Background
Fitusiran, an investigational small interfering RNA therapy, reduces antithrombin production to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors.
...Objectives
To evaluate the safety and efficacy of fitusiran treatment for people with moderate/severe hemophilia A or B with inhibitors.
Patients/Methods
In this open‐label phase 1, part D study, 17 males with hemophilia A or B with inhibitors received three once‐monthly subcutaneous injections of fitusiran 50 mg (n = 6) or 80 mg (n = 11); followed for up to 112 days. Endpoints included safety (primary), pharmacokinetics/pharmacodynamics (secondary), annualized bleeding rate, and patient‐reported outcomes (exploratory).
Results
The most common adverse event was injection site erythema (n = 8). No thrombotic events were reported. At nadir, mean (standard error of the mean SEM) antithrombin activity decreased from baseline by 82.0% (2.2) and 87.4% (0.7) in the 50 mg and 80 mg groups, respectively. Antithrombin reduction was associated with increased thrombin generation. 11/17 (64.7%) participants had no bleeds during the observation period (mean standard deviation 69.4 16.3 days). Mean (SEM) changes from baseline in Haemophilia Quality of Life Questionnaire for Adults total (−9.2 2.9) and physical health (−12.3 3.9) domain scores suggested clinically meaningful improvement.
Conclusions
Monthly fitusiran was generally well tolerated, lowered antithrombin levels from baseline, and resulted in improved thrombin generation. These preliminary results suggest that monthly fitusiran treatment may reduce bleeding episodes and improve quality of life in participants with hemophilia A or B with inhibitors.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Antithrombin (AT) reduction has been shown to improve thrombin generation (TG) in haemophilia with or without inhibitors. As treatment with bypassing agents (BPAs) may be required in patients with ...breakthrough bleeding while receiving AT-lowering therapy, we assessed TG in platelet-poor plasma samples from haemophilia patients in the presence of BPA (recombinant activated factor VII rFVIIa; 1.25 or 2.5 μg mL−1 or activated prothrombin complex concentrate aPCC; 0.5 or 1 U mL−1) and AT reduction (anti-AT antibody).
Mean ± SEM baseline peak thrombin height was 19.9 ± 4.3 nM in plasma from haemophilia patients (n = 12) and 230.5 ± 9.8 nM in healthy males (n = 24). Reduced AT improved mean peak thrombin height in haemophilia patient plasma to 75.4 ± 17.4 nM. Spiking of 90% AT-reduced haemophilia patient plasma with 2.5 μg mL−1 rFVIIa or 1 U mL−1 aPCC increased the mean peak thrombin height to 82.5 ± 12 nM and 134.8 ± 18.7 nM, respectively.
Peak thrombin levels did not exceed the range for healthy volunteers when plasma samples from haemophilia patients with in vitro AT reduction were treated with BPAs, suggesting the potential use of BPAs in conjunction with AT reduction. Further clinical investigations are needed to confirm the safety of this approach.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction: Super-enhancer (SE) mapping in non-APL AML patient (pt) blasts identified RARα as a novel therapeutic target in approximately 30% of pts, who have elevated RARA gene expression. It was ...observed that the enhancer profile of this novel pt segment, where RARA expression was elevated, overlapped with the profile of mature monocytes (McKeown, 2017). Recently, several reports describe AML with monocytic features associated with resistance to venetoclax (Ven), a BCL-2 inhibitor that has emerged as a standard of care for treatment of pts with newly diagnosed (ND) unfit AML in combination with hypomethylating agents (HMAs) (Zhang, 2018; Kuusanmäki, 2019; Pei, 2020). Approximately one-third of pts do not respond to Ven plus HMAs including azacitidine (Aza) (DiNardo, 2019 and 2020), highlighting a continuing significant unmet need in ND unfit AML. SY-1425, a potent and selective RARα agonist, is in development for non-APL AML in combination with Aza and has demonstrated clinical activity with high rates of complete remission (CR) and deep CRs in RARA-positive (RARA+) ND unfit AML (DeBotton, 2019). Based on the overlap of monocytic features with RARA gene expression, we evaluated clinical samples of pts treated with SY-1425 plus Aza to correlate features of Ven resistance with the RARA biomarker and with clinical response to SY-1425 plus Aza.
Methods: RARA gene expression in non-APL AML was evaluated in the TCGA and Beat AML RNA-seq datasets. AUC of cell viability curves were used to evaluate ex vivo sensitivity to compounds, including Ven, in the Beat AML dataset. A monocytic expression signature (MES) was developed using the expression of monocytic and primitive RNA markers in the TCGA dataset to analyze the monocytic phenotype. The MES used a logistic regression model with lasso regularization to distinguish FAB M4/5 (monocytic) from FAB M0/1/2 (primitive) using 10-fold cross-validation with 85% sensitivity and 80% specificity. The MES was then applied to the RNA-seq datasets from Beat AML and AML blasts from ND unfit AML pts in the ongoing SY-1425 plus Aza trial (NCT02807558), in which RARA+ pts were determined by an RT-qPCR based biomarker clinical trial assay (CTA). The MES, RARA expression, and Ven resistance-associated features were compared using Spearman's rho correlation; the association of the MES with the RARA biomarker and with IWG clinical responses in SY-1425 plus Aza treated pts was evaluated.
Results: Analysis of RNA-seq in TCGA non-APL AML pts demonstrated higher RARA expression in monocytic AML (FAB M4/M5) than primitive AML (FAB M0/M1/M2) (p<10-7, t-test). TCGA and Beat AML datasets also demonstrated that RARA expression was associated with the MES (rho=0.6 and 0.58), with approximately 70% of RARA-high pts across both databases having a high MES.
We further elucidated the relationships of RARA expression, AML monocytic phenotypes, and Ven resistance. Of 121 inhibitors tested ex vivo in primary Beat AML pt samples, Ven was the inhibitor most associated with treatment resistance in RARA+ vs. RARA- samples. Additionally, MES (rho=0.58), RARA (rho=0.48) and BCL-2 expression (rho=-0.49) had similar magnitude of association with ex vivo Ven resistance, with RARA+ samples showing much lower ex vivo sensitivity to Ven than RARA- samples (p=3×10-8). In 12 AML pt samples (Pei, 2020) treated with Ven ± Aza ex vivo, RARA expression was higher in the monocytic leukemia stem cells resistant to Ven ± Aza (p=0.005).
To evaluate whether the RARA+ ND unfit AML pts in the ongoing SY-1425 plus Aza clinical trial were enriched for the monocytic phenotype of Ven resistance, RNA-seq was performed on enrolled pt AML blasts. Among 51 treated pts, 86% (19/22) of RARA+ and 83% (24/29) of RARA- pts yielded RNA-seq results. RARA+ pts were more monocytic than RARA- pts, as demonstrated by higher MES (p=0.002), with higher MCL-1 (p=0.001), and lower BCL-2, CD34, and CD117 expression (p=0.03, 8×10-6, 2×10-4, respectively). In pts with the best IWG response of CR/CRi, RARA+ pts (n=10) had higher MES than RARA- pts (n=8) (p=0.008).
Conclusion: In ND unfit AML, RARA+ pts, including those with clinical responses to SY-1425 plus Aza, are enriched for monocytic features associated with resistance to Ven. SY-1425 plus Aza shows potential as a novel targeted regimen for the treatment of RARA+ ND unfit AML and warrants further development in this genomically defined subset of AML pts who may be resistant to upfront SOC therapy with Ven.
Fiore:Syros Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Kelly:Syros Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Volkert:Syros Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Zhou:Incyte: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Syros Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Madigan:Syros Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Eaton:Syros Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Hodgson:Syros Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Roth:Syros Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kang-Fortner:Syros Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Most patients (pts) with histone-lysine N-methyltransferase 2A (KMT2A)-rearranged (KMT2Ar) acute leukemia, relapse after conventional chemotherapy and hematopoietic stem cell transplant ...(HSCT). Remission rates after relapse (complete remission CR, 5%) and median overall survival (2.4 mo) in ≥2nd salvage therapies in adults remain low (Blood Cancer J. 2021;119:162). In KMT2Ar leukemia, interaction of menin with KMT2A fusion proteins is a key driver of leukemogenesis. However, no therapies targeting the menin-KMT2A interaction have been approved. Revumenib (SNDX-5613; rev), a small-molecule inhibitor of menin-KMT2A interactions, demonstrated preliminary efficacy and safety in a phase 1 study of R/R KMT2Ar and nucleophosmin 1-mutated (NPM1m) acute leukemias. We report topline efficacy and safety for pts with R/R KMT2Ar acute leukemia treated with rev in a pivotal phase 2 study (AUGMENT-101; NCT04065399).
Methods: Pts aged ≥30 days with R/R KMT2Ar acute leukemia were enrolled in cohort A (acute lymphoblastic leukemia ALL/mixed phenotype acute leukemia MPAL) and B (acute myeloid leukemia AML); cohort C continues to enroll pts with NPM1m and is not included in this analysis. Pts received rev (163 mg or 95 mg/m2 if body weight <40 kg) q12h with a strong cytochrome P450 3A4 inhibitor orally in 28-day cycles. Treatment continued until unacceptable toxicity or lack of at least morphological leukemia-free state (MLFS) after 4 cycles of treatment. Phase 2 primary objectives were safety and tolerability of rev and CR+CR with partial hematologic recovery (CRh) rate. Key secondary endpoints included composite CR rate (CRc, CR+CRh+CR with incomplete platelet recovery CRp+CR with incomplete count recovery CRi) and overall response rate (ORR, CRc+MLFS+partial remission). A planned interim analysis (IA) of pooled adult and pediatric pts with KMT2Ar acute leukemia was conducted.
Results:As of July 24, 2023, 94 pts with R/R KMT2Ar acute leukemia received ≥1 dose of study drug and were included in the safety analysis (Table 1). Median age was 37.0 y (range, 1.3-75.0). Of the 94 pts, 23 (24.5%) were aged <18 y and 13 (13.8%) were aged ≥65 y. Seventy-eight (83%) had AML and 16 (17.0%) had ALL or MPAL. Over half of pts were female; 17.5% of pts were non-White. Pts were heavily pretreated (median 2 range, 1-11 prior lines of therapy), with 41 pts (43.6%) having received ≥3 prior lines. Fifty-four pts (57.4%) had refractory relapse disease (unresponsive to most recent salvage treatment), and 47 pts (50%) had prior HSCT. Treatment-related adverse events (TRAEs) were reported in 81.9% of the safety population. Most common TRAEs (≥20%) were nausea (27.7%), differentiation syndrome (26.6%), and QTc prolongation (23.4%). Grade ≥3 TRAEs were observed in 51 pts (54.3%), the most common being differentiation syndrome (16.0%), febrile neutropenia (13.8%), and QTc prolongation (13.8%) (Table 2). Overall, 6.4% of pts discontinued therapy due to TRAEs; none discontinued rev due to differentiation syndrome or QTc prolongation.
The pooled efficacy population for the IA (n=57) included all phase 2 pts with centrally confirmed KMT2Ar and ≥5% blasts in bone marrow at baseline who had received ≥1 dose of study drug and started treatment on or before the 38th adult AML efficacy evaluable patient. The IA was specified to occur when the 57 patients have had the opportunity to be followed for 6 months. After median follow-up of 6.1 mo, 13 pts (22.8% 95% confidence interval (CI), 12.7-35.8) achieved CR+CRh, surpassing the predefined IA efficacy boundary for the pooled KMT2Ar population; CR+CRh rate was similar in adult and pediatric pts. Median duration of CR+CRh was 6.4 mo (95% CI, 3.4-not reached). CRc was 43.9% (95% CI, 30.7-57.6); ORR was 63.2% (95% CI, 49.3-75.6). Most pts with a CR or CRh response, and for whom measurable residual disease (MRD) status was reported, achieved MRD negativity (7/10, 70.0%); most pts with CRc and MRD reported also achieved MRD negativity (15/22, 68.2%). Fourteen of 36 responders (38.9%) proceeded to HSCT, with half resuming rev post HSCT.
Conclusions: Rev demonstrated clinically meaningful results in a heavily pretreated KMT2Ar population, including high ORR and rates of MRD negativity and subsequent HSCT. At IA, this pivotal study met its primary endpoint and the KMT2Ar cohorts were stopped early for efficacy.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
Background: Revumenib (SNDX-5613), a potent, selective small-molecule inhibitor of the menin-histone-lysine N-methyltransferase 2A (KMT2A) interaction, is being investigated in patients (pts) with ...relapsed/refractory (R/R) KMT2A-rearranged ( KMT2Ar) and nucleophosmin 1-mutated ( NPM1m) acute leukemias. An initial analysis of the phase 1 of AUGMENT-101 (NCT04065399) has been reported ( Nature. 2023;615:920-924). Here we report an update of >1 year additional experience in the phase 1 portion of the study, which has completed enrollment, with safety data from 131 treated pts and efficacy data in 80 pts with R/R KMT2Ar leukemia. Demographic data from pivotal phase 2 cohorts are included; safety and efficacy data of a preplannedanalysis will be reported at the meeting. Methods: In phase 1, pts aged ≥30 days with R/R acute leukemias were assigned to 1 of 6 dose-escalation arms designed to identify a recommended phase 2 dose (RP2D) for concomitant administration of weak, moderate, or strong cytochrome P450 3A4 inhibitor (CYP3A4i) azole antifungal or no CYP3A4i. Pts received revumenib every 12 hours (q12h) or 3 times a day at a flat dose (≥40 kg) or a body surface area-based dose (<40 kg). Safety was assessed in all pts who received ≥1 dose of revumenib; responses are reported for all treated pts with KMT2Ar. In pts who underwent hematopoietic stem cell transplant (HSCT), responses reported are those achieved before HSCT. The Phase 2 study was initiated following identification of an RP2D of 163 mg (95 mg/m 2 if <40 kg) q12h with a strong CYP3A4i in 28-day cycles until unacceptable toxicity, lack of at least morphological leukemia-free state (MLFS) by end of cycle 4, or progressive disease without clinical benefit as defined by the investigator. The phase 2 primary objectives are evaluation of safety and tolerability of revumenib and assessment of the complete remission (CR) + CR with partial hematologic recovery (CRh) rate. The safety and efficacy of revumenib at an RP2D is being explored in 3 expansion cohorts: Cohort 2A, KMT2Ar acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia; Cohort 2B, KMT2Ar acute myeloid leukemia (AML); and Cohort 2C, NPM1m AML. A preplanned pooled analysis of adult and pediatric pts with KMT2Ar acute leukemia will be conducted when a subset of Cohorts 2A+2B pts have completed a minimum of 4 cycles or have discontinued therapy. Results: Phase 1: As of June 19, 2023, 80 pts with R/R KMT2Ar acute leukemia were treated with revumenib in the 6 dose-escalation arms (Table 1). In adults with AML (n=51), the largest KMT2Ar subgroup, CR+CRh was 28% and overall response rate (ORR) was 59%. Responses were consistent in ALL/other leukemia subtype (n=15), with 27% CR+CRh and 53% ORR. ORR (61%) was similar in pediatric pts (<18 years, n=18), with 22% proceeding to HSCT. Although similar percentages of adult and children proceeded to transplant, consistent with common clinical practice in pediatrics, 75% of children transplanted went on to HSCT prior to achieving a CR/CRh (2 MLFS, 1 CRp) versus 17% of adults. In the safety population (n=131), 24% of pts had a ≥Grade 3 treatment-related adverse event (TRAE), with Grade 3 QTc prolongation in 8% and differentiation syndrome in 2% (Table 1). QTc prolongation remained as the only dose-limiting toxicity; no patients experienced ventricular arrhythmias. In addition, based on updated phase 1 pharmacokinetics, clinical activity, and safety data, an RP2D of 276 mg q12h without a strong CYP3A4i was established. Phase 2: In a preliminary analysis of Cohorts 2A and 2B (June 19, 2023), 88 pts with KMT2Ar acute leukemia were enrolled and treated with revumenib at an RP2D (Table 2). Ages ranged from 1.3 to 75 years (22 aged <18 y; Table 2). Leukemia subtypes included ALL (15%), AML (81%), and other (3%). Pts were heavily pretreated, having received a median of 3 prior lines of therapy (range 1-12); 38% received ≥4 prior lines and 48% had prior HSCT. Conclusions: These phase 1 data continue to demonstrate deep responses to revumenib and a manageable safety profile in heavily pretreated patients with R/R KMT2Ar acute leukemia across ages and subtypes. The lack of targeted therapies approved for KMT2Ar leukemia indicate the need for further investigation of novel, potentially transformative therapies such as revumenib. Enrollment in the AUGMENT-101 trial is ongoing. Pivotal Phase 2 safety and efficacy data for the KMT2Ar population will be reported at the meeting.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
Introduction: Hemophilia is a bleeding disorder characterized by ineffective clot formation due to insufficient thrombin generation. Fitusiran is a subcutaneously (SC) administered investigational ...RNA interference (RNAi) therapeutic targeting antithrombin (AT) as a means to improve thrombin generation (TG) and promote hemostasis in patients with hemophilia A or B with and without inhibitors. Previously reported data have shown that monthly administration of fitusiran led to dose dependent AT lowering, improved thrombin generation and decreased bleeding frequency. (Pasi et al. Blood . 2016.; Pasi et al. New Engl J Med . 2017.) Data from an open-label extension study demonstrated an encouraging safety and tolerability profile, including when used in combination with factor or bypassing agents to treat breakthrough bleeds. (Pasi et al. Res Pract Thromb Haemost . 2017.) The management of operative procedures while on novel, non-factor therapies for hemophilia, such as fitusiran, is of clinical interest. The purpose of this abstract is to describe details as reported by study investigators on the perioperative hemostatic management during dental/surgical procedures in patients with hemophilia receiving fitusiran in a clinical trial.
Methods: The fitusiran Phase 1 study (NCT02035605) followed by the Phase 2 open-label extension (OLE) study (NCT02554773) included patients with hemophilia A or B with and without inhibitors. After the Phase 1 dose-escalation study, patients eligible to continue dosing in the Phase 2 OLE received monthly, fixed SC doses of fitusiran, 50 mg or 80 mg. Data on perioperative hemostatic treatment and hemostatic response were collected for patients undergoing dental/surgical procedures while AT was lowered on study.
Results: Four patients, ages 22-36, with severe hemophilia A (2 with inhibitors) underwent 5 surgical procedures: endoscopic cholecystectomy and septoplasty; thoracotomy/partial lung segmentectomy; molar teeth extraction; premolar tooth extraction. Prior to the procedures, the AT level for each of these patients was <20% (range: 10.7 - 19%) relative to baseline. At the Investigators' discretion, perioperative hemostatic treatments (FVIII, rFVIIa, and/or aPCC) were administered for 4 of the 5 procedures. The duration of hemostatic treatment coverage varied depending on the type of procedure: 15 hours post-procedure (premolar tooth extraction), 7 days post-procedures (endoscopic cholecystectomy and septoplasty), and 13 days post-procedure (thoracotomy/partial lung segmentectomy). No thromboprophylaxis was used in any procedure. All procedures were rated by the respective investigator as resulting in minimal blood loss or blood loss similar to a patient without hemophilia. Further details on the perioperative treatment regimens and hemostatic responses will be presented.
Conclusion: Successful perioperative hemostatic management of patients in the context of AT lowering with fitusiran has been observed; the number of dental/surgical procedures is limited and additional data are needed to further define appropriate perioperative hemostatic management plans.
Negrier:Baxter: Research Funding; Inspiration: Research Funding; LFB: Honoraria, Speakers Bureau; Octapharma: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Baxalta: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Alnylam: Research Funding; Bayer: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; Biogen/SOBI: Honoraria, Research Funding, Speakers Bureau. Ragni:Alnylam: Consultancy, Honoraria, Research Funding; Biomarin: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; MOGAM: Consultancy, Honoraria; Sangamo: Research Funding; Genentech/Roche: Research Funding; Bioverativ: Consultancy, Honoraria, Research Funding; NovoNordisk: Honoraria; SPARK: Research Funding; Shire: Consultancy, Honoraria, Research Funding. Georgiev:Alnylam: Consultancy. Van Nguyen:Alnylam: Employment, Equity Ownership. Madigan:Alnylam: Employment, Equity Ownership. Pasi:Bayer HealthCare; Biotest; Novo Nordisk; Pfizer Inc.; Roche: Speakers Bureau; Alnylam Pharmaceuticals, Inc; Biogen Idec Inc.; BioMarin Pharmaceutical Inc.; Octapharmal; Roche; Shire; SOBI: Consultancy; Pfizer, SOBI, Octapharma, Shire, Bayer, Alnylam, Biomarin, Biotest: Honoraria; Alnylam Pharmaceuticals; BioMarin Pharmaceutical Inc.; SOBI: Membership on an entity's Board of Directors or advisory committees; Roche, NovoNordisk, Pfizer: Other: paid instructor; BioMarin Pharmaceutical Inc.; Octapharma, Alnylam Pharmaceuticals, Bioverativ: Research Funding.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
Introduction
Hemophilia A and hemophilia B are rare bleeding disorders characterized by insufficient thrombin generation due to deficiencies in factors VIII or IX, respectively. Standard treatment ...for hemophilia is currently based on replacement of the deficient factor with factor concentrate. This, unfortunately, subjects the patient to the risk of developing neutralizing antibodies, or inhibitors, against replacement factor VIII or IX. Individuals with inhibitors become refractory to standard replacement therapy, a serious complication for as many as one-third of patients with severe hemophilia A and a lower proportion of patients with hemophilia B. Fitusiran is a once-monthly subcutaneously administered investigational RNA interference therapeutic that targets antithrombin (AT) to improve thrombin generation (TG) and promote hemostasis in patients with hemophilia A or hemophilia B with or without inhibitors. In September 2017, fitusiran dosing in the Phase 2 open-label extension (OLE) study was temporarily suspended to investigate a case of fatal cerebral venous sinus thrombosis. Following this investigation, fitusiran dosing resumed in December 2017 with protocol amendments for bleed management dosing and safety monitoring. During the temporary dosing suspension, AT levels, TG, bleeding events, and frequency of factor replacement and bypassing agents were assessed.
Methods
Before the dosing suspension, 33 patients (hemophilia A=27, hemophilia B=6) were enrolled, of whom 28 patients continued treatment over 20 months in the Phase 2 OLE study, with a median of 11 months on study. As of June 2018, data collected monthly during the clinical hold included AT levels, TG, and description and management of treated bleeding events before and during the clinical hold, which were used to estimate annualized bleeding rates (ABRs) and bleeding rates per month.
Results
AT activity in patients previously receiving fitusiran demonstrated a progressive increase during the interruption of fitusiran dosing. Median %AT increased to >60% after a 5-month period compared with the last data point before dosing interruption. These data confirm our previous findings that discontinuation of fitusiran results in gradual recovery of AT activity over time. Subjects also demonstrated a concomitant steady decrease in TG during the interruption of fitusiran dosing, which occurred over a similar time course to that of AT recovery. Consistent with both the increase in AT activity and decrease in TG, preliminary analysis shows the median overall ABR increased from 1.43 events/year before the dosing interruption to 6.07 events/year during the dosing interruption.
Conclusions
During a period of fitusiran dosing suspension, recovery of AT activity was accompanied by a decrease in TG and an increase in bleeding events. These observations provide support for the therapeutic hypothesis that AT activity lowering by fitusiran leads to an increase in TG and improved hemostasis. Phase 3 studies of fitusiran are ongoing.
Ragni:Bioverativ: Consultancy, Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; SPARK: Consultancy, Research Funding; Shire: Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Sangamo: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding. Georgiev:Alnylam: Consultancy. Lissitchkov:Novo Nordisk: Other: Investigator fees as a participant of the clinical trial. Austin:Pfizer: Research Funding. Chowdary:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Freeline: Consultancy; Bayer: Honoraria; Baxalta (Shire): Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum AB (Sobi): Honoraria; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Foster:Sanofi Genzyme: Employment. Yu:Sanofi Genzyme: Employment. Benson:Sanofi Genzyme: Employment. Madigan:Alnylam Pharmaceuticals Inc: Employment. Nguyen:Alnylam Pharmaceuticals Inc: Employment. Ali:Sanofi Genzyme: Employment. Kadam:Sanofi Genzyme: Employment. Jain:Sanofi Genzyme: Employment. Pasi:Octapharma: Honoraria; Catalyst Bio: Honoraria; Bayer: Speakers Bureau; Shire: Speakers Bureau; NovoNordisk: Speakers Bureau; Sobi: Honoraria; Apcintex: Honoraria; Biomarin: Honoraria, Research Funding; Pfizer: Speakers Bureau; Alnylam: Honoraria, Research Funding; Bioverativ: Honoraria, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Tamibarotene plus azacitidine was associated with a high CR rate and a rapid onset of response in RARA-positive newly diagnosed unfit AML.•Tamibarotene-based treatment in AML with RARA ...overexpression is a novel-targeted approach with potential to improve current therapy.
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A superenhancer at the retinoic acid receptor alpha (RARA) gene is associated with RARA mRNA overexpression in ∼30% of non-acute promyelocytic leukemia acute myeloid leukemia (AML) and in ∼50% of myelodysplastic syndromes (MDS). RARA overexpression is an actionable target for treatment with tamibarotene, an oral potent and selective RARα agonist. Sensitivity to the RARα agonist tamibarotene was demonstrated in RARA-high but not RARA-low preclinical AML models. The combination of oral tamibarotene plus azacitidine was evaluated in a phase 2 clinical study in 51 newly diagnosed unfit patients with AML identified as RARA-positive (n = 22) or RARA-negative (n = 29) for RARA mRNA overexpression in peripheral blasts using a blood-based biomarker test. In 18 response-evaluable RARA-positive patients, complete remission (CR)/CR with incomplete hematologic recovery rate was 61%, CR rate was 50%, and time to initial composite CR was rapid at 1.2 months. Transfusion independence was attained by 72% of RARA-positive patients. In contrast, 28 response-evaluable RARA-negative patients had response rates that were consistent with azacitidine monotherapy. Tamibarotene in combination with azacitidine was well tolerated. The majority of nonhematologic adverse events were low grade and hematologic adverse events were comparable to single-agent azacitidine, demonstrating that there was no additional myelosuppression when tamibarotene was combined with azacitidine. These results support further evaluation of tamibarotene-based treatment strategies in patients with AML or MDS with RARA overexpression to provide a targeted approach with the goal of improving patient outcomes. This trial was registered at www.clinicaltrials.gov as #NCT02807558.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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