Clinical Trial Insight: Cell and Gene therapy
Cell Gene Therapy Insights 2015; 1(1), 35-38.
10.18609/cgti.2015.006
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.
Japanese iPSC Trial Suspension
The most important news of this summer was a suspension of the first induced pluripotent stem cell (IPSC)-based clinical trial in Japan [1,2]. The trial, led by Dr Masayo Takahashi (RIKEN Institute), is assessing the safety of autologous iPSC-derived retinal pigment epithelium in age-related macular degeneration. The first patient was treated in September 2014 without any safety issues. While preparing the cell product for the second patient, some mutations were detected. The decision was made to not proceed with the second patient and to change strategy to partially matched, banked allogeneic iPSCs. Masayo Takahashi noted [3] that mutations were not the main reason for trial suspension, but rather a regulatory change, which came in effect after treatment of the first patient. While disappointing, this news could potentially have a big impact on the field.
Phase 2b Cystic Fibrosis outcomes
Results of a Phase 2 gene therapy trial for cystic fibrosis were published in the Lancet Respiratory Medicine [4]. The randomized, double-blind, placebo-controlled, Phase 2b trial [5], conducted in two UK centers, assessed non-viral CFTR gene therapy. The authors reported modest, but significant improvement in lung function in the experimental group over placebo. The team is now working on a follow-up study design.
Mesoblast publishes Phase 2 results
Australian stem cell therapeutic company Mesoblast Ltd, has published results [6] of their Phase 2 placebo-controlled trial, assessing allogeneic mesenchymal precursor cells in chronic heart failure patients [7]. The study included three cell doses (25, 75, or 150 million) groups of patients, randomized to receive cells versus placebo at a ratio of 15:5. The experimental treatment was safe and feasible (primary endpoints). As for efficacy, I interpret the results as mixed, because secondary endpoints were missed. In post-hoc analysis, however, the higher cell-dose group performed significantly better than controls. The authors concluded that “high-dose allogeneic MPCs may provide benefits”. Larger or re-designed studies should be performed to conclude efficacy.
Chinese Cardiac Trial Results
Another cardiac cell therapy clinical trial [8] conducted in China, yielded good results [9]. The randomized, placebo-controlled multicenter trial assessed allogeneic Wharton’s jelly-derived (part of umbilical cord) mesenchymal stem cells in patients with acute myocardial infarction. 160 patients were randomized to cells versus placebo group at a 1:1 ratio. The ‘cells’ group significantly outperformed the placebo group, meeting efficacy endpoints.
Promising results from Phase 3 trial in Crohn’s Disease
Belgian cell therapy company Tigenix announced preliminary results [10] of their Phase 3 trial assessing the efficacy of local injections of allogeneic adipose stem cells in Crohn’s disease fistulas. The study met efficacy endpoints – moderate, but significant difference compared with placebo. In a population of 204 patients, “the combined remission rates at week 24 were 51.5% and 35.6%” for cells and placebo, respectively. This is a big event for the cell therapy industry, as for the first time Tigenix has demonstrated the efficacy of an allogeneic adipose-derived stem cell product in a Phase 3 trial. I’d like to draw your attention however to the very high remission rate (~35%) in the placebo group.
Disappointing outcome from Macrocure Phase 3
Israeli-based company Macrocure announced preliminary results of their Phase 3 clinical trial using their cell product CureXcell in venous leg ulcers [11,12]. CureXcell is an allogeneic leukocyte product, which is injected directly into the skin wound. Although the results are preliminary, Macrocure states that “the study is not expected to meet its primary endpoint”. This is very disappointing news.
AdaptImmune publish Myeloma results
Immunocellular therapeutic company AdaptImmune published results of their myeloma trial [13,14]. Autologous T-cells were gene-modified with T-cell receptor recognizing cancer-testis antigens NY-ESO-1 and LAGE-1. Similar to CAR T-cell trials, TCR-modified T-cells engrafted and persisted in the bone marrow. T-cell persistence was observed in the majority of patients up to 2 years and was associated with good clinical response in 83% of patients.
Postmortem anaylsis provides insight into alzheimers gene therapy
A very interesting study, which cannot be missed, was published in JAMA Neurology [15]. This is an analysis of postmortem findings from Alzheimer’s disease patients, who underwent experimental gene therapy treatment with nerve growth factor between 2001 and 2012. Brain pathology showed a response of degenerating neurons to growth factor stimulation evidenced by axonal growth. Though the study does not provide any information regarding the efficacy of the experimental treatment, it does provide some insight into potential mechanisms of action of the gene therapy and the persistence of induced changes. Phase 2 of the trial is currently ongoing.
Disappointing efficacy data from Bellerophon
Finally, I cannot overlook the very important regenerative medicine industry trial [16], which assessed efficacy of implanted acellular biodegradable matrix in heart failure. The trial, sponsored by Bellerophon Therapeutics, was conducted in 61 sites in Europe, Australia and North America and involved 303 patients. According company’s press release, there was no difference with placebo [17].This the first big failure of a commercial regenerative medicine trial using biomatrix implantation. Bellerophon licensed Bioabsorbable Cardiac Matrix from BioLineRx in 2009 [18].
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References
1. www.ipscell.com/2015/07/firstipscstop/
2. Kagimoto HTS. The Path Forward. Cell & Gene Therapy Insights 2015; 1(1) XXX.
CrossRef
3. www.ipscell.com/2015/07/firstipscstop/#comment-32084
4. Alton EWF, Armstrong DK, Ashby A et al. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respiratory Medicine;
CrossRef
5. www.clinicaltrials.gov/show/NCT01621867
6. Perin EC, Borow KM, Silva GV et al. A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Non-Ischemic Heart Failure. Circulation Res.
CrossRef
7. https://clinicaltrials.gov/ct2/show/NCT00721045
8. https://clinicaltrials.gov/show/NCT01291329
9 Gao LR, Chen Y, Zhang NK. Intracoronary infusion of Wharton’s jelly-derived mesenchymal stem cells in acute myocardial infarction: double-blind, randomized controlled trial. BMC Medicine 2015, 13:162
CrossRef
10. www.tigenix.com
11. http://investor.macrocure.com/releasedetail.cfm?ReleaseID=928245
12. https://clinicaltrials.gov/ct2/show/NCT02130310
13. Rapoport AP, Stadtmauer EA, Binder-Scholl GK et al. NY-ESO-1–specific TCR–engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nature Medicine 21, 914–921 (2015) doi:10.1038/nm.3910
14. https://clinicaltrials.gov/show/NCT01352286
15. Tuszynski MH, Yang JH, Barba D et al. Nerve Growth Factor Gene Therapy. Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurol.
CrossRef
16. https://clinicaltrials.gov/ct2/show/NCT01226563
17. http://investors.bellerophon.com/phoenix.zhtml?c=253899&p=irol-newsArticle&ID=2071108
18. www.bellerophon.com/pipeline/bioabsorbable-cardiac-matrix
Affiliation
Alexey Bersenev,
Director, Cell Therapy Processing/Advanced Cell Therapy Labs,
Yale University,
USA