Rethinking fatigue in Gaucher disease

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Abstracts

40 Metallothionein transcripts are dynamic markers for brain disease in lysosomal disorders Martina Cesania, Eleonora Cavalcaa, Romina Maccoa, Giuseppe Leoncinia, Maria Rosa Terrenia, Laura Loriolia, Giancarlo Comia, Claudio Doglionia, Daniele Zacchettia, Maria Sessaa, Clemens R. Scherzerb, Alessandra Biffia, a San Raffaele Scientific Institute, Milan, Italy, bBrigham and Women's Hospital, Boston, MA, USA To facilitate development of novel disease-modifying therapies for lysosomal disorders (LSD) characterized by nervous system involvement, molecular markers for monitoring disease progression and therapeutic response are needed. To this goal we sought to identify blood transcripts associated with the progression of a prototypical LSD, metachromatic leukodystrophy (MLD). A genome-wide expression analysis was performed in primary T lymphocytes of 24 patients with MLD compared to 24 age- and sex-matched healthy controls. Members of the family of metallothioneins (MTs) were identified as overexpressed in MLD patients, confirmed on a quantitative PCR platform, and replicated in an independent patient cohort. High mRNA and protein levels of MTs were observed in post-mortem patient brains and in mouse models representing six other LSD characterized by nervous tissue damage. Moreover, MT over-expression correlated with measures of disease progression in mice and patients, whereas their levels decreased in mice upon therapeutic treatment. Finally, a set of in vitro studies was performed to dissect the biological functions exerted by this class of molecules. Results indicated that MT expression is regulated in response to oxidative stress and inflammation that are biochemical hallmarks of LSD. Thus, we propose metallothioneins as potential markers of neurologic disease processes and treatment response in LSD. doi:10.1016/j.ymgme.2013.12.052

41 EDGE: A Phase 3 study evaluating once versus twice daily dosing of eliglustat in patients with Gaucher disease type 1: interim results from the lead-in-period Joel Charrowa, Hiroyuki Idab, Carla Hollakc, Dominick Amatod, Renata Cravoe, Osamu Kawaguchif, Yong Xueg, aAnn & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA, bJikei University School of Medicine, Tokyo, Japan, cAcademic Medical Center, University of Amsterdam, Amsterdam, Netherlands, dMount Sinai Hospital, Toronto, ON, Canada, e HEMORIO, Rio de Janeiro, Brazil, fSanofi K.K., Tokyo, Japan, gGenzyme, a Sanofi Company, Naarden, Netherlands Gaucher disease type I (GD1) is a rare autosomal recessive lysosomal disorder caused by deficient activity of acid β-glucosidase, which leads to the accumulation of the substrate glucosylceramide throughout the body. Eliglustat, a ceramide analogue, is a novel oral substrate reduction therapy that selectively inhibits glucosylceramide synthase, and is currently in development for adults with GD1. EDGE (NCT01074944, sponsored by Genzyme, a Sanofi company) is a randomized, multi-center, multinational, double-blind Phase 3 trial evaluating once versus twice daily dosing during the blinded primary analysis period of 12 months. We report on an interim analysis of the ongoing open-label lead-in period (LIP) in which patients received eliglustat twice daily in order to attain therapeutic goals before randomization. Adult patients with mild to moderate GD1 previously untreated, off-treatment, or receiving enzyme replacement therapy, who met hematologic and visceral criteria, received 50 mg or 100 mg of eliglustat twice daily based on eliglustat plasma concentrations. The primary LIP endpoint was percent of patients achieving all five of the following therapeutic goals in ≤ 18 months: ≤1

bone crisis and no symptomatic bone disease; hemoglobin ≥ 11 g/dL (female) or ≥ 12 g/dL (male); platelets ≥ 100,000/mm3; spleen ≤10 times normal; liver ≤1.5 times normal. Of the 170 patients who entered the trial as of January 2013, the mean age was 37 years and 52% were male. Mean time on treatment was 10 months. Overall, 83% of patients met all five therapeutic goals, mostly within 6-12 months. Individually, 100% of patients met the goal for bone, 94% for hemoglobin; 92% for platelets, 99% for spleen, and 95% for liver. Most (96%) of the treatmentemergent events (TEAE) were mild or moderate. TEAE occurring in more than 10% of patients included nasopharyngitis (14%), headache (12%), and dizziness (12%). Diarrhea occurred in 6% of patients. Three serious TEAE in three patients (2%) were considered by the investigator to be related to eliglustat but did not result in trial withdrawal. Twelve patients (7%) withdrew from the LIP, including two patients (1%) who discontinued treatment because of one or more non-serious TEAE. There were no deaths during the LIP as of the database cut-off date of 31 January 2013. In this interim LIP analysis, the majority of patients met treatment goals and few patients discontinued treatment. doi:10.1016/j.ymgme.2013.12.053

42 Intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis type I Agnes Chena, Patricia Dicksona, Elsa Shapirob, Paul Harmatzc, aLos Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA, bUniversity of Minnesota, Minneapolis, MN, USA, c Children's Hospital of Oakland Research Institute, Oakland, CA, USA Patients with attenuated MPS I have been found to suffer from progressive decline in memory and intelligence which is inadequately treated with intravenous enzyme replacement therapy (ERT). This ongoing study investigates intrathecal (IT) ERT with recombinant human alpha-L iduronidase (formulated as laronidase) as a treatment for cognitive decline. This study is a twenty-four month open label prospective randomized study in 16 MPS I patients age 6 or older with intellectual impairment or functional decrease over time. Subjects receive baseline neuropsychological, clinical, radiological, and biochemical evaluations and then are monitored for change in these parameters during first monthly, then quarterly IT ERT. The study randomizes subjects to a treatment and a control group for 12 months, and then all subjects receive treatment on a 12-month open-label continuation. Nine subjects have enrolled and eight have received treatment (some after a 12 month non-treatment control period). Adverse events possibly related to IT ERT include low back pain, groin pain, neck stiffness, headache, and transient blurry vision. There have been no serious adverse events related to treatment. Further study is needed to determine whether IT ERT can be used to treat cognitive decline in MPS I patients who do not qualify for and/or are unable to have hematopoietic stem cell transplantation. This study is funded by the Lysosomal Disease Network (NIH/NINDS #U54NS065768), UCLA Clinical and Translational Science Institute at Harbor-UCLA Medical Center (1UL1-RR033176), Ryan Foundation, Genzyme Corporation, and BioMarin Pharmaceutical Inc.

doi:10.1016/j.ymgme.2013.12.054

43 Rethinking fatigue in Gaucher disease Yehudit Chen Ziona, Elizabeth Pappadopulosb, Michael Wajnrajchb, David E. Sandbergc, Hanna Rosenbauma, aRambam Medical Center,

Abstracts

Haifa, Israel, bPfizer Inc., New York, NY, USA, cUniversity of Michigan Medical School, An Arbor, MI, USA Gaucher disease (GD) is a rare, lysosomal disorder caused by functional defects in the enzyme acid β-glucosidase. Along with hematologic and visceral symptoms of GD, patients can experience chronic fatigue resulting in functional disability and reduced quality of life. Although patients with GD consider fatigue a core symptom, few clinical studies have systematically assessed it. The absence of practice guidelines regarding the measurement of fatigue in GD may discourage health care providers from measuring this domain. This significant gap is reflected in the scientific literature; a MEDLINE search of “Gaucher disease” AND “fatigue” generated minimal results (MeSH terms, n = 4; text terms, n = 14). Of these studies, one showed that patients with GD considered fatigue one of the most debilitating symptoms of the disease, negatively impacting the ability to perform school, work, and social activities. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) is a short, 13-item, tool that measures a patient’s level of fatigue during daily activities over the past week. FACIT-F has demonstrated equivalence in interview vs self-report formats, can be used in clinical settings, and has been translated in N45 languages. The modified Fatigue Severity Scale (mFSS) is a 9-item, self-report questionnaire that rates fatigue severity on a scale of 0 to 10, and has been highly correlated with the FACIT-F. Finally, the National Institutes of Health Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form is a 7-item, patient self-assessment of fatigue severity on a scale of 1 (not at all) to 5 (very much). These symptom-specific scales have been used to assess fatigue severity in numerous chronic illnesses (eg, depression, cancer, rheumatoid arthritis, stroke), but generally not in GD. Evidence of FACIT-F sensitivity to treatment effects in GD comes from a recent study reporting significant improvements in fatigue following weekly acupuncture sessions. The effects of approved enzyme replacement therapies (ERT), imiglucerase, velaglucerase alfa, or taliglucerase alfa, on GD-related fatigue has yet to be determined. A limited number of early studies reported improvements in fatigue symptoms following ERT, although no fatigue-specific scales were used. We plan to draw upon the literature discussed above to inform the development of a culturally sensitive measure of fatigue that is not linked to literacy. The goals of this presentation are to: 1) establish the need for reliable, validated, and highly specific tools for assessing fatigue in clinical trials and the clinical treatment of GD; 2) set forth an approach to develop such a measure; and 3) propose an expert consensus project to establish the criteria for clinically significant fatigue in GD. Editorial and medical writing support was provided by Peloton Advantage, LLC, and was funded by Pfizer.

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an allogeneic hematopoietic stemand progenitor cell (HSPC) transplant to be conducted at University of California, Los Angeles. This trial was based on the preclinical studies we performed in the mouse model of cystinosis, the Ctns-/- mice, which showed that transplantation of HSPCs expressing a functional Ctns gene led to the abundant tissue integration of bone marrow-derived cells, a significant decrease of cystine accumulation and kidney preservation. However, allogeneic transplants are associated with high risks of mortality and morbidity. Thus, our long-term goal is to develop an autologous transplantation strategy of HSPCs genetically modified ex vivo to express a functional CTNS gene as a treatment for cystinosis. Preclinical studies using a SINlentivirus vector containing CTNS to transduce Ctns-/- HSPCs and transplanted in Ctns-/- mice were promising. Transduced cells were capable of reducing cystine in all tissues and of improving kidney function. We submitted a pre-IND in March 2013 and had the teleconference with the FDA in April 2013. CBER/FDA committee approved our plan for the pharmacology/toxicology studies to test the safety of our lentiviral vector construct in vitro and in vivo. These studies should lead to an IND for a phase I clinical trial for autologous, lentiviral vector-modified, CD34+ HSPC transplantation for cystinosis. We are now conducting the toxicology studies using a batch of pCCL-CTNS lentiviral vector preparation produced under comparable Good Manufacturing Practice. In parallel, we are investigating the mechanism by which HSPC are able to lead to tissue repair in the context of a nonhematopoietic multi-systemic lysosomal disorder, especially when the protein involved is a lysosomal transmembrane protein such as cystinosin. Our preliminary data showed that HSPC differentiate into tissue resident phagocytic cells that are a key player for tissue repair and that cross-correction occurs even if the protein involved is a lysosomal transmembrane protein.

doi:10.1016/j.ymgme.2013.12.056

45 Survival and developmental milestones among Pompe registry patients with classic infantile-onset Pompe disease with different timing of initiation of treatment with enzyme replacement therapy (ERT)

Stephanie Cherqui, University of California, San Diego, La Jolla, CA, USA

Yin-Hsiu Chiena, Ans van der Ploegb, Simon A. Jonesc, Barry Byrned, Ashok Vellodie, Nancy Leslief, Eugen Mengelg, Suma Shankarh, Pranoot Tanpaibooni, David W. Stocktonj, Julia B. Hennermannk, Zsuzsanna Devecseril, Judy Kempfl, Joan Keutzerl, Priya S. Kishnanim, aNational Taiwan University Hospital, Taipei, Taiwan, bErasmus MC University Medical Center, Rotterdam, Netherlands, cUniversity of Manchester, Manchester, UK, dUniversity of Florida, Gainesville, FL, USA, eGreat Ormond Street Hospital for Children NHS Foundation Trust, London, UK, fCincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA, gUniversity of Mainz, Mainz, Germany, hEmory University School of Medicine, Atlanta, GA, USA, iChildren’s National Medical Center, Washington, DC, USA, jWayne State University School of Medicine, Detroit, MI, USA, kCharite Universitaetsmedizin Berlin, Berlin, Germany, lGenzyme, a Sanofi company, Cambridge, MA, USA, mDuke University Medical Center, Durham, NC, USA

Cystinosis is an autosomal metabolic disease belonging to the family of lysosomal disorders. Mutations in the CTNS gene, encoding a lysosomal cystine transporter, lead to cystine accumulation and multiorgan failure such as blindness, myopathy, diabetes and central nervous system defects. Affected individuals also develop proximal tubulopathy and eventually progress to end stage renal failure. Treatment is available with the drug cysteamine to reduce intracellular cystine content. However, cysteamine only delays the progression of the disease. In April 2012, the first clinical trial using stem cells for cystinosis was approved as

Pompe disease presents as a clinical spectrum with variable severity, progression, and muscle involvement. Early clinical diagnosis and initiation of enzyme replacement therapy (ERT), before the development of serious, irreversible symptoms, is important, especially in classic infantile-onset Pompe disease (IOPD). Untreated classic IOPD, characterized by symptom onset at ≤12 months of age with progressive cardiomyopathy and generalized muscle weakness causing severely delayed motor development and compromised respiratory function, has reported 12-month survival rates ranging from 8% to 25.7% overall, and

doi:10.1016/j.ymgme.2013.12.055

44 Hematopoietic stem cell gene therapy for cystinosis: a new hope for a multi-systemic degenerative disorder