European and US regulators do not always agree. But recent developments with SGLT inhibitors in type 1 diabetes highlight a rare instance of the FDA being stricter than its European counterparts.
Today’s European approval of Astrazeneca’s SGLT2 inhibitor, Forxiga, was at odds with Friday’s FDA rejection of Sanofi and Lexicon’s anti-SGLT1/2 project Zynquista (sotagliflozin). With both candidates linked to an increased risk of diabetic ketoacidosis, Astra might also run into problems across the pond.
Ketoacidosis is a known complication of diabetes, but there are concerns that the risk is heightened with the SGLT inhibitors. Of course, there is the possibility that the projects’ slightly different mechanisms mean this is an issue unique to Zynquista. But this does not appear to be the case: pivotal trials in type 1 diabetes found similar rates of diabetic ketoacidosis at one year, at 3.4-4.2% with Zynquista and 3.4-4% with Forxiga – or Farxiga, as it is known in the US (ADA – Lexicon and Astra’s oral drugs face off in type 1 diabetes, June 26, 2018).
And European regulators do not seem to have any qualms about giving Zynquista the green light, either, with the project bagging a positive CHMP opinion in March.
Is this just a case of the FDA being more cautious? Things could become clearer in the next few months, as Astra is expecting a US decision on Farxiga in type 1 diabetes by the end of the year. The drug is already approved for type 2 diabetes and its US label flags up a risk of ketoacidosis.
Meanwhile, Zynquista is not yet approved for any indication; Lexicon and Sanofi had hoped that type 1 diabetes would be its first use, although the groups are also testing the project in type 2 disease.
A spokesperson for Astra told Vantage that diabetic ketoacidosis occurs more frequently in type 1 than type 2 diabetes. When asked whether Farxiga could run into the same issues that Zynquista has in the US, he replied that no head-to-head trials of the drugs have been carried out, and it was inappropriate to compare their performance across the type 1 diabetes trials due to "differing study designs and patient populations".
Stifel analysts do not believe that Farxiga will remain immune to the FDA’s concerns. They highlighted “even less compelling” phase III efficacy data with the Astra project, as well as the fact that around half as many type 1 diabetes patients have been treated with Farxiga versus Zynquista.
Lexicon’s chief executive, Lonnel Coats, predictably agrees. When asked during a conference call on Friday whether the issues raised by the agency were specific to Zynquista or a class effect with the SGLT inhibitors, he replied: “Whatever we’re doing, you can certainly assume others who come after us will have to do the same.”
Mr Coats did not give details of the issues raised in the FDA's complete response letter – more information should be available once Lexicon’s partner Sanofi has met the FDA, which could happen in the second or third quarter, although the chief exec would not be drawn on the exact timing.
Presumably, the FDA is concerned about the risk of ketoacidosis, which was highlighted during an advisory committee meeting in January that was split on whether Zynquista should be approved (Ketoacidosis worries could scupper Lexicon, January 18, 2019).
However, based on other comments at the adcom, the agency might also have worries about the drug’s efficacy, the Stifel anlaysts speculated. It is unclear at present whether Lexicon and Sanofi will need to carry out any more studies of Zynquista in type 1 disease.
The analysts reckon a best-case scenario would be a resubmission in the second half of the year, followed by a three to six-month review – but suggested a 2021 launch might be more realistic.
Lexicon is apparently taking comfort from past US setbacks with other diabetes drugs. On Friday’s call Mr Coats pointed to a delay to US approval for Farxiga, with the FDA initially knocking it back on concerns over bladder cancer before eventually giving it the nod in 2014.
Lexicon and Sanofi are also making a big push in type 2 disease, where a huge phase III programme for Zynquista is underway, with eight studies due to complete this year. However, the type 2 market is crowded, and Zynquista will need to show it is better than the incumbents in order to make a mark.
Lexicon’s best chance of carving out a space for Zynquista was getting to market first in type 1 diabetes. Perhaps Astra will have similar issues with Farxiga but, if not, Lexicon and Sanofi could find themselves playing second fiddle in both type 1 and 2 disease.
|Zynquista's type 2 diabetes trials|
|Trial Name||Setting||N||Trial ID||Primary completion|
|-||Patients on metformin||500||NCT02926950||Mar 2019|
|Sota-Empa||Zynquista vs Jardiance and placebo||700||NCT03351478||May 2019|
|-||Previously untreated patients||400||NCT02926937||May 2019|
|-||Patients on sulfonylurea +/- metformin||500||NCT03066830||May 2019|
|Sota-Ins||Patients on insulin +/- oral antidiabetics||560||NCT03285594||Aug 2019|
|Sota-Glim||Zynquista vs glimepiride and placebo||930||NCT03332771||Aug 2019|
|Sota-CKD3||Patients with moderate renal impairment||780||NCT03242252||Oct 2019|
|Sota-CKD4||Patients with severe renal impairment||276||NCT03242018||Dec 2019|
|Sota-Bone||Efficacy and bone safety||360||NCT03386344||Dec 2020|
|Soloist-WFH||CV events post worsening heart failure||4,000||NCT03521934||Jan 2021|
|Scored||CV/renal events in pts with renal impairment||10,500||NCT03315143||Mar 2022|
|Source: EvaluatePharma, clinicaltrials.gov.|