Industry Update: Clinical trials

Latest clinical trial developments compiled from April 01 — May 31, 2016.

Latest clinical trial developments in the field of stem cell research and
regenerative medicine compiled from publicly available information and
press releases from non-academic institutions from March 01 — 31 2016, scheduled to be published in Volume 11 Issue 6 of Regenerative Medicine.

Astellas

At the 2016 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Seattle, WA, USA, a team from Moorfields Hospital, London, UK, reported one-year follow up data from a pilot clinical study featuring a transplantation of hESC-derived retinal pigment epithelium (RPE) in 12 patients aged 34-45 years in advanced Group 3 Stadgardt disease. Following pars plana vitrectomy we injected subretinally a suspension of hESC-derived RPE cells at doses at doses of 50, 100, 150 and 200 thousand cells. The cells were developed by Astellas Institute of Regenerative Medicine (MA, USA), a branch of Japanese company Astellas (www.astellas.com) [4]. The study assessed systemic and ocular safety, indicators of cell survival and retinal function for 12 months. The development of areas of subretinal hyperpigmentation in all participants, suggested survival and engraftment of hESC-derived RPE cells. The extent of hyperpigmentation correlated positively with the dose of cells administered (R2=0.58, p<0.05). Hyperpigmentation was associated with areas of both hypo- and hyper-autofluorescence. The study identified no evidence of tumorigenicity, immune adverse events or other serious safety concerns related to the transplanted cells. Assessment of Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity, microperimetry, static full field perimetry, color vision testing and electoretinography demonstrated no significant loss of visual function in the study eye of any participant. Additional information about this clinical trial is available at http://clinicaltrials.gov (ID: NCT01469832).

Asterias

Asterias Biotherapeutics (CA, USA; www.asteriasbiotherapeutics.com) announced new positive long-term follow-up results from its Phase 1 clinical trial assessing the safety of AST-OPC1 (oligodendrocyte progenitor cells) in patients with spinal cord injury. The results showed that in four of the five patients, serial MRI scans performed throughout the 4 to 5 year follow-up period indicate that reduced spinal cord cavitation occurred and that AST-OPC1 appeared to have positive long-term effects on reducing spinal cord tissue deterioration. The company also filed a new patent application with the US Patent and Trademark Office (USPTO) that included this new safety data. In the Phase 1 clinical trial, five patients with neurologically complete thoracic spinal cord injury, as classified by the American Spinal Injury Association Impairment Scale (AIS), were administered a relatively low dose of two million AST-OPC1 cells at the spinal cord injury site 7-14 days post-injury. The aim of this first human clinical study was to evaluate the safety of AST-OPC1 when administered at a low dose. The patients also received low-level immunosuppression for the next 60 days. Delivery of AST-OPC1 was successful in all five patients with no serious adverse events associated with the administration of the cells, with AST-OPC1 itself, or with the immunosuppressive regimen. No evidence of rejection of AST-OPC1 was observed in detailed immune response monitoring of all patients. In four of the five patients, serial MRI

scans indicated that reduced spinal cord cavitation occurred. Cavitation is a destructive process which takes place within the spinal cord following spinal cord injuries and typically results in permanent loss of a patient’s motor function. The patients in the study have now been followed for 4 to 5 years through numerous clinical visits, MRIs, and neurological assessments.

CardioCell

CardioCell (CA, USA; www.stemcardiocell.com) fulfilled enrollment for its Phase IIa chronic heart failure clinical trial. A total of 23 randomized participants were enrolled at multiple study centers. The Phase IIa study protocol delivers ischemia-tolerant MSC (itMSCs) via intravenous infusion and investigates if the itMSCs show signs of improvement in participants with non-ischemic cardiomyopathy. itMSCs, which are exclusively licensed from CardioCell’s parent company Stemedica. Unlike MSCs grown under normoxic conditions, Stemedica’s bone-marrow-derived, allogeneic itMSCs are grown under hypoxic conditions. In vivo experiments demonstrate cells that are exposed to hypoxic conditions show greater homing and engraftment than cells grown under normoxic conditions. Compared to MSCs manufactured under normal oxygen condition, itMSCs secrete higher levels of growth factors and other important proteins associated with neoangiogenesis and healing. Additional information about this clinical trial is available at http://clinicaltrials.gov (ID: NCT02123706).

Gamida

At the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in Valencia, Spain, Gamida Cell (Israel; www.gamida-cell.com) presented positive results with the use of NiCord®, an experimental treatment for patients with high-risk blood cancers. The analysis compared 18 patients with high risk hematological malignancies transplanted with NiCord to a control group of 101 similar patients transplanted with standard umbilical cord blood (UCB), following myeloablative conditioning. All of the patients were transplanted at the Duke Cancer Institute. The results showed a statistically significant improvement (p<.001) in time to 95% engraftment in NiCord patients of 12.5 versus 27 days in the control group. Patients transplanted with NiCord also had a significantly lower frequency of grade 2-3 bacterial infections in comparison to the standard UCB patients, 22% vs. 54%, respectively (p=.015). And, during the first hundred days post-transplantation, patients transplanted with NiCord spent a median of 74 days alive and out of the hospital, significantly better than median 53 days (p=0.002) in patients transplanted with standard UCB. NiCord is an ex vivo expanded cell graft, utilizing Gamida Cell’s proprietary NAM platform technology to expand cells from the UCB. NAM platform uses nicotinamide, a form of vitamin B3, in the culture medium, which inhibits the loss of functionality that usually occurs during the culture process of cells.

Kiadis

Kiadis Pharma (the Netherlands; www.kiadis.com), a clinical stage biopharmaceutical company developing innovative T-cell immunotherapy treatments for blood cancers and inherited blood disorders, presented positive results on the primary endpoint of its single dose Phase II trial (NCT01794299/EudraCT 2012-004461-41) with its lead product ATIR101â„¢ in 23 leukemia patients. The presented data confirm that ATIR101â„¢ can be safely infused, does not cause grade III-IV Graft-versus-Host-Disease (GVHD) and shows a significant reduction in Transplant Related Mortality (TRM) and a significant improvement in Overall Survival (OS) in comparison to a historical control group of patients undergoing a T-cell depleted haploidentical donor transplantation only. Based on the positive results from this Phase II trial, the Company will proceed with the development of ATIR101â„¢ as an adjunctive immuno-therapeutic treatment to a haploidentical hematopoietic stem cell transplant for patients with acute leukemia, initiating a randomized Phase III trial in the second half of 2016. In addition, the Company will discuss the opportunity for potential accelerated approval of ATIR101â„¢ with the regulatory authorities.

Osiris

Osiris Therapeutics (MD, USA; www.osiris.com) announces the results of a retrospective study that compared the efficacy of Osiris’ product Grafix® to EpiFix®, a dehydrated Human Amnion/ Chorion Membrane allograft manufactured by MiMedx (GA, USA; www.mimedx.com). Grafix is a cryopreserved placental membrane comprised of an extracellular matrix rich in collagen, growth factors and viable cells native to the tissue. Grafix is processed using Osiris’ proprietary BioSmartâ„¢ technology. Per a protocol, all patients over the age of 18 that received at least one application of either Grafix or EpiFix for the management of any head-to-toe acute or chronic wound between February 2014 and March 2016 were included in the study. The primary analysis was the proportion of index wounds that achieved complete closure during the retrospective treatment period. Blinded statistical analyses for both Grafix and EpiFix treatment groups were performed by an independent third party clinical research organization. A total of 79 patients with 101 wounds were identified for study analysis: 39 patients with 55 wounds received EpiFix and 40 patients with 46 wounds received Grafix. There were no patients or wound types excluded. Researchers used a pre-defined protocol to collect de-identified electronic health records from the wound care management software. The mean wound surface area at presentation was 7.7 cm in the Grafix group and 7.0 cm in the EpiFix group. The mean wound volume at presentation was 8.3 cm in the Grafix group and 2.7 cm in the EpiFix group. There were no statistical differences in the basic demographics between the two groups. When compared to EpiFix, researchers determined that Grafix closed more wounds with surface areas that were over 4x greater in size and 19x greater in volume. The Grafix-treated wounds that did not achieve closure during the study period demonstrated clinically effective improvement with an average surface area and volume reduction of greater than 40%. By comparison, the unclosed EpiFix-treated wounds demonstrated a deterioration in clinical condition as evidenced by an average increase in surface area and volume of greater than 104%. The results demonstrated by Grafix in this real world study are consistent with the previously published data in which authors reported a 62% complete wound closure rate by 12 weeks in a large, blinded, multicenter diabetic foot ulcer trial [5].

RIKEN

At the 2016 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Seattle, WA, USA, a team from Kobe, Japan, reported one-year follow up data from a pilot clinical study featuring a transplantation of autologous induced pluripotent stem cell (iPSC)-derived RPE cell sheets for exudative age related macular degeneration of retina. The submacularly transplanted RPE sheet survives well without any findings of immune rejection nor adverse proliferation, and any significant adverse events associated with the therapeutic protocol were not observed for a year. Retinal imaging examinations showed improvement of the pre-existed exudative change. Best corrected visual acuity was maintained at 0.09 (=18/200) without additional anti-VEGF therapy and the score of Visual Function Questionnaire-25 improved from 40.7 to 58.3. Additional information about this clinical trial is available at www.umin.ac.jp/ctr/index-j.htm (ID: UMIN000011929).

TiGenix

TiGenix (Belgium; www.tigenix.com) has selected TFS International (Sweden; www.tfscro.com) for the first clinical trial (SEPCELL) to use stem cell therapy in the SEPCELL project, a randomized, double-blind, placebo-controlled, Phase Ib/IIa trial in severe sepsis secondary to severe community acquired pneumonia. Subjects in the trial must have severe community acquired pneumonia requiring mechanical ventilation and/or vasopressors. The trial is expected to enroll 180 patients, and will be conducted at approximately 50 centers throughout Europe. Subjects will be randomized 1:1 to receive active investigational product or placebo on days 1 and 3. All patients will also be treated with the standard of care, which generally includes antibiotics

and anti-inflammatory drugs. The primary endpoint is the number, frequency and type of adverse events during a 90-day period. Secondary endpoints include the reduction in the duration of mechanical ventilation and/or vasopressors, overall survival, clinical cure of severe community acquired pneumonia, and other infection-related endpoints. This study will assess the safety and efficacy of Cx611, an intravenously-administered product of expanded allogeneic adipose-derived stem cells. TFS medical and operational expertise in sepsis studies and strong experience with hospital-based trials were decisive factors for TiGenix selecting TFS. SEPCELL has been awarded a US$ 6 (€5.4) million grant by the European Union under the Horizon 2020 Research and Innovation Program under Grant Agreement 681031.

In an unrelated news, TiGenix presented the week 24 positive results from its Phase III ADMIRE-CD pivotal study of Cx601 at the 2016 Digestive Disease Week in San Diego, CA, USA. In this double-blind, placebo controlled, randomized Phase III study, Cx601 met the primary endpoint of combined remission of complex perianal fistulas at week 24. TiGenix submitted a Marketing Authorization Application for Cx601 in first quarter of 2016 to the European Medicines Agency, and expects to begin marketing in European markets in the second half of 2017. Additional information about this clinical trial is available at http://clinicaltrials.gov (ID: NCT01541579).

References

[4] Klimanskaya I, Hipp J, Rezai KA, West M, Atala A, Lanza R. Derivation and comparative assessment of retinal pigment epithelium from human embryonic stem cells using transcriptomics. Cloning Stem Cells. 6: 217-45 (2004)

[5] Lavery LA, Fulmer J, Shebetka KA, Regulski M, Vayser D, Fried D, Kashefsky H, Owings TM, Nadarajah J and The Grafix Diabetic Foot Ulcer Study Group. The efficacy and safety of Grafix® for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. 11: 554—560 (2014)