Limited real-world data from routine clinical care are available on the safety and effectiveness of treatment with taliglucerase alfa in patients with Gaucher disease (GD).
Taliglucerase Alfa ...Surveillance (TALIAS), a multinational prospective Drug Registry of patients with GD, was established to evaluate the long-term safety (primary objective) and effectiveness (secondary objective) of taliglucerase alfa. We present an interim analysis of the data from the Drug Registry collected over the 5-year period from September 2013 to January 2019.
A total of 106 patients with GD (15.1% children aged < 18 years; 53.8% females) treated with taliglucerase alfa have been enrolled in the Drug Registry, as of January 7, 2019. The median duration of follow-up was 795 days with quartiles (Q1, Q3) of 567 and 994 days. Fifty-three patients (50.0%) were from Israel, 28 (26.4%) were from the United States, and 25 (23.6%) were from Albania. At the time of enrollment, most patients (87.7%) had received prior enzyme replacement therapy (ERT). Thirty-nine of the 106 patients had treatment-emergent adverse events (AEs). Twelve of the 106 patients experienced serious AEs; two patients experienced four treatment-related serious AEs. Four patients died, although none of the deaths was considered to be related to taliglucerase alfa treatment by the treating physicians. Nine patients discontinued from the study, including the four who died. At baseline, patients with prior ERT had a higher mean hemoglobin concentration and platelet counts than treatment-naïve patients, likely reflecting the therapeutic effects of prior treatments. During follow-up, the hemoglobin concentration and platelet counts increased in the treatment-naïve patients and remained relatively constant or increased slightly in patients with prior ERT. Spleen and liver volumes decreased in treatment-naïve patients.
The interim data showed no new or emergent safety signals. The overall interim data are consistent with the clinical program experience and known safety and effectiveness profile of taliglucerase alfa.
Background
The humanistic burden of transthyretin amyloid cardiomyopathy (ATTR-CM) is poorly defined.
Methods
An international study to comprehensively characterize the burden of ATTR-CM on patients ...naïve to disease-modifying therapy and their unpaid primary caregivers using study-specific and established surveys (patients: Kansas City Cardiomyopathy Questionnaire Overall Summary KCCQ-OS, 12-Item Short Form Health Survey SF-12, Hospital Anxiety and Depression Scale HADS, Patient-Reported Outcomes Measurement Information System PROMIS Fatigue and Dyspnea; caregivers: SF-12, HADS, PROMIS Fatigue, Zarit Burden Interview ZBI). All data were summarized descriptively.
Results
208 patient and caregiver pairs were included. 86% of patients were male, median age was 81 years, and 91% (141/155 with genetic testing) had wild-type ATTR-CM. Patient responses characterized the mental and physical burden of ATTR-CM, which was numerically higher among those who were New York Heart Association (NYHA) class III (
n
= 43) vs. class I/II (
n
= 156). NYHA class III patients had particularly low KCCQ-OS (36) and SF-12 physical component (27) scores, and 67% had a HADS depression score ≥8. Caregivers (median age 68 years; 85% female; 59% spouse of the patient; median duration of caregiving 1.5 years) reported that NYHA III patients more frequently required help with a range of physical activities than NYHA class I/II patients. 51% of caregivers to NYHA class III patients reported at least a mild-to-moderate burden in the ZBI. A plain language summary of this paper can be found as a supplemental material.
Conclusions
Untreated ATTR-CM is a burden to both patients and their caregivers.
Tofacitinib is a novel, oral JAK inhibitor that is being investigated as a targeted immunomodulator. Tofacitinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by ...CYP2C19. Two Phase 1, randomized, open‐label, single sequence studies in 24 healthy subjects (12 per study) characterized the effects of fluconazole (moderate CYP3A4/potent CYP2C19 inhibitor) and ketoconazole (potent CYP3A4 inhibitor) on tofacitinib pharmacokinetics. In the fluconazole study, subjects received a single tofacitinib 30 mg dose. After 72 hours, subjects received fluconazole 400 mg, followed by 200 mg once daily (QD; days 2–7) plus tofacitinib 30 mg on day 5. In the ketoconazole study, a single tofacitinib 10 mg dose was administered. After 24 hours, subjects received ketoconazole (400 mg QD; days 1–3) plus tofacitinib 10 mg on day 3. Treatment comparisons were made using mixed‐effect models. Tofacitinib area under the curve and maximal plasma concentration increased by 79% and 27%, respectively, with fluconazole co‐administration and by 103% and 16%, respectively, with ketoconazole co‐administration. Tofacitinib half‐life increased by approximately 1 hour during co‐administration with fluconazole or ketoconazole. Co‐administration of moderate to potent CYP3A4 inhibitors is likely to increase the systemic exposure of tofacitinib and thus may warrant dosage adjustments or restrictions.
Abstract Aims Patients with transthyretin amyloid cardiomyopathy (ATTR‐CM) present with diverse left ventricular ejection fraction (LVEF). This study assessed tafamidis efficacy by baseline LVEF in ...the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) and its long‐term extension (LTE) study. Methods and results Patients were randomized to 30 months of tafamidis or placebo treatment in ATTR‐ACT. On completion, patients could join an LTE study to receive tafamidis. All‐cause mortality (death, heart transplant, or cardiac mechanical assist device implantation) from baseline to the end of follow‐up was assessed in patients continuously treated with tafamidis (80 mg meglumine or 61 mg free acid) or delayed tafamidis treatment (placebo in ATTR‐ACT; tafamidis in the LTE study) according to baseline LVEF (<50% or ≥50%). Supportive outcomes were evaluated over a shorter follow‐up. Patients with baseline LVEF <50% ( n = 177: 88 tafamidis‐ and 89 placebo‐treated) had signs of more severe heart failure, a higher proportion were Black, and had variant ATTR‐CM than those with LVEF ≥50% ( n = 171: 85 tafamidis‐ and 86 placebo‐treated). At the end of follow‐up (median 60–64 months), all‐cause mortality was numerically higher in patients with baseline LVEF <50%; however, consistent with supportive findings, continuous tafamidis treatment was associated with a 47% reduction in mortality risk compared with delayed tafamidis treatment in patients with LVEF <50% and ≥50% (hazard ratio 0.53 95% confidence interval 0.367–0.758; p < 0.001, and 0.53 0.344–0.818; p < 0.01, respectively). Conclusions Early initiation of tafamidis is associated with reduced mortality in patients with ATTR‐CM, irrespective of initial LVEF value. Clinical Trial Registration: ClinicalTrials.gov NCT01994889, NCT02791230.
To determine if a validated Level A in-vitro in-vivo correlation (IVIVC) could be achieved with the extrudable core system (ECS) osmotic tablet platform. Tofacitinib is an oral JAK inhibitor for the ...treatment of rheumatoid arthritis.
Fast-, medium-, and slow-release modified-release formulations of 11 mg tofacitinib ECS tablets, and one formulation of 22 mg tofacitinib ECS tablet, were manufactured. In vitro dissolution of the tofacitinib ECS tablets was performed using USP Apparatus 2 (paddles) and in vivo pharmacokinetic (PK) data were obtained from a Phase 1 study in healthy volunteers. A 5 mg immediate-release formulation tablet was included to support deconvolution of the tofacitinib ECS PK tablet data to obtain the in vivo absorption profiles. A linear, piecewise correlation and a simple linear correlation were used to build and validate two IVIVC models.
The prediction errors (PEs) for the linear, piecewise correlation met the Food and Drug Administration's criteria for establishing a Level A IVIVC, with a maximum absolute individual internal PE of 4.6%, a maximum absolute average internal PE of 3.9%, and a maximum absolute external PE of 8.4% obtained.
This study demonstrates that the tofacitinib ECS osmotic tablet platform can achieve a Level A IVIVC, similar to other osmotic delivery systems.
Display omitted
Somatrogon is a long-acting recombinant human growth hormone used to treat patients with paediatric growth hormone deficiency (pGHD). This global phase 3 study compared the efficacy and safety of ...once-weekly somatrogon with once-daily somatropin in children with GHD.
Prepubertal patients were randomized 1:1 to once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. The primary endpoint was height velocity (HV) at month 12; secondary endpoints included HV at month 6 and change in height standard deviation score (SDS) at months 6 and 12 and insulin-like growth factor 1 (IGF-1) SDS.
This
subgroup analysis focused specifically on Asian children (somatrogon: n=24 and mean age=7.76 years; somatropin: n=21 and mean age=8.10 years) across eight countries. Mean HV at month 12 was 10.95 cm/year (somatrogon) and 9.58 cm/year (somatropin); the treatment difference of 1.38 cm/year favoured somatrogon. The lower bound of the two-sided 95 % CI of the treatment difference (somatrogon-somatropin) was -0.20, similar to the overall study population (-0.24). Compared with the somatropin group, the somatrogon group had numerically higher HV at month 6 (8.31 vs. 11.23 cm/year); a similar trend was observed for height SDS and IGF-1 SDS at months 6 and 12. Safety and tolerability were similar between treatment groups; adverse events occurred in 83 % of somatrogon-treated children and 76 % of somatropin-treated children.
This subgroup analysis demonstrated that somatrogon efficacy and safety in Asian children were consistent with the overall study population, where once-weekly somatrogon was non-inferior to once-daily somatropin. Clinicaltrials.gov: NCT02968004.
Aims
The transthyretin (TTR) stabilizer, tafamidis, has demonstrated efficacy and safety in the treatment of TTR familial amyloid polyneuropathy (20 mg day−1). Tafamidis use in TTR cardiomyopathy led ...to the study of the potential effect of tafamidis on the QTc interval in healthy subjects.
Methods
This randomized, three treatment, three period, six sequence crossover study with placebo, a positive control (moxifloxacin 400 mg) and tafamidis (400 mg, to achieve a supra‐therapeutic Cmax of ~20 µg ml−1) was conducted in healthy volunteers at three clinical research units. Oral dosing in each of the three treatment periods was separated by a washout period of ≥ 14 days. Serial triplicate 12‐lead electrocardiograms were performed. QTc intervals were derived using the Fridericia correction method. Safety and tolerability were assessed by physical examination, vital signs measurement, laboratory analyses and monitoring of adverse events (AEs).
Results
A total of 42 subjects completed the study. The upper limit of the two‐sided 90% confidence intervals (CIs) for the difference in baseline‐adjusted QTcF between tafamidis 400 mg and placebo was <10 ms (non‐inferiority criterion) for all time points. The lower limit of the two‐sided 90% CI between moxifloxacin 400 mg and placebo exceeded 5 ms at the pre‐specified moxifloxacin tmax of 3 h post‐dose, confirming assay sensitivity. Cmax and AUC(0,24 h) for tafamidis were 20.36 µg ml−1 and 305.4 µg ml−1 h, respectively. There were no serious/severe AEs or treatment discontinuations due to AEs.
Conclusions
This thorough QTc study suggests that a supra‐therapeutic single 400 mg oral dose of tafamidis does not prolong the QTc interval and is well‐tolerated in healthy volunteers.
Abstract
Background
Somatrogon is a long-acting recombinant human growth hormone (hGH) currently in development as a once-weekly injectable treatment for children with growth hormone deficiency ...(GHD). In a phase 2 (NCT01592500) and a phase 3 (NCT02968004) study, patients received either once-weekly somatrogon or once-daily Genotropin.
Aims
Compare the phase 2 and 3 study results with growth data from published literature and a database of children treated with once-daily Genotropin.
Methods
In the 12-month main portion of the phase 2 study (004), patients were randomized to 1 of 3 once-weekly somatrogon doses (0.25, 0.48, and 0.66 mg/kg/week) or once-daily Genotropin (0.24 mg/kg/week). After the main portion of 004, patients continued into the open-label extension (OLE), consisting of an additional 12 months at the original somatrogon dose (Genotropin recipients were randomized to 1 of the 3 somatrogon dose regimens), after which all patients received somatrogon at 0.66 mg/kg/week. In the 12-month main portion of the phase 3 study (006), patients were randomized to once-weekly somatrogon (0.66 mg/kg/week) or once-daily Genotropin (0.24 mg/kg/week). After the main portion of 006, all patients received somatrogon (0.66 mg/kg/week) in an OLE. Four year growth data from 004 and 006 were pooled and analyzed, then compared with growth data from matched subsets of hGH-treated patients as reported by Ranke and Lindberg1 (Genotropin dose: 0.22-0.31 mg/kg/week) and Bakker et al,2 (hGH dose: most patients received 0.3 mg/kg/week) and with data from a matched cohort from the Pfizer International Growth Study Database (KIGS), in which patients received once-daily Genotropin (0.20-0.28 mg/kg/week).
Results
The combined mean height velocity (HV) at the end of the 12-month main portions of study 004 and 006 was 10.37 cm/year for somatrogon-treated patients. The Year 1 mean HV reported by Ranke and Lindberg for children with a chronological average-centered age of 7.5 years was 9.4 cm/year and 8.3 cm/year for children with severe and moderate GHD, respectively. The Year 1 mean HV reported by Bakker et al for children with idiopathic GHD aged 7.5 years at the beginning of hGH therapy was ∼10 cm/year (for males and females). The mean annual HVs during the OLE period were 9.37, 8.97, and 9.03 cm/year at OLE Year 1, 2 and 3 in somatrogon-treated patients, which were numerically greater than HVs of 7.09, 6.35, and 6.08 cm/year at the corresponding annual visit in the matched KIGS cohort (Genotropin dose: 0.20–0.28 mg/kg/week).
Conclusions
Comparisons with published literature and the KIGS database indicate that children treated with once-weekly somatrogon (0.66 mg/kg/week) showed good growth, compared with children treated with once-daily hGH, strengthening the expectation that somatrogon-treated children are likely to achieve a satisfactory final adult height.
References
1.Ranke and Lindberg. JCEM. 2010;95(3): 1229-1237. 2.Bakker, Frane, et al. JCEM. 2008;93(2): 352-357.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 12:37 p.m. - 12:42 p.m.
Aims
The transthyretin (TTR) stabilizer, tafamidis, has demonstrated efficacy and safety in the treatment of TTR familial amyloid polyneuropathy (20 mg day
−1
). Tafamidis use in TTR cardiomyopathy ...led to the study of the potential effect of tafamidis on the QT
c
interval in healthy subjects.
Methods
This randomized, three treatment, three period, six sequence crossover study with placebo, a positive control (moxifloxacin 400 mg) and tafamidis (400 mg, to achieve a supra‐therapeutic
C
max
of ~20 µg ml
−1
) was conducted in healthy volunteers at three clinical research units. Oral dosing in each of the three treatment periods was separated by a washout period of ≥ 14 days. Serial triplicate 12‐lead electrocardiograms were performed. QT
c
intervals were derived using the Fridericia correction method. Safety and tolerability were assessed by physical examination, vital signs measurement, laboratory analyses and monitoring of adverse events (AEs).
Results
A total of 42 subjects completed the study. The upper limit of the two‐sided 90% confidence intervals (CIs) for the difference in baseline‐adjusted QT
c
F between tafamidis 400 mg and placebo was <10 ms (non‐inferiority criterion) for all time points. The lower limit of the two‐sided 90% CI between moxifloxacin 400 mg and placebo exceeded 5 ms at the pre‐specified moxifloxacin
t
max
of 3 h post‐dose, confirming assay sensitivity.
C
max
and AUC(0,24 h) for tafamidis were 20.36 µg ml
−1
and 305.4 µg ml
−1
h, respectively. There were no serious/severe AEs or treatment discontinuations due to AEs.
Conclusions
This thorough QT
c
study suggests that a supra‐therapeutic single 400 mg oral dose of tafamidis does not prolong the QT
c
interval and is well‐tolerated in healthy volunteers.
Abstract
Disclosure: Z. Zadik: None. N. Zelinska: Consulting Fee; Self; Novo Nordisk, Berlin-Chemie, Medtronic, Sanofi-Aventis. Research Investigator; Self; MacroGenics, Novo Nordisk, Pfizer, Inc., ...Merck, OPKO Health, Ferring Pharmaceuticals, Teva Pharmaceutical Industries Ltd., Parexel, Genexine. Speaker; Self; Medtronic, Berlin-Chemie, ACINO, Novo Nordisk, Pfizer, Inc., Sanofi-Aventis, Johnson &Johnson, Wörwag Pharma. V. Iotova: Grant Recipient; Self; Pfizer, Inc. Speaker; Self; Novo Nordisk, Pfizer, Inc., Swixx, Sandoz, Berlin-Chemie. Y. Skorodok: None. O.A. Malievskiy: None. N. Mauras: Consulting Fee; Self; Agios. Grant Recipient; Self; Novo Nordisk, Abbvie. Research Investigator; Self; OPKO Health, Abbvie, Beta Bionics. S.R. Valluri: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. A. Pastrak: Employee; Self; OPKO Health. Stock Owner; Self; OPKO Health. R.G. Rosenfeld: Advisory Board Member; Self; Lumos, DNARx, BioMarin. Consulting Fee; Self; OPKO Health. C.T. Taylor: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. M. Nijher: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C. Roland: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. R. Wang: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. M.P. Wajnrajch: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J.F. Cara: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc.
Introduction: Somatrogon, a long-acting recombinant human growth hormone, is approved in multiple countries as a once-weekly treatment for pediatric growth hormone deficiency (pGHD). This abstract describes results from up to 8 y of study (main study + open label extension OLE) evaluating the efficacy and safety of somatrogon in pGHD. Methods: This randomized, open-label, dose-finding Phase 2 study comprised 5 treatment periods. Subjects were randomized 1:1:1:1 to once-weekly somatrogon (titrated up to 0.25, 0.48, or 0.66 mg/kg/wk) or once-daily Genotropin (0.24 mg/kg/wk) for 12 mo of the main study (periods I and II), after which they were eligible to enroll in the OLE (periods III-V). In period III, somatrogon recipients continued at their previous dose; Genotropin recipients were re-randomized to 1 of the 3 somatrogon doses. In period IV (OLE Year (Y)2–4), all subjects switched to somatrogon 0.66mg/kg/wk; in period V (OLE Y5 onward), all subjects switched from single-use somatrogon vials to prefilled pen devices (somatrogon 0.66 mg/kg/wk). Results: Of 53 subjects who completed the main study, 48 entered the OLE. At OLE entry, 66.7% were male, all but 1 were pubertal Tanner stage 1, and mean (SD) age was 7.7 (2.1) y. At OLE Y6 end, there were 30 subjects with a mean±SD height velocity (HV) of 6.47±2.07 cm/y and a mean±SD height SD score (HT SDS) of 0.43±0.94. At OLE Y7 end, 26 subjects had a mean±SD HV of 5.31±1.68 cm/y and a mean HT SDS of 0.44±0.96. Four subjects achieved final height (defined as HV <1 cm/y). Their HVs in the last 6-mo interval and last assessed heights were: subject 1: 0.54 cm/y, 174.5 cm; subject 2: 0.7 cm/y, 173.2 cm; subject 3: 0.56 cm/y, 179.5 cm; and subject 4: 0.19 cm/y, 168.7 cm. Somatrogon efficacy was not affected by positive test results for antidrug antibodies (ADA). HV and cumulative ΔHT SDS (cΔHT SDS) were similar between subjects who tested ADA+ vs ADA-: at OLE Y6 end, 15 who tested ADA+ had HV 6.47±1.69 cm/y and cΔHT SDS 3.09±1.04; and 15 who tested ADA- had HV 6.48±2.46 cm/y and cΔHT SDS 3.62±1.40. At OLE Y7 end, 14 subjects who tested ADA+ had HV 5.22±1.52 cm/y and cΔHT SDS 3.06±0.98; 12 who tested ADA- had HV 5.42±1.91 cm/y and cΔHT SDS 3.75±1.39. In OLE Y7, TEAEs were reported in 35.5% subjects, which was lower than the main study (69.0%) and OLE Y1–6 (range: 41.9–57.5%). No serious TEAEs or TEAEs leading to study drug withdrawal occurred in OLE Y7. Study drug–related TEAEs occurred in 2 subjects: keeled chest acquired and scoliosis in 1 and arthralgia in 1. No deaths were reported throughout the OLE.
Conclusion: Following up to 8 y of somatrogon treatment, including 7 y of the OLE, subjects demonstrated continued growth, 4 achieved final height, and somatrogon maintained a favorable safety profile. Testing ADA+ did not appear to affect subject growth. Clinicaltrials.gov: NCT01592500. Acknowledgements: The authors wish to thank all the investigators involved in this study.
Presentation: Saturday, June 17, 2023
PDF
