Industry Update: Latest developments in stem cell research and regenerative medicine

Business Development

▪ Collaborations, partnerships & alliances

Collaboration agreement: 360ip & Canadian Centre for Commercialization of Regenerative Medicine

360ip, a global technology commercialization, investment and fund management company, headquartered in Singapore (www.360ip.com), and the Canadian Centre for Commercialization of Regenerative Medicine (CCRM; www.ccrm.ca), a not-for-profit organization funded by the Government of Canada‘s Networks of Centers of Excellence program and six academic partners, are signing a collaboration agreement to work together in a variety of areas, including developing a fund to invest in best-in-class regenerative medicine technologies and companies in Asia, Europe and North America.

Collaboration agreement: Harvard University & Evotec

Harvard University, MA, USA (www.harvard.edu), professors Kevin Eggan and Lee Rubin will conduct amyotrophic lateral sclerosis trials in partnership with German company Evotec (www.evotec.com), the University and the Company announced.

Distribution agreement: MiMedx Group & Medtronic

MiMedx Group, GA, USA (www.mimedx.com), developer, manufacturer and marketer of patent-protected regenerative biomaterials and bioimplants processed from human amniotic membrane, has entered into a distribution agreement with Medtronic, MN, USA (www.medtronic.com) and SpinalGraft Technologies, TN, USA, a wholly-owned subsidiary of Medtronic. Through the agreement, MiMedx will provide its PURION^® processed allograft products to Medtronic to be marketed by SpinalGraft Technologies for spinal applications. The MiMedx allografts produced from the Company‘s proprietary PURION Process for amniotic membrane tissue can be stored at room temperature for 5 years without the need for refrigeration or freezing. The grafts can be utilized right out of the package without a complicated thawing process.

Licensing agreement: Novartis & Regenerex

Novartis, Switzerland (www.novartis.com), has entered into an exclusive global licensing and research collaboration agreement with Regenerex, KY, USA (www.regenerex.com), for use of the Company‘s novel Facilitating Cell Therapy (FCRx) platform. FCRx is a novel allogeneic hematopoietic stem cell-based therapy platform that also contains facilitating cells derived from a donor. The platform supports the development of tolerance, or ‘bone marrow chimerism‘, in transplant recipients, providing a better side-effect profile than current human hematopoietic stem cell transplantation protocols. Chimerism may eventually render the recipient tolerant to cell, tissue or organ transplants from the same donor, thereby enabling transplant patients to discontinue immunosuppressive medications after building stable immunological tolerance. Results from a Phase II study in 15 kidney transplant recipients are encouraging with six patients fully withdrawn from immunosuppression without loss of engraftment, and a further two with planned full withdrawal at 1 year. Currently, solid organ transplant recipients must take immunosuppressive drugs for life to prevent rejection. This approach may also allow for treatment of inherited metabolic diseases like metachromatic leukodystrophy or sickle cell disease.

▪ Launching new projects, products & services

Americord

Americord, NY, USA (http://cordadvantage.com), has validated a revised process for the preservation of mesenchymal stem cells from placenta tissue. The new method greatly improves the success rate for preserving viable mesenchymal stem cells from placenta tissue, a service first developed in 2012.

Bioheart

Bioheart, FL, USA (www.bioheartinc.com), has signed a contract with African-Middle East Medical (AFRIMID; no website found) to implement Bioheart therapies for patients in Uganda. Bioheart will begin distributing MyoCell™ (muscle-derived stem cells) and AdipoCell™ (adipose-derived stem cells) for a variety of indications in Uganda.

Cell Medica

Cell Medica, UK (www.cellmedica.co.uk), opened a commercial manufacturing facility at the Max Delbrück Center for Molecular Medicine (www.mdc-berlin.de) within the biotechnology park of Campus Berlin-Buch in Germany. This state-of-the-art facility for the cGMP production of cell and gene therapies includes approximately 350 m² clean room space. Initial manufacturing will focus on Cytovir™ CMV – an innovative treatment that uses the immune cells of a healthy donor to restore viral immunity against cytomegalovirus infections in patients who are immunocompromised following allogeneic bone marrow hematopoietic stem cell transplant. The commercial launch of this product is planned in early 2014.

Crioestaminal

Crioestaminal, Portugal (www.crioestaminal.pt), has recently invested EUR€750,000 to expand the laboratory‘s storage capacity from 50,000 to 300,000 samples, making it Europe‘s second largest cord blood bank.

Life Technologies Corporation

Life Technologies Corporation, CA, USA (www.lifetechnologies.com), has extended its collaborative agreement with Japanese firm DNAVEC Corp. (www.dnavec.co.jp/en), to launch the CytoTune™-iPS 2.0 Sendai Reprogramming Kit, the next-generation research technology that enables an efficient method for developing induced pluripotent stem cells from human somatic cells. The newest kit doubles the number of colonies that can be produced and represents the latest in a series of products that are planned from the collaboration.

Rainbow Scientific

Rainbow Scientific, CT, USA (www.rainbowscientific.com), now offers advanced research products for human mesenchymal stem cell and human embryonic stem cell culture from Biological Industries, Israel (www.bioind.com). The company claims that these chemically defined, nonanimal origin culture media provide superior growth and maintenance of mesenchymal stem cells and human embryonic stem cell lines.

STEMSOFT Software

STEMSOFT Software, BC, Canada (www.stemsoft.com), released a new cord banking software STEMSOFT CORD. The STEMSOFT CORD software is designed to track all operational and manufacturing details in one location while assisting with accreditation compliance, ensuring processing standardization and increasing access to data.

Clinical Trials

Bioheart

Bioheart, FL, USA (www.bioheartinc.com), a biotechnology company focused on the discovery, development and, subject to regulatory approval, commercialization of autologous cell therapies for the treatment of chronic and acute heart damage, announced preliminary data from its Phase I ANGEL trial. Fully funded by Bioheart, the trial is being conducted in Mexico at the Hospital Angeles (www.hospitalesangeles.com) with the Regenerative Medicine Institute. This Phase I study will provide necessary safety and preliminary efficacy of adipose-derived stem cells (AdipoCell) in patients with congestive heart failure. End points include safety, exercise capacity, quality of life, and ejection fraction at 3, 6 and 12 months. The Company claims that the patients are also reporting an average improvement of 13 points in their Minnesota Living with Heart Failure questionnaire. An improvement of five points or greater is considered clinically meaningful and 80% of the patients in the trial had a greater than five-point improvement.

Sernova

Sernova, ON, Canada (www.sernova.com), presented at the World Congress of the International Pancreas and Islet Transplantation Association in Monterey, CA, USA (24–27 September 2013), safety and biocompatibility results for the Cell Pouch™. Following islet transplant, proof of islet cell survival and the presence of insulin have been demonstrated in the first two patients of an up to 20 patient study. In this study, patient volunteers with insulin-dependent diabetes and hypoglycemia unawareness who are receiving an islet transplant following informed consent are being implanted with the Cell Pouch, which is subsequently transplanted with human donor islets. To protect the islets from immune cell attack, the patients are given an antibody and immunosuppressive medications. In an initial assessment, the Cell Pouches in the first two patients were shown to meet the primary end point of being safe after implantation and prior to transplantation. The Cell Pouches were then transplanted with human donor islets followed by removal up to 30 days post-transplantation and islet survival was assessed. The Cell Pouches were prepared for comprehensive histological analysis and assessed by experts in an independent blinded analysis for key features including device biocompatibility, tissue and microvessel development into the device, islet survival and the presence of insulin, glucagon, somatostatin and polypeptide, as well as protection of islets from immune system attack. Further information about the clinical trial is available at http://clinicaltrials.gov (ID: NCT01652911).

StemCells

StemCells, CA, USA (www.stemcellsinc.com), announced the results of a 4-year observation study in patients with neuronal ceroid lipofuscinosis, also referred to as Batten disease, who had been transplanted with the Company‘s proprietary HuCNS-SC^® cells (purified human neural stem cells) in the initial Phase I study. Key results include long-term evidence of safety, up to 5 years post-transplantation, for the surgical transplantation of the HuCNS-SC cells into multiple sites in the brain and at doses of up to one billion cells. The study results represent the first, and thus far only, multiyear data set following transplantation of neural stem cells into human subjects, and supports the feasibility of the Company‘s approach in multiple neurological disorders. Six patients were enrolled in the Company‘s Phase I clinical study. All six were transplanted with HuCNS-SC cells and followed for 12 months after transplantation. Five patients completed the Phase I study and subsequently enrolled in a 4-year, long-term observational study, with three of the five surviving to the end of the 4-year study. The long-term clinical data appear to be consistent with the natural history of the disease and conclusions about impact on the disease course cannot be made in an open-label trial. The reported adverse events are consistent with the underlying disease and there have been no safety concerns attributed to the HuCNS-SC cells. MRI scans of the brain show progressive atrophy consistent with the patient‘s neuropsychological performance. Quality-of-life measures remained stable across all three surviving patients. The Company previously reported post-mortem evidence of engraftment, migration and long-term survival of the HuCNS-SC cells following transplantation and the planned cessation of immunosuppression. The data were based on examination of the brains from three patients who expired from causes related to the underlying disease.

Regulations, Approvals & Acquisitions

▪ Green light

America Stem Cell

America Stem Cell, TX, USA (www.americastemcell.com), has received clearance from the US FDA for its Phase I/IIa nationwide multicenter dual-umbilical cord transplantation study evaluating ASC-101 in patients with hematologic malignancies and myelodysplastic syndrome. ASC-101 is currently undergoing evaluation in a single-center study at The University of Texas MD Anderson Cancer, TX, USA (www.mdanderson.org). To date, 12 patients have been enrolled in the study with nine patients evaluable. On the basis of data obtained in the single-center study, the FDA has given approval to proceed with a multicenter trial.

BioTime

BioTime, CA, USA (www.biotimeinc.com), has received approval from The Spanish Agency of Medicines and Medical Devices (AEMPS) to begin human clinical trials of Renevia™, a unique biomaterial used as a delivery matrix for autologous adipose-derived cells to treat the loss of subcutaneous adipose tissue (lipoatrophies) arising from trauma, surgical resection, and congenital defects and disease. This AEMPS approval follows the earlier approval this year from the Balearic Island Ethics Committee Approval for the first of a multiphase clinical investigation of Renevia. The clinical studies will be conducted at The Stem Center in Palma de Mallorca, Spain.

Cardio3 BioSciences

Cardio3 BioSciences, Belgium (www.c3bs.com), has received authorization from the Spanish Agency for Medicines and Health Products (AEMPS) to begin its Congestive Heart failure Cardiopoietic Regenerative Therapy (CHART-1) European Phase III trial for C-Cure^® in Spain. Spain is the sixth country to have authorized this study after the UK, Belgium, Israel, Serbia and Hungary. The Phase III trial is a prospective, multicenter, randomized, sham-controlled, patient- and evaluator-blinded study comparing treatment with C3BS-CQR-1 with a sham treatment. The trial will recruit a minimum of 240 patients with chronic advanced symptomatic heart failure. The primary end point of the trial is a composite end point including mortality, morbidity, quality of life, Six Minute Walk Test, and left ventricular structure and function at 9 months postprocedure. Further information about the clinical trial is available at http://clinicaltrials.gov (ID: NCT01768702).

Dendreon Corporation

Dendreon Corporation, WA, USA (www.dendreon.com), announced that the European Commission (EC) has granted marketing authorization for PROVENGE^® (autologous peripheral blood mononuclear cells activated with PAP-GM-CSF or sipuleucel-T) in the EU for the treatment of asymptomatic or minimally symptomatic metastatic (nonvisceral) castrate-resistant prostate cancer in male adults in whom chemotherapy is not yet clinically indicated. This final decision by the EC follows recent positive opinions from both the EMA Committee for Advanced Therapy (CAT) and the Committee for Medicinal Products for Human Use (CHMP) recommending that PROVENGE be granted marketing authorization in the EU. The marketing authorization provides approval for the commercialization of PROVENGE in all 28 countries of the EU, as well as Norway, Iceland and Liechtenstein.

Osiris Therapeutics

Osiris Therapeutics, MD, USA (www.osiris.com), has reached agreement with the US FDA regarding the regulatory pathway for its biosurgery products, Grafix^® and Ovation^®. After discussions with the FDA, the regulatory status of Grafix is confirmed and the product will remain on the market as a wound cover for the treatment of acute and chronic wounds. For certain expanded indications for Grafix, Osiris has committed to submit a Biologics License Application. Osiris will leverage existing clinical data in the preparation of the applications, including data from Protocol 302, its multicenter, randomized controlled trial, which demonstrated a 192% relative improvement in closure rate of chronic diabetic foot ulcers as compared with patients receiving conventional therapy (p < 0.0001). Additionally, Osiris will continue transitioning its Ovation product line over to the Company‘s newly launched OvationOS™ formulation and has agreed to complete this transition no later than the second half of 2014.

Pluristem Therapeutics

Pluristem Therapeutics, Israel (www.pluristem.com), announced that the US FDA has lifted the clinical hold previously placed on the Company‘s US Phase II Intermittent claudication study (IND 15038) on 4 June 2013. In its letter to Pluristem, the FDA indicated Pluristem had satisfactorily addressed all the clinical hold issues and the Company may proceed with the study.

In unrelated news, the Israeli Ministry of Health has approved the Company‘s request to initiate a Phase II study using its PLacental eXpanded (PLX) cells in the treatment of intermittent claudication. This approval is part of the Company‘s previously announced strategy to conduct a multinational study for this indication. The protocol will be the same one used for the study previously approved in the USA.

ReNeuron

ReNeuron, UK (www.reneuron.com), announced that the ReN003 retinal stem cell therapy candidate for retinitis pigmentosa has been granted Orphan Drug Designation in both Europe and the USA by the EC and the US FDA, respectively. ReNeuron is using its proprietary human retinal progenitor cells as the basis of its ReN003 therapeutic candidate targeting retinitis pigmentosa, a group of hereditary diseases of the eye that lead to progressive loss of sight due to cells in the retina becoming damaged and eventually dying. Retinitis pigmentosa affects approximately four in 10,000 people in the EU and USA.

Tissue Regeneration Systems

Tissue Regeneration Systems, MI, USA (http://tissuesys.com), has received 510K approval from the US FDA for its Cranial Bone Void Filler product, indicated for use in the repair of neurosurgical burr holes. This is the first of a family of craniomaxillofacial surgery products that incorporates the Company‘s novel skeletal reconstruction and bone regeneration technology platform.

▪ Pending

Advanced Cell Technology

Advanced Cell Technology, MA, USA (www.advancedcell.com), has filed an Investigational New Animal Drug (INAD) application with the US FDA to test its proprietary ‘off-the-shelf‘ mesenchymal stem cells in a range of different disease indications. The studies will evaluate the safety and efficacy of Advanced Cell Technology‘s pluripotent stem cell-derived mesenchymal stem cells in ten spontaneous disease models in dogs, which are similar to various human inflammatory and immune-mediated diseases, including hepatitis, glomerulonephritis, osteoarthritis, Crohn‘s disease, inflammatory bowel disease, spinal cord/disc disease, meningoencephalitis, hemolytic anemia, pancreatitis and sepsis.

▪ Acquisitions

Medical Australia & Medivet

Medical Australia, Australia (www.medaust.com), has signed an agreement to acquire Medivet, Australia (www.medivet.net.au), a private company with proprietary ownership technology for regenerative stem cell technology for domestic animals and the equine industry. Consideration for the deal will buy approximately 36.6 million shares at US$0.30 for total of US$11 million.

Mesoblast & Osiris

Mesoblast, Australia (www.mesoblast.com), announced the acquisition of the entire culture-expanded mesenchymal stem cell business of Osiris Therapeutics, MD, USA (www.osiris.com), including 110 granted patents globally and clinical data from over 1500 patients. Osiris‘ hallmark product Prochymal^® is the world‘s first approved stem cell therapeutic and the only stem cell therapeutic designated by the US FDA as both an Orphan Drug and Fast Track product. Prochymal has already received conditional approval in Canada and New Zealand for the treatment of children with acute graft-versus-host disease, and is available in the USA under an Expanded Access Program for treatment of acute graft-versus-host disease in both children and adults. Mesoblast will pay Osiris US$20 million upon closing of the transaction, with US$15 million in Mesoblast stock payable upon transfer of the assigned assets. Osiris will receive an additional US$15 million of cash in 6 months and may receive up to US$50 million in milestones that are contingent on the successful achievement of future late-stage clinical or regulatory targets (e.g., USA or European product regulatory approvals). All contingent milestones are payable in cash or Mesoblast stock, at Mesoblast‘s discretion. Osiris may also receive earnout on sales of acquired products, ranging from low single digits to a 10% cap on annual sales in excess of US$750 million.

Sartorius Stedim Biotech & TAP Biosystems

Sartorius Stedim Biotech, Germany (www.sartorius.com), made a cash offer to acquire TAP Biosystems, UK (www.tapbiosystems.com). The proposed transaction, which is subject to customary closing conditions, including the approval of TAP‘s shareholders, values the equity of TAP Biosystems at approximately US$45.5 (EUR€33) million. The transaction has been unanimously approved by the boards of directors of both companies and is expected to close at the end of 2013.

Stratus Media Group & Histogen

Stratus Media Group, CA, USA (www.stratusmediagroup.com), is planning to expand its entrance into the biotechnology industry with the execution of a letter of intent between the Company and Histogen, CA, USA (www.histogen.com), a regenerative medicine company developing innovative therapies for conditions including hair loss and cancer. The nonbinding letter of intent outlines the primary terms of a merger of San Diego-based Histogen into Stratus, to be renamed Restorgenex Corporation. The boards of directors of both companies have approved the letter of intent and the parties are engaged in completing a formal merger agreement.

Vitro Diagnostics & Neuromics

Vitro Diagnostics, dba Vitro Biopharma, CO, USA (www.vitrobiopharma.com), signed a nonbinding letter of intent to acquire and merge with Neuromics, MN, USA (www.neuromics.com). The merger would be structured as a reverse triangular merger, with Neuromics becoming a wholly owned subsidiary of Vitro Biopharma. Based upon the current financial conditions of both parties, the consideration for the merger would consist of Vitro issuing 4.0 million shares of common stock and paying an additional US$250,000 on terms yet to be determined. The letter of intent also contemplates the conversion of accrued debt to Vitro Biopharma‘s president into 1.0 million shares of common stock and other balance sheet restructuring.

Capital Market & Finances

Adaptive Biotechnologies

Adaptive Biotechnologies, WA, USA (www.adaptivebiotech.com), has received a US$2.53 million Phase II Small Business Innovation Research award from the National Heart, Lung, and Blood Institute (NHLBI), a division of the NIH, to commercialize a test to measure the ability of a cancer patient‘s adaptive immune system to fight infection after a cord blood transplant.

Arteriocyte

Arteriocyte, MA, USA (www.arteriocyte.com), has been awarded a contract valued at up to US$101.1 million (if all contract options are exercised) by the US Department of Health and Human Services. The Biomedical Advanced Research and Development Authority (BARDA), an agency within the Office of the Assistant Secretary for Preparedness and Response, awarded this contract. The contract supports research and development of the Magellan^® Bio-Bandage™ and clinical evaluation to improve the existing standard of care in definitive burn treatments.

AxoGen

AxoGen, FL, USA (www.axogeninc.com), announced that the underwriters of its recent public offering of common stock have exercised their option to purchase an additional 184,332 shares. The total gross proceeds to AxoGen from this offering, including from the exercise of the over-allotment option, are expected to be US$18.6 million, excluding deductions for underwriting discounts and commissions and estimated expenses. AxoGen will use the net proceeds from the offering to expand product commercialization and marketing efforts for its portfolio of peripheral nerve repair products (Avance^® Nerve Graft, AxoGuard^® Nerve Connector and AxoGuard^® Nerve Protector), to further develop its product pipeline and for general working capital purposes.

NeoStem

NeoStem, NY, USA (www.neostem.com), has been awarded funds for the second year of a 2-year grant totaling US$1,221,854 for ‘Repair of Bone Defects with Human Autologous Pluripotent Very Small Embryonic-Like Stem Cells (VSEL),‘ from the National Institute of Craniofacial Research, a division of the NIH. This peer-reviewed grant is to support a Phase II investigation and first approved clinical study of VSELs™ in humans. Enrollment for this study is expected in 2014. The Company, along with other partner institutions, has already received US$4.5 million in government research grants, including grants from the Department of Defense and the NIH.

The research has stirred controversy due to NeoStem‘s marketing partnership with the Vatican and because three independent studies have been unable to confirm the cells are present [1–3].

Numerate

Numerate, CA, USA (www.numerate.com), has been awarded an early translational grant of US$1,333,795 from the California Institute for Regenerative Medicine (www.cirm.ca.gov) for the use of human induced pluripotent stem cell-derived neurons from Huntington‘s disease patients to develop novel, disease-modifying small molecule structural corrector drug candidates targeting the unique, neurotoxic conformation of mutant huntingtin.

Opexa Therapeutics

Opexa Therapeutics, TX, USA (www.opexatherapeutics.com), a biotechnology company developing Tcelna^®, a patient-specific T-cell immunotherapy for the treatment of multiple sclerosis, announced the closing of the partial exercise of the over-allotment option granted to the underwriters to purchase an additional 650,000 shares of its common stock, at a price to the public of US$1.50 per share. This is in connection with the Company‘s recently announced underwritten public offering of 12,000,000 shares of common stock, bringing total gross proceeds from the offering to US$18,975,000, before deducting underwriting discounts and commissions, and other offering expenses payable by the Company.

Roslin Cells

Cell Therapy Catapult (https://ct.catapult.org.uk) and Roslin Cells, UK (http://roslincells.com), are partnering to establish a source of clinical-grade induced pluripotent stem cells banked according to GMP standards in the UK. The iPS bank is being established with an initial US$3.2 (GB£2) million investment. The induced pluripotent stem cell lines will be isolated and banked at Roslin Cells in Edinburgh and will be available for clinical research in both academia and industry, with availability of the initial six expected by the end of 2014. From these banks, research-grade lines will be created and made available for early-stage work and preclinical research.

StemCells

StemCells, CA, USA (www.stemcellsinc.com), has closed its previously announced underwritten public offering of common stock and warrants. The Company sold a total of 12,845,500 units at a public offering price of US$1.45 per unit and received total proceeds, net of offering expenses, underwriting discounts and commissions, of approximately US$17.3 million. In connection with the offering, the Company terminated its US$30 million equity purchase agreement with Lincoln Park Capital. Lincoln Park Capital participated in the offering as an investor.

TissueTech

TissueTech, FL, USA (website not available), completed a US$10 million round of growth equity financing from Ballast Point Ventures and River Cities Capital Funds. TissueTech offers its portfolio of amniotic membrane and umbilical cord-based tissue and device products through its commercial entities, Bio-Tissue, FL, USA (www.biotissue.com), focused on regenerative therapies for ocular surface diseases, and Amniox Medical, GA, USA (www.amnioxmedical.com), a provider to the musculoskeletal and wound care markets. The funding will be largely used to accelerate commercial efforts and further research and development in both divisions.

Vital Therapies

Vital Therapies, CA, USA (http://vitaltherapies.com), known for its ELAD^® bioartificial liver therapy, has filed for an US$86.3 million initial public offering. Vital Therapies, which was founded in 2003, has raised about US$150 million from private investors so far.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.