Venglustat inhibits the enzymatic conversion of ceramide to glucosylceramide, reducing available substrate for the synthesis of more complex glycosphingolipids. It offers a potential new approach to ...the treatment of patients with Fabry disease (α-Gal A deficiency), in whom progressive accumulation of such glycosphingolipids, including globotriaosylceramide (GL-3), in the lysosomes of a wide range of cell types often leads to vital organ complications in adulthood. An international, open-label, single-arm, Phase 2a uncontrolled 26-week clinical study (NCT02228460) and a 130-week extension study (NCT02489344) were conducted to assess the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of 15 mg once daily oral venglustat in treatment-naïve adult male patients with classic Fabry disease. Of 11 patients (18–37 years old) who initially enrolled, nine completed the 26-week study and seven completed the extension study. A total of 169 treatment-emergent adverse events (TEAEs) were reported by nine patients, the majority being mild (73%) and unrelated to the study drug (70%). Nine serious TEAEs (serious adverse events) and 11 severe TEAEs, including a self-harm event, were reported. No deaths or treatment-related life-threatening adverse events were reported. Skin GL-3 scores in superficial skin capillary endothelium (SSCE), estimated by light microscopy, were unchanged from baseline at Week 26 in five patients, decreased in three patients, and increased in one patient. There was no significant change in GL-3 scores or significant shift in grouped GL-3 scores. Five of six patients had reductions from baseline in GL-3 score at the end of the extension study. At Weeks 26 and 156 the mean (standard deviation) changes from baseline in the fraction of the volume of SSCE cytoplasm occupied by GL-3 inclusions, measured by electron microscopy unbiased stereology, were − 0.06 (0.03) (p = 0.0010) and − 0.12 (0.04) (p = 0.0008), respectively. Venglustat treatment reduced markers in the synthetic and degradative pathway of major glycosphingolipids; proximal markers reduced rapidly and more distal markers (plasma GL-3 and globotriaosylsphingosine) reduced progressively. There were no biochemical or histological indications of progression of Fabry disease over 3 years of follow-up. These findings confirm target engagement and the pharmacodynamic effects of venglustat in adult males with classic Fabry disease. However, further clinical evaluation in larger studies is needed to determine efficacy and safety.
•Substantial pharmacodynamic effects of venglustat in adult males with Fabry disease.•Adverse events were mostly mild (73%) and unrelated to study drug (70%).•No deaths or treatment-related life-threatening adverse events.•Nine serious and 11 severe treatment-emergent adverse events.•Exploratory efficacy justifies further clinical evaluation in patients with Fabry disease.
Background Homozygous familial hypercholesterolemia (HoFH) is a rare, inherited condition resulting in severely elevated low-density lipoprotein cholesterol levels (LDL-C) leading to premature ...cardiovascular disease and, often, death. Mipomersen is an antisense oligonucleotide that inhibits apolipoprotein B (apo B) synthesis, lowering LDL-C levels. Mipomersen has demonstrated efficacy in adult HoFH patients, possibly providing a therapeutic option for pediatric patients. Study objectives were to summarize mipomersen efficacy and safety in the pediatric cohort of a phase 3 randomized controlled trial (RCT) and subsequent open-label extension study (OLE). Methods Seven patients aged 12–18 years were randomized to 200-mg mipomersen or placebo weekly (26 weeks) and received mipomersen in the OLE (52 or 104 weeks). Plasma LDL-C and apo B concentrations and adverse events were assessed. Results All pediatric patients completed the RCT and entered OLE. The 3 mipomersen patients in the RCT experienced mean reductions from baseline to RCT end of 42.7% and 46.1% for LDL-C and apo B, respectively. Of the 4 placebo patients, 3 responded well to mipomersen during OLE, with reductions in LDL-C of 26.5%–42.1%. Three patients completed OLE treatment, and 4 patients discontinued therapy due to adverse events. Lipid level fluctuations were observed and were likely due to poor compliance. Conclusions Long-term mipomersen treatment was successful regarding efficacy parameters for pediatric HoFH patients. The safety profile was consistent with other phase 3 clinical trials. Long-term compliance was an issue. Measures supporting adherence should be encouraged.
•verITI-8 is the first prospective study of first-time rFVIIIFc ITI for severe hemophilia A and high historical peak titers.•A rFVIIIFc offered rapid time to tolerization with durable responses in ...almost two-thirds of patients, no recurrence, and good tolerability.
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Inhibitor development remains a major challenge in factor VIII (FVIII) replacement therapy. verITI-8 is the first prospective study of a recombinant FVIII Fc fusion protein (rFVIIIFc; efmoroctocog alfa) for first-time immune tolerance induction (ITI) in males with severe hemophilia A and high-titer inhibitors (historical peak ≥5 Bethesda units BU/mL). In this single-arm, open-label, multicenter study, screening was followed by ITI (rFVIIIFc 200 IU/kg per day until tolerization or maximum of 48 weeks). Those who achieved ITI success entered a tapering period, returning to standard prophylaxis, and then entered follow-up. Primary end point was time to tolerization with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg), and half-life (t½) ≥7 hours within 48 weeks. Sixteen patients received ≥1 rFVIIIFc dose. Twelve (75%), 11 (69%), and 10 patients (63%), respectively, achieved negative inhibitor titers, an IR ≥66%, and a t½ ≥7 hours (ie, tolerance) within 48 weeks. Median times in weeks to achieve these markers of success were 7.4 (interquartile range IQR, 2.2-17.8), 6.8 (IQR, 5.4-22.4), and 11.7 (IQR, 9.8-26.2), respectively. All patients experienced ≥1 treatment-emergent adverse event (TEAE), and 1 reported ≥1 related TEAE (injection site pain). Nine patients experienced ≥1 treatment-emergent serious AE. No thrombotic events, discontinuations because of AEs, or deaths were reported during the study. As the first extended half-life rFVIII with prospective data in ITI, rFVIIIFc offered short time to tolerization with durable responses in almost two-thirds of patients and was well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT03093480.
Inhibitor development is a major challenge to treatment of severe hemophilia. Malec and colleagues report on the results of the first prospective study of immune tolerance induction (ITI) using a recombinant factor VIII Fc fusion protein with an extended half-life. The authors found that durable ITI is achieved by a median of 3 months in 10 of 16 patients, setting the stage for further evaluation of this product.
Introduction: Inhibitor development is a major complication of factor VIII (FVIII) replacement therapy, affecting approximately 30% of people with severe hemophilia A (Peyvandi et al Lancet 2016). ...Inhibitor eradication is the standard of care to restore responsiveness to FVIII; however, ITI regimens often require frequent high-dose factor injections over a long period (DiMichele et al Haemophilia 2007; Carcao et al Haemophilia 2021). Median (interquartile range IQR) time (months) to negative titer in the International ITI Study with high-dose FVIII was 4.6 (2.8-13.8) (n=31); negative titer to normal recovery was 6.9 (3.5-12.0) (n=23); and normal recovery to tolerance was 10.6 (6.3-20.5) (n=22) (Hay and DiMichele Blood 2012). Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life (EHL) FVIII that showed potential benefits for ITI in retrospective clinical data and case reports (Malec et al Haemophilia 2016; Groomes et al Pediatr Blood Cancer 2016; Carcao et al Haemophilia 2021). VerITI-8 (NCT03093480) is the first prospective study of rFVIIIFc in first-time ITI and follows on from the reITIrate (NCT03103542) study of rFVIIIFc for rescue ITI (Königs et al Res Pract Thromb Haemost, ISTH 2021).
Aim: Describe outcomes in the verITI-8 study of first-time ITI with rFVIIIFc over 48 weeks in subjects with severe hemophilia A and high-titer inhibitors.
Methods: VerITI-8 is a prospective, single-arm, open-label, multicenter study exploring efficacy of rFVIIIFc for first-time ITI in people with severe hemophilia A with high-titer inhibitors. Initial screening was followed by an ITI period in which all subjects received rFVIIIFc 200 IU/kg/day until tolerization or 48 weeks had elapsed (Figure). This was followed by tapered dose reduction to standard prophylaxis and follow-up. Key inclusion criteria included males with severe hemophilia A, high-titer inhibitors (historical peak ≥5 Bethesda units BU/mL), and prior treatment with any plasma-derived or recombinant standard half-life or EHL FVIII. Key exclusion criteria included coagulation disorder(s) other than hemophilia A and previous ITI. The primary endpoint was time to tolerization (successful ITI) with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg) (both at 2 consecutive visits), and t ½ ≥7 hours (h) within 48 weeks. Secondary endpoints included number of subjects achieving ITI success, annualized bleed rates (ABR), and adverse events (AEs).
Results: Sixteen subjects were enrolled and received ≥1 rFVIIIFc dose. Median (range) age at baseline was 2.1 (0.8-16.0) years, and historical peak inhibitor titer was 22.4 (6.2-256.0) BU/mL (Table). Twelve (75%), 11 (69%), and 10 (63%) subjects, respectively, achieved a negative inhibitor titer, an IR >66%, and a t½ ≥7 h (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2-17.8), 6.8 (5.4-22.4), and 11.7 (9.8-26.2) (ie, 2.7 2.3-6.0 months to tolerance), respectively. One subject achieved partial success (negative inhibitor titer and IR ≥66%), and 5 subjects failed ITI, of which 2 had high inhibitors throughout, 2 experienced an increase in inhibitor levels, and 1 recorded a negative inhibitor titer at 282 days. Most bleeds occurred in the ITI period when median (IQR) ABRs (n=13) were 3.8 (0-10.1) overall, 0 (0-2.6) for spontaneous, 1 (0-4) for traumatic, and 0 (0-3.1) for joint. During tapering, median (IQR) ABRs (n=10) were overall, 0 (0-2.4); spontaneous, 0 (0-0); traumatic, 0 (0-1.3); and joint, 0 (0-0). All 16 subjects experienced ≥1 treatment-emergent AE (TEAE), the most frequent of which was pyrexia in 7 subjects (44%). One subject reported ≥1 related TEAE (injection site pain). Nine subjects (56%) experienced ≥1 treatment-emergent serious AE (TESAE). TESAEs occurring in ≥2 subjects included vascular device infection, contusion, and hemarthrosis. No treatment-related TESAEs, discontinuations due to AEs, or deaths were reported.
Conclusions: rFVIIIFc is the first EHL FVIII with prospective data for first-time ITI in patients with severe hemophilia A with historical high-titer inhibitors. Evaluated within a 48-week timeframe, rFVIIIFc offered rapid time to tolerization (median 11.7 weeks; 2.7 months) with durable responses in almost two-thirds of subjects and was well tolerated. Optimizing ITI to eradicate inhibitors remains a priority.
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Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Bioverativ: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy; Bayer: Consultancy. Van Damme: Pfizer: Consultancy; Shire: Consultancy; Bayer: Consultancy. Chan: Bioverativ: Consultancy. Jain: Sanofi: Ended employment in the past 24 months; Takeda: Current Employment, Current holder of stock options in a privately-held company. Sensinger: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Lethagen: Sobi: Current Employment, Current holder of stock options in a privately-held company. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ablynx, Grifols, Kedrion, Novo Nordisk, Roche, Shire, and Sobi: Other: Personal Fees.
adheres to routine clinical practice
Pompe disease is a rare, autosomal recessive, degenerative neuromuscular disease caused by deficiency of acid α‐glucosidase, a lysosomal enzyme that degrades α‐1,4 and α‐1,6 linkages in glycogen. The ...objectives of this study (PAPAYA; NCT01410890) were to (1) characterize the pharmacokinetics of 20 mg/kg body weight alglucosidase alfa manufactured at the 4000‐L scale following a single intravenous dose in participants aged less than 18 and 18 years or older with Pompe disease and (2) evaluate the relationship between anti–alglucosidase alfa antibody titers and the pharmacokinetics of alglucosidase alfa. Mean maximum plasma concentration and area under the concentration–time curve from time zero and extrapolated to infinite time were 204 μg/mL and 1110 μg • h/mL for participants aged less than 18 years (n = 10), respectively, and 307 μg/mL and 1890 μg • h/mL for participants aged 18 years or older (n = 10), respectively. Mean terminal half‐life was 5.43 hours in participants aged less than 18 years with a high variability (70%) and 3.84 hours in participants aged 18 years or older with a low variability (21%). Mean maximum plasma concentration and area under the concentration–time curve from time zero and extrapolated to infinite time were 256 μg/mL and 1452 μg • h/mL, respectively, in anti–alglucosidase alfa–negative participants (n = 12) and 262 μg/mL and 1703 μg • h/mL, respectively, in anti–alglucosidase alfa–positive participants (n = 7). The study findings enrich available data from existing information on alglucosidase alfa without changing its known risks and benefits.
Abstract
Background and Aims
Fabry disease (FD) is a rare, X-linked, genetic disorder caused by mutations in the gene for the lysosomal enzyme alpha-galactosidase A (αGal-A). The progressive ...accumulation of glycosphingolipids, most notably globotriaosylceramide (GL-3), in lysosomes of a variety of organs and cell types leads, over decades, to renal, cardiovascular, and other clinical manifestations. In a phase 2 study, glucosylceramide synthase inhibition with venglustat led to a progressive reduction in plasma GL-3 to low-normal levels. Scoring by light microscopy showed a reduction in lysosomal GL-3 inclusions in skin capillary endothelial cells (EC) after 3 years of therapy, although not after 6 months. To further characterize the effect of venglustat using more precise methods, we applied unbiased stereological methods to quantitate GL-3 inclusions in skin ECs.
Methods
Skin biopsies were obtained from classic male Fabry disease patients (N = 11) at baseline and during daily treatment with venglustat in a phase 2 study (NCT02228460, NCT02489344). Images from at least 50 superficial skin capillaries were obtained using transmission electron microscopy at 7,500 X magnification. The fraction of the volume (Vv) of cytoplasm occupied by GL-3 inclusions Vv(Inc/Endo) in all ECs in these capillaries was estimated using point counting by a masked reader. Two-sided paired t tests were used to evaluate differences between baseline and post-treatment values at each time point.
Results
Venglustat therapy led to a significant reduction from baseline in Vv(Inc/Endo) of 21.1% after 6 months and 38.7% after 3 years of treatment (Figure).
Conclusions
Treatment with venglustat led to a reduction in GL-3 inclusion fractional volume in skin capillary ECs which was detectable after 6 months using precise quantitative methods. This was followed by further reduction over the next 2 1/2 years. We posit that, in the absence of αGal-A activity, inhibition of GL-3 production with venglustat allowed other enzymatic or non-enzymatic mechanisms to progressively reduce EC lysosomal GL-3 content, and that long-term venglustat therapy may therefore prevent or reverse progressive tissue injury in Fabry disease.
Figure:
Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat avalglucosidase alfa dosing (5, 10, or 20 mg/kg qow) for 6 months were evaluated in NEO1 (NCT01898364) in ...late-onset Pompe disease patients either treatment-naïve (Naïve) or having received alglucosidase alfa for ≥9 months (Switch). In NEO-EXT (NCT02032524), an ongoing NEO1 extension, long-term safety and pharmacokinetics of repeat avalglucosidase alfa dosing will be monitored over 6 years. Interim safety results after 4.5 years of NEO-EXT are reported here. Mean ages at NEO1 enrollment were: Naïve: 44.8 (SD:20.3, range:20-78) years and Switch: 46.7 (SD:14.1, range:21-68) years. Of the 24 NEO1 participants, 19 entered NEO-EXT (8/10 Naïve 11/14 Switch) 17 are currently participating (7/8 Naïve 10/11 Switch) 2 participants discontinued NEO-EXT (personal reasons). During 2016, all NEO-EXT participants switched to avalglucosidase alfa 20 mg/kg qow. By May 2018, total infusions reached 731 (Naïve) and 1174 (Switch) mean infusions were Naïve: 73 (SD:43, range:9-113) and Switch: 84 (SD:40, range:8-118). Mean avalglucosidase alfa exposure duration reached 1025 (SD:611, range:109-1572) days for Naïve and 1179 (SD:570, range:102-1658) days for Switch participants. Treatment-emergent adverse events (AEs) were generally mild across doses. Most frequently reported treatment-related AEs were nausea, fatigue, and headache (3 participants each) and dizziness, dyspnea, erythema, myalgia, muscle spasms, and rash (2 participants each) and are unchanged since the last safety update (WORLDSymposium™ 2018). One Switch participant discontinued NEO1 for a study drug-related serious AE (respiratory distress/chest discomfort) no deaths/life-threatening serious AEs have occurred. Anti-avalglucosidase IgG/IgM antibodies developed in 9/10 Switch (median titer:1600, range:200-51,200) and 9/14 Naïve (median titer:400, range:50-12,800) participants. No patient developed IgE antibodies or tested positive for enzyme activity inhibition. In NEO-EXT, the avalglucosidase alfa safety profile is consistent with the initial 6 months’ treatment during NEO1, with no additional participants developing anti-avalglucosidase alfa IgG/IgM antibodies or new allergic reactions. Funding: Sanofi Genzyme.
Abstract only Aim: Mipomersen is an antisense oligonucleotide inhibitor of apolipoprotein B-100 synthesis, FDA-approved to treat homozygous familial hypercholesterolemia. The primary objective of ...this study was to determine whether mipomersen significantly reduced atherogenic lipid levels in patients with severe heterozygous familial hypercholesterolemia (HeFH). Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study comprised of two cohorts (NCT01475825). Cohort 1 had severe HeFH (LDL-C ≥200 mg/dL + coronary heart disease, or LDL-C ≥300 mg/dL) and Cohort 2 had milder HeFH (LDL-C ≥160 and <200 mg/dL). For each cohort, patients were randomized 1:1 to 200 mg SC once weekly or 70 mg SC thrice weekly, then 2:1 to receive mipomersen or placebo for 60 weeks. The primary outcome was percent change from baseline in LDL-C in Cohort 1. The % change from baseline in LDL-C at Week 61 for mipomersen treated patients was compared to placebo using a mixed model for repeated measures (MMRM), as well as by ANCOVA on the value closest to 7 days post last treatment (LOCF). Results: Mean baseline LDL-C levels were 265 mg/dL in Cohort 1 (N=200) and 176 mg/dL in Cohort 2 (N=109). In Cohort 1, mipomersen 200 mg weekly reduced LDL-C levels by -29.7% (vs -7.9% placebo, P <.001) in the mixed model, and by -36.3% (vs -7.6% placebo, P <.001) using the LOCF. Analysis of LDL-C over time (Figure) showed a mean absolute reduction of 138 mg/dL in mipomersen patients who completed the blinded treatment period (n=32), achieving a mean level of 147 mg/dL from a mean 285 mg/dL baseline level. Tolerability to treatment and adverse events were similar between dose regimens. Adverse events were consistent with the drug’s known safety and tolerability profile. Conclusions: The primary analysis showed a significant reduction in LDL-C levels in patients with severe HeFH who received mipomersen 200 mg once weekly versus placebo. A highly relevant absolute reduction in LDL-C was achieved over time.
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