Ash 2021 – Sanofi takes its time with fitusiran

Sanofi reckons it has a universal haemophilia therapy on its hands – but first it needs to test a lower dose.

The choice of Sanofi’s fitusiran for both a late-breaking and plenary slot at this year’s Ash meeting is puzzling. True, the small interfering RNA could become a universal haemophilia therapy, suitable for both patients with the A and B form of the disease, and those with and without inhibitors.

But the project is far from ready for prime time. Crucially, Sanofi has abandoned the 80mg once-monthly dose featured at Ash in two ostensibly positive presentations, after previous blood clot scares. A lower dose is being tested in ongoing pivotal studies, and the company will have to hope that this new regimen does not mean a compromise on efficacy.

While the Ash presenters talked up the transformative potential of fitusiran, pressing forward with 80mg was not an option, Sanofi’s chief medical officer, Dietmar Berger, told Evaluate Vantage. “We had discussions with regulatory authorities. Obviously, we want to bring forward a therapy that’s safe and effective – and getting more data is what we want as well.”

Shifting the dosage has contributed to delays for the project, which was licensed from Alnylam. Fitusiran's regulatory filings are now expected in 2024, versus a previous estimate of 2022, Sanofi said recently (Delays hit Sanofi, October 28, 2021).

Anti-antithrombin

The universal promise of fitusiran comes from its novel mechanism of action. While conventional haemophilia treatments aim to replace the blood-clotting factors that are lacking in the disease, fitusiran targets antithrombin to restore thrombin generation, thereby rebalancing haemostasis.

However, this mechanism can also lead to an increased risk of blood clots, particularly in patients whose antithrombin levels are pushed too low. In general, thrombotic events with fitusiran have occurred in patients who had antithrombin of around 10% of normal levels.

Sanofi previously disclosed that its new dosing regimen would aim to get patients’ antithrombin levels into the 15-35% range. To achieve that the group is starting with 50mg every other month, Mr Berger said.

“Then antithrombin levels are monitored, and then you dose according to that.” If levels drop too far, the fitusiran dose can be lowered to 20mg every other month; on the other side of the coin, the dose can be increased to 50mg monthly if necessary.

Sanofi has switched to the new dosing regimen in the phase 3 Atlas-INH and Atlas-A/B trials, which both featured at Ash.

The company is also generating data with the new dosing schedule in newly diagnosed patients; Mr Berger declined to give more details, apart from saying that this would not involve another large phase 3 study. Neither would he say when the group expects to report data with low-dose fitusiran.

Fitusiran will need to maintain the efficacy reported at Ash – which was consistent with the data already revealed in the abstracts – without the spectre of thrombotic events.

Liver enzyme elevations

Dosage is not the only issue that Sanofi has to contend with. Liver enzyme elevations were also seen in both trials, although the presenters stressed that these were all mild to moderate and resolved. It is possible that these events could lessen with low-dose fitusiran, Mr Berger said, though he conceded that: “We’ll need to see the data.”

Could all of this mean that fitusiran, even if approved, might end up as a therapy for those with no other options, such as haemophilia B patients with inhibitors? Sanofi is clearly thinking bigger. 

“It has the potential to be broader than that, as it provides unique benefits for patients across the board,” replied Mr Berger.

Dr Steven Pipe of the University of Michigan, who presented the Atlas-A/B data, noted that one of these benefits would be freeing patients from the peaks and troughs seen with intravenous factor therapy, and the impact this has on bleeding.

“Fitusiran has the opportunity to transform the day-to-day lives of patients,” he told a press briefing. First, though, the low dose has to prove its worth.

Sanofi's phase 3 data with fitusiran
  Atlas-A/B (pts without inhibitors, n=120) Atlas-INH (pts with inhibitors, n=57)
  Fitusiran Standard of care Fitusiran Standard of care
Estimated mean ABR 3.1 31.0 1.7 18.1
Reduction in ABR 90% 91%
P value <0.0001 <0.0001
Pts with zero treated bleeds 51% 5% 66% 5%
TEAESIs* 19% 3% 24% 5%
Thromboembolic events 0 0 2 (1 pt discontinued) 0
Standard of care was on-demand factor replacement (Atlas-A/B) or bypassing agents (Atlas-INH). *TEAESI=treatment-emergent adverse events of special interest, includes ALT or AST elevation >3 x upper limit of normal and suspected or confirmed thromboembolism. Source: Ash, Dr Pipe & Dr Young.

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