Memorandum

J&J’s Invokana CREDENCE study stopped one year early given disease-modifying renal-protection - major positive, meets primary efficacy endpoint – July 16, 2018

Executive Highlights

  • J&J made major headlines today by stopping the CREDENCE trial early – according to its Independent Data Monitoring Committee, SGLT-2 inhibitor Invokana (canagliflozin) has already demonstrated renal protective efficacy. Wow! The study (n=4,401 type 2s with diabetic kidney disease[DKD]) was not expected to complete until June 2019, but we now anticipate data far earlier than the original 2H19 estimate. Stopping the trial means that keeping the trial going would be unethical for those in the “non-Invokana” arm – wow!

  • We can’t overstate the implications of positive CREDENCE results (so positive that Invokana met its efficacy endpoint with fewer than expected primary endpoint events). DKD is notoriously challenging to treat, and no new drugs have been approved for this diabetes complication since 2000 (irbesartan and losartan, both for high blood pressure). SGLT-2s could fill this unmet need, and indeed, positive CREDENCE findings bode well for Lilly/BI’s EMPA-KIDNEY (Jardiance in CKD) and for AZ’s Dapa-CKD (Farxiga in CKD). Above all, the discovery of SGLT-2 inhibitors as renal protective medicine would be a major win for patients (and for diabetes care providers)  - so far, Invokana is there!

  • This news is also an important piece of the “beyond A1c” story. CREDENCE enrolled type 2s with eGFR between 30-90 ml/min/1.73m2, and even if Invokana lost some of its glucose-lowering efficacy with impaired kidney function, it still preserved or improved that kidney function. As Dr. David Fitchett explained at ESC, despite attenuated glucose-lowering, SGLT-2s may exert their greatest benefits in terms of CV/renal protection in patients with low eGFR. This reflects a shift from glucose-centric approaches to diabetes management toward outcomes-based medicine that’s focused on CV and renal risk reduction. A renal indication for Invokana would be a significant “outcomes beyond A1c” win, as FDA would be approving a diabetes drug for use in diabetes patients for reasons entirely unrelated to A1c reduction.

  • As a reminder, the last major news of “primary outcomes” note on chronic kidney disease came nearly 2,100 days ago and was negative – Adam remembered very well October 18, 2012, nearly six years ago, when we woke up to news of Reata’s bardoxolone failure, a compound for which there had been very high hopes. (John remembers us wondering “what next?” and we’re so happy to have today’s news for people with chronic kidney disease.)

  • We are reminded of McKinsey’s prescient report from 2016 “Preventing and treating complications: the opportunity in diabetes care” where authors Dr. Jeff Algazy and Sachin Nichal recommended companies focus on microvascular complications, even as scores of companies were exiting diabetes – Amgen, BMS, Genentech, Gilead, to name a few particularly notable examples.

    There is very exciting news today for people with diabetes with chronic kidney disease – and those at risk of it. Earlier today, J&J announced that the CREDENCE renal outcomes trial for SGLT-2 inhibitor Invokana (canagliflozin) has been stopped early – and it’s good, VERY good, news. An Independent Data Monitoring Committee conducted a pre-specified interim analysis and reported that Invokana has already shown efficacy on the primary composite endpoint (end-stage renal disease, doubling of serum creatinine, renal or CV death).

    Originally expected to complete in June 2019, CREDENCE has now wrapped, and presumably we’ll see data well before the initial 2H19 estimate.

    We can’t overstate the implications of positive CREDENCE results. Not if we tried! The early study stop implies that Invokana significantly reduced risk for adverse renal outcomes in a population with DKD (n=4,401), and it met its threshold for efficacy with fewer than expected primary endpoint events. No new DKD indications have been approved in nearly 20 years (since high blood pressure medications irbesartan and losartan in 2000, which are challenging for some patients to take), making this a serious unmet need. As Dr. James List (Global Therapeutic Head, CV&M, Janssen) put it, “Chronic kidney disease is a progressive condition that impacts a person’s overall health and well-being, and with millions of people worldwide suffering from the disease, we know that there is a clear need for new treatment options. We are excited about the possibility of bringing forth Inovkana as the first therapy to treat patients with CKD and type 2 diabetes in more than 15 years." 

    It’s beyond exciting that SGLT-2 inhibitors could be renal protective therapy (in addition to cardioprotective, weight loss-promoting, glucose-lowering therapy). Lilly/BI and AZ are each investigating their SGLT-2s in CKD (participants need not have diabetes), and positive CREDENCE results bode well for EMPA-KIDNEY and Dapa-CKD, respectively – as a reminder, Dapa-CKD began last year and EMPA-KIDNEY hasn’t yet begun. 

    Moreover, several recent analyses have led up to these CREDENCE findings: One post-hoc analysis by Dr. George Bakris and colleagues showed that canagliflozin’s renal benefits were sustained regardless of a patient’s baseline eGFR in CANVAS; another post-hoc, just presented at ADA by Dr. Dick de Zeeuw, found significant MACE benefit to Invokana across all baseline eGFR subgroups.

    Notably, most SGLT-2 inhibitors are currently contraindicated or not recommended in patients with advanced kidney disease, starting around eGFR <60 ml/min/1.73m2 (this varies from product to product). CREDENCE enrolled type 2 diabetes patients with eGFR between 30-90 ml/min/1.73m2, and even if Invokana lost some of its glucose-lowering efficacy with impaired kidney function, it still preserved or improved that kidney function. As Dr. David Fitchett explained at ESC last year, despite attenuated glucose-lowering, SGLT-2s may exert their greatest benefits in terms of CV/renal protection in patients with low eGFR.

    This reflects a shift from glucose-centric approaches to diabetes management toward outcomes-based medicine that’s focused on CV and renal risk reduction. We’re certainly happy about this paradigm shift (long term outcomes are incredibly important in addition to daily glucose levels that can be watched to avoid severe hypoglycemia), and we’ll be very eager to see how CREDENCE data is incorporated into canagliflozin drug labels. A renal indication for Invokana would also be a significant win for the outcomes beyond A1c movement, as FDA would be approving a diabetes drug for use in diabetes patients for reasons entirely unrelated to A1c reduction.

    J&J has also filed for a CV indication on Invokana, Invokamet, and Invokamet XR, and we recently learned that FDA has delayed its decision three months.

    Lastly, we imagine the Invokana sales/marketing team at J&J is very happy for patients about this news on CREDENCE. Invokana revenue has been falling consistently since 1Q17 – management has attributed this financial performance to pricing pressure, and while that’s definitely a factor, we know the black box warning for amputations can’t be helping uptake. Renal protection gives Invokana a more favorable benefit/risk profile, and to this end, J&J management has highlighted CREDENCE as an upcoming bright spot for the SGLT-2 business. From our view, while amputations are still a factor, it’s a much smaller percentage of patients that are at risk for amputations than could benefit from the renal protection.

    We’ll be looking for more commentary on Invokana, renal protection, and CREDENCE during J&J’s 2Q18 earnings call tomorrow morning (Tuesday, July 17). Given that this is particularly material news for J&J (even though due to its size, nothing is really material), we are assuming that the news came just over the weekend or today for J&J and the that timing on earnings is a fluke. We’ll find out for sure tomorrow though it’s hard to guess to what degree J&J will highlight this news.

    See our Chronic Kidney Disease Competitive Landscape for more details. 

     

    -- by Payal Marathe and Kelly Close