HUMAN GENE THERAPY CLINICAL DEVELOPMENT 25:109–111 (September 2014) ª Mary Ann Liebert, Inc. DOI: 10.1089/humc.2014.2512


Gene Therapy Briefs

Avalanche Biotechnologies (; Menlo Park, CA) said on August 5 that it raised $106.8 million through its initial public offering (IPO). The company sold 6.9 million shares of its common stock at a public offering price of $17 per share—including all 900,000 shares of common stock sold to underwriters after they exercised in full their 30-day option to purchase the shares at the IPO price, less discounts and commissions (Avalanche Biotechnologies, 2014a). Avalanche began trading its shares on July 31 on the NASDAQ Global Market, under the symbol AAVL. The company first disclosed plans for an IPO in a June 30 filing with the U.S. Securities and Exchange Commission (U.S. Securities and Exchange Commission, 2014a), and raised its anticipated price range twice before launching the offering. Jefferies, Cowen & Co., and Piper Jaffray & Co. were joint book-running managers for the offering, while William Blair & Co. was comanager. Founded in 2006, Avalanche is a clinical-stage biotechnology company focused on discovering and developing new gene therapies for sight-threatening ophthalmic diseases. Avalanche’s lead product, AVA-101, is currently under development in a phase IIa trial for wet age-related macular degeneration, and is under preclinical study for diabetic macular edema (DME) and retinal vein occlusion (RVO). Studies designed to enable the filing of an Investigational New Drug application for DME and RVO are planned later this year and in 2015. Avalanche’s Ocular BioFactory platform technology is an adeno-associated virus–based gene therapy discovery and development technology that is designed to treat the cause of ophthalmic diseases by enabling patients’ own cells to express a therapeutic protein for a sustained period of time. In May, Regeneron Pharmaceuticals (www.regeneron .com; Tarrytown, NY) said that it will use Ocular BioFactory to discover and develop gene therapy vectors for ophthalmologic diseases. Regeneron agreed to pay Avalanche an undisclosed upfront cash payment, $640 million tied to achieving development and regulatory milestones, plus royalties (Regeneron Pharmaceuticals and Avalanche Biotechnologies, 2014). Avalanche’s IPO came 3 months after it successfully raised $55 million in series B financing that the company said would be used to advance its clinical programs in retinal disorders, including AVA-101, as well as to fund manufacturing and clinical infrastructure for the lead program and accelerate the development of pipeline programs based on Ocular BioFactory. The financing attracted new investors led by Venrock, and included Deerfield, Adage Capital Management, Redmile Group, Rock Springs Capital, Sabby Capital, as well as an affiliate of Cowen & Co. and two undisclosed ‘‘blue chip’’

healthcare funds joining the existing investors (Avalanche Biotechnologies, 2014b). Cedars-Sinai Heart Institute (; Los Angeles, CA) said that its cardiologists have developed a gene transplant procedure that successfully reprogrammed unspecialized heart cells into ‘‘biological pacemaker’’ cells capable of keeping the heart steadily beating without electronic hardware. ‘‘We have been able, for the first time, to create a biological pacemaker using minimally invasive methods and to show that the biological pacemaker supports the demands of daily life. We also are the first to reprogram a heart cell in a living animal in order to effectively cure a disease,’’ said Eduardo Marba´n, MD, PhD, director of the Cedars-Sinai Heart Institute, who led the research team. ‘‘Originally, we thought that biological pacemaker cells could be a temporary bridge therapy for patients who had an infection in the implanted pacemaker area. These results show us that with more research, we might be able to develop a long-lasting biological treatment for patients’’ (Cedars-Sinai, 2014). Dr. Marba´n’s team created the biological pacemaker as a ‘‘bridge to device,’’ providing temporary, hardware-free rhythmic support. The process involved a gene transfer of the human embryonic transcription factor T-box 18 (TBX18) to ventricular cardiomyocytes that were converted, or ‘‘reprogrammed,’’ into ‘‘pacemaker’’ cells. The cells determine an individual’s heart rate by firing electrical impulses (Hu et al., 2014). The team published details in Science Translational Medicine of the successful procedure—the result of a dozen years of research aimed at developing biological treatments for patients with heart rhythm disorders. Researchers previously demonstrated a successful TBX18 gene transfer in mice. In their new study, the investigators showed that their method was feasible in a large-animal model by restoring normal heart rate in pigs with complete heart block. Pigs with complete heart block were injected with TBX18 during a minimally invasive catheter procedure. On the second day after the gene was delivered to the animals’ hearts, pigs that received the gene had significantly faster heartbeats than pigs that did not receive the gene. The stronger heartbeat persisted for the duration of the 14-day study. The heart beat and heart size of pigs is similar to that of humans—a factor, the researchers said, that made their latest study a significant step toward translating the genetic reprogramming to human patients in clinical settings, perhaps as soon as in 3 years. According to Cedars-Sinai, the procedure may prove especially valuable to people who have heart rhythm disorders but who suffer side effects from



implanted mechanical pacemakers, such as infection of the leads that connect the device to the heart. ‘‘This work by Dr. Marba´n and his team heralds a new era of gene therapy, in which genes are used not only to correct a deficiency disorder, but to actually turn one kind of cell into another type,’’ stated Shlomo Melmed, MB ChB, MACP, FRCP, dean of the Cedars-Sinai medical faculty, the Helene A. and Philip E. Hixson distinguished chair in investigative medicine, and senior vice president of academic affairs (Cedars-Sinai, 2014). The development of chimeric antigen receptor T-cell (CAR-T) therapies against cancer reached a pair of important milestones in recent weeks. The U.S. Food and Drug Administration on July 7 awarded its breakthrough therapy designation to CTL019, a personalized cellular immunotherapy developed by the University of Pennsylvania (UPenn;; Philadelphia, PA) for relapsed and refractory adult and pediatric acute lymphoblastic leukemia (ALL). CTL019 is the first personalized cell-therapy cancer treatment to receive the classification. The treatment consists of removing patients’ T cells via apheresis, and then genetically reprogramming them at UPenn’s Clinical Cell and Vaccine Production Facility. After being infused back into patients, these ‘‘hunter’’ cells multiply and attack, targeting tumor cells that express the CD19 protein. In early-stage trials at the Hospital of the University of Pennsylvania and the Children’s Hospital of Philadelphia, 89% of the first 27 ALL patients (22 children and 5 adults) treated with CTL019 went into complete remission. The first pediatric patient celebrated the second anniversary of her remission in May, while the first adult patient has been cancer-free for 1 year. ‘‘Our early findings reveal tremendous promise for a desperate group of patients, many of whom have been able to return to their normal lives at school and work after receiving this new, personalized immunotherapy,’’ Carl June, MD, the UPenn research team leader, said in a statement. He is the Richard W. Vague professor in immunotherapy in the Perelman School of Medicine, and director of Translational Research in UPenn’s Abramson Cancer Center (University of Pennsylvania, 2014). Additional trials are underway in adults and children with ALL, and in patients with non-Hodgkin lymphoma, myeloma, mesothelioma, and ovarian, breast, and pancreatic cancer. UPenn is codeveloping CTL019 with Novartis (; Basel, Switzerland) under an exclusive global research and licensing agreement signed in 2012. Separately, Cellectis (; Paris, France), a developer of cancer immunotherapies based on its engineered allogenic CAR-T platform, said on July 29 that it will sell its Swedish stem-cell subsidiary Cellectis AB to Takara Bio (; Otsu/Shiga, Japan). While the price was not disclosed, Cellectis said that the deal would account for a loss of about e5 million (about $6.7 million) this year (Cellectis, 2014a). The sell-off reflected Cellectis’s ongoing focus on CAR-T therapies, both alone and in partnerships with Pfizer and Servier. In June, Cellectis launched a CAR-T collaboration with Pfizer that required the pharma giant to pay $80 million upfront, up to $2.775 billion in milestone payments, plus tiered royalties (Pfizer, 2014). And in February, Servier


agreed to pay Cellectis up to $850 million plus royalties (Cellectis, 2014b). Cellectis AB focuses on applications of human embryonic stem cell–based products and technologies for industry and researchers. Cellectis said that it was selling the Swedish subsidiary as part of a reorganization of its tools and services business unit. The sale is expected to be completed in coming weeks, subject to customary closing conditions. The U.S. Food and Drug Administration (FDA) has issued a draft guidance detailing how sponsors of virus- or bacteria-based gene therapy (VBGT) products should design and carry out shedding studies during preclinical and clinical development. As defined by the FDA, ‘‘shedding’’ means release of oncolytic or VBGT products from the patient through feces, urine, saliva, nasopharyngeal fluids, pustules, sores, and/or wounds. The agency distinguishes shedding from biodistribution since the former describes how it is excreted or released from the patient’s body, while the latter describes how a product is spread within the patient’s body from the site of administration. ‘‘The possibility that infectious product-based viruses and bacteria may be shed by a patient treated with an oncolytic or VBGT product raises safety concerns related to the risk of transmission to untreated individuals. To understand this risk, shedding studies that are conducted in the target patient population(s) may be appropriate before licensure,’’ the draft guidance concluded (U.S. Food and Drug Administration, 2014). The document added, however, that the infectious viruses or bacteria from which oncolytic and VBGT products are derived are generally not as infectious or as virulent as the parent strain of virus or bacterium. In the draft guidance, the FDA laid out its expectations for shedding studies of oncolytic or VBGT products, with the aim of determining the likelihood of transmitting viruses and bacteria—and offering ways to prevent their spread. The main considerations in designing shedding studies, according to the agency, include the choice of clinical samples collected from subjects in a trial, such as feces and urine; the periodicity of sample collection and duration of the monitoring period; and the assay methodology selected to test for the presence of the oncolytic or VBGT product that may be shed in the clinical sample. Both a product’s tropism and its route of administration should be considered in the selection of sample types to collect in a shedding study, according to the draft guidance: ‘‘For example, to assess shedding in patients administered an oncolytic virus by the intradermal route, we recommend the collection of skin swabs at the site of injection in addition to the other samples routinely assessed for shedding, such as urine, feces and saliva’’ (U.S. Food and Drug Administration, 2014). Shedding studies, the FDA concluded, should be guided by the ability of the oncolytic or VBGT product to multiply and amplify in the human host: the product’s immunogenicity, its persistence and latency, and tropism. To assess the potential of transmission to untreated individuals because of shedding, the draft guidance recommended that an analysis of shedding data for oncolytic or VBGT products should address the nature of the shed material, and the extent of shedding. According to the agency, raw


data in the shedding report should be accompanied by a comprehensive analysis that describes the number of patients who are shedding as a percentage of total patients for each sample type, dose, and regimen studied; the duration and peak periods of shedding; samples that were positive and negative for shedding; and the quantity of product shed in a clinical sample. Celladon (; San Diego, CA) said on July 21 that it was granted an exclusive worldwide license, and the assignment of patents held by Enterprise Partners Venture Capital (; La Jolla, CA) for gene therapy applications of the membrane-bound form of the stem cell factor (mSCF) gene for treatment of cardiac ischemia. Celladon said that it planned to begin further preclinical work on mSCF gene therapy, which successfully reversed heart damage following myocardial infarction in animal models tested at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai. The results were recently published in the journal Circulation Research and are available on the company’s website. ‘‘We believe mSCF gene therapy has the potential to be a powerful therapeutic approach, harnessing the potency of stem cell therapy without the associated complications of developing cells as products,’’ Celladon’s CEO Krisztina Zsebo, PhD, said in a statement. ‘‘Our initial focus will be to generate clinically acceptable gene therapy vectors in support of potentially conducting a future clinical trial in patients who have suffered cardiac damage, as well as exploration for potential other applications’’ (Celladon, 2014). Celladon said that its planned approach with mSCF gene therapy is to express the cytokine locally at sites of injury and to recruit and expand resident stem cells, in diseases in which stem cells have shown promise in clinical and preclinical testing. In preclinical cardiac applications, mSCF gene therapy demonstrated a regenerative response characterized by an enhancement in hemodynamic function after injury; an improvement in survival; a reduction in fibrosis, infarct size, and cell death; and an increase in cardiac c-kit + progenitor cells recruitment to the injured area, Celladon said. In a Form 8-K filing with the U.S. Securities and Exchange Commission, Celladon said that it paid an upfront fee of $160,000 to Enterprise Partners, and is required to pay Enterprise a $1 million milestone payment tied to Celladon, an affiliate or a sublicensee obtaining the first regulatory approval in the United States of a product covered by the licensed patents. Celladon, its affiliates, and sublicensees are also required to pay to Enterprise Partners a 2% royalty on net sales of products covered by those patents (U.S. Securities and Exchange Commission, 2014b). References

Avalanche Biotechnologies (2014a). Avalanche Biotechnologies announces closing of initial public offering and exercise of underwriters’ option to purchase additional shares. Available at 10092935.htm (accessed August 5, 2014).


Avalanche Biotechnologies (2014b). Avalanche Biotechnologies secures $55 million in oversubscribed series B financing. Available at c = 253634&p = irol-newsArticle&ID = 1952745&highlight = (accessed August 4, 2014). Cedars-Sinai (2014). Transplanting gene into injured hearts creates biological pacemakers. Available at About-Us/News/News-Releases-2014/Transplanting-Geneinto-Injured-Hearts-Creates-Biological-Pacemakers.aspx (accessed August 5, 2014). Celladon (2014). Celladon Corporation announces in-license of Stem Cell Factor development program. Available at http://ir = 860817 (accessed August 6, 2014). Cellectis (2014a). Cellectis sells its Swedish subsidiary, Cellectis AB, to the Japanese company Takara Bio Inc. Available at .pdf (accessed August 4, 2014). Cellectis (2014b). Cellectis and Servier announce collaboration in allogeneic cell therapy: UCART19 to treat leukemia and 5 product candidates targeting solid tumors. Available at (accessed August 5, 2014). Hu, Y., Dawkins, J.F., Cho, H.C., et al. (2014). Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Sci. Transl. Med. 6, 245ra94. Pfizer (2014). Pfizer and Cellectis enter into global strategic cancer immunotherapy collaboration. Available at .com/press-release/pfizer-and-cellectis-enter-global-strategiccancer-immunotherapy-collaboration (accessed August 6, 2014). Regeneron Pharmaceuticals and Avalanche Biotechnologies (2014). Regeneron and Avalanche Biotechnologies announce collaboration to develop next-generation gene therapy products in ophthalmology. Available at releasedetail.cfm?ReleaseID = 845170 (accessed August 6, 2014). U.S. Food and Drug Administration (2014). Draft guidance for industry: Design and analysis of shedding studies for virus or bacteria-based gene therapy and oncolytic products. Available at ComplianceRegulatoryInformation/Guidances/Cellularand GeneTherapy/UCM404087.pdf (accessed August 4, 2014). U.S. Securities and Exchange Commission (2014a). Form S-1, Registration Statement for Avalanche Biotechnologies. Available at = 253634&p = IROL-secToc&TOC = aHR0cDovL2FwaS50ZW 5rd2l6YXJkLmNvbS9vdXRsaW5lLnhtbD9yZXBvPXRlbmsma XBhZ2U9OTY3OTYwMiZzdWJzaWQ9NTc%3d&ListAll = 1 (accessed August 4, 2014). U.S. Securities and Exchange Commission (2014b). Form 8-K for Celladon Corp., Entry into a material definitive agreement, financial statements and exhibits. Available at http://ir = 1193125-14-274285& CIK = 1305253 (accessed August 6, 2014). University of Pennsylvania (2014). University of Pennsylvania’s personalized cellular therapy for leukemia receives FDA’s Breakthrough Therapy designation. Available at www.uphs (accessed August 5, 2014).

—Alex Philippidis

Gene therapy briefs.

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