Good afternoon from San Francisco, one piece of good news to start off your weekend~

The FDA just announced that it has approved J&J's Invokana (canagliflozin) for the treatment of type 2 diabetes - the FDA's press release is available online. This decision makes Invokana the first SGLT-2 inhibitor cleared in the US, opening the door for the promising drug class. 

Invokana will be the second SGLT-2 inhibitor on the worldwide market behind BMS/AZ's dapagliflozin (Forxiga), which has already launched in Europe. The FDA is requiring five (!) post-marketing studies for canagliflozin including a cardiovascular outcomes study (CANVAS), a bone safety study, two pediatric studies, and a pharmacovigilance program. That's a lot to require but J&J has got the resources and is well on its way through CANVAS (it began in 2009 and will finish in 2018).

We're celebrating this afternoon's news, since we believe the novel mechanism in particular will be very useful for patients and had the FDA given a CRL, the class would have been DOA. We're very happy, in other words, not only for J&J that it received positive news but also, for the class (BMS/AZ, BI/Lilly, Lexicon), and for the field (all companies pursuing novel therapies), we're very glad that J&J didn't receive negative news. 

We speculate that the FDA's willingness to approve canagliflozin - compared to its complete response letter for dapagliflozin in 2012 - stems from the fact that there is more well-defined risk observed for canagliflozin - i.e., the most serious safety concern raised at the Advisory Committee meeting was renal safety in patients with moderate renal impairment, and there was a well-defined patient segment to exclude in order to minimize safety risk. In contrast, for dapagliflozin it was not immediately clear whether a patient segment could be excluded to mitigate any potential cancer concerns. No doubt, it also helped that the Agency had greater familiarity with the SGLT-2 inhibitor drug class after reviewing dapagliflozin last year. 

Our analysis is divided into three sections: 1) market potential; 2) additional questions; and 3) implications for other SGLT-2 inhibitor therapies.

Part 1: Market Potential for Invokana

If dapagliflozin's performance in Europe is any indication of the excitement for SGLT-2 inhibitors, we think uptake of canagliflozin could be fairly strong in the US. AZ provided a first look at Forxiga's first 10-week performance during its Investor Day last week showing that Forxiga's uptake by volume (measured by patient-days on therapy) trended just slightly below Januvia's first 10-week performance back in 2007. Broadly speaking, SGLT-2 inhibitors will likely play a versatile role in the treatment paradigm. For many patients, they may represent a better alternative to DPP-4 inhibitors, due to their associated weight loss and greater glycemic efficacy. The drawback for SGLT-2 inhibitors is their lack of longer-term safety data, their reduced efficacy in people with renal impairment, and some at least relative uncertainty on the side effect profile front. Beyond these barriers to success, we think the class could perform very well, particularly down the line given the potential for combination therapy (discussed below).

On the side effect profile front, we should consider that canagliflozin appears to have a less attractive side effect profile compared to dapagliflozin (i.e., slightly higher rates of genitourinary infections) due to its greater effect on urinary glucose excretion. Lilly and BI have not yet released detailed phase 3 data for empagliflozin (only topline results), though we've heard that canagliflozin also causes more urinary glucose excretion than empagliflozin and, thus, may also have higher rates of infection compared to empagliflozin as well. Thus, if dapagliflozin and empagliflozin are eventually approved in the US, they could potentially outperform canagliflozin on the basis of safety/tolerability. Of course, canagliflozin has the advantage of being first to market, and empagliflozin's and dapagliflozin's uptake would also depend on several other factors.

Part 2: Additional questions

J&J has yet to post a press release, which we hope will have more details on the launch schedule, pricing, and reimbursement. We're curious about several remaining questions, including the drug's potential limited use in people with moderate renal impairment - as noted above, during the FDA advisory committee meeting on January 10, agency members and panelists expressed the greatest concern over Invokana's effect in this patient population; specifically, panelists debated whether the minimum eGFR level should be 45 ml/min/1.73m3 (to allow some people with moderate renal impairment to use the drug) or the more restrictive threshold of 60 ml/min/1.73 min3 (which would exclude all patients with moderate renal impairment). The FDA press release states that Invokana should not be used in "those with several renal impairment" suggesting that the label may not place restrictions in people with better renal function. We're keen to gain more clarity on this front, as patients with renal impairment are among those in greatest need of more therapy options.

Part 3: Implications for other SGLT-2 inhibitor therapies

Looking forward, the FDA approval hopefully reflects a greater comfort with the SGLT-2 inhibitor mechanism - this would bode well for Lilly/BI's recent filing of empagliflozin, as well as BMS/AZ's planned resubmission of dapagliflozin (targeted for mid-2013 - see the 4Q12 report for details). Other candidates in the field include Astellas/Kotobuki's ipragliflozin (phase 3), Chugai's tofogliflozin (phase 3 in Asia), Pfizer's ertugliflozin ("phase 3-ready"), Lexicon's SGLT-1/SGLT-2 dual inhibitor LX4211 (phase 3 initiation expected in 1H13), and Novartis' SGLT-1/SGLT-2 dual inhibitor LIK066 (phase 2). 

The FDA decision today also sets a positive precedent for SGLT-2 inhibitor combination therapies. As a reminder, J&J submitted a canagliflozin/metformin fixed-dose combination (FDC) to the FDA in December and to the EMA earlier this month. BMS/AZ are also developing a dapagliflozin/metformin FDC, which was submitted in the EU in 4Q12 (FDA submission is planned for 2H13). The companies are also working on a dapagliflozin/saxagliptin FDC, which they plan to submit to the FDA and EMA in 2015; Lilly/BI are also investigating the possibility of an empagliflozin/linagliptin FDC. 

The Invokana news makes for a positive end of week for those pursuing new treatments for patients - for those celebrating, we hope you had a wonderful Passover and send our wishes for a very happy Easter. Thank you everyone for all your continued work on diabetes for patients and providers. 

very best, kelly

Kelly L. Close
Close Concerns
T. 415 241 9500
M. 415 518 5336

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