BIOCHEMISTRY, BIOMEDICINE & PHARMACEUTICS

Gene Therapy for Rare Diseases:  CONSIDERATIONS FOR CLINICAL TRIALS      Many rare disorders are serious, with no approved treatments, and represent substantial unmet medical needs for patients. Because of phenotypic heterogeneity, disease manifestations are likely to vary in onset and severity. Information obtained from a natural history study can potentially provide critical information to guide every stage of drug development from drug discovery to determining effectiveness and safety of the drug in treating a disease. If there is insufficient information on the natural history of the disease to inform the selection of a historical comparator or to inform clinical endpoint selection, additional natural history data may be needed. In a majority of these disorders, clinical manifestations appear early in life, and there are ethical and regulatory considerations regarding enrollment of children into clinical trials. These considerations should inform the design of b...

FDA Guidance on Human Gene Therapy for Rare Diseases CONSIDERATIONS FOR CHEMISTRY, MANUFACTURING, AND CONTROLS  The general chemistry, manufacturing, and controls (CMC) considerations for product manufacturing, testing, and release of GT products for rare diseases are the same as those described for other GT products.  However, some aspects of the development programs for rare diseases, such as limited population size and fewer lots manufactured, may make it challenging to follow traditional product development strategies. In traditional product development, critical quality attributes (CQAs) of the product are evaluated during each phase of clinical development, and characterization data from many drug product lots are correlated to clinical outcomes.  Smaller study populations may result in the need for fewer manufacturing runs, which can make it difficult to establish the critical process parameters (CPP) necessary for ensuring CQAs. In addition, GT products may have C...

 Immune responses to therapeutic protein products may pose problems for both patient safety and product efficacy. Immunologically based adverse events, such as anaphylaxis, cytokine release syndrome, and cross-reactive neutralization of endogenous proteins mediating critical functions, have caused sponsors to terminate the development of what otherwise may have been efficacious therapeutic protein products. Unwanted immune responses to therapeutic protein products may also neutralize their biological activities and result in adverse events not only by inhibiting the efficacy of the therapeutic protein product but also by cross-reacting to an endogenous protein counterpart, leading to loss of its physiological function (e.g., neutralizing antibodies to therapeutic erythropoietin cause pure red cell aplasia by also neutralizing the endogenous protein).  The regulatory agencies including FDA& EMA have outlined and recommended the risk-based approach to evaluating and mitigati...

 The Food and Drug Administration (FDA), European Medicinal Agency (EMA), and International Consortium for Harmonization (ICH)  have issued guidances that are intended to provide recommendations for the validation of bioanalytical assays for chemical and biological drug quantification and their application in the analysis of study samples.  Type of Bioanalytical Method Validation Full Validation  Bioanalytical method validation is essential to ensure the acceptability of assay performance and the reliability of analytical results. A bioanalytical method is defined as a set of procedures used for measuring analyte concentrations in biological samples.  Full Validation Full validation of a bioanalytical method should be performed when establishing a bioanalytical method for the quantification of an analyte in clinical and in pivotal nonclinical studies. Full validation should also be performed when implementing an analytical method that is reported in the literatu...

Disorders of Heme Synthesis & Porphyrias  X-Linked Sideroblastic Anemia  - is an inherited disorder caused by the lack of an enzyme in ALA synthase 2 - results in decreased hemoglobin synthesis in erythroid tissues - manifest as microcytic and hypochromic anemia Prevalence  -  Rare genetic disorder Inheritance Pattern X-linked disorder Pathological Manifestation  - Mutation of the  ALAS2  gene impairs the activity of ALA synthase 2 in erythroid tissue - Decreases heme and hemoglobin synthesis  - An increased build-up of the excess iron in the erythroblast forming a ring sideroblast (visualized by Prussian blue staining) Diagnosis  - Complete blood count and reticulocyte count - Decreased hemoglobin & Microcytic and Hypochromic RBC - Iron overload - Bone Marrow aspirate shows sideroblasts ring Confirmatory Diagnosis - Mutation analysis of  ALA2 g ene  Treatment  - Treatments are available to relieve the symptoms - Survei...

Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by dystrophin gene (DMD) mutations. The Estimated incidence of DMD worldwide is 1 in 5000 live male births.  The DMD gene encodes for the cytoskeletal protein dystrophin. Dystrophin is a 427-kDa cytoskeletal protein required for sarcolemmal stability. The deficiency of the protein leads to susceptibility to repeated cycles of necrosis and regeneration as well as diminished regenerative muscle capacity, resulting in muscle fibrosis. DMD is a progressive disorder with the loss of ambulation between age 9 and 14 years, followed by respiratory complications and cardiac function decline, and ultimately death. Gene Therapy for DMD The dystrophin is one of the large proteins, and the packaging of cDNA that encodes the full protein into the AAV vector (size limit- 4,500 to 5000 bp) is not possible. Evidence suggests that the truncated dystrophin are partially functio...

The Annual J.P. Morgan Healthcare Conference is the largest and most informative healthcare investment symposium in the industry. The 39th J.P. Morgan Healthcare Conference is will be held from January 11-13, 2021 Participating Companies 10x Genomics, Inc. Abbott Abiomed Acadia Pharmaceuticals Inc Acceleron Acceleron Acceleron Pharma Inc. Acutus Medical, Inc. Adaptive Biotechnologies Aeglea BioTherapeutics, Inc. Agile Therapeutics, Inc. Akebia Therapeutics Akero Therapeutics AlloVir Alnylam Alpine Immune Sciences, Inc. Amarin Corporation plc Amedisys, Inc. AngioDynamics Aptinyx Inc Arena Pharmaceuticals, Inc. argenx SE Ascendis Pharma Atea Pharmaceuticals, Inc. Autolus Therapeutics plc Avantor and Financial News Avidity Biosciences, Inc. AVITA Medical B Baxter International Inc. BD (Becton, Dickinson and Company) Berkeley Lights, Inc BeyondSpring, Inc. Biomarin Pharmaceuticals Bio-Techne Corporation BioXcel Therapeutics Boston Scientific Corporation Bristol Myers Squibb C Chinook Thera...