QFITLIA Solution for injection Ref.[115543] Active ingredients: Fitusiran

In clinical studies with QFITLIA in hemophilia patients, the primary pharmacodynamic (PD) measure was plasma AT activity. Lower AT activity levels were associated with lower annualized bleeding rates (ABR); however, persistent AT activity <15% is a risk factor for thrombotic events.

In Study LTE15174, the mean (SD) AT activity on the AT-DR was 24% (4.64).

Simulations to estimate time for AT activity to reach steady state found that regardless of the dose regimen, more than 99% of participants reached steady state AT levels (defined as <10% variability among consecutive measures) within 23 weeks following initiation of QFITLIA dosing or following dose escalation or de-escalation. The duration of persistent AT activity <60% (non-negligible impact of QFITLIA on coagulation) following QFITLIA treatment discontinuation was estimated to be approximately 6 months, after which standard doses of CFC/BPA may be administered. In patients with AT activity <15%, the time required prior to initiation of a lower dose was estimated to be 12 weeks to maximize the AT activity recovery to the target range of 15% to 35%. Extent of AT reduction with QFITLIA did not differ between patients with hemophilia A or B, with or without inhibitors.

The pharmacokinetic (PK) properties of fitusiran were evaluated following administration of QFITLIA in patients with hemophilia A or B, with or without inhibitors as summarized in Table 4. QFITLIA PD is driven by liver PK rather than plasma PK. The QFITLIA dosing strategy is based on maintaining plasma AT activity levels between 15–35% with 10, 20 or 50 mg dosing every month or every two months.

Table 4. Pharmacokinetic Parameters of QFITLIA:

AUC = area under the plasma concentration-time curve extrapolated to infinity; CL/F = apparent clearance; C_max = maximum plasma concentration; CV = coefficient of variation; PK = pharmacokinetic(s); SD = standard deviation; t_1/2 = terminal elimination half-life; t_max = time to maximum concentration; Vss/F = apparent volume of distribution
^* Unless otherwise indicated, the PK parameters in this table are from Study LTE15174. All PK parameters are estimated using non-compartmental analysis and are presented as Mean (SD) [CV%], except for t_max which is presented as median (range)
^† Study TDR14767 (ALN-AT3SC-001)
^‡ QFITLIA distributes primarily to the liver after subcutaneous injection.
^§ In vitro data

Specific Populations

QFITLIA has only been studied in male patients. The pharmacokinetics of fitusiran is not influenced by race. QFITLIA has not been studied in children <12 years old.

No clinical study to evaluate the effect of hepatic impairment or renal impairment on the pharmacokinetics of QFITLIA was conducted. In the pivotal studies, 12 patients had mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m²) and 1 patient had moderate renal impairment (eGFR 30 mL/min/1.73 m² to <60 mL/min/1.73 m²). Population PK analysis indicated no impact of renal impairment on the exposure (C_max and AUC) of QFITLIA in patients with mild renal impairment.

Drug Interaction Studies

Clinical Studies

No clinical drug-drug interaction studies have been conducted to evaluate the potential of QFITLIA to interact with other co-administered drugs which are either substrates, inhibitors or inducers of CYP isozymes, or are substrates or inhibitors of drug transporters.

In Vitro Studies

Results from in vitro studies evaluating the potential of co-administered drugs to increase the PK exposure of QFITLIA, and the potential of QFITLIA to increase the PK exposure of co-administered drugs, indicate that CYP- or transporter-mediated interactions between QFITLIA and co-administered drugs are unlikely at clinically relevant concentrations.

In a 2-year carcinogenicity study in Sprague Dawley rats, fitusiran was not carcinogenic up to the highest dose tested following subcutaneous administration at doses of 0.03, 0.1 or 0.3 mg/kg/week in males and 0.1, 0.3, or 1 mg/kg/week in females. All doses in males and females were below the maximum recommended human dose (MRHD) of 50 mg per month based on body surface area (BSA) comparisons due to the sensitivity of wild type animals to the pharmacological effects of fitusiran. Fitusiran was not carcinogenic in Tg-rasH2 mice following subcutaneous administration at doses of 0.05, 0.15, or 0.5 mg/kg/week in males and 0.025, 0.08, or 0.25 mg/kg/week in females for 26 weeks.

Fitusiran was not mutagenic or clastogenic in a battery of genetic toxicity studies (i.e., in vitro bacterial reverse mutation assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes; in vivo bone marrow micronucleus test in rats).

In a chronic repeat dose toxicology study in Sprague Dawley rats, fitusiran-treated males received subcutaneous doses of 0.25, 0.5, or 1 mg/kg/week for 16 weeks then were cohabitated with fitusiran-naïve females. No adverse effects on male fertility endpoints were observed. All doses used in males were below the MRHD based on BSA comparisons due to the sensitivity of wild type animals to the pharmacological effects of fitusiran.

The efficacy and safety of QFITLIA in adult and pediatric patients aged 12 years and older with hemophilia A or B with or without inhibitors were established in two clinical studies:

• Hemophilia A or B with Inhibitory Antibodies: ATLAS-INH (NCT03417102)
• Hemophilia A or B without Inhibitory Antibodies: ATLAS-A/B (NCT03417245)

Patients in the above parent studies rolled over into the long-term extension study ATLAS-OLE (NCT03754790).

The clinical studies ATLAS-INH and ATLAS-A/B tested an 80 mg monthly fixed dose of QFITLIA. Because of thrombotic events with this dose, the QFITLIA AT-DR targeting AT activity of 15–35% was implemented in ATLAS-OLE. The AT-DR was initiated when studies ATLAS-INH and ATLAS-A/B were nearly completed, therefore, the efficacy of QFITLIA AT-DR treatment was assessed by comparing the QFITLIA AT-DR treatment data from the long-term extension study ATLAS-OLE to the control data from studies ATLAS-INH and ATLAS-A/B. The efficacy analyses were conducted according to the intent to treat (ITT) principle preserving the randomization in the parent studies.

ATLAS-INH

ATLAS-INH was a randomized, multicenter, open-label clinical study in 57 adult and pediatric males (aged ≥12 years) with hemophilia A or B with inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX), who previously received on-demand (episodic) treatment with BPAs for bleeding. Eligible patients were randomized in a 2:1 ratio to receive QFITLIA prophylaxis at a fixed dose 80 mg SC monthly (N=38) or BPA on-demand for treatment of breakthrough bleeding episodes (N=19) for 9 months. The 80 mg dose of QFITLIA is not approved because of an increased risk of serious thrombotic events, gallbladder events (including the need for cholecystectomy) and hepatotoxicity [see Boxed Warning and Warnings and Precautions (5.1, 5.2, 5.3)].

Of the 57 enrolled patients all had inhibitors; 45 patients had Hemophilia A and 12 had Hemophilia B. All patients in the study were male. The mean age of patients was 28.4 years, and 10 (17.5%) patients were 12–17 years of age. A total of 68.4% of patients were Asian, 28.1% were White, 1.8% were other, and 1.8% were multiple races; 5.3% patients identified as Hispanic or Latino and 94.7% identified as not Hispanic or Latino. Generally, the demographic and patient characteristics at baseline were comparable between the patients with hemophilia A and B.

ATLAS A/B

ATLAS A/B was a randomized, multicenter, open-label clinical study in 120 adult and pediatric males (aged ≥12 years) with hemophilia A or B without inhibitory antibodies to FVIII or FIX, who previously received on-demand (episodic) treatment with CFC for bleeding. Eligible patients were randomized in a 2:1 ratio to receive QFITLIA prophylaxis at a fixed dose of 80 mg SC monthly (N=80) or CFCs on-demand to treat breakthrough bleeding episodes (N=40) for 9 months. The 80 mg dose of QFITLIA is not approved because of an increased risk of serious thrombotic events, gallbladder events (including the need for cholecystectomy) and hepatotoxicity [see Boxed Warning and Warnings and Precautions (5.1, 5.2, 5.3)].

Of the 120 enrolled patients none had inhibitors; 93 patients had Hemophilia A and 27 had Hemophilia B. All patients in the study were male. The mean age of patients was 33.8 years, and 14 (11.7%) patients were 12–17 years of age. A total of 59.2% of patients were Asian, 37.5% were White, 1.7% were Black or African American, and 1.7% were multiple races; 3.3% of patients identified as Hispanic or Latino, 90.8% identified as not Hispanic or Latino, and 5.8% had ethnicity information unreported. Generally, the demographic and patient characteristics at baseline were comparable between the patients with hemophilia A and B.

ATLAS-OLE

A total of 227 patients rolled over from two clinical studies (ATLAS-INH and ATLAS-A/B) and ATLAS-PPX, a crossover study in patients previously on CFC or BPA prophylaxis, and were treated with QFITLIA in ATLAS-OLE. This multicenter open-label extension study evaluated the long-term safety and efficacy of QFITLIA in adult and pediatric males aged ≥12 years with hemophilia A or B, with or without inhibitory antibodies to FVIII or FIX. Eligible patients initially received QFITLIA 80 mg SC once monthly. The study was amended to evaluate the efficacy and safety of the AT-DR. A total of 213 patients were subsequently transitioned to AT-DR targeting AT activity of 15–35%.

In the AT-DR, the QFITLIA starting dose was 50 mg every two months, and dosing was individually adjusted based on AT activity level using the INNOVANCE Antithrombin assay. The dose could be increased to 50 mg every month or 80 mg every month or decreased to 20 mg every two months or 20 mg every month. QFITLIA was discontinued if AT activity was <15% at the lowest dose. No patients required escalation to 80 mg every month to achieve the target AT range. The dose required to maintain AT activity 15–35% in patients who initiated dosing on 50 mg every two months was: 50 mg every two months (35.8% of patients), 50 mg every month (15.7% of patients), 20 mg every two months (30.9% of patients), or 20 mg every month (2.9% of patients). A total of 14.7% of patients discontinued QFITLIA due to more than one AT activity <15%.

Patients with known co-existing coagulation disorders other than hemophilia A or B, increased risk of thrombosis as assessed by history of arterial or venous thromboembolism, significant valvular disease or atrial fibrillation, or co-existing thrombophilic disorder (e.g., Factor V Leiden mutation), AT activity <60% at screening, platelet count ≤100,000/μL, eGFR ≤45 mL/min (using the MDRD), or clinically significant liver disease were not eligible for enrollment.

The efficacy of QFITLIA AT-DR in ATLAS-OLE was evaluated for a duration of 7 months (primary efficacy period) following a 6-month dose adjustment period. The median observed annualized bleeding rate (IQR) for treated bleeds was 3.7 (0.0; 7.5) overall, 1.9 (0.0; 5.6) in inhibitor patients and 3.8 (0.0; 11.2) in non-inhibitor patients.

QFITLIA Prophylaxis Compared to On-Demand BPA or CFC

The efficacy results of QFITLIA prophylaxis using AT-DR in ATLAS-OLE compared to on-demand BPA or CFC control data from studies ATLAS-INH and ATLAS-A/B with respect to rate of treated bleeds, treated spontaneous bleeds, and treated joint bleeds are shown in Table 5 (patients with inhibitors) and Table 6 (patients without inhibitors) below.

Table 5. Annualized Bleed Rate for Treated Bleeds with QFITLIA Prophylaxis versus On-Demand BPA in Patients ≥12 Years of Age with Inhibitors:

ABR = annualized bleed rate; AT-DR = AT-Dosing Regimen; BPA = bypassing agents; CI = confidence interval.
^* Based on negative binomial regression model.

Table 6. Annualized Bleed Rate for Treated Bleeds with QFITLIA Prophylaxis versus On-Demand CFC in Patients ≥12 Years of Age without Inhibitors:

ABR = annualized bleed rate; AT-DR = AT-Dosing Regimen; CFC = clotting factor concentrate; CI = confidence interval.
^* Based on negative binomial regression model.