BIOCHEMISTRY, BIOMEDICINE & PHARMACEUTICS

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...

What are Adverse Events? Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, and does not imply any judgment about causality.  An adverse event can arise with any use of the drug (e.g., off-label use, use in combination with another drug) and with any route of administration, formulation, or dose, including an overdose.  What is a suspected adverse reaction?  An adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions where there is reason to conclude that the drug caused the event.  What is a suspected adverse reaction? Suspected adverse reaction means any adverse event for which there is a reasonable po...

Adaptive Design Clinical Trials An adaptive design is defined as a clinical trial design that allows for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial. The modifications may include the eligibility criteria, study dose, treatment duration, study endpoints, laboratory testing procedures, diagnostic procedures, criteria for evaluation, and assessment of clinical responses. Statistical procedures include randomization, study design, study hypotheses, sample size, data monitoring, and interim analysis, statistical analysis plan, and/or methods for data analysis.  Learn More

Lumasiran Lumasiran, an investigational, subcutaneously administered RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene encoding glycolate oxidase (GO) – in development for the treatment of adults and children with primary hyperoxaluria type 1 (PH1). Primary hyperoxaluria type 1 (PH1) PH1 is an ultra-rare orphan disease characterized by excessive oxalate production, which can lead to end-stage renal disease (ESRD) and other systemic complications. PH1 affects approximately 3.5 to 4 individuals per million in Europe and the United States. Heterogeneity in disease manifestation often contributes to delays in diagnosis, with a median time to diagnosis of approximately six years. PH1 leads to progressive kidney damage, and patients with advanced kidney disease require intensive dialysis to help filter waste products from their blood until they are able and eligible to receive a dual or sequential liver/kidney transplant, an invasive procedure associated with a high risk of ...

Highlights of AAV5-RPGR Gene Therapy Program - AAV5-RPGR is an investigational gene therapy product for RPGR-Associated X-Linked Retinitis Pigmentosa - Developed by Janssen (Johnson & Johnson) & MEIRAGTx - 12-months ongoing Phase 1 & 2 clinical trial data  were presented at AAO 2020 conference - Data showed that low and intermediate doses were well-tolerated -  Demonstrated statistically significant sustained or increased vision improvement across multiple metrics and modalities RPGR-Associated X-Linked Retinitis Pigmentosa In patients with XLRP, the photoreceptors that are responsible for converting light into signals that are sent to the brain, function poorly, leading to a degeneration of the retina and legal blindness in adulthood.  Gene Therapy Platform AAV5-RPGR is an investigational gene therapy product. It is delivered via subretinal injection targeting the central retina in the eye that was more affected at baseline. Regulatory Status of AAV5-RPGR Gen...

Witztum  et al. recently published (New England Journal of Medicine, 2019) results from phase 3 clinical trials on efficacy and safety of antisense oligonucleotide Volanesoren in treatment of familial Chylomicronemia. Familial Chylomicronemia is a genetic disorder caused by mutation of enzyme lipoprotein lipase or associated proteins required for its function. Valonesoren inhibits the synthesis of Apoc-III, thereby decreasing the triglycerides level in patients with hypertriglyceridemia. Based on this clinical study, IONIS pharmaceutical obtained a positive opinion and conditional approval to market the product in the European Union region. ( Committee for Medicinal Products for Human Use- CHMP   Public Assessment Report   ) . The following are the excerpts and the result summary from the study: Witztum et al, 2019, NEJM Journal: New England Journal of Medicine Title: Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome. Abstract BACKGROUND: F...

 Zolgensma is the first gene therapy product approved for the treatment of children less than two years of age with Spinal Muscular Atrophy (SMA). Norvastis obtained the approval of the drug May 2019 & has been a blockbuster with a price tag of 2 million dollars. In the recent  FDA inspections, FDA observed that the standards were not meet in accordance to GMP guidance. Those include Failure to follow the standard procedures Failure to report complete data sets for the potency testing of the gene therapy product Failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed. Laboratory records do not include completed records of any testing and standardization of laboratory standards. What action FDA is taking? FDA are carefully assessing the issue of the manipulation of the product testing data used in the production process and are conducting a thorough assessment of the information from a recently com...

Vestronidase alfa, an enzyme replacement therapy, is an approved drug for the treatment of MPS VII. The approval of this drug has set a precedent for future drug development for the regulators and drug developers. First, the pivotal clinical trial was conducted to evaluate the totality of the clinical data for determining the efficacy of the treatment, therefore, no primary clinical endpoint was established. Second, the drug obtains approval positive outcome on the secondary endpoint; changes in the urinary glycosaminoglycan, from placebo control. The glycosaminoglycan is also the pharmacodynamic biomarker that reflected the efficacy of the drug. Third, the novel multi-domain clinical responder index was designed to evaluate the treatment outcomes and included six minutes walk test (6MWT), forced vital capacity (FVC), shoulder range motion, visual acuity, BOT-2 fine, and gross motor activity. While MRDI evaluation per subject suggested the stabilization of clinical condition if no...

What are Hemophilia disorders ? Hemophilia is the group of bleeding disorders that are caused by a deficiency of proteins (factors) of the blood clotting cascade. Hemophilia A is caused by the deficiency of factor VIII protein and Hemophilia B is caused by a downstream protein factor IX. The deficiency of the factors VIII and IX affect the clotting cascade, resulting in higher and spontaneous bleeding episodes. The severe bleeding disorder leads to spontaneous bleeding in joints and soft tissue resulting in arthropathy; and increased risk of intravascular and intracranial hemorrhage. Why the development of new treatment paradigm is necessary? The standard treatment for hemophilia (A and B type) is the intravenous infusion of an exogenous clotting protein more than once a week to prevent bleeding. In addition, the development of inhibitors decreases the efficacy of the exogenous replacement factor and the severe hemophilia patients do not respond to these therapies.  There...

Inherited Biallelic RPE65 Mutation-Associated Retinal Dystrophy Inherited retinal dystrophies are a group of rare blinding conditions that are associated with progressive visual dysfunction. This rare genetic disorder is classified based on the phenotype, and the mutation in any one of more than 220 different genes are causal for this rare blinding condition. Retinitis pigmentosa is the most common subgroup of inherited retinal dystrophy characterized by reduced ability to perceive light and progressive loss of visual field. RP is genetically heterogeneous, and mutations in any one of over one hundred genes can cause the phenotype. RPE65 gene encodes all-trans-retinyl ester isomerase, an enzyme crucial to the retinoid cycle Autosomal recessive biallelic mutations in this gene lead to the inability to regenerate 11-cis-retinal, via 11-cis-retinol, in the retinal pigment epithelial cells RPE cells. This impairs the ability of RPE cells to respond to light, which disrupts the vis...