New Preventative Treatment For Haemophilia Could Help Patients Stop Bleeding
According to randomized controlled trials published simultaneously in The Lancet and The Lancet Haematology journals, monthly prophylactic injections of fitusiran prove to be effective in reducing bleeds among patients with haemophilia A or B.
Haemophilia is a genetic disorder that results in the deficiency of clotting factors, VIII and IX, in patients with haemophilia A or B respectively. This condition mainly affects men and can cause spontaneous bleeding into joints or muscles, as well as prolong the bleeding time after an injury. Current prophylactic treatments involve the regular administration of drugs that enhance haemostasis and aim to reduce spontaneous bleeding.
Fitusiran is a new type of treatment that uses small interfering RNA (siRNA) therapy to interfere with the production of antithrombin, a protein that reduces blood clotting, and increase clotting ability. As the first siRNA developed for haemophilia, fitusiran is a novel prophylactic treatment that works for both haemophilia A and B patients with or without inhibitors, and is currently being tested in clinical trials.
Patients with haemophilia who receive replacement clotting factors may develop an immune reaction against the treatment, triggering the development of inhibitors and the need for alternative treatments. However, the efficacy data of fitusiran in comparison to other prophylactic treatments for haemophilia A or B currently in use is difficult to determine, as the comparator groups in both studies received on-demand rather than prophylactic treatment. The authors note that at the time the trial began, there was no effective prophylactic treatment for patients with inhibitors.
In summary, fitusiran offers a promising new option for prophylactic treatment of haemophilia A or B, especially for patients with inhibitors, and represents an exciting breakthrough in the field of haemophilia research.
“Our study looks at the efficacy of the first siRNA therapy used to treat haemophilia with inhibitors,” adds lead author Professor Guy Young.
And “the data is encouraging and suggests it may be the first prophylactic treatment – meaning it can be given to prevent bleeds rather than to treat them after they have already occurred – that works for both haemophilia A and B patients with inhibitors. Haemophilia B patients’ treatment options are currently limited to on-demand treatments, which treat bleeds after they have occurred.”
Fitusiran use with inhibitors
The phase 3 randomized controlled trial, published in The Lancet, was conducted across 26 hospitals in 12 countries, involving 56 male patients aged 12 years or older who had severe haemophilia A or B with inhibitors. Of these patients, 38 were administered a monthly 80mg dose of fitusiran via subcutaneous injections, while 19 received on-demand bypassing treatment. The primary endpoint of the trial was the annualised bleeding rate, which measures the number of bleeds per year requiring treatment, and safety and tolerability were also evaluated.
Results showed that patients in the fitusiran group had a median annualised bleeding rate of 0, compared to 16.8 in the comparator group receiving on-demand bypassing treatment.
Of the patients receiving fitusiran prophylaxis with inhibitors, 66% (25 out of 38) experienced no bleeds after nine months, whereas only 5% (1 out of 19) in the comparator group given on-demand bypassing agents had the same outcome.
Additionally, 32% (13 out of 38) of participants given fitusiran with inhibitors experienced elevated alanine aminotransferase levels (an enzyme that indicates liver damage), while suspected or confirmed blood clotting was reported in only 5% (2 out of 38) of participants. No fatalities were recorded.
“The safety outcomes in our trial are consistent with previous data on fitusiran and need further monitoring,” comments the lead author.
Two participants who received fitusiran experienced blood clotting, which is a common risk with treatments that seek to rebalance haemostasis. The most common adverse effect was elevated alanine aminotransferase, which indicates liver inflammation and is a known side effect of many medications. However, most of these elevations were temporary and did not result in discontinuation of fitusiran.
“In this context, it suggests that fitusiran did not result in any long-term liver damage, but this adverse effect needs continued assessment in this and other trials of fitusiran. Regulators will need to assess the benefits and risks of the drug when deciding whether to approve its use and for which patients it is suitable.”
Fitusiran use without inhibitors
This phase 3 randomized controlled trial, The Lancet Haematology, was also part of the ATLAS trial and was conducted across 45 hospitals in 17 countries. It involved 120 male patients aged 12 years or older with severe haemophilia A or B, with two thirds of the patients (79) receiving a monthly 80mg dose of fitusiran via subcutaneous injections, while the remaining one third (40) were administered on-demand clotting factor concentrate replacement therapy. The primary endpoint of the trial was the annualized bleeding rate, with safety and tolerability also being evaluated.
Results showed that patients in the fitusiran group had a median annualized bleeding rate of 0, compared to 21.8 in the comparator group receiving on-demand bypassing treatment.
Patients without inhibitors who received monthly injections of fitusiran had a significant reduction in bleeding incidents requiring treatment, with 51% (40 out of 80) of participants experiencing no bleeds, compared to only 5% (2 out of 40) in the comparator group receiving on-demand bypassing agents.
While 23% (28 out of 80) of patients who received fitusiran had elevated alanine aminotransferase levels, indicating liver inflammation, there were no instances of blood clotting or death reported.
In reference to the study published in The Lancet Haematology, Professor Alok Srivastava of Christian Medical College in Vellore, India, who served as the lead author, stated that this “study looks at the use of fitusiran in patients with haemophilia A or B without inhibitors and complements the findings from the study looking at fitusiran with inhibitors – also finding that it is very effective in preventing bleeds.
Fitusiran is delivered via subcutaneous injections that can be self-administered at home, which significantly reduces the treatment burden for patients with haemophilia. The fact that this drug is administered just once a month or even less frequently means that patients can manage their condition with fewer hospital visits, which can be worrisome and disruptive to their daily life.
“This would lead to an improved quality of life as documented in the study.”
The authors of both studies acknowledge some additional limitations. Since the patients were followed up for only nine months, further studies are required to confirm the longer-term efficacy of fitusiran. Additionally, the trials only included patients with severe haemophilia, which means that outcomes may differ in patients with milder cases of the condition.
What other experts say about the new treatment to reduce bleeds in patients with haemophilia A and B:
In a linked Comment published in The Lancet, Professor Flora Peyvandi of the Università degli Studi di Milano highlights that Fitusiran has the potential to become the first prophylactic treatment option for people with haemophilia B and a possible alternative approach to emicizumab, which is the first subcutaneous, non-replacement therapy approved for people with haemophilia A. Given the high efficacy in reducing the annualised bleeding rate, easy route of administration, and low infusion frequency for both drugs, selecting which one to use in patients with haemophilia A will be a difficult decision.
“Potential benefits and harms and the differential responses of new rebalancing products should be examined in comparative studies between similar available treatments. Moreover, standard outcome measure, such as annualised bleeding rate, are subjective and might limit the full assessment of the efficacy of new treatments; therefore, comparative studies should also include outcome measures from both physician and patient perspective.
“The available clinical data on non-replacement and rebalancing drugs are changing the haemophilia therapeutic scenario, but several key challenges remain. Despite the benefits of rebalancing haemostasis, the potential risk of thrombosis, particularly with concomitant use.”