Clinical Trial Insight: Cell and Gene therapy – December 2015

Clinical Trial Insight: Cell and Gene therapy – December 2015

Published: 9 December 2015

Commercial Insights

Dr Alexey Bersenev, Yale University, USA, providing an expert overview of the most important clinical trials, cases and cohort studies conducted in academic and industry with particular focus on later-stage efficacy data. DOI: 10.18609/cgti.2015.027 Citation: Cell Gene Therapy Insights 2015; 1(2), 151-155. Positive Phase 3 data from Spark Therapeutics In October, US-based gene therapy company […]

Dr Alexey Bersenev, Yale University, USA, providing an expert overview of the most important clinical trials, cases and cohort studies conducted in academic and industry with particular focus on later-stage efficacy data.
DOI: 10.18609/cgti.2015.027 Citation: Cell Gene Therapy Insights 2015; 1(2), 151-155.

Positive Phase 3 data from Spark Therapeutics

In October, US-based gene therapy company Spark Therapeutics reported positive data from their Phase 3 pivotal trial in inherited retinal dystrophies [1]. 31 subjects were randomized and assigned to intervention versus control at a ratio of 21:10. The primary endpoint of the study – vision improvement – was met, with a large difference compared with control. However, one of secondary endpoints, visual acuity, was not met. Spark’s results are remarkable, because this is the first success in a Phase 3 gene therapy trial under US Food and Drug Administration (FDA) jurisdiction. Based on the results of this trial, Spark is planning to file a Biologic License Application with the FDA to marketing their gene therapy in USA.

Data from CD19-CAR T trial in CLL

A team from the University of Pennsylvania, USA has reported results of their clinical trial assessing autologous gene-modified CD19-CAR T-cells in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) [2]. The overall response rate was observed in 57% (8 of 14) of patients and complete remission was achieved in four patients. One of the most interesting observations in this study was a correlation between CAR T-cell expansion in vivo and long-term persistence and complete responses without relapses. All responders developed therapy-specific complications, namely B-cell aplasia and cytokine release syndrome. The first patient from the study has recently celebrated their 5-year remission mark. The results of this study demonstrated that the response rate to CD19-CAR T-cell therapy in CLL is not as impressive as in acute lymphoblastic leukemia (where the response rate is up to 90%). The difference in response rates between chronic and acute diseases is not known at this point.

Gene edited T-cell therapy in ALL cells

French company Cellectics and London’s Great Ormond Street Hospital recently made a big splash with news concerning the first pediatric case of acute lymphoblastic leukemia to go into remission following infusion of gene-edited allogeneic T-cells [3]. Overnight Layla became a poster child for the success of genome editing in somatic cells. Some details of this news release are highlighted in an abstract from the American Society of Hematology (ASH) 2015 meeting and will be reported on during the event [4]. Allogeneic T-cells were edited with TALENs to eliminate the risk of graft versus host disease (GVHD). After relapse following hematopoietic stem cell transplant, Layla received 4.5 x 106/kg of UCART19 T-cells. No cytokine release syndrome was observed. Persistence of donor T-cells was detected on day 14 in peripheral blood and on day 28 in bone marrow.

Phase 1 data from T-reg trial for Type 1 Diabetes

Results of a very interesting Phase 1 trial [5], assessing regulatory T-cells (T-regs) in type 1 diabetes, were published in Science Translational Medicine [6]. This study was a collaboration between the University of California San Francisco, USA, Yale University, USA and Caladrius Biosciences, USA. Infusion of ex vivo-expanded sorted polyclonal T-regs was safe and feasible. I would like to highlight the complexity of cell sorting (FACS) used in the study, to purify Foxp3+ T-regs. Furthermore, heterogeneity of the patient population contributed to variability in T-reg expansion from 29.8-fold to 1366.8-fold. Even though the study was not designed to assess efficacy, there were no significant clinical impacts observed. Interestingly, the authors were able to detect expanded T-regs in the circulation 1 year after therapy.

First stem cell therapy approved under Japan’s new regulatory system

On September 18, 2015 the first stem cell drug – TemCell, was approved in Japan under new regenerative medicine law. JCR Pharmaceuticals licensed the mesenchymal stem cell-based product from Australian company Mesoblast. However, the clinical trial assessing this product (known previously as Prochymal), started a few years ago as part of licensing agreement with original developer – Osiris Therapeutics. Very recently, the results of Phase 2/3 clinical trial, assessing TemCell in acute steroid-resistant GVHD were published [7]. Durable complete response at 24 weeks (the primary endpoint of the study) was achieved in 48% of patients (12 out of 25). Importantly, the trial was not placebo controlled. The decision on marketing approval of TemCell was made based on results of this study.

REGENERATE-AMI trial draws to a close

One of the biggest and well-designed cardiac cell therapy – REGENERATE-AMI – conducted since 2008 in five centers in the UK, Switzerland and Denmark is concluded [8]. It was Phase 2 randomized double-blind, placebo controlled trial, assessing efficacy of autologous bone marrow mononuclear cells in 100 patients with acute myocardial infarction. Results of the study were published in European Heart Journal [9]. The trial is failed to achieve primary endpoint – improvement of heart function (measured as LVEF) – there was no difference between “cells” and “placebo” groups. One of secondary endpoints, measured as myocardial salvage index was improved in “cells” group, but it was only assessed on day 3 after therapy.

Cell-assisted lipotransfer study

A group of researchers and physicians from Spain published results of a study assessing cell-assisted lipotransfer (CAL) in breast cosmetic surgery [10]. Stromal vascular fraction (SVF), was derived from adipose tissue, using the GID SVF-1 device. 74 CAL patients were divided for 2 groups allocated either high- or low-dose SVF. The group with higher SVF dose demonstrated better long-term breast volume retention. Unfortunately, the study did not include the “conventional lipotransfer” control group.

Cupistem receives conditional approval

Adipose-tissue-derived allogeneic stem cell product Cupistem® (manufactured by Anterogen) was conditionally approved in South Korea in 2012 for treatment of perianal fistula, a complication of Crohn’s disease. Recently, Anterogen reported results of a multicenter, open-label dose-escalation trial assessing the efficacy of Cupistem in Crohn’s fistulas [11]. The study reports on only six patients (three in each dose group). Only one patient in the higher dose group achieved complete fistula closure at 8 weeks (primary end point). Two patients in the lower dose group achieved closure at 4 and 6 months, and two patients in higher dose group achieved partial closure. The drawback of the study is the low number of patients to date.

Promising results from MSCs in epidermolysis bullosa

A group of researchers from Cairo University published results of randomized controlled double blinded trial, assessing allogeneic bone marrow-derived mesenchymal stromal cells (MSC) in patients with recessive epidermolysis bullosa [12]. 14 patients were randomized in group 1, which received MSC + cyclosporine and group 2, which received MSC only. Cells were infused intravenously. Therapy was equally effective between groups. The efficacy was measured by formation of new skin blisters and healing of skin defects. There were no side effects reported. The results of this study are very promising and require further investigation.