fda ema

The European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) have set up a new ‘cluster’ on rare diseases to share experiences and best practices on each other’s regulatory approach to the development of medicines for these diseases.

The agencies will exchange information on various aspects of the development and scientific evaluation of medicines for rare diseases. These include topics such as:

  1. the design of clinical trials in small populations and the use of statistical analysis methods;
  2. the selection and validation of trial endpoints, i.e. target outcomes of a trial;
  3. preclinical evidence to support development programmes;
  4. the design of post-marketing studies, in particular in the context of early access mechanisms such as EMA’s conditional marketing authorisation and FDA’s accelerated approval;
  5. risk management strategies for long-term safety issues with medicines for rare diseases.

The cluster will provide a forum for confidential exchange of draft documents, policies under development, and more detailed information supporting the scientific basis for decision making on medicine development.

More information: Press release

CooleySAnemia

On September 27, the Cooley's Anemia Foundation (CAF) announced that four new CAF Medical Research Fellowships and one renewal Fellowship have been awarded for the 2016-2017 grant cycle. In addition, this year a new Clinical Research Grant was awarded to support ongoing clinical research in thalassemia. The total amount of funding for the five research Fellowships and one Clinical Research Grant for the current cycle is $202,500.

The following individuals have been awarded the fellowships:

  1. Katie Carlberg, MD, of the Children’s Hospital Oakland, is developing a noninvasive approach to prenatal diagnosis of thalassemia in her study, “SNP Discovery and Characterization of the Human β-Globin Gene for Non-Invasive Prenatal Testing for β-Hemoglobinopathies”
  2. Karen Finberg, MD, of Yale Medical School, is studying the process of how the gene NCOA4 mediates the degradation of ferritin in her study, “The Role of NCOA4 in the Regulation of Hepatic Iron Stores”
  3. Merlin Nithya Gnanapragasam, MD, PhD, of Icahn School of Medicine at Mount Sinai in New York City, is performing experiments in HuDEP-2 cells to examine the consequences of mutation of the EKLF upstream enhancer region in her project, “Genome Editing of EKLF Enhancer Elements for Fetal Hemoglobin Induction”
  4. Kim Vanuytsel, PhD, of Boston University, is studying ineffective erythropoiesis and iron regulation in beta thalassemia using induced pluripotent stem cells in her study, “Induced Pluripotent Stem Cell (Ipsc)-based Modeling of β-Thalassemia”
  5. Daniel Bauer, MD, Children’s Hospital Boston (Renewal Fellowship), is investigating how genome editing may be useful in creating greater expression of fetal hemoglobin in adult thalassemia patients in his project, “Genome Editing of β-Globin Gene Cluster Repressive Elements for β-Thalassemia”
  6. Nathawat Sibmooh, MD, PhD, of Mahidol University in Bangkok (Clinical Research Grant), is investigating the issue of immediate treatment for thalassemia patients who have developed pulmonary hypertension in his study, “Effect of inhaled, nebulized nitrite on pulmonary arterial pressure in beta-thalassemia patients with pulmonary hypertension”

More information: CAF's announcement

Nature

Current clinical gene therapy trials for β-thalassaemia and sickle cell disease (SCD) rely on addition of a functional but reduced β-globin gene to the genome of haematopoietic stem and progenitors cells (HSPCs) of patients [↗]. Early results from the latest trial [↗] indicate that gene addition might be therapeutic even for severe forms of the disease, but concerns over safety and universal applicability remain, and alternative approaches are sought. Notably, individuals with elevated γ-globin levels (and thus hereditary persistence of fetal haemoglobin, HPFH) show extremely mild disease symptoms, spawning attempts to exploit the phenomenon by engineered activation of the endogenous γ-globin. Genome editing instead of gene addition might minimise the risk to patients and has therefore been taken up enthusiastically for preclinical studies [↗]. Using the technology to activate the endogenous γ-globin might moreover be applicable to all β-thalassaemia mutations and sickle cell disease alike.

Genome editing for therapeutic activation of γ-globin has recently seen two landmark papers advancing the field. In 2015, Canver et al. [↗] used genome editing with the CRISPR/Cas9 system to disrupt erythroid-specific expression of the γ-globin repressor BCL11A, achieving high levels of γ-globin in normal HSPCs in the process. A publication by Traxler et al. in Nature Medicine this August [↗] takes an alternative approach based on the same concept of sequence disruption, instead mimicking a naturally occurring HPFH mutation that introduces a 13-bp deletion in the γ-globin promoter [↗] (see mutation details in IthaGenes [↗]). Encouragingly, the study once again shows high levels of γ-globin induction and additionally demonstrates significant phenotypic correction of SCD HSPC-derived erythroid cells in culture. However, at the heart of high efficiencies in HSCPs in both studies are integrating lentiviral vectors for continued expression of the CRISPR/Cas9 elements; while this allows accumulation of correction events in culture, it also accumulates any unwanted (off-target) editing events and moreover also poses the same risk of insertional mutagenesis as gene-addition approaches. Although genome editing therefore still has some way to go towards clinical application for β-globinopathies, γ-globin induction appears to be one of the most promising paths to get there. 

CooleySAnemia

The Cooley’s Anemia Foundation (CAF) announced that is accepting applications from individuals with thalassemia for the 2016 CAF-ApoPharma Distinguished Scholar Award. The CAF-ApoPharma Distinguished Scholar Award, which was established in 2014, is made possible through a grant from pharmaceutical manufacturer ApoPharma.

CAF will award up to two scholarships to a U.S. citizen(s) with a clinically significant form of thalassemia pursuing doctoral studies in biomedical sciences, including medicine, pharmacy, nursing and basic research. (Ph.D., M.D., D.D.S., Pharm.D., D.V.M, etc.) in the United States or abroad. Total annual funding available for the awards is $20,000. Students enrolled in a doctoral program for the fall of 2016 are eligible to apply. A clinically significant form of thalassemia would include alpha thalassemia major, beta thalassemia major, beta thalassemia intermedia, e beta thalassemia, hemoglobin H disease, or hemoglobin H disease-Constant Spring.

Applications must be received at CAF by September 30, 2016.

More information: CAF website

fda ema

The European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) have set up a new ‘cluster’ on patient engagement. The cluster will provide a forum to share experiences and best practices on the way the two agencies involve patients in development, evaluation and post-authorisation activities related to medicines. This is especially important for rare diseases who show a high level of engagement in providing real life experiences, expertise as well as contributing to scientific discussion. The increased interaction through the new cluster will allow EMA and FDA to exchange information on how they engage with and involve patients in their work and on priorities and goals to scale up future engagement with patients. The FDA and EMA currently collaborate effectively for making joint applicants for providing orphan designations.

More information: Press release, Terms of reference [PDF], Orphanews

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