Storm clouds on the horizon?

Storm clouds on the horizon?

It seems since the EMPA-REG data became public the sun has been shining brightly on Lilly (NYSE: LLY). This historic study is changing the competitive balance in the expanding SGLT2 market. Which is somewhat ironic given that when these drugs were in clinical trials many well-known diabetes experts questioned whether they would find much uptake given their adverse event profile, in particular urinary tract infections.

Yet as we have seen since EMPA-REG became public the mindset towards this category has changed dramatically. These same experts who questioned this class before are now stating that the results seen in EMPA-REG will be replicated by all SGLT2’s that the cardiovascular benefits seen with Jardiance will also be seen with Invokana and Farxiga. Yet in an ironic twist the FDA instituted a label change for Invokana and Farxiga due to acute kidney issues but did not include Jardiance in this label change.

Earlier this week an FDA panel voted 12-11 to allow a label change for Jardiance which would allow a claim that the drug cuts cardiovascular related deaths. This same panel also voted unanimously that the drug does not add to cardiovascular risk. Although the FDA does not have to follow the vote of the panel it normally does so. However, with a vote so close some are speculating the FDA may NOT follow the vote, as concerns have arisen over the EMPA-REG data set.

Here is where things get interesting as there is a group of researchers who believe that the FDA is moving too quickly and SGLT2’s may have more issues than originally realized. Given that there are three SGLT2’s on the market and each underwent the rigorous FDA approval process the general belief is the benefits and drawbacks of this class are well known. Yet, some seem to believe that this class of drugs has more serious adverse events looming on the horizon, adverse events which will not appear until after a patient has been on the drug for many years.

As wacky as this may sound there is precedent for such a claim as it wasn’t until TZD’s were on the market for nearly 7 years that it was discovered they also produced an increased incidence in bone fractures. We also heard the same rumblings when DPP4’s were first approved, as many speculated long term use of the drugs could cause cancer, concerns which thankfully have not emerged.

What concerns Diabetic Investor here is how the EMPA-REG data is being analyzed and picked apart. Something we have seen before when the Avandia controversy was in full swing. The reality is study data is not full of absolutes that events are open to interpretation. In the FDA’s briefing documents released before the panel meeting it states:

“Issues to consider when interpreting the robustness of the primary endpoint results include

– The trial was designed to address both a pre-approval and post-approval a safety question. The primary intent of the trial was not to establish a benefit on a specific outcome. Some unblinding occurred as the trial was ongoing to support pre-approval analyses and worldwide regulatory submissions4 . All unblinded individuals were to keep results confidential and signed agreements to that effect.

– The risk of MACE appeared to diverge early and was almost exclusively accounted for by an effect on the CV death component (HR 0.62; 95% CI 0.49, 0.77). Empagliflozin did not reduce nonfatal stroke (HR 1.24; 95% CI 0.92, 1.67) or non-fatal MI (HR 0.87; 95% CI 0.70, 1.09).

– Many deaths (n=124) were categorized as “non-assessable” and adjudicated as presumed CV deaths (71 versus 53 for empagliflozin versus placebo). Deaths that were “non-assessable” but presumed to be CV-deaths comprised 40% of CV deaths, and 27% of overall deaths in the trial. In a sensitivity analysis that removes all “non-assessable” deaths from the primary endpoint, empagliflozin was no longer demonstrated to be superior to placebo (HR 0.90, 95% CI 0.77, 1.06). “

It is this last concern over the 124 non-assessable deaths that has many speculating the FDA will not follow the panels vote. That allowing such a dramatic label change when there is some question over the EMPA-REG data set may be overreaching.

According to a report issued by the Institute for Safe Medication Practices:

“The risks of introducing new drugs for long-term use without long-term clinical trials are illustrated in the growing safety questions about the SGLT2 inhibitors, the new class of diabetes medications now rapidly moving into clinical practice. Whether the drugs have clinical benefits (such as reduced cardiovascular risks or less kidney or nerve injury) remains unknown, while safety problems grow increasingly apparent. Since May 2015, the FDA has issued Drug Safety Communications about life-threatening ketoacidosis, severe electrolyte imbalances, acute kidney injury, possible increased risk of limb amputation, higher risk of bone fracture, sepsis, and urosepsis. Given that drugs intended for long-term therapy for hyperglycemia in Type 2 diabetes need to be low risk, we conclude that current data provide insufficient evidence that the benefits of SGLT2 inhibitor drugs outweigh their risks. The FDA should re-evaluate its decision to allow unrestricted long-term use of this drug class.”

Now we have no idea if there is an agenda here but we have seen this movie before and not sure we are going to like the remake. We suspected that when the EMPA-REG data became public that Johnson and Johnson (NYSE: JNJ) the makers of Invokana and AstraZeneca (NYSE: AZN) the makers of Farxiga would try to muddy the waters in an attempt to protect their respective SGLT2’s. The reality is Lilly has hard data, they don’t so in the absence of hard data they had to punt. But this didn’t stop the positive impact generated from EMPA-REG as Jardiance is on a major roll.

Besides having hard data Lilly now has won the vote of the panel and for all practical purposes is on its way to owning a larger share of the expanding SGLT2 market. That is of course assuming nothing blindsides everyone which given the way things are going is a distinct possibility. Way back in the day when the Avandia controversy was raging out of control when the now debunked meta-analysis which started the controversy was being analyzed six ways from Sunday we speculated that no matter the final outcome the damage inflicted could not be undone and would have repercussions for years to come.

Ironically EMPA-REG was done because of the Avandia controversy and its own way could once again turn the diabetes drug world upside down. The players may have changed here but the game has not. The reality is this thought process that there is a completely “safe” drug has not gone away. There are still people who have lost perspective and believe the needs of the few outweigh the needs of the many. That one adverse event outweighs the beneficial impact for millions of patients.

Even worse this data parsing will just create more data parsing and in the long run nothing substantive will result. Unfortunately, in today’s world where anyone can publish their thoughts on Twitter, Facebook or Instagram it really doesn’t matter if this is just speculation rather than fact. Let’s hope for the sake of all involved that this coming attack on the SGLT2 class is not a repeat of the Avandia controversy. A controversy which created no winners and lots of losers.