Fitusiran for hemophilia

Last updated Aug. 22, 2024, by Margarida Maia, PhD
Fact-checked by Inês Martins, PhD

What is fitusiran for hemophilia?

Fitusiran, formerly known as ALN-AT3 and SAR439774, is an injectable investigational therapy that’s being developed to prevent bleeding episodes in adults and adolescents with hemophilia A or B, with or without inhibitors.

The medication is designed to be administered via a subcutaneous, or under-the-skin, injection. It was first developed by Alnylam Pharmaceuticals, but Sanofi then acquired global rights to develop and commercialize the therapy in 2018.

Fitusiran has been granted orphan designation in the European Union, a status expected to accelerate its development by providing a number of incentives to the company. An application requesting the approval of fitusiran for the treatment of adults and adolescents with hemophilia A or B, with or without inhibitors, is under review in the U.S. A decision is expected by March 28, 2025, according to Sanofi. Similar applications also have  been accepted and are under review in other countries.

Therapy snapshot

How does fitusiran work in hemophilia?

Hemophilia is a genetic condition in which blood cannot clot properly because a clotting protein is faulty or missing. In hemophilia A, patients have deficient levels of factor VIII (FVIII) due to mutations in the F8 gene. In turn, F9 gene mutations that impact the production of factor IX (FIX) are the cause of hemophilia B.

Due to the reduced levels of these clotting factors, people with hemophilia often experience prolonged bleeding episodes, either spontaneously or following an injury, that can be difficult to control.

Fitusiran is an RNA-based therapy designed to limit the production of antithrombin, a natural anticoagulant protein that inhibits multiple clotting factors.

The antithrombin protein is coded in the genome by the SERPINC1 gene. When that gene is read, an intermediary molecule called SERPINC1 messenger RNA (mRNA) is made to be used by the cell’s protein-making machinery as template for antithrombin’s production.

As a small interfering RNA (siRNA), fitusiran works by binding to and promoting the degradation of SERPINC1 mRNA molecules, thereby interfering with the synthesis of antithrombin and reducing its levels.

A particular feature of fitusiran is that it contains a molecule called N-acetylgalactosamine attached to the siRNA molecule. This is designed to deliver the therapy directly to liver cells, which are the main producers of clotting factors.

By limiting the production of antithrombin in the liver, fitusiran is expected to improve the body’s ability to form blood clots. This may help to control excessive bleeding or bruising in hemophilia patients, regardless of the presence of neutralizing antibodies (inhibitors) against FVIII or FIX.

How will fitusiran be administered in hemophilia?

Fitusiran has been tested in hemophilia clinical trials as a weekly or monthly subcutaneous injection, at doses that varied by body weight (from 0.015 to 1.8 mg/kg) or at fixed doses of 50 or 80 mg.

Data from early trials supported the selection of the 80 mg fixed dose for testing in Phase 3 clinical trials. The therapy is being administered as a monthly subcutaneous injection in these advanced trials.

Fitusiran in hemophilia clinical trials

The safety, efficacy, and pharmacological properties of fitusiran were first tested in a four-part Phase 1 clinical trial (NCT02035605). The trial also attempted to determine the dose and dosing schedule that provided the greatest benefits to patients without causing side effects.

Phase 1 trial

After showing that a single subcutaneous injection of fitusiran was well tolerated in healthy volunteers in part A, parts B and C tested weekly or monthly dosing in patients without inhibitors, and part D tested monthly injections in hemophilia patients who had developed inhibitors.

Parts B and C included 25 men with moderate or severe hemophilia who had been receiving prophylactic (preventive) or on-demand replacement therapy to temporarily supply the missing clotting protein. Patients received three fitusiran injections, either once weekly at a dose of 0.015, 0.045, or 0.075 mg/kg (part B), once monthly at a dose of 0.225, 0.45, 0.9, or 1.8 mg/kg or at a fixed dose of 80 mg (part C).

Results showed that fitusiran was taken rapidly into the bloodstream and achieved peak levels in the blood about two to six hours after dosing. However, monthly dosing resulted in greater drug levels and antithrombin reductions than weekly injections, with patients experiencing an average 89% reduction in antithrombin levels with the 1.8 mg/kg dose and an 87% reduction with the fixed 80 mg dose.

In part D, 17 men with moderate to severe hemophilia who tested positive for inhibitors received three monthly injections of fitusiran at a fixed dose of 50 or 80 mg. Data showed that levels of antithrombin were more profoundly reduced with the 80 mg dose (by 87%).

Over an average of 69 days of observation, nearly two-thirds (65%) of these patients experienced no bleeding episodes while on fitusiran treatment and most also reported improvements in life quality.

Phase 2 trial

After completing the Phase 1 clinical trial, a total of 34 participants rolled over into a Phase 2 open-label extension study (NCT02554773), where they continued to receive a fixed, once-monthly 50 mg or 80 mg dose for up to seven years.

An interim analysis conducted after a median follow-up of 2.6 years (up to 4.7 years) showed a sustained reduction in antithrombin levels by up to 85%.

Fitusiran also reduced the frequency of annual bleeding episodes, assessed by the annualized bleeding rate (ABR). The strongest drops were seen in people with inhibitors (median ABR decreased from 42 to 0.44), but patients without inhibitors who were previously receiving on-demand therapy also experienced an ABR decrease from 12 to 1.01. Those without inhibitors on prophylactic treatment in turn experienced a drop from 2 bleeds per year to 1.01.

Overall, the ABR for the whole population was low, at 0.84 bleeding episodes per year, and the median annualized rate for spontaneous bleeding episodes was even lower, at 0.38. For patients with and without inhibitors, fitusiran treatment also resulted in better quality of life.

While the treatment was generally well tolerated, one patient died from cerebral venous sinus thrombosis, a condition in which a blood clot prevents blood from exiting the brain, resulting in a hemorrhage and brain swelling. This resulted in a voluntary clinical hold and in a subsequent protocol amendment to mitigate the risk of blood clots.

Phase 3 clinical trials

Following the early trials, Sanofi launched a series of Phase 3 clinical trials to compare the once-monthly 80 mg dose of fitusiran versus standard on-demand or prophylactic therapies in people with and without inhibitors.

ATLAS-INH

Building on fitusiran’s striking effects on bleeding rates in people with inhibitors, the open-label ATLAS-INH trial (NCT03417102) was designed to compare the experimental therapy against on-demand treatment with bypassing agents in people who had developed inhibitors to conventional factor replacement therapies.

Bypassing agents are treatments that promote blood clotting through mechanisms that aren’t dependent on the missing clotting proteins. They’re often used to bypass the need for replacement therapies when these are being targeted by neutralizing antibodies.

The trial enrolled 57 male adults and adolescents, ages 12 and older, with severe hemophilia A or B, who had experienced at least six bleeding episodes in the past six months requiring on-demand bypassing agents. They were randomly assigned to continue on their on-demand treatment or switch to fitusiran for nine months.

​​Findings demonstrated that the mean annual number of bleeding episodes was 90.8% lower with prophylactic fitusiran treatment than with on-demand agents (1.7 vs. 18.1), representing a statistically and clinically significant reduction in bleeding rates.

After fitusiran reached its desired effects on antithrombin, one month after the first dose, 66% of fitusiran-treated patients experienced no bleeding episodes, while 5% of those receiving on-demand treatment remained without bleeds in that period. Findings were similar for spontaneous bleeds, and were observed regardless of age, hemophilia type, and number of previous bleeding episodes.

ATLAS-A/B

The open-label ATLAS-A/B (NCT03417245) was in turn launched to compare fitusiran prophylaxis against on-demand treatment in people without inhibitors. The trial was mostly similar to ATLAS-INH, but because these patients had no neutralizing antibodies against conventional replacement therapies, they were receiving clotting protein concentrates to treat their bleeds.

A total of 120 male adults and adolescents, ages 12 and older, with hemophilia A or B were recruited into the trial. Participants had required on-demand treatment for at least six bleeds in the past six months, and were randomly selected to either continue that treatment or switch to fitusiran (80 mg once a month) for nine months.

Over a median of 7.8 months, the average annualized bleeding rate was significantly lower in fitusiran-treated patients than in those who continued on on-demand treatment — 3.1 versus 31 bleeding episodes per year; a 90% reduction. Starting one month after the first dose, more than half (51%) of patients on fitusiran had no bleeding episodes requiring treatment, compared with 5% of those given on-demand replacement therapies.

There was also a greater improvement in quality of life among patients given fitusiran.

ATLAS-PPX

While the other two trials established the superiority of fitusiran against standard on-demand treatments, the ATLAS-PPX open-label trial (NCT03549871) instead compared the experimental therapy with standard prophylactic therapies in people with or without inhibitors.

The trial enrolled 80 male participants, ages 12 and older, who had previously received preventive treatment with bypassing agents or clotting protein concentrates. Then, all were switched to once-monthly 80 mg fitusiran for up to nine months.

While patients were experiencing a median of 6.5 bleeding episodes per year with their former prophylactic treatment, the median annual number of episodes dropped to zero with fitusiran. Nearly two-thirds (63.1%) of patients remained free of bleeding episodes requiring additional treatment, and significant improvement in life quality was also observed with fitusiran.

Ongoing Phase 3 trials

Sanofi is currently conducting a number of Phase 3 clinical trials to assess the long-term safety and efficacy of fitusiran in adults and adolescents — ATLAS-OLE (NCT03754790) and ATLAS-NEO (NCT05662319) — and to establish whether the therapy is also safe and effective in children.

The open-label ATLAS-PEDS trial (NCT03974113) is enrolling boys ages 1 to 11 with severe hemophilia A or B who are positive for neutralizing antibodies. The primary goal is to measure blood activity levels of antithrombin over 256 weeks (nearly five years) of treatment. Secondary outcome measures include safety and levels of fitusiran in the blood.

Common side effects of fitusiran

The most common side effects that have been reported with fitusiran during late-stage clinical trials include:

• elevated levels of liver enzymes, a sign of liver damage
• upper respiratory tract infections
• headache
• pain and redness at the injection site
• abdominal pain
• joint pain
• the common cold.

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