; BLA supplement; Indication = various revisions to the product insert (3 sBLAs the same day)
Date = 20120406; BLA supplement; Indication =
Date = 20120524; BLA supplement; Indication = approval for the treatment of type 1 diabetes in patients aged 2–5 years
Date = 20120408; BLA supplement; Indication = addition of information about clinical superiority of compared to Januvia (drug from Merck) for controlling blood sugar and helping patients lose weight. Also, data were added regardng adding Novo's Levemir insulin to Victoza treatment in combination with metformin.
Indications: [Full text of the "Indications: and Usage" section of the U.S. product insert/labeling]:
Victoza is a glucagon−like peptide−1 (GLP−1) receptor agonist indicated as an adjunct to diet and
exercise to improve glycemic control in adults with type 2 diabetes mellitus (1).
Important Limitations of Use (1.1):
Indications: [The approved indications: in the EU are]:
"Victoza is indicated for treatment of adults with type 2 diabetes mellitus to achieve glycaemic control:
Status: A MAA for European Union approval with standard review (no exceptional circumstances or an accelerated review requested) was filed on May 23, 2008. This sought approval for both monotherapy and dual and triple combination use. The claims for monotherapy were later withdrawn. EMEA/EU granted approval on July 3, 2008.
Also on May 23, 2008, Novo Nordisk filed a NDA with FDA, with standard 10-month review, presumably for the same indications: approved in the EU. Development and approval of liragulide in the U.S. has been delayed by about four years from original expectations.
In Sept. 2008, 6 months before the end of the 10-month PDUFA date, FDA reported it would not meet this schedule (generally not a good sign). This was expected to allow Novo Nordisk to incorporate feedback from an Advisory Committee meeting. The Endocrinologic and Metabolic Drugs Advisory Committee, FDA, was scheduled to consider liragulide on March 2, 2009 (but this was rescheduled to April. The 3 weeks between the meeting and the user fee deadline was not considered enough time for FDA to complete its review. FDA was cited as "obviously taking it a bit slow on liraglutide given the pancreatitis safety signal seen with another GLP-1: Amylin’s exenatide (Byetta)."
In April 2009, the Endocrinologic and Metabolic Drugs Advisory Committee, FDA, considered the NDA for liragulide. The Committee voted that appropriate evidence of cardiovascular safety had been provided to rule out excess cardiovascular risk of liraglutide relative to comparators. A majority of Committee members voted that Novo Nordisk, based on the available data, had ruled out that the finding of C-cell tumors in rats and mice was not relevant to humans, but the Advisory Committee was split (6 to 6) on an FDA question related to whether the available data on C-cell tumors permitted approvability. The Advisory Committee unanimously supported approvability of liraglutide with regard to risk of papillary thyroid cancer. Overall, the drug was viewed as offering some distinct advantages over standard therapy. It doesn't risk pushing blood sugar too low and there's clear evidence that the drug triggers weight loss.
On May 6, 2009, EMEA/EU recommended approval of Victoza for use an adjunct to diet and exercise to improve blood sugar control in adults with type 2 diabetes mellitus, with market entry expected in July.
On Sept. 23, 2009, Novo Nordisk reported that formal feedback from FDA concerning liragulide NDA had been deferred until the fourth quarter of 2009.
On Jan. 29, 2010, the NDA was approved by FDA.
In many respects, this was a worse case-type approval. A black box warning includes a potential increased risk of thyroid cancer (despite Novo Nordisk's repeated claims that this applies only to rodents, not monkeys or humans). No first-line usage was allowed. Sgnificant post-approval requirements included a CV safety study, a 5-year epidemiological study to evaluate thyroid cancer risks, a 15-year cancer registry to monitor thyroid cancer cases, and a REMS. However, FDA's approval of Victoza for second line treatment of Type-2 diabetes (following its approval in many ex-US markets) confirmed that FDA is comfortable with risk evaluation and mitigation monitoring for the rare and likely unrelated side effects of acute pancreatitis and medullary thyroid cancer. On the positive side, Victoza is once-daily, can be taken anytime, prompts some weight loss, isn't associated with hypoglycemia or significant nausea, and is relatively easy to titrate.
As port of FDA approval, Novo Nordisk is required to study the cardiovascular safety of the drug and conduct a five-year review using a database to evaluate “thyroid and other cancer risks as well as risks for seriously low blood glucose levels (hypoglycemia), pancreatitis, and allergic reactions.”
U.S. product insert/labeling includes serious warnings regarding safety, including a "black box" warning regarding potential increased risk of thyroid cancer, (despite Novo Nordisk's claims that this applies only to rodents, not monkeys or humans); there was no first-line usage approved (termed a worst case for labeling by some); and with significant post-approval requirements, including a CV safety study, a 5-year epidemiological study to evaluate thyroid cancer risks, a 15-year cancer registry to monitor thyroid cancer cases, and a REMS. Upon approval FDA reported that "safety concerns included: Clinical trials that suggested Victoza may be associated with pancreatitis (see Q3). Other drugs that work through similar mechanisms as Victoza have also been associated with pancreatitis. Animal data that showed a rare type of thyroid cancer known as medullary thyroid cancer associated with liraglutide, although the relevance of this finding to humans remains unknown".
To ensure that the benefits of Victoza continue to outweigh any risks, FDA required a Risk Evaluation and Mitigation Strategy (REMS) as part of the Victoza approval. This includes a patient Medication Guide and a Communication Plan. FDA also required additional studies to better understand the risks associated with this medicine. In addition, FDA has required a large cardiovascular safety trial, that is now required as part of the development of most diabetic medications." Also, "In five clinical trials including more than 3,900 people, there were seven cases of pancreatitis in patients using Victoza and one case in a patient using another diabetes medicine. This constituted a 4:1 imbalance of pancreatitis cases, when considering the number of patient exposures. Although there were too few cases to know if Victoza causes pancreatitis, healthcare professionals and patients should be aware of this potential risk, and know that some common side effects of Victoza may be similar to the symptoms of pancreatitis." And, "As a result of the animal study results, the clinical development program for Victoza included blood tests for a biomarker for medullary thyroid cancer—a blood calcitonin test. Data from a two-year study did not show any difference in calcitonin levels between patients treated with Victoza compared to other diabetes medicines. With these data, FDA is of the opinion that this safety concern was adequately addressed during Victoza's development. However, as part of FDA's commitment to post-marketing safety evaluation, the Agency is requiring the manufacturer of Victoza to conduct a 5-year epidemiological study using a large healthcare claims database to compare the development of thyroid cancer among patients with T2DM who use Victoza to those who are not using this medicine. In addition, FDA is requiring the manufacturer to develop a medullary thyroid cancer registry to monitor how many cases of medullary thyroid cancer occur each year for at least 15 years to see whether there is any association of this specific type of thyroid cancer with Victoza therapy."
Upon approval FDA also reported, "In December 2008, FDA issued a Guidance for Industry that required manufacturers of new treatments for diabetes to carefully design and evaluate their clinical trials for cardiovascular safety. The Victoza application for approval was submitted before the December 2008 guidance was issued; therefore, the manufacturer had not designed the recommended cardiovascular safety trials. FDA, however, reviewed the available cardiovascular safety data, and determined there was no evidence of excess cardiovascular risk associated with Victoza. The April 2009 FDA Endocrinologic and Metabolic Drugs Advisory Committee met, discussed, and a majority of the members voted that the available data adequately addressed the cardiovascular safety concern to support approval. Still, FDA is requiring a post-approval study that specifically evaluates cardiovascular safety in a higher risk population as part of the Agency's commitment to post-marketing safety evaluation."
At the time of FDA approval, Victoza had been approved by the European Medicines Agency (EMEA) in all 27 European Union member states, Mexico and Iceland. On Jan. 20th, 2010, Victoza was also approved in Japan. A New Drug Application was submitted for China in August 2009.
On Feb. 25, 2010, Novo Nordisk launched Victoza in the U.S.
In June 2010, Novo Nordisk launched Victoza in India.
On Oct. 21, 2010, Novo Nordisk launched Victoza in the U.S. market. Victoza was the “first and only once-daily GLP-1 analog.” Print ads were handled by ghg (grey healthcare group) and the Web site was developed by Digitas Health.
On June 13, 2011, Novo Nordisk issued a letter to U.S. healthcare professionals with important safety information about Victoza . The letter was issued because a recent assessment of healthcare providers showed that some primary care providers are not fully aware of the serious risks associated with the use of Victoza. FDA required Novo Nordisk to communicate the following risk information to potential prescribers: Victoza causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Additionally, in clinical trials studying Victoza, there were more cases of pancreatitis in patients treated with Victoza than in patients treated with comparators."
As of Feb. 2012, Victoza had received approvals in 38 countries.
In April 2012, Public Citizen (advocacy group) filed a citizen's petition with FDA noting the risks of thyroid cancer, pancreatitis and kidney failure far exceed Victoza's benefits and that the produc is not need, that there are lots of alternative treatments for type 2 diabetes. Citing FDA internal documents it had obtained, Public Citizen pointed out that FDA had given approval to Victoza over the recommendation of 3 reviewers.
Tech. transfer: The U.S. product insert reports, "Victoza is covered by U.S. Patent Nos. 6,268,343 ["Derivatives of GLP-1 analogs,"expiring Aug 22, 2017], 6,458,924 ["Composition containing human alpha interferon species proteins and method for use thereof," expiring Oct 14, 2014] and 7,235,627 ["Derivatives of GLP-1 analogs," expiring 2022] and other patents pending."
The Orange Book cites 6004297 expiring Jan 28, 2019;
6268343 expiring Aug 22, 2017;
6458924 expiring Aug 22, 2017;
7235627 expiring Aug 22, 2017;
8114833, Propylene glycol-containing peptide formulations which are optimal for production and for use in injection devices," expiring Aug 13, 2025;
RE41956, "Dose setting limiter," a delivery device patent, expiring Jan 21, 2021 and;
RE43834 expiring Jan 28, 2019. Although these are the only patents for which Novo Nordisk could challenge a approval of a generic drug version of Victoza, with all biopharmaceuticals now redefined by the BPCIA to be in line with definitions for biopharmaceuticals/biologics, with follow-ons of Victoza now approvable as biologics, other patents could be prosecuted for infringement by the company (i.e., if approvals are for biosimilars or biobetters, other relevant patents can be asserted).
BMS has received patents apparently covering or related to liraglutide including U.S. 7,417,028; 7,238,671; and 7,238,670; each entitled "Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions." BMS has pending applications apparently or perhaps covering liraglutide including U.S. 20080045461, "N-Terminally Modified GLP-1 Receptor Modulators;" and 20070287670, "Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions."
EP 0944648, "GLP-1 DERIVATIVES," assigned to Novo Nordisk, expires in 2017. EP 1060191, "DERIVATIVES OF GLP-1 ANALOGS, expires in 2019.
Trials: Overall, the liraglutide clinical development program comprised 38 completed trials, with some patients followed for up to 2 years. The trials were conducted world-wide, with the majority conducted in Europe. Core studies of the EU MAA application were five Phase III trials ("therapeutic confirmatory trials"). Based on these trials, a marketing authorisation for liraglutide initially as monotherapy, as well as dual and as triple therapy was initially sought. Given in dual therapy, when added to metformin, liraglutide (1.2 or 1.8 mg) was equally effective as glimepiride, and better than metformin monotherapy. The formation of anti-liraglutide antibodies has not been observed.
Victoza was evaluated in The Liraglutide Effect and Action in Diabetes (LEAD) phase III trials, the most comprehensive clinical development program conducted to date by Novo Nordisk in type 2 diabetes. In clinical studies including use as monotherapy and in combination with standard diabetes treatments, Victoza produced significant reductions in A1C and also was associated with weight loss.
Results from a direct comparison study were published in the in the June 8, 2009 online issue of The Lancet. Patients who received liraglutide once a day had a greater reduction in average blood sugar levels at the end of the 26-week study than did Byetta twice a day. This once-a-day injections should be preferred by many patients because of the convenience -- and administration is not tied to meals. Liraglutide can be taken any time as long as taken at the same time each day.
A study of how well liraglutide and Byetta lowered A1c, a measure of blood-sugar control over time enrolled 464 patients with poor blood-sugar control despite standard treatment with metformin and/or a sulfonylurea. At the start of the study, which enrolled 464 patients with poor blood-sugar control despite standard treatment with metformin and/or a sulfonylurea, study participants' average A1c level was 8.2%. The American Diabetes Association (ADA) recommends that patients keep their A1c level below 7%. Byetta helped patients lower their A1c by 0.79%; 43% of patients were able to get their A1c under 7%. Patients on liraglutide had a 1.12% drop in A1c -- and 54% got their A1c under 7%.
Byetta, which requires two injections daily, makes many patients feel nauseous, although this side effect gets better over time. Nausea is also a side effect of liraglutide, but patients get over it much more quickly. In its comparative study (paragraph above), by week six the proportion of patients with nausea in the liraglutide group was below 10%, whereas it took patients on Byetta] 22 weeks to reach that..
Patients on liraglutide had about half as many episodes of hypoglycemia (too-low blood sugar) as those on Byetta. And patients on liraglutide lost a little more weight (7.1 pounds) than patients on Byetta (6.28 pounds), although this was not statistically significant.
It was concluded that Victoza shows extremely good durability in terms of blood-sugar control without any loss of the weight loss benefit or any other features that plysician like to see in terms of blood-sugar reduction. Many physician will likely prescribe Victoza as a first-line treatment for newly diagnosed patients. That's because Victoza stimulates insulin production by the beta cells of the pancreas. As diabetes progresses, beta cells die off, so patients get the most benefit if treated early in their illness. And Victoza does have benefits with regard to blood pressure, particularly systolic blood pressure, which is a problem with diabetic patients.
In Oct. 2009, Novo Nordisk reported that Victoza was far more effective than Roche's Xenical in cutting weight and reducing blood pressure in treated patients.
In Jan. 2013, an article published in The Lancet reported results of the DURATION-6 open-label, head-to-head trial in patients with type 2 diabetes found very little difference between the two-a once-weekly injection of exenatide (Bydureon, Lilly/Amylin Pharmaceuticals) and a once-daily dose of liraglutide (Victoza, Novo Nordisk) in terms of improvements in glycemic control, although liraglutide had the slight edge. However, gastrointestinal side effects-nausea, vomiting and diarrhea-were twice as common with liraglutide. DURATION-6 had the primary hypothesis that the glycated hemoglobin (HbA1c)-lowering capability of weekly exenatide would be at least noninferior to that of liraglutide, but that did not turn out to be the case.
Medical: Liraglutide provides greater improvements in glycemic control and is better tolerated than Byetta (exenatide) from Amylin Pharmaceuticals and Eli Lilly, probably its primary competitor, which also has biological properties similar to human glucagon-like peptide-1 (GLP-1).
Victoza offers convenience for patients, with once daily (SC) injections anytime during the day (same time each day), while Byetta is administered SC twice daily in association with a meal.
Although there are many anti-diabetic medications already available for use, often people with T2DM will require different or additional anti-diabetic medications to control their blood sugar, given the chronic nature of this disease.Therefore, Victoza is another medication that can be used to help control blood sugar, but it is not recommended as first-line therapy for patients whose blood sugar is not controlled through diet and exercise.
Victoza may eventually be found useful for treatment of pancreatitis, another major indication.
Market: Victoza primarily competes with Byetta and future GLP-1 analogs for treatment of type 2 diabetes. Where approved, liraglutide is the second GLP-1 diabetes medicine on the market. The first is exenatide (Byetta), which was approved by the FDA in 2005. Other approved drugs are orally administered DPP-IV inhibitors, sitagliptin and vildagliptin.
Upon U.S. approval, Novo Nordisk reported that Victoza would cost $8 per 1.2 mg ($2,920/year). This compares to $4.3 for the same quantity in Europe. The company also reported that it expects Victoza will reach sales of over $1 billion by 2015 (Byetta was then at about $700 million and it had been on the US market since 2005).
The cost
of Victoza in the US is about $240/month for the 1.2 mg
treatment dose and $360/month for the 1.8 mg dose.
This compares with about $240 for twice daily Byetta, in
the year of the Victoza U.S. launch.
Upon U.S. approval, the Novo Nordisk CEO projected Victoza may generate in excess of $1 billion in revenue annually by 2012.
Upon U.S. approval, Sanford C. Bernstein Ltd. analysts projected $750 million in annual sales by 2015. This was largely based on the presumption that Victoza appears to be a rather more tolerable drug and has a better real-world efficacy than Byetta, the first of the class of type 2 diabetes GLP-1 analogs. Note, Byetta is a drug/chemical substance, manufactured synthetically, and is not a biopharmaceutical (not included in this database).
Upon U.S. launch, it was reported that the Victoza sales forces were emphasing weight loss with use fo Victoza. Novo Nordisk had expanded its diabetes sales forces to 1,900 in 2007.
In July 2010, it was reported that the U.S. launch of Victoza in the U.S had gone well. Victoza had captured 26% of the market in that category in five months, and 33.9% of prescriptions to new patients; largely gaining share in that market at the expense of Byetta. FDA is unlikely to remove Victoza's black box for several years at least, until the 5-year follow-up cancer study data is available.
The market for Victoza has grown with some unexpected assistance from Lilly, a competitor. Victoza was elevated above “me-too” status
by a head-to-head study conducted by Lilly - a trials of once-daily Victoza versus once-weekly
Bydureon. The Lilly drug failed to match the efficacy
of Victoza, in terms of mean A1c reduction from
baseline levels. Subsequently, Victoza has become
the new standard-of-care for this drug class. This is a
rare outcome, though, because drug companies
generally avoid conducting head-to-head clinical trials.
In Sept. 2010, U.K. National Institute for Health and Clinical Excellence (NICE) published draft guidance recommending the use of Victoza 1.2 mg daily for type II diabetes under certain conditions, making it the first incretin-based diabetes therapy to receive statutory funding. NICE approved the use of once-daily Victoza as part of dual therapy regimens, i.e. in combination with metformin or a sulphonylurea, when the patient cannot take one of these drugs, or thiazolidinediones and dipeptidyl peptidase-4 (DPP-4) inhibitors. As part of triple therapy regimens, Victoza can be used in combination with metformin and a sulfonylurea, or metformin and a thiazolidinedione – but only when control of blood glucose is inadequate and the either patient has a Body Mass Index over 35kg/m2 or where weight loss would benefit other significant obesity-related co-morbidities. NICE rejected use of 1.8mg formulation after concluding that the available evidence “does not suggest any significant additional benefit.” Victoza 1.2 mg costs around £2.62 a day.
In 2012/13, high-dose Victoza is starting to show potential for weight reduction in those morbidly obese. This would be a blockbuster market. FWeight loss is often a side benefit of its ability to control insulin production in people with type 2 diabetes. DA and the health care communities have by now come to accept that behavior change is not enough for weight reduction, with drug therapy more acceptable and reimbursable.
Competition: Victoza no competes with drugs including once-weekly version of their incumbent GLP-1 analog, Bydureon, from Lilly/Amylin/Alkermes.
In June 2012, with positive results from clinical trials, Novo Nordisk decided to concentrate further development efforts on semaglutide, a once-weekly human GLP-1 (Glucagon-Like Peptide-1) analog, rather than Victoza (taken daily), with no new trials planned for Victoza.
Companies involvement:
Full monograph
166.5 Glucagon-like peptide-1, rDNA
• Not recommended as first-line therapy for patients inadequately controlled on diet and exercise
(5.1).:
• Limited data in patients with a history of pancreatitis. (5.2).:
• Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.:
• Has not been studied in combination with prandial insulin.:
In combination with: Metformin or a sulphonylurea, in patients with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin or sulphonylurea.
In combination with:
Metformin and a sulphonylurea or metformin and a thiazolidinedione in patients with insufficient glycaemic control despite dual therapy."
Nomenclature:
Liraglutide [USAN; INN]
Liraglutide (genetical recombination) [JAN]
Glycine, L-histidyl-L-alanyl-L-alpha-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-alpha-glutamylglycyl-L-glutaminyl-L-alanyl-L-alanyl-N6-(N-(1-oxohexadecyl)-L-gamma-glutamyl)-L-lysyl-L-alpha-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L-arginylglycyl-L-arginyl- [CAS]
N26-(Hexadecanoyl-gamma-glutamyle)-(34-arginine)glucagon-like-peptide-1-(7-37)-peptide; Glycine, L-histidyl-L-alanyl-L-alpha-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-alpha-glutamylglycyl-L-glutaminyl-L-alanyl-L-alanyl-N6-(N-(1-oxohexadecyl)-L-gamma-glutamyl)-L-l [CAS]
204656-20-2 [CAS RN]
Arg34-GLP-1[7-37] [SY]
Arg34-GLP-1[7-37] [SY]
Arg34Lys26-(N-є-(γ-Glu(N-α-hexadecanoyl)))-GLP-1[7-37] [SY]
D06404 [SY]
N26-(Hexadecanoyl-gamma-glutamyle)-(34-arginine)GLP-1-(7-37)-peptide [SY]
N26-(Hexadecanoyl-gamma-glutamyle)-(34-arginine)glucagon-like-peptide-1-(7-37)-peptide [SY]
NN 2211 [SY]
NN2211 [SY]
NNC 90-1170 [SY]
NDC 0169-4060-12 [NDC]
NDC 0169-4060-13 [NDC]
molecular weight (kDa) = 3.75
FDA Class: Biologic BLA
Year of approval (FDA) = 2010
Date of 1st FDA approval = 20100125
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2025, based on 8,114,833, a formulation patent; NCE exclusivity expird in 2015 |
U.S. Patent Expiration Year: | 2018 |
U.S. Biosimilars Data Exclusivity Expiration: | 2022 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2017 |
U.S. Biosimilars Launchability Year: | 2022 |
U.S. Biobetters Launchability Year: | 2022 |
Biosimilars/biobetters-related EU Patents: | 2019, based on EP 1060191 |
EU Patent Expiration Year: | 2019 |
EU Biosimilars Data Exclusivity Expiration: | 2018 |
EU Biosimilars Orphan Exclusivity Expiration: | 2018 |
EU Biosimilars Launchability Year: | 2019 |
EU Biobetters Launchability Year: | 2019 |
Index Terms:
biopharmaceutical products
recombinant DNA
mannose-terminated oligosaccharides
pIXY498 plasmid
plasmid pIXY498
Saccharomyces cerevisiae (yeast)
Saccharomyces cerevisiae (yeast)
Yersinia pestis prophylaxis
bromide
disodium phosphate
hydrochloric acid (HCl)
petrolatum gauze
phenol red
ProLease microencapsulation
sodium hydroxide
Water for Injection
XV2181, Saccharomyces cerevisiae (yeast) strain
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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