Positive data with the SGLT1/2 inhibitor sotagliflozin in heart failure and chronic kidney disease might have come too late for its beleaguered developer, Lexicon. But signs that the project worked in heart failure patients with both reduced and preserved ejection fractions raise hopes that a similar effect might be seen with the approved SGLT2s.
Heart failure with preserved ejection fraction (HFpEF) has proven a tough nut to crack, and there are reasons to be cautious about the results. But with data due next year from HFpEF studies of Lilly/Boehringer Ingelheim’s Jardiance and Astrazeneca’s Farxiga, it should not be too long until the potential of this drug class here becomes clearer.
As for sotagliflozin, which was abandoned by Sanofi last year, the future is far less certain. The two studies presented at the American Heart Association, Soloist – in type 2 diabetes patients with heart failure – and Scored – in type 2 diabetes patients with chronic kidney disease – were prematurely terminated due to loss of funding, which Lexicon blamed partly on the coronavirus pandemic (Clinical trial delays become reality as Covid-19 risk spreads, March 20, 2020).
The results reported yesterday were, therefore, from truncated versions of the trials, with endpoints changed to accommodate fewer accrued events. These events were investigator-assessed rather than independently adjudicated, further decreasing the rigour of the studies.
Notwithstanding these issues, Soloist and Scored were deemed successes, with both meeting their new primary endpoints of deaths from cardiovascular causes and hospitalisations and urgent visits for heart failure: Soloist with a 33% relative risk reduction, and Scored with 26% relative risk reduction, both with p values of less than 0.001.
However, the sotagliflozin train has “already left the station”, at least in type 2 diabetes, according to Stifel analysts. “While these are very interesting data…we don’t see how they change the regulatory or strategic narrative for this asset.”
The best hope for Lexicon, the analysts added, was that the results could help the company find a path forward in type 1 diabetes, given the raised underlying cardiovascular risk in these patients. Sotagliflozin, branded Zynquista, is approved in the EU in type 1 disease but not yet launched; in the US, the project was knocked back by the FDA last year.
Therefore, the biggest implications for Soloist and Scored in type 2 diabetes could be for the other SGLT2 inhibitors, such as Jardiance and Farxiga.
For one, it could expand SGLT2 inhibitors’ use into patients hospitalised for worsening heart failure, the population enrolled in Soloist – the Dapa-HF and Emperor-Reduced studies of Farxiga and Jardiance respectively recruited patients with stable disease.
“I think these results are generalisable to SGLT2 inhibitors as a class,” said Dr Deepak Bhatt of the of the Brigham and Women's Hospital in Boston, summarising the data he presented at the virtual AHA.
But the most intriguing finding was that, in Soloist, sotagliflozin appeared to have an effect in HFpEF patients, as well as those with heart failure with reduced ejection fraction (HFrEF) – Farxiga and Jardiance have so far only shown a benefit in the latter.
Soloist grouped patients into those with ejections fractions of less than 50%, classed as reduced, and 50% or more, classed as preserved. The effect across the two groups on the primary endpoint was consistent: among the HFrEF patients the hazard ratio was 0.72, while among the HFpEF patients this was 0.48.
Still, the authors cautioned against drawing any firm conclusions here, noting the early termination of the trial and the small size of the HFpEF subgroup, which made up only around 21% of patients in Soloist.
However, with the SGLT2s’ efficacy in HFrEF looking like a class effect, Astra and Lilly/Boehringer will no doubt hope that Soloist provides an early indication that this could be the case in HFpEF, too.
|Upcoming readouts with SGLT2 inhibitors in HFpEF|
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|Source: EvaluatePharma, clinicaltrials.gov.|