HUMAN GENE THERAPY CLINICAL DEVELOPMENT 24:143–146 ( December 2013) ª Mary Ann Liebert, Inc. DOI: 10.1089/humc.2013.2501


Gene Therapy Briefs

GlaxoSmithKline (GSK; and Prosensa ( said their investigational drug drisapersen for Duchenne muscular dystrophy (DMD) failed to meet its primary end point in a phase III clinical study— namely, statistically significant improvement in the 6-Minute Walking Distance (6MWD) test compared with placebo. Worse, there was no treatment difference in three key secondary assessments of motor function: a 10-m walk/run test, a 4-stair climb, and the North Star Ambulatory Assessment. Results have been submitted for presentation at forthcoming scientific meetings and will also be submitted for publication in a scientific peer-reviewed journal, the companies said. A full evaluation of drisapersen’s benefit-to-risk profile across all studies is anticipated to be completed by year’s end. GSK and Prosensa had been expected to apply for U.S. Food and Drug Administration (FDA) marketing approval early next year. ‘‘We are committed to evaluating the outcome of this study in the context of the overall development program with experts in the field, and we expect such evaluation to help inform our next steps for drisapersen,’’ Carlo Russo, senior vice president and head of GSK Rare Diseases Research and Development, said in a statement. Prosensa CEO Hans Schikan said his company remained ‘‘committed to the overall program and will continue to work closely with GSK,’’ while disappointed that the trial’s primary end point was not met. Drisapersen (previously known as GSK2402968 and PRO051) is an antisense oligonucleotide that induces exon skipping of exon 51. The drug is one of two DMD treatments seeking to become the first to reach the market; the other is Sarepta’s eteplirsen, which showed improvement in all of a dozen boys studied in a phase II trial. According to results published in June, boys who had taken eteplirsen showed a 6MWD improvement of 46.4 m. GSK obtained an exclusive worldwide license to develop and commercialize drisapersen from Prosensa in 2009, in a deal that offered Prosensa up to £428 million (about $694 million) in milestone payments, plus a low-teen percentage of royalties on any sales. Drisapersen has been designated orphan drug status in the European Union, United States, and Japan. In June, the drug candidate also was granted Breakthrough Therapy designation by the FDA. Pluristem Therapeutics ( said the FDA has lifted the clinical hold previously placed in June on its U.S. phase II intermittent claudication (IC) study (IND 15038) ( In a

letter to Pluristem, the FDA said Pluristem may proceed with the study after satisfactorily addressing all issues behind the clinical hold. The study protocol will be modified by tightening patient eligibility criteria, and by adding oral antihistamines and a safety follow-up period for 24 hr after study treatment, according to Pluristem. ‘‘Pluristem applauds the FDA’s vigor to resolve this clinical hold as quickly as possible. We look forward to resuming this important study that addresses the growing, costly and potential serious indication of intermittent claudication,’’ Zami Aberman, Pluristem’s chairman and CEO, said in a statement. Pluristem will use its PLX-PAD cells for the phase II study in the treatment of IC, a subset of peripheral artery disease (PAD). The cells derive their name from the company’s PLacental eXpanded (PLX) cells, a drug delivery platform that releases a cocktail of therapeutic proteins in response to a host of local and systemic inflammatory and ischemic diseases. PLX cells are grown using the company’s proprietary three-dimensional microenvironmental technology and are an ‘‘off-the-shelf’’ product that requires no tissue matching before administration. Up to 150 patients will be enrolled in this dose escalation, randomized, double-blind, multicenter, multinational, placebo-controlled trial, the primary end points of which at 12 months will be safety and maximal walking distance relative to baseline. The multinational study will be expanded to Israel, after approval by that nation’s Ministry of Health to initiate the phase II study using its PLX cells, Pluristem said on October 2 (http:// The protocol will be the same one used for the study in the United States, which will assess the safety and efficacy of two doses of PLX-PAD cells versus placebo, administered via intramuscular injections, in patients with IC: Fontaine class IIb, Rutherford category 2-3. Novartis ( will develop the Regenerex Facilitating Cell Therapy (FCRx) platform by studying its use beyond transplantation, in serious genetic deficiencies such as inherited metabolic storage disorders and hemoglobinopathies. Reasoning that the platform potentially has curative potential for multiple underserved inherited metabolic diseases such as metachromatic leukodystrophy or sickle cell disease, Novartis entered into an exclusive global licensing and research collaboration agreement for FCRx with Regenerex (Louisville, KY). The value of the collaboration was not disclosed. FCRx is a novel allogeneic hematopoietic stem cell-based therapy platform that also contains facilitating cells derived


144 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 of FCRx in 15 kidney transplant recipients are extremely encouraging, with 6 patients fully withdrawn from immunosuppression without loss of engraftment, and a further 2 with planned full withdrawal at 1 year. FCRx will broaden the current Novartis cell therapy portfolio, which includes two cell therapy platforms initially being investigated in hematological malignancies: HSC835, which enables an expanded single umbilical cord bloodderived hematopoietic stem cell transplant in patients with limited treatment options; and HSC835, now in a phase II trial in patients with high-risk hematological malignancies. A second cell therapy product, CTL019, is a chimeric antigen receptor T cell therapy currently in phase II development for acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). ‘‘Thirty years ago, Novartis developed cyclosporine, which changed transplantation treatment paradigms and enabled countless lives to be saved. Now, this collaboration, along with our internal cell therapy assets, has the potential to transform medicine once again through innovation,’’ Timothy Wright, MD, global head of development, Novartis Pharmaceuticals, said in a statement. Sangamo BioSciences ( presented data from an ongoing phase II clinical trial (SB-728-902 Cohort 5) showing that a single infusion of the company’s ZFP Therapeutic SB-728-T for HIV/AIDS led to what the company called profound suppression of viral load in the blood, and functional control of the virus at or below the limit of detection in CCR5-D32-heterozygous HIV-infected subjects receiving the drug candidate. Data also showed that the viral load became undetectable during a treatment interruption from antiretroviral therapy (ART) in three of seven evaluable CCR5-D32-heterozygous HIV-infected subjects, including two of six subjects who had completed a treatment interruption in the ongoing SB-728902 Cohort 5 study, and an additional subject from an earlier phase I clinical trial of SB-728-T. For another Cohort 5 subject, viral load has remained undetectable—at or below the limits of quantification of the current ultrasensitive assays for HIV—for 7 weeks from when the last measurement was taken; the treatment interruption is ongoing. Reduction in viral load from peak during treatment interruption showed a statistically significant correlation with estimated numbers of engrafted zinc finger nuclease (ZFN)modified cells (SB-728-T) in which both copies of the CCR5 gene had been disrupted (biallelic modification). The finding is in line with previously presented data. ‘‘This is the first evidence that sustained functional control of HIV in the absence of ART is possible. The fact that three of the seven evaluable CCR5-D32 subjects achieved undetectable levels is a major step toward immunological func-

GENE THERAPY BRIEFS tional control of HIV,’’ Dale Ando, MD, Sangamo’s vice president of therapeutic development and chief medical officer, said in a statement. ‘‘We look forward to following these Cohort 5 subjects and presenting a complete data set from this study by the end of the year.’’ The data also showed that treatment of HIV-infected subjects with SB-728-T leads to a long-term increase in CD4 counts. The effect on total CD4 counts in SB-728-T-treated subjects was significantly greater than that observed in previously published T cell infusion studies without CCR5 modification and correlated with increased CD4 central memory and increased CCR5-disrupted central memory cells. In addition, a median 0.6-log reduction in the size of the HIV reservoir at 12 months was seen, as demonstrated by measurement of HIV total DNA in peripheral blood mononuclear cells (PBMCs). The decrease showed a statistically significant correlation with the improvement in CD4 count. The data will be used to optimize development of the therapy as a functional cure for HIV, said Geoff Nichol, MB, ChB Sangamo’s executive vice president of research and development. The data were reported in Host Immune Environment Significantly Impacts the Level of CD4 Reconstitution and the Effects on Latent Reservoir in HIV Subjects Receiving ZFN CCR5 Modified CD4 T-cells (SB-728-T), selected as a ‘‘late-breaker’’ presentation at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 10–13 in Denver. During ICAAC 2013, data were also presented demonstrating depletion of the HIV viral reservoir in SB-728-Ttreated subjects in cohorts 1–3 of the SB-728-902 study. Nine HIV-infected subjects (three subjects in each cohort) with suboptimal T cell levels and no detectable viral load on longterm ART were enrolled an open-label phase I clinical trial to evaluate the safety and tolerability of single infusions of an escalating dose of an autologous CD4 + T cell product genetically modified at the CCR5 gene by CCR5-specific ZFNs (SB-728-T). Subjects remained on their existing antiviral therapy while receiving treatment with SB-728-T. Adenoviral platforms for HIV vaccines—specifically, the best way forward for evaluating them—was the topic of a day-long Mini-Summit held by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) on September 19. The Mini-Summit brought together experts in all aspects of HIV vaccinology, including those working with nonhuman primate models, virologists, clinical trialists, immunologists, epidemiologists, and statisticians. The goal, according to the NIAID, was to determine the best way forward for evaluating Ad-HIV vectors, based on an in-depth discussion about HIV vaccine platforms using recombinant adenoviral vectors. The Mini-Summit included a focused discussion on questions pertaining to the impact of adenovirus type 5 (Ad5) vaccines on HIV acquisition, potential mechanisms involved, and how this informs future human clinical trials. NIAID Director Anthony S. Fauci, MD, opened the MiniSummit by posing four key questions: (1) Is there a problem with some or all Ad5 vectors? (2) Is this a problem with Ad5 vectors only or with any adenovirus vector? (3) Is it a problem with any vaccine that causes activated cells to migrate to mucosal surfaces? (4) Is this a universal problem that is seen only when the vaccine is not efficacious in preventing acquisition of infection?

GENE THERAPY BRIEFS The Mini-Summit gave professionals a chance to evaluate the sobering results of three trials assessing two vaccine strategies using Ad5 as a vector. None of these trials found benefit, and two of the trials produced data linking the vaccine to increased risk of HIV infection. In April, the NIAID stopped administering injections in its HVTN 505 phase IIb clinical trial of an investigational Ad5vectored HIV prime–boost vaccine regimen developed by the agency’s Vaccine Research Center. The study’s independent data and safety monitoring board found during a scheduled interim review that the vaccine regimen did not prevent HIV infection or reduce viral load among vaccine recipients infected with HIV. Thirty participants showed measurable viral load (15 vaccine recipients; 15 placebo recipients). Details of the clinical trial were published October 7 in the New England Journal of Medicine (Hammer et al., 2013), which concluded: ‘‘Our study gave a definitive, albeit disappointing, result but should provide useful information as newer vaccine regimens and approaches are developed.’’ ‘‘Thirty years after the discovery of HIV, a safe and effective vaccine is still not in sight,’’ concluded the study, whose corresponding author was Scott M. Hammer, MD, chief of the Division of Infectious Diseases at Columbia University, College of Physicians & Surgeons (P&S). Dr. Hammer is also Harold C. Neu professor of medicine at P&S, and professor of public health (epidemiology) at Columbia’s Mailman School of Public Health. In May, the NIAID said follow-up data showed more infections in vaccinated participants compared with those who were given placebo in the ‘‘Phambili’’ trial, the African component of the STEP clinical trial cosponsored by NIAID, Merck & Co. and the HIV Vaccine Trials Network (HVTN). After the full 3.5-year follow-up period, researchers found that 100 study participants had become HIV-infected: 63 who had received the investigational vaccine and 37 who had received a placebo injection. Merck/NIAID’s V520 failed and even increased the number of infected patients, likely due to use as a vector of an adenoviral strain already exposed to a sizeable percentage of people from earlier infections. Vaccination was halted in both trials in 2007. ‘‘I don’t think it’s likely that we’re going to be moving forward with another Ad5 vector for an HIV vaccine. We can all agree on that,’’ Mini-Summit Co-Chair Susan P. Buchbinder, MD, assistant clinical professor in the Departments of Medicine and Epidemiology/Biostatistics at the University of California, San Francisco, said toward the end of the event. Co-Chair Eric Hunter, PhD, a professor at Emory University’s Emory Vaccine Center, added that based on the evidence presented at the Mini-Summit: ‘‘To have a broad sweep that any Ad vector may be enhancing the risk of HIV would not be valid.’’ Hunter additionally cited the Ad4/7 replicating vector developed by the U.S. armed forces in the 1960s to prevent lower respiratory tract disease in military recruit camps, which he noted showed no evidence of increased risk of HIV infection. Reviewing current approaches to T cell immunotherapy, discussing results seen in clinical trials, and optimizing trial design were among the purposes of ‘‘T Cell Immunotherapy—Optimizing Trial Design,’’ a 2-day conference held by the NIH’s Office of Biotechnology Activities on September 10–11 at the agency’s campus in Bethesda, Maryland.

145 ‘‘This seems an opportune time to revisit some of the issues with the goal of improving clinical trial design to optimize efficacy and safety,’’ said Donald Kohn, MD, of the University of California, Los Angeles, in opening remarks. Dr. Kohn co-chaired the conference with Hans-Peter Kiem, MD, PhD, of the Fred Hutchinson Cancer Research Center. ‘‘The field has experienced a number of additional clinical successes in which some research participants have benefited from long-term remissions of their cancers and leukemias. There’s now beginning to attract pharmaceutical funding interest to help the development and commercialization of these technologies and immunotherapies. There are unexpected developments including adverse events,’’ Dr. Kohn added. Carl June, MD, director of Translational Research in the University of Pennsylvania’s Abramson Cancer Center, and Steven Rosenberg, MD, PhD, chief of surgery at NIH’s National Cancer Institute, discussed ‘‘Dilemmas and Challenges: Approaches and Assessments’’ related to target selection, including the screening needed for new target antigens, the value of murine models, and the need for largeanimal models in selecting novel targets. Both speakers discussed the challenges of off-target toxicity, with Dr. Rosenberg citing among other factors the dearth of potential targets: ‘‘There are very few targets other than CD19 that have been identified thus far. We can put T cell receptors into cells and even there we’re quite limited in terms of the number of targets.’’ Dr. June, who is also the Richard W. Vague Professor of Immunotherapy in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania, detailed two instances of off-target toxicity in clinical trials carried out with Adaptimmune, using a T cell receptor against the cancer testis antigen MAGE A3. The natural T cell receptor had almost had no measurable affinity for MAGE A3. The affinity-enhanced receptor showed outstanding antitumor effects in a preclinical model. But in phase I, two patients—one being treated for metastatic melanoma (Protocol #1007-1057), the other for advanced myeloma (Protocol #1007-1057)—died with severe cardiogenic shock 4 days after T cell infusion. According to a study of the two toxicity events published in Blood (Linette et al., 2013), toxicity was unexpected and occurred because of recognition of an epitope derived from an unrelated protein expressed by contracting normal cardiac tissue—a protein that would not be identified by typical preclinical screening strategies. ‘‘What we had was sort of a perfect storm where we had no cells in the cell panel that expressed the unknown antigen where the off-target reactivity had occurred,’’ Dr. June noted. ‘‘Can this be done with bioinformatics? I think eventually in silico there will be predictive algorithms or perhaps the abilities to use iPSCs to differentiate into at least critical target organs, such as neural tissues, cardiac and endothelial cells, and to be able to screen new TCRs [T cell receptors].’’ Another promising approach to identify potential off-target effects of engineered T cells, Dr. June said, was the use of induced pluripotent stem cells (iPSCs). ‘‘In the world of cancer drug therapy, off-target effects have traditionally been established in phase I trials and that’s

146 where we’re obviously saw it in this case as well. I think that’s going to be the case for engineered receptors in the end that a well-designed phase I trial will be the way to identify this,’’ Dr. June added. The conference’s final discussion focused on ‘‘Moving the Field Forward to Licensed Products for Commercialization.’’ The discussion touched on topics that included key scientific questions to be addressed, resource needs and sources, the path to licensing and how different it will be compared with other therapies, evaluation of targets in small trials without costly GMP products, and commercialization issues, such as partnering with pharma.

GENE THERAPY BRIEFS References Hammer, S.M., Sobieszczyk, M.E., Janes, H., et al. (2013). Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine. N. Engl. J. Med. 2013 (in press). Available at full/10.1056/NEJMoa1310566?query = featured_home#t = articleResults (accessed October 2013). Linette, G.P., Stadtmauer, E.A., Maus, M.V., et al. (2013). Cardiovascular toxicity and titin cross-reactivity of affinity enhanced T cells in myeloma and melanoma. Blood 122, 863–871.

—Alex Philippidis

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