NIH-NHLBI/NIDDK Thalassemia Workshop:
Clinical Priorities and Clinical Trials

Fishers Lane Conference Center
Rockville, MD
May 20-21, 2009

• Executive Summary
• Structure and Content of the Workshop
• Reports From Subcommittees
• Clinical Trials in Thalassemia
• List of Abbreviations

Executive Summary

On May 20 and 21, 2009, the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) convened a workshop to discuss priorities for thalassemia research and clinical trials. Thalassemia major affects approximately 1,000 persons in the U.S., however, increased immigration to the U.S. is increasing the prevalence and broadening the demographics of thalassemia. The goal of the workshop was to identify clinical research needs and trials to reduce the burden of disease.

Investigators, clinicians, and patient advocates identified priorities for clinical research and discussed study infrastructure and international collaborative opportunities. Key areas for the successful completion of clinical trials in thalassemia include:

• Forming international collaborations to increase and expand patient recruitment
• Keeping the goals, protocols and organizational structure as simple as possible
• Facilitating cooperation among the investigators designing and conducting the studies and clinical research organizations with expertise in regulatory issues for each country
• Enhancing protocol design by seeking input from thalassemia patients and families
• Developing a framework that rewards key investigators for timely attainment of study milestones

Meeting attendees identified high priority scientific areas including:

• Studying chelation therapy to determine factors that may predispose to poor responses to chelation and determining optimal management of chelation therapy in children to prevent iron overload; preventing iron injury and identifying factors that modulate iron distribution and toxicity
• Investigating the molecular and cellular mechanisms that underlie globin gene activation and silencing; developing robust laboratory drug screening techniques that are applicable to thalassemia
• Determining the optimal period of bisphosphonate treatment to improve the low bone mass of thalassemia patients and studying the long-term safety profile of bisphosphonate therapy; investigating the risks and benefits of vitamin D therapy in children, adolescents and chronically transfused patients
• Testing the feasibility and efficacy of haplo-identical transplantation for thalassemia; developing a reduced intensity transplantation regimen that will permit hematopoietic stem cell transplantation in a broader range of patients
• Improving the efficiency of stem-cell targeted gene transfer; determining the degree of myelosuppression required for high-level engraftment of genetically modified stem cells

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Structure and Content of the Workshop

Subcommittees of experts assembled before the workshop to develop opinions on five topics:

• Iron Overload: Clinical Monitoring and Chelation Therapy
• Fetal Hemoglobin
• Stem Cell Transplantation
• Gene Therapy
• Endocrine Disorders/Bone Disease/Growth and Development

Each subcommittee considered four questions:

1. What are the clinical research priorities currently facing the thalassemia community?
2. What are the most important clinical trials (Phase I, II, and III) that should be undertaken?
3. How can successful study completion and patient recruitment be optimized?
4. What is the role of international collaborations in thalassemia clinical research?

The first day of the workshop, representatives from each subcommittee presented recommendations for clinical research priorities. On the second day of the workshop, experts in thalassemia clinical trial research described the current status of clinical trials conducted in the U.S. and Thailand. The workshop was co-chaired by Drs. Suthat Fucharoen of the Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University, Thailand and Dr. Cheryl Hillery, Professor of Pediatrics at the Medical College of Wisconsin. The NHLBI Deputy Director, Dr. Susan Shurin, underscored the need for workshop attendees to address issues of public health, critical scientific questions and opportunities in thalassemia globally, such as the state of curative and supportive care, how to prolong longevity, and priorities for undertaking research activities that would yield the largest payoff for the most patients. Drs. Griffin Rodgers, Director, NIDDK, and Dr. W. Keith Hoots, Director, Division of Blood Diseases and Resources, NHLBI welcomed the participants and endorsed the need for a global approach to thalassemia clinical research. Information provided at the workshop will help inform NHLBI and NIDDK in the development of future thalassemia research initiatives.

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Reports From Subcommittees

Iron Overload: Clinical Monitoring and Chelation Therapy

• Chelation therapy studies should evaluate: combined and/or serial usage of licensed drugs such as deferasirox and deferoxamine or deferasirox and deferiprone; novel iron chelators; genetic or other factors that may predispose to poor chelation response; optimal management of chelation therapy in young children to prevent iron overload; optimal usage of T2* and magnetic resonance imaging to guide chelation therapy; and prospective long-term chelation compliance.
• Studies should determine whether antioxidant therapies are beneficial in preventing iron injury.
• Studies of hepcidin are needed in thalassemia animal models and patients to: understand the role of anemia, hypoxia, ineffective erythropoiesis and iron overload on hepcidin synthesis; determine whether measurement of plasma hepcidin has prognostic utility; and determine whether hepcidin agonists modify transfusional iron overload and decrease iron distribution to the heart and gastrointestinal tract.
• Clinical studies are needed to: identify factors that modulate iron distribution and toxicity; study variations in distribution of extra-hepatic iron from patient to patient; determine genetic modifiers that may affect iron distribution; and examine environmental or treatment-related differences (other than chelation therapy) such as blood transfusion strategy that affect iron distribution.
• Non-transferrin bound plasma iron (NTBI) should be studied to: better determine the mechanisms of cellular uptake; define the nature and speciation of NTBI; identify the factors determining NTBI levels; and clarify the relationship between NTBI and speciation with extra-hepatic iron distribution.
• Magnetic resonance imaging studies should be conducted to study the relationship between endocrine iron loading and end-organ dysfunction.

Fetal Hemoglobin

• Molecular and cellular studies are needed to better understand globin gene activation, switching and silencing. It is important to identify the drivers of globin activation and silencing to enable therapeutic interventions that are more locus restricted.
• A central database of all compounds identified as having HbF induction potential and a central drug development resource should be developed.
• Robust laboratory drug screening techniques need to be developed that are applicable to thalassemia.
• Clinical trials should be undertaken with DNA methyl-transferase inhibitors and short-chain fatty acids.
• The Electronic Infrastructure for Thalassemia Research Network (Ithanet), a Euro-mediterranean network of research centers conducting molecular and clinical research of thalassemia and related hemoglobinopathies, should be used for conducting international clinical trials.

Endocrine Disorders/Bone Disease/Growth and Development

• Low bone mass affects approximately two-thirds of thalassemia patients. Treatment with bisphosphonates improves the low bone mass of thalassemia patients, however, additional trials are needed, especially in children and adolescents, to determine the optimal duration, dose and schedule of treatment and a long-term safety profile of bisphosphonate therapy.
• Trials of anti-resorptives, bone anabolic agents, vitamin D, physical activity, and combination therapies are needed for patients who fail to respond to bisphosphonate therapy.
• Vitamin D abnormalities are prevalent in thalassemia. Studies are needed, particularly in children, adolescents and chronically transfused patients, to evaluate vitamin D dosage on bone mass, inflammation, immune responses and cardiac function.
• Studies are needed to determine the effects of iron overload and chelation on gonadal function and fertility.
• Trace element deficiencies (zinc, copper and selenium) are more common in thalassemia than healthy cohorts and have been linked to altered immune function and low bone mass. Deferiprone induces zinc deficiency in approximately 15 percent of thalassemia patients. Studies are needed to determine the effects of optimal deferasirox dosage on trace elements and the effect of micronutrient replacement on chelator efficacy.
• Diabetes occurs in 10 percent of thalassemia patients. Studies are needed to define the cardiovascular complications of glucose abnormalities and to identify optimal treatment options for impaired glucose tolerance in aging thalassemia patients.

Stem Cell Transplantation

• More than 900 thalassemia patients have received sibling-matched blood or marrow hematopoietic stem cell (HPSC) transplants with an overall survival rate of 73 percent. Since only 25 percent of patients have a matched HSPC related donor, there is a vital need for alternative donors and transplantation strategies. Pilot studies are needed to test the safety and efficacy of haplo-identical transplantation and reduced intensity conditioning regimens.
• Transplantation studies should evaluate the role of alloimmunization in transplant outcomes and optimal strategies to prevent and control graft versus host disease.
• Prognostic factors which predict complications and early death in thalassemia should be refined to better identify transplantation risks.

Gene Therapy

• For gene therapy to succeed in ß-thalassemia patients, clinically effective levels of vector-transduced, normal ß-globin gene expression and HPSC chimerism are necessary. Small scale, pilot clinical studies and concurrent primate studies are needed to improve the efficiency of HSPC-targeted gene transfer and to determine the myelosuppression level required for stable engraftment of genetically modified cells.
• Patients should be carefully screened to identify those who have residual capacity for red cell production to enhance the efficacy of gene therapy.
• Studies are needed to determine the safety and feasibility of cytokine (Granulocyte-Colony Stimulating Factor and other agents) mobilization and transduction of peripheral HSPC from thalassemia patients.

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Clinical Trials in Thalassemia

The Thalassemia Clinical Research Network: Accomplishments and Challenges

Janet Kwiatkowski, MD, Thalassemia Program, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Ellis Neufeld, M.D., Ph.D., Children's Hospital Boston reviewed the accomplishments and challenges of the Thalassemia Clinical Research Network (TCRN).

The TCRN, funded by the NHLBI (2000-2005 and competitively renewed 2005-2010), consists of six core clinical sites, 26 satellite sites throughout the United States, Canada, and England, and a Data Coordinating Center (New England Research Institute). The TCRN's goal is to accelerate research in the management of thalassemia through multicenter trials.

The TCRN strengths include: the thalassemia experts and statisticians who develop studies and identify important research goals and findings; access to a critical mass of patients for studies; a website that facilitates communication, data analysis and publications; collaborations between core and satellite sites, and with CDC Surveillance Project, the Cooley's Anemia Foundation, other countries, other networks, and pharmaceutical companies; and, support for junior investigators to perform and publish clinical studies.

The TCRN developed a study Registry and the following Registry-based studies:

• The Longitudinal Cohort Study (TLC) builds baseline data and other information from the Registry by adding annual data collection to describe genotype-phenotype variability, the prevalence and incidence of complications specific to thalassemia and its treatment, assessments of iron burden and therapeutic adherence, and quality of life.
• Objectives of the Cross Sectional Observational Study of Low Bone Mass in Thalassemia are to determine the prevalence of low bone mass, fractures, and bone pain and evaluate the interaction of endocrine, genetic and environmental factors as well as transfusion and chelation regimens on the development of low bone mass.
• The Pilot Study of Response of Oxidant-Stress Induced Injury and Mitochondrial Dysfunction Biomarkers to Treatment with Iron Chelators is an ancillary study to the Novartis ICL-670 107 study which estimates the magnitude of iron-induced oxidative stress and inflammation and compares deferoxamine with deferasirox treatments.
• The Assessment of Pain Survey is a survey to assess the prevalence of pain in subjects with transfusion and non-transfusion dependent thalassemia.

Five major interventional trials in the TCRN include:

1. Safety and efficacy of Peg-interferon and ribavirin for the treatment of hepatitis C
2. Phase 2 randomized, double-blind, placebo controlled trial comparing the effect of deferoxamine with and without oral deferiprone on left ventricular function in adults with transfusion-dependent thalassemia
3. Phase 2A study of subcutaneous decitabine in patients with thalassemia intermedia
4. Pilot study of oral sildenafil for the treatment of pulmonary hypertension in thalassemia
5. Reduced intensity unrelated donor HSPC transplantation protocol

The major challenges for the TCRN include: the slow pace of protocol development, patient enrollment, data analysis and manuscript completion; the need to recruit patients from outside the U.S. because of the small number of thalassemia patients in the U.S.; and, difficulties for launching international sites (translation of numerous trial forms, differences in local regulatory authorities, indemnification and insurance requirements in the European Union).

Facilitating NIH-Funded International Clinical Trials in Thalassemia

Francis P. Crawley, MA, FFPM, Good Clinical Practices Alliance Europe reviewed the European Directive as it pertains to conducting clinical trials in the European Union (EU). EudraLex includes the rules governing medical products in the EU, however, clinical investigators also must also adhere to local and national rules. The International Good Clinical Practices (GCP) framework includes: general—International Council on Harmonization Good Clinical Practices and World Health Organization (WHO) Good Clinical Practices; regional/applied—U.S. Code of Federal Regulations and EU GCP; and national/applied—GCP guidelines apply to India, China, Russia, Singapore, Malaysia, Indonesia, South America, South Africa, and Turkey.

The European Directive, implemented in 2001, directs national governments to implement laws on GCP in the conduct of clinical trials for medicinal projects for human use. This applies not only to pharmaceutical companies, but also to investigators conducting clinical trials. It defines the roles of the investigator, sponsor, competent authority (EU GCP inspections), and has a review timeline of 60 days from the date of receipt of a valid application to give its reasoned opinion. The structures and regulations differ in Member States for IRBs and ethics committees. Many of these countries have developed their own regulations for implementing the EU Directive. Differences among member states pose special challenges including:

• Cooperation across member state borders and with third countries (including U.S.)
• Education programs for Ethics Committee members
• Reviewing Suspected/Unexpected Serious Adverse Reactions
• Reviewing financial matters, including payments to subjects, investigators, and sites
• Reviewing insurance and indemnity
• Patient representation on Ethics Committees
• Phase I clinical trials
• Pediatric clinical trials

Regulations governing pediatric clinical trials are similar to U.S. regulations. To undertake pediatric studies in Europe, the European Medicines Agency requires an early plan for review. The EU has regulations for orphan drug development.

Major challenges include the lack of consistency across member states for:

• The contents of the Clinical Trials Application
• The definition of an Investigational Medicinal Product
• The definition of substantial amendment
• Good Manufacturing Practices requirements for Investigational Medicinal Medicinal Products

Clinical Trials in Thalassemia: Imperatives and Insights from the Community

Gina Cioffi, National Cooley's Anemia Foundation, reviewed the Cooley's Anemia Foundation (CAF) perspective of clinical trials and provided recommendations to enhance patient enrollment in studies.

Patient recruitment and enrollment in clinical trials is a major challenge. Among people who suffer from severe chronic illness, only 6 percent participate in clinical trials. Almost 50 percent of trial delays result from patient enrollment problems and 86 percent of all U.S. clinical studies fail to recruit the required number of subjects on time. Industry wide there is a 20-30 percent patient dropout rate in Phase II/III studies.

The CAF informs patients and families about trials to further the conversation between the patient and the clinical investigator and the patient and his/her physician without dispensing medical advice or encouraging consent to take part in a trial. The CAF maintains a balance in presenting studies available without overtly promoting an opportunity through a Thalassemia Action Group newsletter, conferences and an interactive website listing studies and other relevant information.

Consideration of the patient point of view can enhance an investigational concept and lead to more rapid enrollment. Enrollment success depends on a good fit among the protocol design, participant sites, and the target population. The major challenges for patient are:

• Lack of patient/family role in design
• Participating while working
• Lack of follow up on trial conclusions.

Patients would like trials designed more to their convenience:

• Allow for hospital stays no longer than 3 days
• Conduct studies outside of TCRN sites
• Facilitate transportation.
• Consider motivators such as:
  • Financial incentives
  • Trials offering "hope"
  • More assurance about safety
  • More participation from younger adult patients
  • More direct benefit to the adult patients
  • A report showing academic and career success among patients

Recommendations for specific areas of study include:

• Effectiveness of L1 in raising T2*
• Quality of Life studies
• Additional study of chelation therapy
• Additional study on noninvasive iron measurements
• Clotting Risks
• Infection
• Gene therapy
• Patients with low ferritins and abnormal T2*

Thalassemia in Southeast Asia – An Overview

Suthat Fucharoen, MD, Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University provided on overview of thalassemia demographics in Southeast Asia.

There is a high prevalence of thalassemia and abnormal hemoglobin in Southeast Asia with variability of different ethnic-specific mutations in each country: α-, β-thalassemia and abnormal hemoglobins (Hb) such as Hb E and Hb Constant Spring are common in Southeast Asia; β-thalassemia and Hb Constant Spring are scattered throughout the region at 1-8 percent, however, α-thalassemia and Hb E are focal. In the northeastern part of Southeast Asia, near Laos and north Thailand, α-thalassemia occurs at frequencies of 30-40 percent. Hb E is common among the Thai-speaking population living at the junction of Cambodia, Laos, and Thailand where the prevalence of Hb E reaches 50-60 percent.

Thalassemia presents an increasingly severe public health burden for many countries in Southeast Asia.

• It is difficult to diagnose thalassemia at small health care units because of the heterogeneity of the disease and because carriers have no symptoms.
• Treatment of severe thalassemia with regular blood transfusions and iron chelation is expensive. Therapy is usually performed only in large cities, which requires some patients to travel long distances. Bone marrow transplantation, the only cure, is less expensive than long-term transfusion and iron chelation therapy.
• Policies addressing prevention, such as screening for all pregnant women, would be more cost effective than therapy.
• It is difficult to persuade international health agencies and governments that thalassemia is a serious public health issue when compared with communicable diseases that the countries are handling.

A WHO report adopted by the 57th World Health Assembly in 2004, Genomics and World Health, recommended that local networks should be established to help member countries evolve services. An Asian Network for Thalassemia Control was formed to disseminate good practice in the control and management of thalassemia in Asia and to provide a central forum for interacting with individual governments and international health agencies to provide support for the objectives. The objectives are:

• Develop and disseminate adequate screening techniques for determining the frequency of the different forms of thalassemia in Asian countries,
• Develop education and screening programs for prenatal diagnosis of thalassemia,
• Develop more adequate approaches to treatment.

Recent Clinical Trials of Chelation Therapy in Thailand

Vip Viprakasit, MD, DPhil, FRCPT, Division of Haematology-Oncology and WHO Collaborating Centre for the Control of Thalassaemia and Haemoglobinopathies, Siriraj Hospital, Mahidol University Bangkok, Thailand reviewed the status of clinical trials of chelation therapy in Thailand.

There are at least 500,000 people with thalassemia in Thailand, with approximately 12,000 new cases annually, and 48,000 at-risk pregnancies. More than 20,000 transfusion-dependent patients require regular transfusion and life-long chelation therapy. An analysis of treatment compliance and related health and social determining factors in Thai thalassemia patients under long-term deferrioxamine (DFO) administration at Faculty of Medicine Siriraj Hospital, Bangkok revealed that 40 percent of 112 pediatric patients with severe thalassemia (49 percent receiving DFO therapy for 2-7 yrs and 51 percent receiving DFO therapy for 7-17 yrs) were reported by their parents as having good compliance with DFO therapy. However, only 14 percent of the cases studied had an average serum ferritin (assayed during the prior year) of less than 2,500 ng/ml (a surrogate marker for adequate chelation therapy with well-controlled iron burden).

Thailand is an ideal location for conducting an iron chelation trial because of its large patient population and its experience with: operating clinical studies under the GCP standard; thalassemia patient care; protecting patient safety; and excellent technical and MRI capabilities. Thailand has four transplant centers and is conducting a multi-center national study on Thai Government-made oral chelator (GPO-L-ONE or deferiprone, DFP) and also international studies on oral chelation therapy on Exjade (deferasirox, DFX).

Recent clinical studies on iron chelation therapy in Thailand include ICL670 (Exjade) trials:

• 2409 (EPIC) & Cardiac sub-studies
• 2206 (DFO VS Exjade)
• 2209 (Exjade in Thal Intermediate)
• 2411 (Exjade in young patients; 2-6yrs)
• Exjade in other anemias: myelodysplastic syndrome.; and pre-transplantation-DFX

Thailand also has undertaken multi-center national studies for clinical efficacy and adverse effects of GPO-L-ONE (deferiprone). This trial, which takes place at five centers in Bangkok, expects to enrol 150 patients (75 pediatric/75 adult) and to complete enrolment by the end of May 2009.

Fetal Globin Induction in Beta Thalassemia: Potential and Pitfalls from Prior Trials—A Model for a Global Health Initiative

Susan Perrine, MD, Hemoglobinopathy Thalassemia Unit, Boston University School of Medicine reviewed her clinical trial experience with hemoglobin-switching agents.

The hemoglobin switching field was founded decades ago for the sole purpose of defining the molecular and cellular mechanisms of fetal globin gene reactivation, with the goal of developing therapeutics to reverse the natural silencing of the gene as a natural remedy for the beta globin diseases. Fetal globin gene induction as a therapeutic modality is particularly appealing because:

• It is endogenous in all living humans.
• Continued expression is safe.
• Adequate expression is effective (thalassemia trait).
• It is integrated in hematopoietic stem cells.

Although there are challenges to reactivating the endogenous fetal globin genes to therapeutic levels in the diverse thalassemias, the necessary target level has been accurately identified to induce γ globin expression enough for non-α globin chains to balance α globin chain synthesis by 65-70 percent (thalassemia trait ratios).

The proof of concept in reducing anemia and eliminating long-term transfusion dependency in thalassemia has been established with three classes of therapeutic candidates. These classes of therapeutics have produced significant hematologic responses with rises in total hemoglobin (of 1-5 gms/dl) in the thalassemias:

• Chemotherapeutic (cytotoxic) agents – 5 azacytidine, hydoxyurea
• Short chain fatty acids (butyrate, phenylbutyrate, and isobutyramide)
• Erythropoietin (EPO) and darbopoietin

The agents have corrected the phenotypes from thalassemia major, intermedia, and trait. Synergistic activity has been found when combining two groups of therapeutics: 5 azacytidine (demethylating agent) with butyrate, and butyrate with EPO.

Therapeutic agents are needed that are more feasible for widespread, global application—oral agents that act at lower doses and are patient friendly, ideally have dual actions of improving red blood cell survival, not reducing red blood cell proliferation, and are safe for long term use (not cytotoxic or mutagenic). One agent, HQK -1001, which was developed entirely with NIH funding, has begun clinical testing in Thailand and Lebanon for beta thalassemia and in the U.S. for sickle cell disease, supported by the biotechnology company HemaQuest Pharmaceuticals, Inc.

Factors that influence responses in to Hb F induction and require attention in clinical trial design include: baseline Hb F levels, baseline EPO levels, splenectomy status, and iron supplements. Other factors that affect responses include genetic modifiers and metabolism differences.

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List of Abbreviations

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