FDA approves Lilly/BI’s Jardiance (empagliflozin) – August 1, 2014

Today, the FDA announced its approval of Lilly and Boehringer Ingelheim’s partnered SGLT-2 inhibitor Jardiance (empagliflozin), making it the third SGLT-2 inhibitor approved in the US behind J&J’s Invokana (canagliflozin) and AZ’s Farxiga (dapagliflozin). As of Friday afternoon (PDT), neither Lilly nor BI had put out a press release on the announcement. This news follows the EMA’s approval of Jardiance in May, and marks the end of a rather complicated regulatory review process for empagliflozin: Lilly/BI received a Complete Response Letter from the FDA in March of this year due to “previously observed deficiencies” at BI’s manufacturing facility – at that point, we feared that US approval would be pushed back into 2015. However, BI worked quickly to remedy the issue, and in June Lilly/BI resubmitted the NDA for empagliflozin with a Class 1 designation (a two-month review). The FDA’s initial CRL did not require any additional pre-approval studies (which would have been very surprising and would have been a major negative), and so while the rapid turnaround time from the CRL to now was impressive, the positive decision from the agency was not unexpected.

The FDA is requiring four postmarketing studies for Jardiance:

• The completion of the EMPA-REG OUTCOME CVOT, which earlier this year had its estimated primary completion date moved up from 2018 to early 2015 – as we understand it, the original estimated date was based on a conservative assumption about event rates, which has since been updated based on the actual event rate seen in the trial;
• A pediatric PK/PD study;
• A pediatric safety study, which will evaluate bone health and development (among other factors);
• A nonclinical (animal) juvenile toxicity study, with a focus on renal development, bone development, and growth.

All in all, this is a fairly standard set of mandated postmarketing trials, as the FDA required five for Invokana (including an enhanced pharmacovigilance program) and six for Farxiga (including a bladder cancer CVOT sub-study and an enhanced pharmacovigilance program) – there were some unique safety questions that arose with those two candidates, but the lower requirement for Jardiance might also signify the agency’s growing comfort with the SGLT-2 inhibitor class.

Although Jardiance’s full US label is not yet available, the renal safety contraindication in the FDA’s announcement only excluded patients with severe renal impairment – this is the same wording used for Invokana (which can be used in patients with moderate renal impairment, but with a dose adjustment), but the announcement for Farxiga fully contraindicated the drug in patients with moderate renal impairment as well – so a relative win for Lilly/BI.

• In 2Q14, we estimated global Invokana sales at $84-$93 million (mostly in the US), and estimated US Farxiga sales at $20-$30 million – these estimates were based on a number of assumptions (see our J&J 2Q14 Report and AZ 2Q14 Report for more details on how we calculated those figures). During AZ’s update, we learned that Farxiga (launched in the US in 1Q14) has been performing particularly well, capturing a 40% new-to-brand prescription share among SGLT-2 inhibitors (leaving Invokana with the remaining 60%).
• In our view, the most exciting potential use for empagliflozin is not as a standalone therapy but rather as part of a fixed-dose combination with Lilly/BI’s DPP-4 inhibitor Tradjenta (linagliptin). The empagliflozin/linagliptin combination was filed in the US in 1Q14, putting it well ahead of AZ’s saxagliptin/dapagliflozin (US/EU filings planned for 4Q14) in the US. However, empagliflozin/linagliptin will only be submitted in EU in 2015, meaning that saxagliptin/dapagliflozin stands to be the first to market there. See our Lilly 2Q14 Report for more details. Also, see our ADA coverage for the first phase 3 data on both empagliflozin/linagliptin and saxagliptin/dapagliflozin – we saw A1c reductions solidly and consistently above 1.0% in those trials, impressive for an oral agent alone.
• Lilly’s financial workbooks already have an empty slot for empagliflozin – this makes us optimistic that we will get early insight to how the product’s launch progresses.

Close Concerns Questions:

• How will Lilly’s broad range of diabetes products (insulin, non-insulin injectables, oral therapies) impact it and BI’s positioning of Jardiance in the US? Will its broad portfolio provide it with more leverage with payers?
• Will Jardiance run into the same sort of comparative effectiveness challenges in Germany that other diabetes drugs have run into recently?
• How will other European payers and authorities (i.e.: UK’s NICE) view Jardiance’s value proposition?
• How will physicians and patients perceive SGLT-2 inhibitor/DPP-4 inhibitor combinations, especially relative to other exciting combinations on the horizon such as GLP-1 agonist/basal insulin combos?
• Is there some potential for patients or HCPs to mix up the name Jardiance with Merck’s Januvia franchise?

-- by Manu Venkat and Kelly Close