Safety and efficacy of a fitusiran antithrombin-based dose regimen in people with hemophilia A or B: the ATLAS-OLE study

Key Points

• •Fitusiran lowers AT to increase thrombin generation and restore hemostasis in people with hemophilia A/B with or without inhibitors.
• •The AT-DR was well tolerated and maintained meaningful bleed protection with as few as 6 injections per year.

Visual Abstract

Abstract

Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, lowers antithrombin (AT) to increase thrombin generation and rebalance hemostasis in people with hemophilia. This phase 3 open-label extension study (ATLAS-OLE) evaluated safety and efficacy of an AT-based dose regimen (AT-DR) in males aged ≥12 years with severe hemophilia A/B, with/without inhibitors. The original dose regimen (ODR) of 80 mg monthly was optimized to AT-DR targeting AT activity levels 15% to 35% to mitigate thrombotic risk (starting dose of 50 mg once every 2 months, individually adjusted to 20 mg once every 2 months, or 20/50/80 mg monthly as needed). Primary and secondary end points were safety and efficacy, respectively. Integrated safety analyses assessed safety of AT-DR and ODR across all fitusiran studies and integrated efficacy analyses compared efficacy of AT-DR in ATLAS-OLE with phase 3 parent study control groups. At interim data cutoff, 213 participants were enrolled on AT-DR (78% on regimens of once every 2 months). Integrated safety analyses of participants receiving AT-DR (n = 286) demonstrated that AT-DR was well tolerated. In ATLAS-OLE, median observed annualized bleeding rate (ABR) with AT-DR was 3.7 (interquartile range, 0.0-7.5). Integrated efficacy analyses demonstrated superiority of AT-DR over on-demand clotting factor concentrates (CFCs; 71% mean ABR reduction; P < .0001), and on-demand bypassing agents (BPAs; 73% mean ABR reduction; P = .0006); improvement over BPA prophylaxis (70% mean ABR reduction); and ABR comparable with that observed with CFC prophylaxis. Fitusiran AT-DR was well tolerated and maintained bleed protection with as few as 6 injections per year. This trial was registered at www.ClinicalTrials.gov as #NCT03754790.

Fitusiran, a subcutaneous investigational small interfering RNA antithrombin (AT)–lowering therapeutic, increases thrombin generation to restore hemostasis in people with hemophilia A or B, irrespective of inhibitor status. Thrombotic complications were seen in previous trials. Young et al report on a phase 3 open-label extension study and show that when using a different AT-based dose regimen, fitusiran was well tolerated and maintained clinically meaningful protection against bleeding in people with hemophilia A and B, with as few as 6 injections per year; thrombotic event rates were similar to those seen in the general hemophilia population. Longer follow-up is ongoing to confirm the durability of this favorable safety profile.

Introduction

Hemostasis depends on a delicate balance of procoagulants and anticoagulants to generate sufficient thrombin to control bleeding.¹ Hemophilia A and B result from deficiency of coagulation factor VIII (FVIII) or FIX, respectively, leading to insufficient thrombin generation.¹ Prophylaxis sufficient to prevent bleeding is recommended for people with hemophilia (PwH).^2,3 However, clotting factor concentrate (CFC) prophylaxis can be burdensome because of frequent IV infusions and venous access difficulties^2,4,5 and may not provide sufficient bleed control due to peaks and troughs in factor levels.^6,7 Furthermore, 20% to 35% of PwHA and 1% to 6% of PwHB develop inhibitory antibodies, rendering CFCs ineffective and limiting treatment options.^2,8,9 Unmet needs remain for additional treatment options that prevent bleeding and reduce treatment burden for PwHA/B, with or without inhibitors.^{2,4,10, 11, 12, 13} Recent advancements include subcutaneous (SC) emicizumab prophylaxis, which provided effective bleed protection in PwHA, irrespective of inhibitor status,^11,14,15 and anti–tissue factor pathway inhibitor therapies for PwHA/B, with or without inhibitors.^{16, 17, 18, 19} Notwithstanding, breakthrough bleeds, injection site pain, and neutralizing antidrug antibodies (ADAs) may still occur with emicizumab and anti–tissue factor pathway inhibitor therapies.^{11,12,20, 21, 22, 23, 24} Novel therapeutics are required to address unmet needs and provide safe and effective treatment options for all PwH.

Antithrombin (AT) is a major physiological inhibitor of thrombin.²⁵ In PwH, AT deficiency results in increased thrombin generation, which decreases bleeding.²⁶ Fitusiran is an investigational, SC prophylactic small interfering RNA (siRNA) therapeutic that lowers AT to increase thrombin generation and rebalance hemostasis in PwH.^27,28 In completed phase 3 trials, once-monthly 80 mg fitusiran prophylaxis significantly reduced annualized bleeding rate (ABR) vs on-demand CFC/bypassing agent (BPA) and prior CFC/BPA prophylaxis in PwHA/B, with or without inhibitors.^{29, 30, 31} After a misdiagnosed thrombotic event that was fatal in the phase 1/2 OLE study, revisions to the breakthrough bleed management guidelines (BMGs) were introduced as a risk mitigation measure. In the phase 3 studies, dosing was paused when additional nonfatal thrombotic events were observed. Persistent AT activity levels of <10% for prolonged periods of time were identified as a potential modifiable target for risk mitigation, and an AT-based dose regimen (AT-DR) targeting AT activity levels of 15% to 35% was introduced to mitigate the risk of thrombosis and enhance the benefit-risk profile of fitusiran.^29,32 ATLAS-OLE assesses long-term safety and efficacy of fitusiran AT-DR in PwHA/B, with or without inhibitors; here, we report interim analyses.

Methods

Study design

This multicenter, multinational, open-label, long-term extension study (ATLAS-OLE; ClinicalTrials.gov identifier: NCT03754790) was initiated in January 2019 at 66 sites in 20 countries, rolling over participants from previous phase 3 studies (ATLAS-INH, NCT03417102; ATLAS-A/B, NCT03417245; ATLAS-PPX, NCT03549871). A separate China cohort included 13 sites enrolling de novo participants who were not randomized and, thus, not included in this primary analysis. Here, we report interim analyses of ATLAS-OLE (data cutoff, 14 June 2023) and results of separate integrated safety and efficacy analyses. All versions of the protocol were approved by independent ethics committees or institutional review boards. An external independent data-monitoring committee oversaw the safety and overall conduct of this study. This study was conducted in accordance with the Declaration of Helsinki, Council for International Organizations of Medical Sciences International Ethical Guidelines, and the International Conference on Harmonisation guidelines for good clinical practice. Informed consent was obtained before study conduct.

Participants

Eligible participants were male, aged ≥12 years, with severe hemophilia A or B, with or without inhibitors, who completed a previous fitusiran phase 3 study as part of the active arm (receiving fitusiran) or control arm. Full inclusion/exclusion criteria are reported in the supplemental Methods, available on the Blood website. Further eligibility screening procedures were performed for de novo participants (supplemental Methods).

Procedures

Demographic and disease-specific baseline characteristics were summarized for the all-enrolled analysis set (supplemental Methods). The study was initiated with fixed-dose 80 mg once-monthly SC fitusiran prophylaxis (original dose regimen [ODR]). In October 2020, a voluntary dosing pause was implemented because of nonfatal thrombotic events that occurred during the fitusiran clinical program. The dosing strategy was revised to an individually adjusted AT-DR targeting AT levels between 15% and 35%.³² At treatment restart, participants initiated AT-DR at 50 mg once every 2 months, individually adjusted as needed to regimens of 20, 50, or 80 mg once monthly, or 20 mg once every 2 months, based on monthly AT measurements (Figure 1; supplemental Methods). The study objective was modified from an extension study to long-term safety and efficacy of AT-DR. To account for the regimen change, the analysis strategy was to separate per ODR and AT-DR.

Figure 1.

Fitusiran AT-DR. ∗Clinical criteria for dose escalation at AT activity levels of <35% may also be considered; †Start of dosing after deescalation from higher dose to occur only after centrally measured AT activity levels of ≥22%. Participants receiving fitusiran at a dose of 20 mg q2m who experience >1 AT level of <15% (as per central laboratory assessment) within a 12-month period must permanently discontinue fitusiran treatment. q2m, every 2 months; qm, once monthly; SS, steady state.

After the dosing pause, the trial consisted of a screening period of up to 60 days; a 6-month dose adjustment period; and a 6-month primary efficacy period. The open-label treatment period varied depending on timing of dosing restart to interim analysis cutoff date. In participants who discontinued fitusiran, the treatment period was followed by an ∼6-month AT follow-up period after final dose (supplemental Figure 1).

Per the BMGs, reduced doses and frequencies of CFCs/BPAs were used to treat breakthrough bleeds (supplemental Methods; supplemental Table 1).³² Treated bleeding episodes were defined as any occurrence of hemorrhage that required administration of CFCs/BPAs (supplemental Methods). It was recommended that participants continue with their standard CFC/BPA regimens for the first week after initiation or reinitiation of fitusiran dosing, with institution of the protocol-specific BMGs with reduced CFC/BPA starting the second week after initiation or reinitiation of fitusiran dosing (Table 1). Participants recorded bleeding events and doses of CFCs/BPAs administered in an electronic diary.

Table 1.

Breakthrough bleed management dosing guidelines

Guideline	FVIII	FIX standard half-life	FIX extended half-life	aPCC	Recombinant FVIIa
Recommended single dose	10 IU/kg	20 IU/kg	20 IU/kg	30 U/kg	≤45 μg/kg
Single dose should not exceed	20 IU/kg	30 IU/kg	30 IU/kg	50 U/kg	45 μg/kg
Repeat dose instructions	Mandatory to call the clinical study center before second dose. Consider evaluation and treatment at the clinical study center.				Mandatory to call site before third dose
	Should not repeat in <24 h	Should not repeat in <24 h	Should not repeat in <5 to 7 d	Should not repeat in <24 h	Should not repeat in <2 h
	Should be seen at site within 48 to 72 h if >2 doses are required				Should be seen at site within 48 to 72 h if >3 doses are required

For situations requiring higher doses, more frequent administration, multiple repeated doses, discussion with a study medical monitor and clinical adviser was recommended, and AT replacement considered.

aPCC, activated prothrombin complex concentrate.

Health-related quality of life (HRQoL) was assessed using the Haemophilia Quality-of-Life Questionnaire for Adults (Haem-A-QoL) in participants aged ≥17 years at baseline (last nonmissing value on or before the enrollment date in the parent study) and at last visit with AT-DR (supplemental Methods).

Safety assessments included treatment-emergent adverse events (TEAEs), treatment-emergent serious AEs (TESAEs), TEAEs of special interest (TEAESIs), and laboratory tests, including markers of coagulation and liver function. Predefined TEAESIs included alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations of >3× the upper limit of normal (ULN), suspected or confirmed thrombosis, cholecystitis/cholelithiasis, and severe or serious injection site reactions (full list of TEAESIs in supplemental Methods). Cholecystitis/cholelithiasis were identified as TEAESIs during the conduct of this study. Transaminases were measured monthly for the first 12 months (supplemental Methods) and resolution of ALT/AST elevations of >3× ULN required 2 normal values.

For the first 12 months, AT activity levels were measured monthly from blood samples collected within 4 hours before dosing and determined by the validated Siemens Innovance Antithrombin III assay at a central laboratory (supplemental Methods). In participants who discontinued fitusiran, AT levels were monitored at approximately monthly intervals for 6 months, or as necessary, until AT activity levels returned to ≥60%, whichever came first.

Blood samples were collected periodically within 4 hours before dosing to evaluate ADAs to fitusiran (supplemental Methods).

End points

The primary end point was safety and tolerability with ODR and AT-DR. Safety end points included incidence, severity, seriousness, and relatedness of TEAEs.

Secondary end points included ABR, annualized spontaneous bleeding rate (AsBR), annualized joint bleeding rate (AjBR) in the primary efficacy period, and change in transformed Haem-A-QoL physical health score in the treatment period from baseline. Subgroup analysis included ABR by inhibitor status. Exploratory end points included change in AT levels over time and incidence and titer of ADAs during the treatment period.

Integrated safety analyses assessed safety of ODR and AT-DR across all participants aged ≥12 years treated with fitusiran prophylaxis across all studies in the clinical program (phase 1 study, phase 1/2 OLE, ATLAS-INH, ATLAS-A/B, ATLAS-PPX, and ATLAS-OLE; supplemental Methods; supplemental Figure 2).

The primary end point of the integrated efficacy analysis was ABR in the fitusiran primary efficacy and control periods in parent phase 3 studies (ATLAS-INH, ATLAS-A/B, and ATLAS-PPX). Secondary end points included AsBR, AjBR, total weight-adjusted consumption of CFCs/BPAs, and change from baseline in Haem-A-QoL transformed physical health score in the primary efficacy and control periods.

Statistical analysis

The number of participants enrolled in ATLAS-OLE was not driven by hypothesis testing but was dependent upon the number of eligible participants who successfully completed a phase 3 parent study. Safety and efficacy analyses included all participants who received ≥1 dose of fitusiran ODR before dosing pause (safety analysis set 1, and full analysis set 1 [FAS1], respectively) and ≥1 dose of fitusiran on the AT-DR after dosing pause (safety analysis set 2, and FAS2, respectively). All analysis sets are described in the supplemental Methods. Safety, pharmacodynamics, immunogenicity, and clinical laboratory assessments were summarized descriptively.

ABR was estimated using a negative-binomial model (supplemental Methods; supplemental Table 2). Estimated mean ABR and 95% confidence intervals (CIs) were calculated. Summary statistics, including median and interquartile range (IQR) were calculated for observed ABR.

AsBR, AjBR, and subgroups were analyzed using the same methodology as the ABR analysis. Change in Haem-A-QoL transformed physical health score and exploratory end points were summarized descriptively.

Integrated safety analysis data were categorized into 2 periods: ODR and AT-DR periods. Safety and clinical laboratory assessments were summarized descriptively.

The integrated efficacy analysis used an intention-to-treat pooling strategy relying on parent studies to provide statistical comparison of AT-DR to control. Each pool represented a subset of participants from ATLAS-OLE and the control arm from the respective parent study, maintaining the original randomization in the parent studies (supplemental Methods; supplemental Figure 3). Missing data were imputed using multiple imputation methods maintaining the intent-to-treat/FAS analysis principle.

Results

Study population

At the interim data cutoff (14 June 2023), 227 participants were enrolled into ATLAS-OLE from a parent study (ATLAS-INH, n = 57; ATLAS-A/B, n = 109; and ATLAS-PPX, n = 61). Overall, 180 participants receiving the ODR who had completed a parent study rolled over into ATLAS-OLE. After the dosing pause, 166 of 180 participants restarted on AT-DR, 10 participants rolled over from parent study control arms (fitusiran naïve), and 37 enrolled directly onto AT-DR, resulting in a total of 213 participants receiving AT-DR (Figure 2). Baseline demographics and characteristics were balanced across the study population (Table 2). The proportion of participants on each dose regimen is shown in Figure 2.

Figure 2.

ATLAS-OLE: participant disposition and proportion of participants on each dose regimen. ∗Percentage denominator is 180 patients who had the ODR; †93.9% of participants required no or only 1 dose change to achieve AT activity levels of 15% to 35%; ‡These participants were permitted to continue receiving 80 mg qm after the introduction of the AT-DR because they had not experienced >1 AT activity level of <15% during prior fitusiran treatment (based on at least 3 months of prior AT measurements); §Percentage denominator is 213 patients who had AT-DR. qm, once monthly.

Table 2.

ATLAS-OLE: demographics and baseline characteristics (all-enrolled analysis set)

Characteristics	Hem A (n = 174)	Hem B (n = 53)	Inhibitor (n = 78)	Noninhibitor (n = 149)	Total (N = 227)
Age, mean (SD), y	31.8 (13.3)	27.1 (12.8)	27.9 (11.8)	32.1 (13.9)	30.7 (13.3)
Min-max	13-72	13-69	13-72	13-69	13-72
Aged <18 y, n (%)	24 (13.8)	15 (28.3)	17 (21.8)	22 (14.8)	39 (17.2)
Region, n (%)
North America	3 (1.7)	9 (17.0)	6 (7.7)	6 (4.0)	12 (5.3)
Europe	65 (37.4)	18 (34.0)	26 (33.3)	57 (38.3)	83 (36.6)
Asia	96 (55.2)	22 (41.5)	44 (56.4)	74 (49.7)	118 (52.0)
Other	10 (5.7)	4 (7.5)	2 (2.6)	12 (8.1)	14 (6.2)
BMI, mean (SD), kg/m2	24.5 (5.2)	24.8 (5.3)	23.9 (5.1)	25.0 (5.2)	24.6 (5.2)

The end-of-study visit tests and assessments in the respective parent study were used as baseline results. Baseline assessments that were not part of the end-of-study visit in the parent study were performed after informed consent for ATLAS-OLE was obtained. Baseline was defined as the last nonmissing value before first ever fitusiran dose. Percentages were based on the number of participants with nonmissing data in the all-enrolled analysis set. All participants who were enrolled in the study, regardless of whether they were dosed with fitusiran or not.

BMI, body mass index; Hem, hemophilia; max, maximum; min, minimum.

Integrated safety analysis: AEs

The integrated safety analysis included all participants exposed to AT-DR (N = 286) and ODR (N = 270) during the fitusiran clinical development program. A summary of TEAEs with the ODR is reported in supplemental Table 3.

Total patient-years of exposure with AT-DR was 486.0; 237 participants had ≥12 months exposure with AT-DR. Overall, 238 (83.2%) participants with AT-DR experienced ≥1 TEAE (Table 3). TESAEs were reported in 41 (14.3%) participants with AT-DR; 6 (2.1%) experienced TESAEs considered related to fitusiran by the investigator. Five (1.7%) participants with AT-DR experienced TEAEs leading to fitusiran discontinuation. TEAEs that resulted in discontinuation of AT-DR included cerebral infarction, postoperative deep vein thrombosis (DVT), hepatocellular carcinoma, transaminase elevation, and pruritus (n = 1 each); of which DVT, transaminase elevation, and pruritus were assessed as related to fitusiran by the investigator. There were no fatal TEAEs with AT-DR. TEAEs of injection site reactions occurred in 16 (5.6%) participants with AT-DR, including injection site pain in 2 (0.7%) participants, corresponding to 6.0 events per 100 patient-years. No severe or serious injection site reactions were reported. The safety profile of the fitusiran-naïve participants (n = 65) did not differ from those that had previous exposure.

Table 3.

Integrated safety analysis: summary of TEAEs with AT-DR

	AT-DR (N = 286)
Total patient-years of exposure	486.0
Participants with any TEAE, n (%)	238 (83.2)∗
Participants with any severe TEAE, n (%)	28 (9.8)
Participants with any TESAE, n (%)	41 (14.3)†
Participants with any TESAE related to fitusiran	6 (2.1)‡
TEAESIs
Participants with any ALT/AST elevations of >3× ULN, n (%)§	10 (3.5)
EAIR (per 100 patient-years)	2.06
Participants with any cholecystitis/cholelithiasis, n (%)||	11 (3.8)
EAIR (per 100 patient-years)	2.26
Participants with any thrombotic event, n (%)	4 (1.4)
EAIR (per 100 patient-years)	0.82
Participants with any TEAE leading to fitusiran discontinuation, n (%)	5 (1.7)¶
Participants with any TEAE leading to study withdrawal, n (%)	6 (2.1)#
Participants with any TEAE leading to death, n (%)	0

Safety analyses included all participants exposed to fitusiran. For the ODR, the exposure was calculated starting from the first significant dose (≥20 mg). Events reported during major surgery periods were excluded.

^∗Most frequent (≥5%) TEAEs with AT-DR were COVID-19 (46 [16.1%] participants); upper respiratory tract infection (43 [15.0%]); arthralgia (23 [8.0%]); nasopharyngitis (21 [7.3%]); ALT increased (20 [7.0%]); pyrexia (19 [6.6%]); pain in extremity (18 [6.3%]); prothrombin fragment 1.2 increased (17 [5.9%]); diarrhea (16 [5.6%]); and influenza, hemophilic arthropathy, headache, and cough (15 [5.2%] each).

^†Most frequent (≥2 participants) TESAEs with AT-DR were hematuria (7 [2.4%] participants), hemarthrosis (5 [1.7%]), muscle hematoma (3 [1.0%]), cholecystitis (2 [0.7%]), and gastrointestinal hemorrhage (2 [0.7%]).

^‡TESAEs considered related to fitusiran by the investigator while on AT-DR were cholecystitis and hematuria (2 [0.7%] participants each); and ALT increased, AST increased, cholangitis, large intestine infection, limb mass, and pancreatitis (1 [0.3%] participant each).

^§ALT/AST elevations of >3× ULN were identified by using central laboratory data.

^||Cholecystitis/cholelithiasis were identified by high-level group terms of “bile duct disorders” and “gallbladder disorders” in the Medical Dictionary for Regulatory Activities 26.0.

^¶TEAEs leading to fitusiran AT-DR discontinuation were hepatocellular carcinoma (assessed by the investigator as serious, severe, and not related to fitusiran), transaminase elevation (assessed by the investigator as nonserious, mild, and related to fitusiran), cerebral infarction (assessed by the investigator as nonserious, mild, and not related to fitusiran), pruritus (assessed by the investigator as nonserious, moderate, and related to fitusiran), and postoperative DVT (assessed by the investigator as nonserious, moderate, and related to fitusiran; 1 [0.3%] participant each).

^#TEAEs leading to study withdrawal were hepatocellular carcinoma, cerebral infarction, embolic stroke, cholecystitis, transaminase elevation, and pruritus (1 [0.3%] participant each).

TEAESIs of “any ALT/AST elevations >3× ULN” were reported in 10 (3.5%) participants with AT-DR, corresponding to an exposure-adjusted incidence rate (EAIR) of 2.06 per 100 patient-years (Table 3). ALT/AST elevations of >3× ULN in 5 participants with AT-DR were associated with alternative etiologies including excessive exercise associated with protein powder consumption, nonsteroidal anti-inflammatory drugs, and alcohol consumption. Liver conditions reported in participants included hepatitis B (n = 1), hepatitis C (n = 1), gastritis (n = 1), nonalcoholic steatohepatitis (n = 1), and hepatic steatosis (n = 3). All 14 ALT/AST elevations of >3× ULN were asymptomatic, transient, and resolved spontaneously by the data cutoff date, or shortly thereafter. Median time to recovery (≤3× ULN) and normalization (ULN or less) were 54.5 and 46.0 days, and 87.5 and 49.0 days for ALT and AST elevations, respectively. Three (1.1%) participants had an ALT/AST value of >5× ULN and ≤10× ULN. No potential cases of the Hy's law were identified in any participant with AT-DR.

High alkaline phosphatase (>1.5 × ULN) values and high total bilirubin (all grades) were reported in 28 (9.8%) participants and 35 (12.3%) participants with AT-DR, respectively. One (0.4%) participant had concurrent high ALT and total bilirubin values with AT-DR. No participants had ALT/AST of >3× ULN and total bilirubin of >2× ULN concurrently with AT-DR.

TEAESIs of cholecystitis and/or cholelithiasis were reported in 11 (3.8%) participants with AT-DR, corresponding to an EAIR of 2.26 per 100 patient-years (Table 3). Of 16 cholecystitis/cholelithiasis events, 13 were assessed as related to fitusiran by the investigator, and 9 events were reported as recovered/resolved without clinical sequelae. Three (1.0%) participants experienced a serious TEAESI of cholecystitis/cholelithiasis (cholecystitis [n = 2] and cholangitis [n = 1]). Three participants with cholecystitis/cholelithiasis (27.3%) had ALT/AST elevations of >3× ULN. No participants discontinued fitusiran because of cholecystitis/cholelithiasis. One participant underwent a cholecystectomy while on AT-DR.

TEAESIs of “any suspected or confirmed thromboembolic events” were reported in 4 (1.4%) participants with AT-DR, corresponding to an EAIR of 0.82 per 100 patient-years (Table 3). None of these events were associated with AT levels of <15% (range, 15.5%-65.3%). Two arterial events (embolic stroke and incidental finding of cerebral infarction) and 2 postoperative venous events (venous thrombosis and DVT) occurred in 1 (0.3%) participant each. Three events were deemed unrelated to fitusiran treatment by the investigator. All 4 participants with thrombotic events had predisposing clinical risk factors; furthermore, doses and frequency of CFC/BPA administered exceeded BMGs in both postoperative venous events (Table 4).

Table 4.

Integrated safety analysis: summary of predisposing risk factors in participants who experienced thrombotic events with fitusiran AT-DR

Investigator-reported term	Age, y	Hemophilia subtype and inhibitor status	Clinical risk factors	CVAD-related risk factors	Noncompliance with BMGs	Relatedness to fitusiran	AT level before event, %
Old cerebral infarction	26	PwHB with inhibitor	Diabetes mellitus Dyslipidemia Hepatic steatosis Obstructive sleep apnea Nephrotic syndrome	—	—	An MRI performed for evaluation of vertigo revealed an incidental finding of old cerebral infarction unrelated to presenting symptoms Discovered 7 mo after fitusiran initiation (4 mo ODR and 3 mo AT-DR) Resulted in treatment discontinuation Assessed by investigator as not related to fitusiran	15.5
Embolic stroke of unknown origin	51	PwHA without inhibitor	Uncontrolled hypertension Hyperlipidemia Diabetes mellitus	—	—	Event occurred 5 mo after fitusiran discontinuation (because of >1 AT value of <15%) with AT of >60% Assessed by investigator as not related to fitusiran	65.3∗
Postoperative venous thrombosis (left axillary, brachial, and basilic vein)	13	PwHB with inhibitor	Postoperative (inguinal hernia)	History of central line thrombosis Extended PIV line	aPCC dosing exceeding BMG (30 IU/kg, bid)	Thrombosis of the deep veins in the anatomic location of the PIV line Assessed by investigator as not related to fitusiran	23.3
Postoperative DVT (left common femoral vein)	43	PwHA without inhibitor	Postoperative (knee arthroplasty) Morbid obesity Hypertension	—	FVIII dosing exceeding BMGs for >14 d (divided daily dose of 13 IU/kg and 8 IU/kg)	Resulted in treatment discontinuation Assessed by investigator as related to fitusiran	24.4

bid, twice daily; CVAD, central venous access device; MRI, magnetic resonance imaging; PIV, peripheral IV line.

^∗AT level from 2 days after event.

Integrated safety analysis: coagulation parameters

Post hoc analyses demonstrated that 128 (44.8%) participants without reported thrombotic events experienced D-dimer elevations (≥0.5 mg/L at any time point) with AT-DR. Prothrombin fragment 1 + 2 values were increased in 17 (5.9%) participants with AT-DR.

ATLAS-OLE: safety analysis

Additional safety findings from ATLAS-OLE are reported in the supplemental Results and supplemental Table 4.

ATLAS-OLE: efficacy

In the primary efficacy period, observed median ABR with AT-DR was 3.7 (IQR, 0.0-7.5) overall; 1.9 (IQR, 0.0-5.6) in PwH with inhibitors, and 3.8 (IQR, 0.0-11.2) without inhibitors (supplemental Figure 4). Estimated mean ABR was 6.4 (95% CI, 5.3-7.7) overall; 3.9 (95% CI, 2.9-5.3) in PwH with inhibitors; and 7.4 (95% CI, 5.9-9.3) without inhibitors. Overall, 62 (31.5%) participants had 0 treated bleeds and 93 (47.2%) participants had 0 to 1 treated bleeds with AT-DR. Median AsBR was 1.9 (IQR, 0.0-5.6), and median AjBR was 1.9 (IQR, 0.0-6.8) with AT-DR. ABRs with an ODR are reported in supplemental Table 5. Mean annualized weight-adjusted doses of FVIII and FIX, and activated prothrombin complex concentrate and recombinant activated FVII, required to treat breakthrough bleeds in participants with AT-DR were 12.3 IU/kg (standard deviation [SD], 4.3) and 20.5 IU/kg (4.9), and 25.2 U/kg (10.3) and 45.5 μg/kg (23.6), respectively.

ATLAS-OLE: HRQoL

There was an improvement in mean Haem-A-QoL transformed physical health score of −8.06 (SD, 22.2) from baseline to last visit with AT-DR during the primary treatment period. Mean change in transformed physical health score from baseline was meaningful (≥10-point reduction) for PwH with inhibitors (−11.55 [SD, 23.63]) with AT-DR. Overall, 83 (48.0%) participants achieved a meaningful improvement (≥10 points) in physical health score from baseline.

ATLAS-OLE: pharmacodynamics and immunogenicity

Mean AT level was 23.5% (SD, 4.6) with AT-DR during the primary efficacy period (supplemental Figure 5). Most participants were within the target AT range of 15% to 35%; 78% of participants were on once-every-2-month regimens at final dose and 94% required 0 to 1 dose adjustment to achieve target AT levels. Of participants at the lowest dose evaluated (20 mg once every 2 months, n = 88), 28.4% had >1 AT activity level of <15% and required fitusiran discontinuation.

Four (1.8%) participants previously enrolled in parent studies developed treatment-emergent ADAs during the extension study. One participant had developed ADAs in a parent study and did not develop a boosted response during the extension study. No impact on safety or efficacy associated with ADA development was observed; no patients discontinued because of an ADA.

Integrated efficacy analysis

AT-DR provided superior bleed control over on-demand CFC/BPA in parent studies, demonstrating reductions in mean ABR of 73% vs on-demand BPA (P = .0006), and 71% vs on-demand CFC (P < .0001; Table 5). AT-DR showed substantial reduction in mean ABR vs BPA prophylaxis (70% reduction) and was comparable with CFC prophylaxis. AsBR and AjBR were lower with AT-DR vs CFC/BPA on-demand and prophylaxis (Table 5).

Table 5.

Integrated efficacy analysis: ABR with fitusiran AT-DR vs control arms in parent studies

	Pool A (inhibitor)		Pool B (noninhibitor)		Pool C (all)
	On-demand BPA (n = 19)	Fitusiran AT-DR (n = 38)	On-demand CFC (n = 40)	Fitusiran AT-DR (n = 80)	CFC/BPA prophylaxis (n = 67)	Fitusiran AT-DR (n = 69)
Any bleeding event
Estimated mean ABR (95% CI)	19.12 (11.80-30.98)	5.14 (2.78-9.52)	31.42 (20.48-48.21)	9.01 (5.59-14.54)	7.54 (5.62-10.12)	5.65 (3.88-8.24)
Reduction (95% CI), %	73.1 (43.4-87.3)		71.3 (53.0-82.5)		25.1 (−20.2 to 53.3)
P value	.0006		<.0001		.2316
Observed median ABR (IQR)	16.33 (5.94-23.76)	2.00 (0.00-7.45)	25.24 (11.88-43.80)	5.59 (0.00-11.18)	4.35 (2.17-10.87)	3.73 (0.00-7.45)
Participants with 0-1 bleeds, n (%)	1 (5.3)	17 (54.8)	1 (2.5)	26 (41.3)	28 (41.8)	26 (48.1)
Joint bleeds
Estimated mean AjBR (95% CI)	14.41 (8.98-23.15)	3.95 (2.50-6.24)	21.56 (14.56-31.93)	6.18 (4.18-9.15)	5.36 (3.75-7.60)	3.87 (2.49-6.03)
Reduction (95% CI), %	72.6 (47.1-85.8)		71.3 (51.6-83.0)		27.7 (−27.9 to 59.1)
P value	.0001		<.0001		.2652
Observed median AjBR (IQR)	11.88 (2.97-19.30)	1.86 (0.00-5.59)	17.82 (5.94-32.67)	3.73 (0.00-9.32)	2.17 (0.00-6.52)	1.86 (0.00-5.59)
Participants with 0-1 bleeds, n (%)	2 (10.5)	19 (61.3)	5 (12.5)	30 (47.6)	35 (52.2)	34 (63.0)
Spontaneous bleeds
Estimated mean AsBR (95% CI)	17.09 (9.87-29.60)	3.11 (1.78-5.43)	20.99 (13.95-31.59)	5.40 (3.65-7.97)	5.14 (3.58-7.37)	4.16 (2.71-6.39)
Reduction (95% CI), %	81.8 (60.7-91.6)		74.3 (57.7-84.4)		19.0 (−39.1 to 52.9)
P value	<.0001		<.0001		.4449
Observed median AsBR (IQR)	14.85 (2.97-22.27)	1.86 (0.00-1.93)	17.99 (5.20-28.98)	2.00 (0.00-9.32)	2.17 (0.00-6.52)	1.86 (0.00-5.59)
Participants with 0-1 bleeds, n (%)	3 (15.8)	26 (83.9)	6 (15.0)	33 (52.4)	38 (56.7)	32 (59.3)

The duration of follow-up for the on-demand CFC/BPA arm refers to the control period from day 1 to day 246 in ATLAS-INH/ATLAS-A/B, or to the last day of bleeding follow-up, whichever was the earliest. The duration of follow-up for the CFC/BPA prophylaxis arm refers to the control period from enrollment date in ATLAS-PPX to the earliest of enrollment date +167 days and 1 day before first fitusiran dose date. For fitusiran prophylaxis, duration of follow-up refers the primary efficacy period from dose restart day 169 to dose restart day 364. Percentages were based on the number of participants with at least 1 dose of treatment in the corresponding period and an evaluable follow-up duration in the period.

Mean total weight-adjusted dose per bleed of FVIII and FIX required to treat breakthrough bleeds in participants without inhibitors was lower with AT-DR (12.0 IU/kg [SD, 6.0] and 22.3 IU/kg [SD, 10.8], respectively) vs CFC prophylaxis (45.3 IU/kg [SD, 41.8] and 73.6 IU/kg [SD, 54.7], respectively). Mean total weight-adjusted dose per bleed of activated prothrombin complex concentrate and recombinant activated FVII required to treat breakthrough bleeds in participants with inhibitors was lower with AT-DR (50.1 U/kg [SD, 32.2] and 86.5 μg/kg [SD, 85.8], respectively) vs BPA prophylaxis (207.8 U/kg [373.5] and 637.3 μg/kg [1090.8], respectively). Fewer injections per bleed were required with AT-DR vs CFC/BPA prophylaxis (supplemental Table 6).

Integrated efficacy analysis: HRQoL

Fitusiran prophylaxis led to an improvement in Haem-A-QoL transformed physical health score from baseline to end of primary treatment period vs on-demand BPA (least squares mean change, −8.72 [95% CI, −17.08 to −0.35] vs −5.03 [95% CI, −9.23 to −0.83], respectively; P = .453) and a significant and clinically meaningful improvement vs on-demand CFC (least squares mean change, −12.00 [95% CI, −18.10 to −5.90] vs −3.84 [95% CI, −8.73 to 1.06], respectively; P = .025). No improvement was observed vs CFC/BPA prophylaxis (level of impairment of participants’ physical health status was mild at time of enrollment to parent study; supplemental Figure 6).

Discussion

This study confirms that fitusiran AT-DR was well tolerated and maintained clinically meaningful bleed protection in all PwHA/B. These outcomes confirm findings from previous fitusiran studies,^{29, 30, 31,33, 34, 35} suggesting that fitusiran provides an efficacious, SC, prophylactic option for PwHA/B, irrespective of inhibitor status.

In ATLAS-OLE, no new safety signals were reported with AT-DR. Incidence of injection site pain (n = 2 [0.7%]) and injection site reactions (n = 16 [5.6%]) were low with AT-DR, as was development of treatment emergent ADAs (n = 4 [1.8%]), indicating limited potential for immunogenicity with fitusiran.

Transaminase elevations have been reported during clinical trials of liver-targeted siRNA therapies in other conditions.^36,37 With AT-DR, ALT/AST elevations were transient and resolved spontaneously. Of 10 participants who experienced ALT/AST elevations on the AT-DR, alternative etiologies for transaminase elevations were reported in 5 (50%). All 14 events were reported as recovered or resolved by the data cutoff date or shortly thereafter. Nine events (56%) of cholecystitis/cholelithiasis with AT-DR were deemed recovered or resolved without clinical sequalae at time of data lock point; no participants discontinued fitusiran because of TEAESIs of cholecystitis/cholelithiasis. EAIRs per 100 patient-years of ALT and AST elevations of >3× ULN, and cholecystitis and cholelithiasis, were substantially reduced (>80%) with AT-DR vs ODR (2.06 and 2.26 vs 18.25 and 14.67; supplemental Results). The underlying pathophysiology of transaminase elevations and events of cholecystitis/cholelithiasis is unknown but may be related to the mechanism of action of fitusiran as a liver-targeted siRNA therapy.

Thrombotic events are AEs of clinical interest for therapies aiming to restore thrombin generation and have been reported with CFCs, BPAs, and other nonfactor therapies.^{15,23,29,31,38, 39, 40, 41} In the fitusiran clinical program, initial risk mitigation for thrombosis included exclusion of participants with thrombophilia or certain thrombotic risk factors, and reducing dose and frequency of CFC/BPA for treating bleeds during fitusiran prophylaxis, as outlined in the BMGs. After nonfatal vascular events with ODR, prolonged periods of AT activity levels of <10% were identified as a potential modifiable target for risk mitigation and the AT-DR targeting AT activity of 15% to 35% was implemented to mitigate the risk of thrombosis and enhance the benefit-risk profile of fitusiran.^29,32 Data from the integrated safety analysis demonstrate successful mitigation of thrombotic risk with AT-DR, resulting in an EAIR of 0.82 per 100 patient-years, lower than that of ODR (2.28 per 100 patient-years), and similar to the general hemophilia population per an Optum claims database analysis.^42,43 Thrombotic events with the ODR were reported in 7 participants in phase 2 and 3 studies, including this study, confirming a substantial reduction in thrombotic risk with AT-DR.^31,32 All 4 thrombotic events on the AT-DR were multifactorial in nature with associated predisposing clinical risk factors. Both events of postoperative DVT with AT-DR (n = 2) were associated with deviations from the BMGs during the perioperative period. Three events were assessed by the investigator as not related to fitusiran, and the 1 event deemed related to fitusiran occurred in the postoperative setting when CFC dosing exceeded the BMGs.

In ATLAS-OLE, AT-DR maintained clinically meaningful bleed protection, indicating that fitusiran is an effective treatment for PwHA/B, irrespective of inhibitor status. Spontaneous bleeds and joint bleeds are hallmarks of severe hemophilia and prevention of such bleeds is a reliable indicator of effective prophylaxis. Participants receiving AT-DR prophylaxis had markedly lower AsBR vs controls in parent studies, and AsBR was comparable in patients with inhibitors and those without. Notably, higher overall ABR in the noninhibitor population vs inhibitor population was driven by a higher rate of traumatic bleeds. Joint bleeds can result in chronic arthropathy, 1 of the leading causes of morbidity in PwH.^44,45 Fitusiran prophylaxis demonstrated low AjBRs with AT-DR.

AT-DR successfully achieved target AT activity range (15%-35%), with a mean AT activity level of 23.5% (SD, 4.6). Most participants (78%) were on once-every-2-month regimens, requiring as few as 6 injections per year, and 94% required 0 to 1 dose adjustment to achieve target AT activity levels. Compared with AT-DR, the ODR resulted in lower mean AT activity levels in parent studies ATLAS-INH (11.0%), ATLAS-A/B (12.0%-14.0%), and ATLAS-PPX (10.6%-13.4%), which may explain lower overall median ABRs of 0 observed in these studies.^{29, 30, 31} The relationship between ABR and AT activity levels will be explored in further publications. Unlike other rebalancing agents, the ability to directly measure the impact of fitusiran on a coagulation factor allows for individualization of treatment.

The integrated efficacy analysis was conducted to compare efficacy of AT-DR in ATLAS-OLE with controls in parent studies, maintaining the original randomization, to fulfill regulatory commitments. AT-DR demonstrated superior efficacy over on-demand BPA and CFC, substantial improvement over BPA prophylaxis, and was comparable with CFC prophylaxis. Total mean weight-adjusted consumption of CFCs and BPAs and number of injections per bleed were lower with fitusiran AT-DR vs CFC/BPA prophylaxis; similar results were observed in the parent study ATLAS-PPX.³¹ Ongoing studies (ATLAS-NEO; ClinicalTrials.gov identifier: NCT05662319) will further characterize the efficacy of AT-DR.

Although reported clinical study data on median observed ABRs for other nonfactor therapies are lower than that observed with fitusiran (3.7), direct comparison of results from clinical studies is challenging given differences in enrolled populations, study design, and collection and reporting of bleed data.^18,24,46 Notably, participants enrolled in the fitusiran clinical program had severe hemophilia and participants in the on-demand CFC/BPA control groups had estimated ABRs of 31.42 and 19.12, respectively, highlighting the severity of their disease. The proportion of participants with 0 to 1 treated bleeds was similar between those who received BPA/CFC prophylaxis and those who received fitusiran prophylaxis (41.8% vs 48.1%, respectively). However, despite the efficacy of currently available therapeutics and recent treatment advancements, there is significant unmet medical need for therapies that can provide consistent bleed protection while minimizing treatment burden and enhancing overall QoL.

HRQoL outcome measures are increasingly important and should be considered a primary goal of hemophilia care.^47,48 AT-DR resulted in improvement in Haem-A-QoL physical health score vs on-demand BPAs and meaningful improvement vs on-demand CFCs. The lack of improvement observed compared with CFC/BPA prophylaxis may be attributed to the mild level of impairment of participants’ physical health status at the time of ATLAS-PPX enrollment.²⁹ These results, alongside reduced consumption of CFC/BPAs and fewer IV injections to treat breakthrough bleeds, suggest fitusiran may provide consistent bleed protection while reducing treatment and disease burden for PwH. ATLAS-NEO (ClinicalTrials.gov identifier: NCT05662319) will further characterize the impact of fitusiran prophylaxis on QoL.

Fitusiran will be an important addition to the treatment options for PwH.^49,50 Consideration of the specific patients for whom fitusiran would be a particularly good fit will depend on individual needs and treatment goals, as well as patient and provider attitudes.

Limitations of the ATLAS-OLE study include that it was originally designed as a long-term extension study evaluating safety of fitusiran ODR and later converted to a pivotal study evaluating safety and efficacy of AT-DR. The open-label design may have resulted in potential biases, particularly in HRQoL outcomes. Most participants in the integrated safety analysis had been exposed to the higher fitusiran dose on the ODR. However, the safety profile of the subgroup of fitusiran-naïve participants (n = 65) did not differ from those that had previous exposure. Fitusiran-naïve participants will be evaluated in ATLAS-NEO. Intention-to-treat analysis of fitusiran efficacy compared with on-demand CFC/BPA and prophylaxis was limited by noncontemporaneous data collection and multiple imputations to account for missing data. Finally, when initial phase 3 studies implementing the ODR were conceived, such trials did not include females. Future trials will expand on the established benefit-risk profile of fitusiran prophylaxis in this subgroup.

Overall, results from ATLAS-OLE and integrated analyses confirm that fitusiran AT-DR was well tolerated. AT-DR provided clinically meaningful bleed protection in PwHA/B, with or without inhibitors, with as few as 6 SC injections per year. Integrated efficacy analyses confirmed superiority of AT-DR over on-demand CFC/BPA regimens and substantial improvement over BPA prophylaxis. Additional studies assessing the benefits of AT-DR are ongoing (ATLAS-NEO) and planned.

Conflict-of-interest disclosure: G.Y. has received grants or contracts from Sanofi; consulting fees from BioMarin, Centessa, CSL Behring, Genentech/Roche, HEMA Biologics/LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi, Spark, and Takeda and speaking fees from BioMarin, CSL Behring, Genentech/Roche, HEMA Biologics/LFB, Novo Nordisk, Octapharma, Pfizer, Rani, Sanofi, Spark, and Takeda. K.K. has received grants or contracts and consulting fees from Novo Nordisk, Roche, and Takeda. R.K. received research funding from Bayer and Leo Pharma; received honoraria from Bayer, Biotest, BioMarin, Bristol Myers Squibb (BMS), CSL Behring, Daiichi Sankyo, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, and Takeda; and has attended speaker bureaus for Bayer, Biotest, BioMarin, BMS, CSL Behring, Daiichi Sankyo, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, and Takeda. T.M. has received honoraria from Bayer, Takeda/Shire, Novo Nordisk, Bioverativ/Sanofi, CSL Behring, and Chugai. F.P. has received honoraria from Roche, Sanofi, Sobi, and Takeda and is a member of advisory boards of Roche, Sanofi, Sobi, and Takeda. S.W.P. has received consultancy fees from Apcintex, ASC Therapeutics, Bayer, BioMarin, CSL Behring, HEMA Biologics, Freeline, LFB, Metagenomi, Novo Nordisk, Pfizer, Precision Bioscience, Poseida Therapeutics, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics, and uniQure; reports research funding from Siemens and YewSavin; and holds a membership on a scientific advisory committee for GeneVentiv and Equilibra Bioscience. S.R. has received consulting fees from Reliance Life Sciences; received support for attending meetings and/or travel from Takeda; and has participated on a data safety monitoring board or advisory board for Pfizer, Sanofi, Sigilon, Takeda, and Vega Therapeutics. M.-C.S. has received research grants from Sanofi (Taiwan). A.S. has received research funding from Roche, Novo Nordisk, Sanofi, and Pfizer and has participated on advisory committees/grant review committees for Sanofi, Takeda, Novo Nordisk, Roche, Pfizer, and Bayer Healthcare. H.T. has received grants or contracts from Sanofi, Takeda, Roche, Pfizer, Novo Nordisk, and CSL Behring. B.Z. has acted on advisory boards of, and/or provided consultancy for, Pfizer, Shire, Novo Nordisk, Roche, Sobi, Bayer, and BioMarin. L.A.M., C.Z., Y.S., M.P., and M.D. are current employees of Sanofi, and may hold shares or stock options in the company. G.K. consults for Bayer, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; receives research grant support from BSF, Pfizer, Roche, Takeda, and Tel Aviv University; and has been involved with advisory boards of, and received honoraria from, Bayer, BioMarin, CSL, Pfizer, Sanofi, Sobi, Spark, Takeda, and uniQure. The remaining authors declare no competing financial interests.

A complete list of the members of the ATLAS-OLE Trial Group appears in the supplemental Appendix.