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Date: 2014-01-08

Type of information: Granting of a Market Authorisation in the US

Product name: Forxiga® (EU)/Farxiga® (USA)

Compound: dapagliflozin

Therapeutic area: Metabolic diseases

Action mechanism:

Dapagliflozin is the first in a class of novel agents for diabetes that inhibit sodium-glucose cotransporter-2 (SGLT2), a specific target located in the kidney. Through this mechanism, dapagliflozin is designed to help control glycemia independently of insulin pathways, as the renal SGLT system plays a major role in overall glucose balance in the body. Forxiga® works in the kidney to selectively inhibit SGLT2, resulting in the removal of excess glucose and its associated calories in the urine. Through the removal of excess glucose, Forxiga® helps to reduce blood sugar levels. In clinical studies, Forxiga® also showed reductions in weight and blood pressure.

Company: AstraZeneca (UK) BMS (USA)

Disease:

type 2 diabetes

Latest news:

* On January 13, 2014, AstraZeneca and BMS announced the FDA approved Farxiga™, a once-daily oral treatment indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus. Farxiga™ should not be used for the treatment of patients with type 1 diabetes or diabetic ketoacidosis. The recommended starting dose of Farxiga™ is 5 mg once daily, taken in the morning, with or without food. In patients tolerating Farxiga™ 5 mg once daily who require additional glycaemic control, the dose can be increased to 10 mg once daily.
An increased number of bladder cancers were diagnosed among Farxiga® users in clinical trials so Farxiga® is not recommended for patients with active bladder cancer. Patients with a history of bladder cancer should talk to their physician before using Farxiga®. Farxiga® can cause dehydration, leading to a drop in blood pressure (hypotension) that can result in dizziness and/or fainting and a decline in renal function. The elderly, patients with impaired renal function, and patients on diuretics to treat other conditions appeared to be more susceptible to this risk.
The FDA is requiring six post-marketing studies for Farxiga®:
* a  cardiovascular outcomes trial (CVOT) to evaluate the cardiovascular risk of Farxiga® in patients with high baseline risk of cardiovascular disease;
* a double-blind, randomized, controlled assessment of bladder cancer risk in patients enrolled in the CVOT;
* an animal study evaluating the role of Farxiga®-induced urinary flow/rate and composition changes on bladder tumor promotion in rodents;
* two clinical trials to assess the pharmacokinetics, efficacy, and safety in pediatric patients; and
* an enhanced pharmacovigilance program to monitor reports of  liver abnormalities and pregnancy outcomes.
In clinical trials the most common side effects observed in patients treated with Farxiga® were genital mycotic (fungal) infections and urinary tract infections.
Dapagliflozin (marketed outside of the United States as Forxiga®) is approved for the treatment of adults with type 2 diabetes, along with diet and exercise, in 40 countries, including European Union countries and Australia.
* On December 12, 2013, AstraZeneca and BMS have aannounced the FDA's Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted 13-1 that the benefits of dapagliflozin use outweigh identified risks and support marketing of dapagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The Advisory Committee also voted 10-4 that the data provided sufficient evidence that dapagliflozin, relative to comparators, has an acceptable cardiovascular risk profile. The Prescription Drug User Fee Act (PDUFA) goal date for dapagliflozin is Jan. 11, 2014.
The EMDAC was provided with data from the extensive dapagliflozin global clinical development program included as part of the New Drug Application (NDA) and resubmission. In response to the FDA’s Jan. 2012 complete response letter, the NDA resubmission included several new studies and additional long-term data (up to four years’ duration) from previously submitted studies, resulting in an overall increase in patient-years exposure to dapagliflozin of more than 50 percent as compared to exposure in the original NDA. The resubmission included data from the dapagliflozin Phase II/III clinical development program, which included more than 11,000 adult patients with diabetes (approximately 6,000 patients received dapagliflozin) in 24 clinical trials.
In accordance with FDA guidelines, the NDA resubmission also included data assessing the CV safety of dapagliflozin in adults with type 2 diabetes. Additionally, the DECLARE study is being conducted in patients with type 2 diabetes to determine the effect of dapagliflozin, when added to the patients’ current anti-diabetes therapy, on the risk of CV events, such as CV death, myocardial infarction or ischemic stroke, compared with placebo. The randomized, double-blind, placebo-controlled study of more than 17,000 patients initiated enrollment in April 2013 and has an anticipated completion date of 2019.
* On July 25, 2013, AstraZeneca and BMS have announced that the FDA has acknowledged receipt of the New Drug Application (NDA) resubmission for dapagliflozin for the treatment of adults with type 2 diabetes. The FDA assigned a new Prescription Drug User Fee Act goal date of January 11 2014. The dapagliflozin Phase II/III clinical development program included more than 12,000 adult patients with diabetes (more than 8,000 patients received dapagliflozin) in 26 clinical trials. In response to the FDA’s January 2012 complete response letter requesting additional data to allow a better assessment of the benefit-risk profile of dapagliflozin, the NDA resubmission includes several new studies and additional long-term data (up to four years’ duration) from previously submitted studies, resulting in an overall increase in patient-years exposure to dapagliflozin of more than 50 percent.
Dapagliflozin is currently approved for the treatment of type 2 diabetes in the European Union, Australia, Brazil, Mexico and New Zealand.
* On November 14, 2012, AstraZeneca and BMS have announced that the European Commission has approved Forxiga® (dapagliflozin) tablets for the treatment of type 2 diabetes in the European Union (EU). Forxiga® is a selective and reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2) that works independently of insulin to help remove excess glucose from the body, a unique mode of action not seen in any other currently available treatments for type 2 diabetes. This is the first medicine in the new SGLT2 class to gain regulatory approval for the treatment of type 2 diabetes.
Forxiga® tablets are indicated as a once-daily oral medication to improve glycaemic control in adult patients with type 2 diabetes. It is intended to be used as an adjunct to diet and exercise in combination with other glucose-lowering medicinal products, including insulin, or as a monotherapy in metformin-intolerant patients.
The approval of Forxiga® in the EU is based on the results of a broad clinical development programme that included 11 double-blind, randomised, placebo-controlled Phase III clinical trials assessing the safety and efficacy of  Forxiga® as a once-daily oral therapy. These 11 trials involved 5,693 patients worldwide with type 2 diabetes, including 3,939 patients treated with FORXIGA. A higher proportion of patients with type 2 diabetes treated with Forxiga® compared to placebo achieved the goal of HbA1c < 7%. The extensive clinical development programme also demonstrated that FORXIGA had a positive benefit-risk profile, with a low risk of hypoglycaemia, across a wide range of patient populations. Researchers also found additional benefits, such as reductions in body weight and systolic blood pressure in double-blind, randomised, placebo-controlled clinical trials.
* On April 20, 2012, the CHMP has recommended the approval of Forgixa® (dapagliflozin) tablets for the treatment of type 2 diabetes, as an adjunct to diet and exercise, in combination with other glucose-lowering medicinal products including insulin, and as a monotherapy in metformin intolerant patients. Dapagliflozin is the first in the new SGLT2 class to receive a positive CHMP opinion for the treatment of type 2 diabetes.
Dapagliflozin 10mg is intended as a once-daily oral dose in adult patients with type 2 diabetes to improve glycaemic control:
As a monotherapy, when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance;
In combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.
Safety concerns with Forxiga® identified in the clinical trials included an increased number of bladder and breast tumours in dapagliflozin-treated patients, limited data available in patients above 75 years, the use in patients at risk of volume depletion, hypotension and electrolytes imbalances. The CHMP assessed these concerns and found that they are satisfactorily addressed in the product information and in the risk management plan for Forxiga®.
As the effects of dapagliflozin are dependent on kidney function, the efficacy of the medicine is reduced in patients with kidney impairment. Therefore, the use of Forxiga® is not recommended in patients with moderate to severe kidney impairment.
Overall there was no imbalance of malignancies between dapagliflozin-treated patients and those on control. The unexpected finding of more bladder (0.16% as compared to 0.03% in the controls) and breast cancers (0.40% as compared to 0.22% in the controls) in dapagliflozin-treated patients is of concern especially in the light of potentially long treatment periods and a possible widespread use. Even though data from carcinogenicity studies in animals did not indicate a genotoxic or carcinogenic effect of dapagliflozin, the CHMP considered it necessary to keep this potential risk under close observation and requested the applicant to conduct an epidemiological study with dapagliflozin.
The potential risk of cancer will also be looked at in the planned cardiovascular outcome study further investigating potential cardiovascular risks of dapagliflozin.
* On January 19, 2012, BMS and AstraZeneca announced they have received a complete response letter from the FDA for dapagliflozin for the treatment of type 2 diabetes in adults. FDA requests additional clinical data to allow a better assessment of the benefit-risk profile for dapagliflozin. This includes clinical trial data from ongoing studies and may require information from new clinical trials. Bristol-Myers Squibb and AstraZeneca will work closely with the FDA to determine the appropriate next steps for the dapagliflozin application, and are in ongoing discussions with health authorities in Europe and other countries as part of the application procedures.
* On July 20, 2011, AstraZeneca and BMS reported the outcome of the FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting on the New Drug Application for the investigational compound dapagliflozin. On the question: “Do the efficacy and safety data provide substantial evidence to support approval of dapagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus?”, the Advisory Committee voted 6 yes and 9 no. Bristol-Myers Squibb and AstraZeneca remain committed to the dapagliflozin clinical development programme and will continue to work closely with the FDA to support the review of this investigational compound.
* On March 8, 2011, AstraZeneca and BMS announced that the FDA has accepted for review this NDA. The Prescription Drug User Fee Act (PDUFA) goal date for the FDA is October 28, 2011.
* On October 26, 2011, AstraZeneca and BMS announced that the FDA has extended the action date for dapagliflozin for the treatment of type 2 diabetes by three months. The new Prescription Drug User Fee Act (PDUFA) goal date is 28 January 2012.

Patents:

Submission of marketing authorization application USA : December 2010

Submission of marketing authorization application UE: December 2010

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2014-01-08

UE authorization: 2012-11-14

Favourable opinion UE: 2012-04-20

Favourable opinion USA: 2013-12-12

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

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