06 Aug Top 5 Emerging Therapeutics for Crigler – Najjar Syndrome
Crigler Najjar Syndrome, also called hyperbilirubinemia, is a chronic condition characterized by high levels of unconjugated bilirubin in the blood. The disease manifests as Jaundice at birth, and can progressively lead to kernicterus, a condition in which the accumulation of unconjugated bilirubin can damage brain and nerve tissues. Those suffering from Kernicterus exhibit hypotonia, lethargy, choreoathetosis, intellectual and hearing disabilities.
There are two types of the disorder; CN1 is the severest form of the disease, with patients succumbing in the childhood due to kernicterus and CN2, which is less severe, with patients progressing into adulthood with proper medication and care. The disease is primarily caused by the lack of a specific UGT1A1 gene in the liver that aids in the metabolism of bilirubin and is inherited as an autosomal recessive trait. It affects 1 in 750,000-1,000,000 people according to an estimate.
The first line of treatment is the use of therapeutics that can reduce the bilirubin levels in the blood; it also helps arrest the progression of the disease to kernicterus. In case of CN2, Phenobarbital is prescribed. For more severe forms of the disease, phototherapy is the mainstay, however it has severe limitations, as with increasing age the therapy becomes less effective owing to changes in skin and body mass.
The use of fluorescent light can also lead to exposure to ultraviolet radiation. There are alternatives such as light-emitting diodes (LEDs) technology that emit a blue light and are safer, but these are not widely available. Plasmapherersis is another treatment option where blood is removed and blood cells are separated from plasma and transfused back into the patient. Liver transplant is the only definitive treatment available, but involves huge costs, availability, and the risk of organ rejection and prolonged use of immunosuppressants.
Emerging scientific research into the field is throwing up possibilities such as enzyme replacement therapies (ERT), gene replacement therapy and stem cell transplantation. We take a look at some of the most promising companies that are engaged in addressing the large unmet medical need in this field.
LogicBio Therapeutics (NASDAQ: LOGC)
Market Cap: $206.97M; Current Share Price: 10.22 USD
Data by YCharts
GeneRide, the company’s genome editing platform aims at creating long-lasting solutions for unmet medical needs through a single injection. It uses the natural DNA repair process, known as homologous recombination of natural cells, to introduce transgene at a predetermined spot to the nuclei of the patient’s cells via an infusion. Currently it is using Stanford University’s library of synthetic, non-pathogenic, AAV vectors for its liver program.
Its pipeline is at present focused on making innovative solutions for liver ailments such as Crigler-Najjar, Hemophilia B and AIATD with plans to extend the line to include Muscle and Central nervous system related disorders. The company’s candidate for treatment of CN is LB-301, which has demonstrated promise in proof-of-concept studies. The company is currently pursuing MMA and plans to focus on other indications in 2019.
Logic Bio’s technology offers numerous advantages over traditional therapeutic approaches; firstly by introducing the corrective gene into the patient’s genome at a precise point, it becomes an integral part of the DNA, and leads to a more durable effect something that the conventional gene therapy does not offer. Secondly, its platform is independent of exogenous (foreign) nucleases which reduce the risk of off-target cuts and fatal changes to the patient’s chromosomes. Since they do not use bacteria derived nucleases they eliminate the risk of provoking a strong defense by immune system and genotoxicities.
The third and most important advantage is that by eliminating the use of exogenous promoters which can change the expression of other genes including oncogenes, it reduces the risk of cancer and other genotoxicities.
Audentes Therapeutics (NASDAQ: BOLD)
Market Cap: $1.58B; Current Share Price: 35.70 USD
Data by YCharts
The company’s lead candidate for the treatment of CN is AT342, an AAV8 vector containing a functional copy of the UGT1A1 gene. Clinical trials have demonstrated the efficacy of a single dose of AT342, which can result in durable, dose-responsive and clinically relevant decreases in total bilirubin levels with no adverse events in mice models.
Audentes initiated a phase 1/2 clinical trial named VALENS, a multicenter, multinational, open-label, ascending dose study to test the efficacy and safety of AT342. The key parameters of evaluation are side-effects, immunological parameters, changes in serum bilirubin levels and number of hours on phototherapy. The company is actively seeking opportunities to out license the program.
The company is focused on creating gene therapy products for potentially life-threatening rare neuromuscular diseases. Its pipeline’s lead candidate is AT132, indicated for the treatment of X-Linked Myotubular Myopathy (XLMTM); in addition it is also working on AT982 for the treatment of Pompe disease, and AT307 for the treatment of the CASQ2 subtype of Catecholaminergic Polymorphic Ventricular Tachycardia (CASQ2-CPVT).
Audentes uses its proprietary technology platform and manufacturing expertise to offer services in three areas with large unmet needs, namely gene replacement, vectorized exon skipping, and vectorized RNA knockdown.
International Stem Cell (OTCQB: ISCO)
Market Cap: $5.35M; Current Share Price: 0.71 USD
Data by YCharts
The company has successfully replicated the functioning of primary human hepatocytes, through human parthenogenetic stem cell (hpSC)-derived hepatocytes in animal models, which augurs well for cases where primary hepatocytes cells or donors may not be easily available. This marks a significant shift from phototherapy and blood transfusions to Hepatocyte transplantation, which can overcome the severe shortage of human livers and the need for donated primary hepatocytes.
It has been demonstrated that a single intrasplenic injection of hpSC-derived hepatocytes can significantly affect the plasma indirect bilirubin level, almost similar to the levels achieved by administration of primary hepatocytes. CytoHep is the name given by the company to a group of homogenous population of hepatocyte-like cells, which were manufactured under cGMP, using a proprietary technology to extract high-purity definitive endoderm.
Its pipeline consists of candidates for the treatment of Parkinsons, brain injury and ischemic stroke and osteoarthritis, in addition to neuromuscular disorders. The company recognizes the potential of human parthenogenetic stem cells (hpSC) as they offer easy replication and diverse applications. The company has over 16 issued patents and 91 patents pending worldwide, covering areas such as specific pluripotent hpSC lines of production, methods for research, therapeutic and commercial uses.
ISCO also has a state-of-the-art cell manufacturing facility that confirms to cGMP standards, which is being utilized for development of its own candidates, as well as contract manufacturing various cell therapy products for other biopharmaceutical companies.
Promethera Biosciences SA (Private)
The company is focusing on development of cell-based therapies for treatment of liver diseases, specifically inherited disorders such as Haemophilia, Acute-on-Chronic-Liver Failure (ACLF), fibrosis and Non-Alcoholic Steatohepatits (NASH). Its work is based on HHALPC (Heterologous Human Adult Liver Progenitor Cells), discovered by Professor Etienne Sokal , the co-founder of the company and its chief scientific officer and Dr Najimi at the UCL laboratories (Brussels).
Promethera has established a proof of concept for the application of its technology to treat pediatric patients suffering from Crigler-Najjar syndrome or urea cycle disorders. It has received funding from the Walloon Region, in the form of conditional loans, to conduct phase I/II clinical study with HepaStem in Britain and Belgium. The study is designed to evaluate the potential of liver progenitor cells to restore the functioning of the missing enzyme in patients suffering from liver-based metabolic diseases.
The treatment involves the administration of a Promethera® HepaStem, into a vein leading to the liver, which can possibly do away with the need for invasive surgery such as liver transplantation. It uses allogeneic stem cells from healthy adult human livers (Heterologous Human Adult Liver Progenitor Cells, HHALPC); to treat a variety of diseases ranging from inborn metabolic disorders or orphan diseases in children, to acquired deficiencies in adults such as fulminant hepatitis or liver fibrosis. It has received an orphan drug designation from the European Medicines Agency and the FDA for these indications.
In addition, its HepaScreen uses adult human liver-derived stem cells for biological evaluation of potential new chemical entities. This serves the purpose of being a predictive model to evaluate the hepatic metabolism of chemical compounds. The model can evaluate the metabolism and toxicity of new drugs in humans, in a far efficient manner than animal testing, thereby eliminating the use of animals for experimentation. Its portfolio also includes anti-TNF-R1 antibody Atrosimab, acquired in 2018.
Selecta Biosciences (NASDAQ: SELB)
Market Cap: $88.68M; Current Share Price: 1.98 USD
Data by YCharts
Selecta is leveraging its proprietary immune tolerance platform technology (ImmTOR), to create biologic therapies that can offer novel solutions for diseases, with large unmet medical needs. The company is targeting rare diseases that have a high immunogenicity, to create a pipeline aimed at therapeutic enzyme and gene therapy product candidates.
In September 2018, the company entered collaboration with CureCN, a European consortium to develop an ImmTOR+AAV gene therapy combination product for the treatment of Criggler-Najjar Syndrome. CureCN is likely to carry out the preclinical toxicology studies in the first half of 2019, followed by a combination product candidate that will enter the clinic in the second half of the year.
The Company’s proprietary ImmTOR therapy stimulates a selective immune tolerance, by prompting the dendritic cells to create T regulatory cells, which in turn make the immune system more responsive to biologic therapies. This mechanism is extremely important for gene therapies that use the adeno-associated virus (AAV) vectors, as neutralizing antibodies (Nabs) are created in response to AAV vector administration, which makes it impossible to repeat the process in patients who need multiple doses.
This technology is ground-breaking, as it allows for determining an optimal dose for patients who require multiple administrations, and also overcomes the problem of non-replicating AAV vectors, that lose their transgene expression as time passes and pediatric patients grow.
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