scholarly journals Why is AAV FVIII gene therapy not approved by the US Food and Drug Administration yet?

2021 ◽  
Vol 5 (20) ◽  
pp. 4313-4313
Author(s):  
Valder R. Arruda
Keyword(s):  
Late Onset ◽  
Ectopic Expression ◽  
Large Animal ◽  
Large Animal Models ◽  
The Us ◽  
Long Term Follow Up ◽  
Manufacturing Platform ◽  
Underlying Mechanisms

Abstract The prospect of a clinical strategy using an adeno-associated virus (AAV) vector for expression of therapeutic levels of factor VIII (FVIII) has been highly desirable. This was initially anticipated by promising data from clinical studies on AAV5-FVIII in men with severe hemophilia A. However, long-term follow-up showed a unique efficacy concern on the sustainability and durability derived from a continuous decline in the FVIII transgene levels starting 1 year after vector injection through year 5. Additional follow-up of early-phase studies and outcomes of an ongoing phase 3 study will likely provide evidence on the feasibility of this approach. Here, the potential underlying mechanisms of the FVIII declining levels, together with the revision of several unique early and late onset findings, are discussed. The lack of long-term preclinical studies in large animal models prevents the firm conclusion that FVIII levels decline was unexpected. It is possible that the combination of vector manufacturing platform and dose, accompanied with ectopic expression of supraphysiologic levels of FVIII at short-term follow-up, may all contribute to the sustainability and durability of the transgene levels. Notably, vector readministration to further improve the FVIII levels is not feasible at this time. Thus, the need of a one-and-done AAV strategy to achieve sustain FVIII levels of expression is sine qua non to impact favorably the disease phenotype.

Late onset hypothyroidism after subtotal thyroidectomy for hyperthyroidism: Implications for long term follow-up

1983 ◽  
Vol 70 (12) ◽  
pp. 740-743 ◽  
Author(s):  
A. J. Hedley ◽  
P. D. Bewsher ◽  
S. J. Jones ◽  
A. S. M. Khir ◽  
P. Clements ◽  
...  
Keyword(s):  
Late Onset ◽  
Subtotal Thyroidectomy ◽  
Long Term Follow Up

Outcomes of 33 patients from the wars in Iraq and Afghanistan undergoing bilateral or bicompartmental craniectomy

2011 ◽  
Vol 115 (1) ◽  
pp. 124-129 ◽  
Author(s):  
Robert D. Ecker ◽  
Lisa P. Mulligan ◽  
Michael Dirks ◽  
Randy S. Bell ◽  
Meryl A. Severson ◽  
...  
Keyword(s):  
Medical Center ◽  
Systemic Infection ◽  
Categorical Variables ◽  
Cerebrovascular Injury ◽  
The Us ◽  
Long Term Follow Up ◽  
Initial Injury ◽  
Gcs Score

Object There are no published long-term data for patients with penetrating head injury treated with bilateral supratentorial craniectomy, or supra- and infratentorial craniectomy. The authors report their experience with 33 patients treated with bilateral or bicompartmental craniectomy from the ongoing conflicts in Iraq and Afghanistan. Methods An exploratory analysis of Glasgow Outcome Scale (GOS) scores at 6 months in 33 patients was performed. Follow-up lasting a median of more than 2 years was performed in 30 (91%) of these patients. The association of GOS score with categorical variables was explored using the Wilcoxon rank-sum test or Kruskal-Wallis analysis of variance. The Spearman correlation coefficient was used for ordinal/continuous data. To provide a clinically meaningful format to present GOS scores with categorical variables, patients with GOS scores of 1–3 were categorized as having a poor outcome and those with scores of 4 and 5 as having a good outcome. This analysis does not include the patients who died in theater or in Germany who underwent bilateral decompressive craniectomy because those figures have not been released due to security concerns. Results All patients were men with a median age of 24 years (range 19–46 years) and a median initial Glasgow Coma Scale (GCS) score of 5 (range 3–14). At 6 months, 9 characteristics were statistically significant: focus of the initial injury, systemic infection, initial GCS score, initial GCS score excluding patients with a GCS score of 3, GCS score on arrival to the US, GCS score on dismissal from the medical center, Injury Severity Score, and patients with cerebrovascular injury. Six factors were significant at long-term follow-up: focus of initial injury, systemic infection, initial GCS score excluding patients with a GCS score of 3, GCS score on arrival to the US, and GCS score on dismissal from the medical center. At long-term follow-up, 7 (23%) of 30 patients had died, 5 (17%) of 30 had a GOS score of 2 or 3, and 18 (60%) of 30 had a GOS score of 4 or 5. Conclusions In this selected group of patients who underwent bilateral or bicompartmental craniectomy, 60% are independent at long-term follow-up. Patients with bifrontal injury fared best. Systemic infection and cerebrovascular injury corresponded with a worse outcome.

scholarly journals Tissue is the issue: when a second biopsy reveals the true diagnosis

2019 ◽  
Author(s):  
Anne-Marie Bogaert ◽  
Anne Hoorens ◽  
Marleen Praet ◽  
Jo Van Dorpe ◽  
Bruce Poppe ◽  
...  
Keyword(s):  
Kidney Biopsy ◽  
Late Onset ◽  
Immunosuppressive Treatment ◽  
Treatment Strategies ◽  
Nephrotic Proteinuria ◽  
Long Term Follow Up ◽  
Generation Sequencing ◽  
Genetic Form

Abstract We describe the case of a woman with minimal glomerular changes on initial kidney biopsy. On long-term follow-up, the patient developed nephrotic proteinuria and a second kidney biopsy was performed, which revealed focal segmental glomerulosclerosis (FSGS). Findings from electron microscopy (EM) examination suggested a genetic form of FSGS. Next-generation sequencing showed heterozygosity for a mutation in COL4A3. Collagen IV nephropathies can be linked to late-onset FSGS. By establishing a genetic cause of FSGS, immunosuppressive treatment can be avoided. This case emphasizes the importance of re-biopsy in cases of a non-explained rise in proteinuria. EM can be helpful in differentiating between primary and secondary FSGS and informing treatment strategies. In cases of adult-onset FSGS that cannot be categorized by clinical–pathological assessment, genetic testing should be considered.

scholarly journals Algorithm approach for revision surgery following late-onset bleb complications after trabeculectomy: long-term follow-up

2017 ◽  
Vol 80 (1) ◽  
Author(s):  
Claudio I. Perez ◽  
María J. Oportus ◽  
Felipe Mellado ◽  
Felipe Valenzuela ◽  
Cristián Cartes ◽  
...  
Keyword(s):  
Revision Surgery ◽  
Late Onset ◽  
Long Term Follow Up

P4684Differential right ventricular adaptation patterns to chronic pressure overload

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
I Garcia Lunar ◽  
D Pereda ◽  
M Ascaso ◽  
P Jorda ◽  
C Galan ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Pressure Overload ◽  
Heart Catheterization ◽  
Sham Operation ◽  
Large Animal ◽  
Continuous Variables ◽  
Pulmonary Shunt ◽  
Large Animal Models ◽  
Underlying Mechanisms

Abstract Background Right ventricular (RV) dysfunction is the most important prognostic factor in chronic pulmonary hypertension (PH), but its underlying mechanisms are unknown. Clinical observation and prior experimental work suggest that RV pressure overload is not the only cause since the degree of RV adaptation varies with similar RV end-systolic pressures. Purpose Our aim was to characterize serial RV adaptation by cardiac magnetic resonance (CMR) in 3 different experimental large-animal models of increased afterload: a model of chronic postcapillary PH, a model of PH secondary to systemic-to-pulmonary shunt and a model of mechanical RV pressure overload (generated by pulmonary artery [PA] banding). Methods Four-week old piglets underwent pulmonary vein banding surgery to generate the chronic postcapillary PH model (n=20), aorto-pulmonary shunt (n=6), PA banding (n=7) or sham operation (n=7). They were followed up monthly with CMR and right heart catheterization (RHC). All procedures followed the “Principles of laboratory animal care”. Comparison of continuous variables among groups was performed with Mann-Whitney U test. Results Animals with either postcapillary PH or PH secondary to aorto-pulmonary shunt presented significant RV dilatation, hypertrophy and dysfunction that was maintained during follow-up (median RV end-systolic volume [RVESV]=32.6 ml/m2 for postcapillary PH and 32.6 ml/m2 for shunt vs. 16.1 ml/m2 in sham controls; median RV ejection fraction [RVEF]=61.5% for postcapillary PH and 60.5% for shunt vs. 69.6% in sham controls at the end of follow-up). Animals with PA banding also presented with significant RV dilatation and hypertrophy at the first month follow-up, but unlike all other groups, they developed reverse RV remodeling from the second month onwards and maintained normal RV volumes and RVEF values until the end of follow-up despite having severe RV hypertrophy (RV mass 22.6 g/m2 in PA banding vs. 16.1 g/m2 in controls at the 4th month follow-up; Figure). CMR parameters (median values). Conclusion In PH there is a maladaptive RV hypertrophy that is not present in a model of progressive RV pressure overload without alterations of the pulmonary circulation. Increased RV pressure overload alone does not fully explain PH-associated RV dysfunction. Further research is needed to clarify the underlying mechanisms of adaptive and maladaptive hypertrophy in PH. Acknowledgement/Funding The CNIC is supported by the Ministerio de Ciencia, Innovaciόn y Universidades and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence

Long-term follow-up of patients (pts) with relapsed or refractory (r/r) follicular lymphoma (FL) treated with copanlisib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7553-7553
Author(s):  
Sirpa Leppä ◽  
Armando Santoro ◽  
Judit Demeter ◽  
George Follows ◽  
Georg Lenz ◽  
...  
Keyword(s):  
Adverse Events ◽  
Median Duration ◽  
Kinase Inhibitor ◽  
Late Onset ◽  
Progression Free Survival ◽  
Duration Of Treatment ◽  
Primary Analysis ◽  
Long Term Follow Up

7553 Background: The pan-class I phosphatidylinositol 3-kinase inhibitor copanlisib was approved by the FDA in September 2017 for treatment of relapsed FL based on results from the CHRONOS-1 study in pts with indolent non-Hodgkin lymphoma. We report efficacy and safety results of a 2-year (yr) follow-up of FL pts. Methods: Pts with indolent FL (grade [G] 1-3a) r/r to ≥2 prior lines of treatment received copanlisib (60 mg i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. The primary endpoint was objective tumor response rate (ORR) per independent radiologic review (Cheson et al. 2007). Adverse events were reported using MedDRA (v20.1). Data cut-off: February 20, 2018. Results: 104 FL pts were enrolled. Median age was 62 yr (39% >65 yr), the median number of prior lines of anti-cancer therapy was 3 (range 2-8), and 27 pts (26%) were classified as having G3a disease. The ORR was 59%, with complete responses (CR) in 20% ( n=21); 14 pts had a CR at the primary analysis in June 2016. The median duration of response (mDoR) was 12.2 months (mo) (range 0.03-43 mo). Stable disease (SD) was observed in 33% of pts; median duration of SD was 7.8 mo (range 1.3-23 mo). Median progression-free survival (mPFS) was 11.2 mo (range 0.03-44 mo) with 33% alive and progression-free at 2 yrs. Median overall survival (mOS) was 3.2 yr (range 0.06-4.2 yr) with 67% alive at 2 yrs. Median duration of treatment was 26 weeks (wk) (range 1-192 wk); median duration of safety follow-up was 29 wk. In the G3a subset, the ORR was 67% (26% CR), mDoR was 10.9 mo, mPFS was 12.5 mo, and mOS was 2.5 yr. The most common treatment-emergent adverse events occurring in >25% of pts included (all grade/G3+): diarrhea (37%/9%), neutropenia (26%/23%), and pyrexia (28%/5%). Hyperglycemia (49%/40%) and hypertension (29%/23%) were transient. Incidences of pneumonitis (6.7%/1.9%) and colitis (1.0% G4) were low. Conclusions: Long-term follow-up of r/r FL pts treated with copanlisib revealed robust and durable responses with CRs exceeding 20%, including in pts with higher grade disease. The safety profile continues to be both manageable and favorable, with no evidence of late-onset severe toxicities. Clinical trial information: NCT01660451.

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