AstraZeneca, Boehringer cry 'no class effect' after Johnson & Johnson's Invokana doubles amputations in study

SGLT2 drug makers certainly wouldn’t mind if the heart-helping benefits Eli Lilly and Boeheringer Ingelheim’s Jardiance—and, now, Johnson and Johnson’s Invokana—have shown in trials turn out to be a feature that spans the class. Amputations, though? Those are J&J’s problem alone, rivals contest.

Execs from both Boehringer and AstraZeneca, which makes Farxiga, made clear over the weekend at the American Diabetes Association’s annual meeting that their medications haven’t turned up the same red flags that Invokana has. In results presented Monday, J&J’s contender showed that it increased the risk of lower-extremity amputations by about double.

AstraZeneca and BI were both quick to tout findings of pooled safety studies that put their drugs in the clear. On Tuesday, Boehringer confirmed that an analysis involving data from 19 studies involving more than 12,500 patients hadn’t turned up an amputation signal. And in its headline-making cardiovascular outcomes study, Empa-Reg, the proportion of patients suffering lower limb amputations was 1.9%, compared with the placebo group’s 1.8%, it said.

AstraZeneca uncovered similar results from a study pooling data from 30 previous trials. “We were particularly interested in looking at amputations,” Jim McDermott, AstraZeneca’s Medical Affairs lead for diabetes, said in an interview, adding that “we found that there was no imbalance whatsoever.”

In 9,000 patients exposed to Farxiga, AZ dug up eight amputations, whereas in the control group of 7,000 patients, it uncovered seven of them. That’s a rate of one amputation per 1,000 patient years for the British drugmaker’s med, versus 1.7 for the placebo.

“We were extremely happy about that, because I know there were a lot of questions regarding whether this was a class effect. We firmly believe it is not,” McDermott said.

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So far, the FDA isn’t treating it like one, either. Last month, it required new warnings be added to Invokana’s label in a communication that applied only to the J&J med.

As Jim List, Janssen’s global therapeutic head for cardiovascular and metabolism, pointed out in an interview, though, when the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee published its own amputation conclusions back in February, it left open the possibility that the risk could apply to other meds in the class.

That, of course, was before the J&J’s rivals unveiled their latest safety findings. But as List stressed, “a very deep collection of data multiplied by the very broad set of patients and long exposures is what brought this to light.”

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That fact doesn’t worry AstraZeneca, which is currently conducting a cardiovascular outcomes study encompassing 17,000 patients worldwide. “We’re very confident about where our market share is going to move from a commercial standpoint,” considering that Farxiga has racked up a “really solid story around the clinical efficacy,” in addition to positive real-world heart data and “a very well understood safety profile that our competition doesn’t have,” Mike Crichton, the company’s head of cardiovascular and metabolic diseases, said in an interview.

The way he sees it, though, J&J “has got some questions to answer.”

“I think what you’re going to see is a shifting probably to two SGLT2s as opposed to three,” he predicted.

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Leerink Partners analyst Seamus Fernandez, for one, last month forecast a similar shift, at least for the near-term, writing in a note to clients that the “immediate reaction” from doctors would be to switch patients away to either Jardiance or AstraZeneca’s SGLT2 entrant, Farxiga, just as they years ago switched patients from GlaxoSmithKline’s Avandia to Takeda’s Actos in the wake of concerns about a potential Avandia cardiovascular risk.

But as he pointed out, J&J’s situation “could be further mitigated by a directionally positive result” from its cardiovascular outcomes trial, which Monday revealed that, as Jardiance had, Invokana had shown a 14% reduction in the combined risk of heart attack, stroke and cardiovascular death among high-risk Type 2 diabetes patients.