Seattle Genetics had an up and down week last week. The FDA’s Advisory Committee gave a positive recommendation for the company’s Hodgekins lymphoma drug ADCETRIS (brentuximasb) yet the stock went down. The Seattle Genetics Chairman is quoted as saying he is still positive about the drug. We tend to agree with him. Some of the press has been questioning the approvability of the drug because there are only two small studies in support of the application.
There are several things that are very much on the positive side for Seattle Genetics on this. The first is the indication – refractory Hodgekins lymphoma, refractory being the operative word here. The second thing is the data. Yes, the definitive trial presented is a Phase 2 single arm study with only 102 patients but the results were outstanding, clearly much better response rates than literature results for other treatments that have been tried in these patients. The third thing appears to be the dialog that the company has been having with the FDA during the course of the development of this drug. In the Briefing Document for last weeks Advisory Committee, the FDA seems to imply that the company has met all of the agreements they made with the FDA to get to this point. The final point is also a reference the FDA makes in the Briefing Document to the February 2011 meeting of the Advisory Committee in which the criteria for acceptability of a single arm study were discussed. Seattle Genetics seems to have met the criteria discussed and agreed to during that AdComm meeting. So, the only thing standing in the way of approval is company agreement and FDA acceptability of the necessary confirmatory trial.
We think it is likely that Seattle Genetics will continue to listen to and agree with the FDA, particularly with regard to the design of the confirmatory trial. That being the case, FDA seems inclined to approve the drug.
Regeneron (REGN) is probably still basking in glory of their recent unanimous recommendation from the Advisory Committee for EYLEA (aflibercept opthalmic solution) Opthalmic Solution for the treatment of age related macular degeneration. The company should now be directing its focus on the upcoming PDUFA Date of Aug 20, 2011 and anticipating an approval.
Transcept Pharma (TSPT) reported that FDA issued a Complete response letter to their resubmission of Intermezzo, a drug indicated for use in treating night time awakening insomnia. The original NDA was submitted in 2008 and not favorably considered by the FDA because of concerns they had about driver impairment. The company reported they did a driver impairment study and resubmitted the NDA. The most recent PDUFA Date was July 14, 2011.
Transcept has reported that the second CRL still has questions about driver impairment. This doesn’t look good for Intermezzo. Either the second driver impairment study was inadequate in design (unlikely if the FDA had input and the company followed the FDA input), or it showed driver impairment. Either case, it looks like another redo of the study.
On Tuesday, July 19, 2011, Bristol-Myers Squibb Company (BMY) will present their case before the FDA Advisory Committee for dapagliflozin for the treatment of diabetes. This drug is the front runner in a new class of diabetes drugs called SGLT2-inhibitors which reportedly enhances excretion of glucose via the kidneys. With such a unique mechanism of action, attention naturally focuses on intact kidney function for a reliable drug effect. Herein lies my first issue. BMY enrolled over 6000 patients in the trials with over 4000 on dapagliflozin. They included a full range of patients with kidney disease – normal, mild, moderate and severe. As would be expected, those with severe kidney failure didn’t do well on the drug. What is surprising is the response of the patients with moderate kidney failure. Using a post hoc analysis, they split the “normal” moderate range of roughly 30-60 mL/min/1.73m2 in half and showed, as would be expected, those with better kidney function performed better. The question is not so much the post hoc analysis (everyone does it to a certain degree) but rather, is it a reasonable to redefine “moderate” kidney function to gain drug approval? If not, they will have to abandon all of the moderate kidney function patients and label the drug for normal and mild kidney function patients. Is this a risk the FDA wants to take?
The efficacy of the drug in these normal and mild kidney function patients seems adequate, so we don’t have to dwell on it. But, we do have to look at the other safety signals that the FDA wants the Advisory Committee to address. While the FDA agrees that there is no CV risk, they curiously state that “a CV outcomes trial is necessary to better charaterize CV safety…”. There is at least one case of dapagliflozin induced liver injury cited by the FDA reviewer. There are 9 cases of bladder cancer on drug compared to 1 on control, and 9 cases of breast cancer on drug compared to 1 on control.
The FDA has only asked 2 basic questions to help them get at the benefit risk determination. Is it an effective glucose lowering agent? The answer to that is probably yes, in patients with normal or mild kidney disease. Does the efficacy outweigh the risk? The answer to this is, we probably don’t know. The bottom line for the Advisory Committee should be there is an unknown benefit/risk ratio associated with this drug. These unknowns about CV safety, liver injury, bladder cancer and breast cancer, not to mention the issues associated with patients with moderate kidney disease should be addressed before the drug is added to all of the other drugs that effectively treat diabetes today.