Monthly injections of the new treatment for haemophilia help to reduce bleeds, according to the findings of a major study published last week.
Patients with haemophilia are often treated with the replacement clotting factor they are missing. However, they can develop an immune reaction against this treatment, which triggers the development of antibodies known as ‘inhibitors’, rendering the replacement therapy ineffective.
The therapy fitusiran is the first small interfering RNA (siRNA) developed for haemophilia, and targets antithrombin to increase clotting ability.
The results of two phase 3 randomised controlled trials of fitusiran in the ATLAS study were published in The Lancet Haematology and The Lancet.
In The Lancet, 66% of participants (25 out of 38) with inhibitors who received fitusiran injections had zero bleeds after nine months, compared to one out of 19 (5%) in the comparator group who were given an on-demand bypassing agent.
The study published in The Lancet Haematology investigated the use of the medication in patients without inhibitors. This found 51% (40 out of 79) participants given monthly injections of fitusiran experienced zero bleeds, compared to two out of 40 (5%) in the comparator group.
The comparator groups in both studies received on-demand rather than prophylactic treatment. When the trial began, there was no effective prophylactic treatment for patients with inhibitors.
For patients without inhibitors, comparison with on-demand treatment was the norm for an investigational agent. However, the ATLAS study researchers concede this means it is difficult to compare the efficacy data in this trial with other prophylactic treatments for haemophilia A or B that are currently in use.
In addition, the researchers stress that further studies are needed to assess its safety profile and refine dosing.
Fitusiran reduces bleeds in haemophilia patients with inhibitors (Lancet study)
Professor Guy Young, from the University of Southern California Keck School of Medicine, USA, and lead author of The Lancet study, said: “Our study looks at the efficacy of the first siRNA therapy used to treat haemophilia with inhibitors.
“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.”
The phase 3 randomised controlled trial, published in The Lancet, was conducted at 26 hospitals in 12 countries. It included 56 male patients, aged 12 years old or over with severe haemophilia A or B with inhibitors.
Two thirds of the patients (38) were given a monthly 80mg dose of fitusiran, while one third of patients (19) was given on-demand bypassing treatment. The primary endpoint was annualised bleeding rate – in which there was a 90.8% reduction in the fitusiran prophylaxis group, compared to the bypassing agents on-demand group.
The median observed annualised bleeding rate for patients in the fitusiran group was 0, compared to 16.8 in the comparator group. Among patients with inhibitors given fitusiran prophylaxis, 66% (25 out of 38) participants had no treated bleeds after nine months, compared to 5% (one out of 19) in the comparator group.
In terms of safety, among participants with inhibitors given fitusiran, 13 (32%) participants had increased alanine aminotransferase, while suspected or confirmed blood clotting was reported in two (5%) participants.
Prof Young added: “The safety outcomes in our trial are consistent with previous data on fitusiran and need further monitoring. Two participants receiving fitusiran experienced blood clotting, which is a risk for treatments that seek to rebalance haemostasis (the mechanism that stops bleeding).
“The most common adverse effect was increased alanine aminotransferase, which is seen with many medications and indicates liver inflammation. Importantly, most of these elevations were temporary and did not result in discontinuation 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 reduces bleeds in haemophilia patients without inhibitors (Lancet Haematology study)
The phase 3 randomised controlled study investigating fitusiran use in patients without inhibitors, published in The Lancet Haematology, was conducted at 45 hospitals in 17 countries.
The participants were 120 male patients aged 12 years old or over with severe haemophilia A or B. Two thirds of the patients (79) were given a monthly 80mg dose of fitusiran, injected under the skin, while the remaining 40 were given on-demand clotting factor concentrate replacement therapy. The primary endpoint was annualised bleeding rate – in which there was a 90% reduction in the fitusiran prophylaxis group, compared to the on-demand clotting factor concentrate group.
The observed median annualised bleeding rate for patients in the fitusiran group was 0, compared to 21.8 in the comparator group.
In this cohort of patients without inhibitors, of those given monthly injections of fitusiran, 51% experienced no bleeds requiring treatment, compared to 5% (two out of 40) in the comparator group.
The lead author of the Lancet Haematology study was Professor Alok Srivastava from the Christian Medical College, Vellore, India. Prof Srivastava said: “Our 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 administered by under the skin injections, which can be easily taken at home. With this drug being administered just once a month or even less frequently, there is marked reduction of treatment burden.
“This means patients with haemophilia could manage their condition with fewer trips to hospital, which can cause worry and be disruptive to daily life. This would lead to an improved quality of life as documented in the study.”
The authors for both parts of the ATLAS trial stress further studies are needed to confirm longer-term efficacy. As the patients in the trials had severe haemophilia, outcomes may be different in patients with milder cases of the condition.
Young G, Srivastava A, Kavakli K, Ross C, Sathar J, You CW, Tran H, Sun J, Wu R, Poloskey S, Qiu Z, Kichou S, Andersson S, Mei B, Rangarajan S (2023) “Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial.” Lancet, doi: 10.1016/S0140-6736(23)00284-2
Srivastava A, Rangarajan S, Kavakli K, Klamroth R, Kenet G, Khoo L, You CW, Xu W, Malan N, Frenzel L, Bagot CN, Stasyshyn O, Chang CY, Poloskey S, Qiu Z, Andersson S, Mei B, Pipe SW (2023) “Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial.” Lancet Haem, doi: 10.1016/S2352-3026(23)00037-6
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