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Overview of Five Briefing Questions Posed by FDA on Dapagliflozin

On Friday, July 15, 2011 the FDA published on its website the questions that it has asked the Endocrinologic and Metabolics Drug Advisory Committee to address in its July 19, 2011 meeting on dapagliflozin. My impression on the initial reading of the questions is that while the tone is by no means benign, it is more positive than I was expecting. Please refer to my note of July 14.

From the questions, I don’t see anything that would absolutely bar approval. However, my experience is that these panels can often take unexpected turns. I believe that the Street expectation is for the FDA to issue a Complete Response Letter at the PDUFA date of October 28, 2011. More often than not, the risk adverse FDA will issue a CRL for a novel new drug unless it meets an unmet need in a deadly or dangerous disease condition, which is not the case with dapagliflozin. The discussion at the upcoming advisory meeting will be much more informative in determining how the FDA and its expert panel view the risk/ reward of this novel new type II diabetes questions and its ultimate approvability.

The approval either now or sometime later of dapagliflozin would make Bristol-Myers a powerful competitor in the huge type II diabetes market. It also has Onglyza, the second approved drug in the large and rapidly growing DPP-IV inhibitor class of type II oral anti-diabetes drugs. The combination of these two products could make BMY the second largest commercial factor in the oral type II anti-diabetes market. Along with the cancer drug Yervoy and the anti-thrombotic apixiban, the combination of dapagliflozin/ Onglyza would give BMY three blockbuster commercial opportunities.

I have included the full set of FDA questions at the end of this note. My first take on each question is as follow:

Efficacy The FDA notes that the efficacy of dapagliflozin decreases with kidney damage and that in diabetes, the incidence of kidney damage resulting from the disease is “a sizable proportion of patients”. The FDA asked for guidance on whether it should ask the company to do more trials to determine the patient groups in which the drug is most effective or whether this could be handled by monitoring kidney function during treatment.

Hepatic (liver) safety Hepatic toxicity is a show stopper for a new drug. In clinical trials involving dapagliflozin, there were five cases of abnormal liver enzymes that are a signal of liver toxicity out of 4,258 patients treated with the drug. In only one case was the hepatic toxicity described as probably drug related. The FDA wants to know if the experts feel that this one possible case of liver toxicity is clinically meaningful.

Breast and bladder cancer The FDA asked if the imbalance detected in the clinical trials for breast and bladder cancer is a signal for cancer risk. It wants the committee to discuss if there were imbalances in the randomization of the trials that could have accounted for this and if there may have been a bias toward detection in the drug treated group.

BMY has reported that in the case of bladder cancer there was an imbalance as 9 patients out of 5,478 patients treated with dapagliflozin were diagnosed with bladder cancer as compared to 1 out of 3,136 patients in the control groups. There were also 9 breast cancers in 2,223 women treated in the dapagliflozin groups as compared to 1 of 1,053 in the control groups. I am not sure why BMY refers to a higher number of patients than the number cited by the FDA in its question on liver toxicity. My guess is that BMY is including all patients treated in phase I, II and III and the FDA has excluded some of these.

Other issues The committee was also asked to discuss the clinical relevance of genital/ urinary tract infections, bone safety concerns and any other safety issues.

The final vote At the conclusion of the meeting, the committee will be asked to vote on whether the data supports approval or if more studies are required. If the committee feels that more studies should are needed, what type of studies should be done in order for dapagliflozin to be approved?

Questions Posed to the Committee by the FDA

Efficacy

Dapagliflozin’s efficacy is dependent on the amount of glucose filtered through the glomeruli. As the glomerular filtration rate (GFR) declines in renal impairment, the efficacy of the SGLT-2 inhibitor is also diminished. Please discuss the implications of this reduced efficacy in T2DM where renal impairment can impact a sizeable proportion of patients with this disease. Please include in your discussion whether additional studies (e.g., in special populations) should be conducted to better characterize the efficacy of dapagliflozin in T2DM or whether monitoring for renal function should be performed prior to and/or during treatment with dapagliflozin.

Hepatic Safety

Five patients treated with dapagliflozin developed ALT or AST > 3x ULN with accompanying total bilirubin > 2x ULN (biochemical Hy’s law). An adequate explanation for the biochemical abnormalities could be identified in all but one case. This one case was classified as a ‘probable diagnosis of mild to moderately severe dapagliflozin-induced liver injury’. Imbalances in severe hepatic transaminase elevations (> 5x and 10xULN) between dapagliflozin and comparators were not observed and no signal for hepatotoxicity was identified in the nonclinical program. Please comment on the clinical relevance of the one case and whether sufficient evaluation has been conducted premarketing to determine if dapagliflozin is associated with a risk of hepatotoxicity.

Breast and Bladder Cancer

Numeric imbalances in breast and bladder cancer were observed in the clinical development program. For both of these types of cancer, please discuss whether these imbalances signify a risk of carcinogenic potential associated with dapagliflozin. In addition, please comment on whether the numeric imbalances were impacted by the following:

a. Any imbalance of baseline risk factors

b. Any detection bias

Other Safety Findings

Please discuss the clinical significance of the following in the T2DM population: (a) increased genital-urinary infections associated with dapagliflozin therapy, (b) bone safety concerns and (c) any other safety issues identified in the premarketing application

The final vote

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 T2DM? (VOTING) If yes, do you recommend any further data be obtained post-marketing? If no, what further data should be obtained?

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