Saxagliptin
Encyclopedia
Saxagliptin previously identified as BMS-477118, is a new oral hypoglycemic (anti-diabetic drug
) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Early development was solely by Bristol-Myers Squibb
; in 2007 AstraZeneca
joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on the marketing of the drug. A New Drug Application for saxagliptin in the treatment of type 2 diabetes was submitted to the FDA in June 2008. It was based on a drug development program with 8 randomized trials: 1 phase 2 dose-ranging (2.5–100 mg/d) study; 6 phase 3, 24-week controlled trials with additional controlled follow-up from 12 to 42 months, double-blinded throughout; and one 12-week mechanism-of-action trial with a 2-year follow-up period. In June 2008, it was announced that Onglyza would be the trade name under which saxagliptin will be marketed.
The FDA approved Saxagliptin with brand name Onglyza on July 31, 2009.
Dipeptidyl peptidase-4's role in blood glucose regulation is thought to be through degradation of GIP
and the degradation of GLP-1
.
Bristol-Myers Squibb announced on 27 December 2006 that Otsuka Pharmaceutical Co.
has been granted exclusive rights to develop and commercialize the compound in Japan. Under the licensing agreement, Otsuka will be responsible for all development costs, but Bristol-Myers Squibb retains rights to co-promote saxagliptin with Otsuka in Japan. Further, on 11 January 2007 it was announced that Bristol-Myers Squibb and AstraZeneca
would work together to complete development of the drug and in subsequent marketing.
. The former is commercially available, whereas the latter is available as the N-Boc analog. The prolineamide moiety is subsequently dehydrated with trifluoroacetic anhydride
to give the cyanide as the trifluoracetate ester, which is hydrolyzed. Removal of the Boc protecting group, followed by neutralization gives the desired product (1):
(DPP-4) inhibitors.
DPP-4 is an enzyme that breaks down incretin hormones. As a DPP-4 inhibitor, Saxagliptin slows down the breakdown of incretin hormones, increasing the level of these hormones in the body. It is this increase in incretin hormones that is responsible for the beneficial actions of Saxagliptin, including increasing insulin production in response to meals and decreasing the amount of glucose (sugar) that the liver produces.
Because incretin hormones are more active in response to higher blood sugar levels (and are less active in response to low blood sugar), the risk of dangerously low blood sugar (hypoglycemia) is low with Saxagliptin.
Table 1: Adverse Reactions (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Trials* Reported in ≥ 5% of Patients Treated with ONGLYZA (saxagliptin tablets) 5 mg and More Commonly than in Patients Treated with Placebo.
The risk of cancer suppression with DPP-4 down-regulation applies to all the DPP-4 inhibitors on the market in addition to saxagliptin (sitagliptin and vildagliptin)
Anti-diabetic drug
Anti-diabetic medications treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents...
) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Early development was solely by Bristol-Myers Squibb
Bristol-Myers Squibb
Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation...
; in 2007 AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on the marketing of the drug. A New Drug Application for saxagliptin in the treatment of type 2 diabetes was submitted to the FDA in June 2008. It was based on a drug development program with 8 randomized trials: 1 phase 2 dose-ranging (2.5–100 mg/d) study; 6 phase 3, 24-week controlled trials with additional controlled follow-up from 12 to 42 months, double-blinded throughout; and one 12-week mechanism-of-action trial with a 2-year follow-up period. In June 2008, it was announced that Onglyza would be the trade name under which saxagliptin will be marketed.
The FDA approved Saxagliptin with brand name Onglyza on July 31, 2009.
Dipeptidyl peptidase-4's role in blood glucose regulation is thought to be through degradation of GIP
Glucose-dependent insulinotropic peptide
Gastric inhibitory polypeptide , also known as the glucose-dependent insulinotropic peptide is a member of the secretin family of hormones....
and the degradation of GLP-1
Glucagon-like peptide-1
Glucagon-like peptide-1 is derived from the transcription product of the proglucagon gene. The major source of GLP-1 in the body is the intestinal L cell that secretes GLP-1 as a gut hormone. The biologically active forms of GLP-1 are: GLP-1- and GLP-1-NH2...
.
Bristol-Myers Squibb announced on 27 December 2006 that Otsuka Pharmaceutical Co.
Otsuka Pharmaceutical Co.
, abbreviated OPC, is a pharmaceutical company headquartered in Tokyo, Osaka and Naruto, Japan. The company was established August 10, 1964, and currently has approximately 27,000 employees worldwide. The company focuses on pharmaceuticals related to nutrition...
has been granted exclusive rights to develop and commercialize the compound in Japan. Under the licensing agreement, Otsuka will be responsible for all development costs, but Bristol-Myers Squibb retains rights to co-promote saxagliptin with Otsuka in Japan. Further, on 11 January 2007 it was announced that Bristol-Myers Squibb and AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
would work together to complete development of the drug and in subsequent marketing.
Production
Saxagliptin is produced industrially by Bristol-Myers Squibb by the amide coupling of N-Boc-3-hydroxyadamantylglycine (2) and methanoprolineamide (3) with EDC1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
EDC is a water soluble carbodiimide usually obtained as the hydrochloride. It is typically employed in the 4.0-6.0 pH range. It is generally used as a carboxyl activating agent for the coupling of primary amines to yield amide bonds...
. The former is commercially available, whereas the latter is available as the N-Boc analog. The prolineamide moiety is subsequently dehydrated with trifluoroacetic anhydride
Trifluoroacetic anhydride
Trifluoroacetic anhydride is the acid anhydride of trifluoroacetic acid. In particular, trifluoroacetic anhydride is the perfluorinated derivative of acetic anhydride. Like many acid anhydrides, it may be used to introduce the corresponding trifluoroacetyl group. The corresponding trifluoroacetyl...
to give the cyanide as the trifluoracetate ester, which is hydrolyzed. Removal of the Boc protecting group, followed by neutralization gives the desired product (1):
How saxagliptin works
Saxagliptin is part of a class of diabetes medications called dipeptidyl peptidase-4Dipeptidyl peptidase-4
Dipeptidyl peptidase-4 , also known as adenosine deaminase complexing protein 2 or CD26 is a protein that, in humans, is encoded by the DPP4 gene.-Function:...
(DPP-4) inhibitors.
DPP-4 is an enzyme that breaks down incretin hormones. As a DPP-4 inhibitor, Saxagliptin slows down the breakdown of incretin hormones, increasing the level of these hormones in the body. It is this increase in incretin hormones that is responsible for the beneficial actions of Saxagliptin, including increasing insulin production in response to meals and decreasing the amount of glucose (sugar) that the liver produces.
Because incretin hormones are more active in response to higher blood sugar levels (and are less active in response to low blood sugar), the risk of dangerously low blood sugar (hypoglycemia) is low with Saxagliptin.
Efficacy
Oral saxagliptin 2.5 or 5 mg once daily suppresses DPP4 activity for 24 hours, significantly improving mean HbA1c levels (relative to placebo) in well designed, 24-week trials in treatment-naive patients with type 2 diabetes. Combination therapy with saxagliptin 5 mg once daily and metformin was more effective than saxagliptin or metformin monotherapy. When the relative benefits of increasing the dose of a sulfonylurea or adding saxagliptin were assessed in a study of 768 patients, combination treatments were shown to have a significantly greater impact on fasting blood glucose than increasing the tested glibenclamide dose alone.Safety
In 4148 patients studdied, 3 adverse reactions were seen higher in saxaglyptin vs placebo.Table 1: Adverse Reactions (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Trials* Reported in ≥ 5% of Patients Treated with ONGLYZA (saxagliptin tablets) 5 mg and More Commonly than in Patients Treated with Placebo.
| ONGLYZA 5 mg N=882 | Placebo N=799 | |
|---|---|---|
| Upper respiratory tract infection | 68 (7.7) | 61 (7.6) |
| Urinary tract infection | 60 (6.8) | 49 (6.1) |
| Headache | 57 (6.5) | 47 (5.9) |
- The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue.
Tolerability
Both monotherapy and combination therapy with other agents was generally well tolerated in clinical trials.Cancer risk of DPP-4 inhibitors
The DPP-4 enzyme is known to be involved in the suppression of certain malignancies, particularly in limiting the tissue invasion of these tumours. Inhibiting the DPP-4 enzymes may allow some cancers to progress. A study of DPP-4 inhibition in human non-small cell lung cancer (NSCLC) concluded that "DPPIV functions as a tumor suppressor, and its downregulation may contribute to the loss of growth control in NSCLC cells.The risk of cancer suppression with DPP-4 down-regulation applies to all the DPP-4 inhibitors on the market in addition to saxagliptin (sitagliptin and vildagliptin)
External links
- Official site
- The race to get DPP-4 inhibitors to market - Forbes.com