The Drug and the Companies Involved.
What is the drug in question, and which companies have an interest in its application and approval?
As mentioned above, the drug under scrutiny is known commercially as Jardiance. Its scientific name is empagliflozin. It was jointly developed by Boehringer Ingelheim Pharmaceuticals and Eli Lilly and Co (NYSE:LLY), as part of the alliance the two companies formed at the turn of the decade. The alliance was put in place to allow collaboration on a number of high ticket diabetes candidates, and since its inception, has produced a strong portfolio of products in the sector, generating billions in revenues annually.
Empagliflozin is an SGLT-2 inhibitor, a type of drug covered in an earlier Market Exclusive diabetes research report. The SGLT-2 here stands for sodium glucose co-transporter-2. Another term for SGLT-2 inhibitors is gliflozin. They essentially block the reabsorption of glucose in the kidney, and promote its removal by way of urination. This prevention means less glucose is retained in the blood, and by proxy, lowers the blood sugar levels in patients with diabetes.
The drug first picked up an approval in August 2014, when the FDA gave it the green light for commercialization in type II diabetes patients as an adjunct to diet and exercise. Boehringer Ingelheim and Eli Lilly split the revenues derived from the drug, which as of first quarter 2016, came in at a little over $38 million.
As an addendum to the FDA’s approving the drug, Eli Lilly was requested to undertake an extension study investigating the impact on cardiovascular risk in diabetes patients that underwent a regimen of Jardiance treatment, versus a placebo. It is this extension on which the sNDA is based.
The Trial and the Data
The trial in question was called the EMPA-REG OUTCOME trial. The primary endpoint (3-point MACE) was the time to first occurrence of CV death (including fatal myocardial infarction and fatal stroke), non-fatal MI, or non-fatal stroke. The key secondary endpoint (4-point MACE) was the time to first occurrence of any component in the 3-point MACE plus hospitalization for heart failure. The MACE endpoint is one that is hotly debated in biotech. It’s the standard efficacy measurement in most of these sorts of cardiovascular trials, but it doesn’t have a standard definition. This makes it difficult to compare like for like trials.
Anyway, looking at this trial specifically, the 3-point MACE outcome occurred in 490 of 4,687 patients (10.5%) in the empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group. For the secondary endpoint, the 4-point MACE which includes hospitalization for heart failure occurred in 599 of 4687 patients (12.8%) in the empagliflozin group and in 333 of 2333 patients (14.3%) in the placebo group.
There are two important takeaways from the data, and it’s on one of these two takeaways that Eli Lilly and Boehringer decided to go for the extended approval.
The first, and the most relevant, is that CV death occurred in 172 of 4687 patients (3.7%) in the empagliflozin group and in 137 of 2333 patients (5.9%) in theplacebo group. To put this another way, the drug reduced CV death by 38%. That’s big, and highly significant.
The second is that all-cause mortality occurred in 269 of 4687 patients (5.7%) in the empagliflozin group and in 194 of 2333 patients (8.3%) in the placebo group. This is a reduction of 32%. Again, highly significant.
Safety issues, tolerability concerns and adverse events across the entire trial were comparable between placebo and active arms, suggesting this shouldn’t be an issue when the FDA comes to making a decision.
The Panel Review
Now let’s get to the primary documents here and here. How did the panel view the application?
The committee reviewed all the material, and then asked a number of questions rooted in the trial and its outcome. The committee then summarized the individual answers to these questions and published summaries as part of the review document. It is these summaries that we will be working from.
