Pathophysiology and Symptoms of Hunter Syndrome
Hunter syndrome is a very rare genetic disorder in which a child’s body is not able to properly break down (digest) certain sugar molecules. When these sugar molecules accumulate in organs and tissues over a period of time, they can cause damage that affects the physical and mental development of the child. Hunter syndrome has been classified as into severe and mild types by the healthcare providers, wherein the severe type progresses faster and involves impaired intellectual abilities in the age of 6 and 8 and occurs in about 60% of all cases. Hunter syndrome is also called mucopolysaccharidosis type II, or MPS II. A genetic mutation in the IDS gene causes Hunter syndrome. IDS gene is responsible for regulating the production of an enzyme called iduronate 2-sulfatase (I2S). The I2S enzyme breaks down complex sugar molecules called glycosaminoglycans (GAGs).
In people with Hunter syndrome, their bodies don’t produce any or enough of the I2S enzyme so, which causes sugar molecules to accumulate inside lysosomes. Urine tests can make a primary diagnosis of Hunter syndrome due to high levels of sugar molecules or blood tests used to check the low or absent levels of iduronate 2-sulfatase enzyme activity. Further genetic testing is used to identify mutations in the IDS gene to confirm the diagnosis. The symptoms of Hunter syndrome start to appear in children between the ages of 2 to 4. Patient with Hunter syndrome shows symptoms such as joint stiffness, thickening of nostrils, lips, and tongue, wide and large spaces between teeth, larger head, hearing loss, delayed growth, and enlarged spleen and liver.
Fig 1: Symptoms of Hunter Syndrome
Epidemiology
Hunter syndrome is diagnosed in nearly about 1 out of every 100,000 to 170,000 children. The estimated incidence of Hunter syndrome is between 0.69 and 1.19 per 100,000 live births. The incidence and prevalence of hunter syndrome varies from country to country. The evidence of the disease case in Germany and the Netherlands is 1 case in 140,000-330,000 live births. Its estimated incidence in Israel is 1 case per 34,000 children, and in Columbia is 1 case per 111,000 children. Further, it is 1 case per 132,000 children in the United Kingdom.
Current Treatment for Hunter Syndrome
Biopharmaceutical companies have developed enzyme replacement therapy to improve the symptoms and quality of life of children with Hunter Syndrome. Currently, three FDA-approved enzyme replacement therapies are available for the treatment of Hunter syndrome.
1] Elaprase: Purified lysosomal idursulfase enzyme used as a replacement therapy for Hunter syndrome. Elaprase in a dose of 2 mg/ml is administered via intravenous injection for the treatment. Elaprase replaces the natural enzyme, increasing the catabolism of certain accumulated glycosaminoglycans (GAG).
2] Izcargo: Pabinafusp alfa is used to treat the neurological complication of Hunter syndrome. Izcargo is a recombinant iduronate-2-sulfatase used as an enzyme replacement therapy (ERT). The J-Brain Cargo® technology delivers therapeutics across the blood-brain barrier. It is administered once every alternate week through an intravenous infusion at a dose of 2.0 mg/kg of body weight.
3] Hunterase: Hunterase® (Idursulfase beta) being used for Mucopolysaccharidosis type II (MPS II) or Hunter syndrome, wherein the dosage is 0.5 mg/kg body weight.
Fig 2: Approved Drugs for Treatment of Hunter Syndrome
Clinical Pipeline for Hunter Syndrome
So far, around thirteen assets are under clinical development for treating Hunter syndrome. Below are some highlights of the clinical pipeline for Hunter syndrome.
- In total, thirteen assets are under clinical development, four of which are in phase III trials and phase II trials, respectively, and the remaining five are in phase I trials.
- Among the thirteen assets under clinical development, six are enzyme replacement therapy, two are cell therapy, and three are genome targeting. The remaining two are in other categories, such as growth hormones and TNF-α inhibitors.
- Recently, Regenxbio completed a pre-BLA meeting with the Food and Drug Administration to gain accelerated approval for its gene therapy RGX-121, which treats Hunter syndrome.
- In May 2022, the U.S. FDA granted Tividenofusp Alfa (DNL310) Fast Track designation for the treatment of patients with MPS II.
- As Sangamo’s zinc finger nuclease technology SB-913 fails to meet the clinical efficacy, Regenxbio’s RGX-121 could be the first gene therapy to treat Hunter syndrome. Further, Homology Medicines is conducting phase 1 clinical trials on HMI-203 (investigational gene therapy) to treat mucopolysaccharidosis II.
- Other companies, such as ArmaGen (AGT-182), Green Cross (GC1123), and BioMarin (Aldurazyme), have enzyme replacement therapy assets in phase I clinical trials to treat Hunter syndrome.
Table 1. Assets in Clinical Trials to Treat Hunter Syndrome
Key Players
Takeda Pharmaceuticals is a top pharmaceutical player, followed by JCR Pharmaceuticals and GC Pharma in Hunter syndrome treatment. US-based biopharmaceutical companies such as Regenxbio, Sangamo Therapeutics, Homology Medicines, and Talaris Therapeutics are conducting clinical trials on innovative gene and cell therapies to treat Hunter syndrome. The USA is the leading country with ten assets in the pipeline, followed by Japan, Europe, and Russia, which have a single asset in the pipeline to treat hunter syndrome.
Fig 3: Key Players in Hunter Syndrome Treatment
Future of Hunter Syndrome Treatment
Hunter syndrome has a strong clinical pipeline with thirteen assets under clinical development, out of which four assets are in phase III trials and phase II trials, respectively, and the remaining five assets are under phase I trials. Drug innovators are exploring different methods, such as enzyme replacement and cell and gene therapies, to treat Hunter syndrome. Currently, six enzyme replacement therapy under clinical development, five cell and gene therapies targeting, and the remaining two assets are under other categories such as growth hormones and TNF-α inhibitors.
Biopharmaceutical companies such as ArmaGen (AGT-182), Green Cross (GC1123), and BioMarin (Aldurazyme) are developing innovative enzyme replacement therapy with improved blood-brain barrier (BBB) transports. US-based biopharmaceutical companies such as Regenxbio, Sangamo Therapeutics, Homology Medicines, and Talaris Therapeutics are conducting clinical trials on innovative gene and cell therapies to treat Hunter syndrome. U.S. FDA has granted fast-track designation to Tividenofusp Alfa (DNL310) for treating patients with MPS II.
In gene therapy, Regenxbio completed a Pre-BLA meeting with the Food and Drug Administration to gain accelerated approval for its gene therapy RGX-121 and Homology Medicines conducting phase 1 clinical trials on HMI-203 (investigational gene therapy) to treat mucopolysaccharidosis II. The USA is the leading country with ten assets in the pipeline, followed by Japan, Europe, and Russia, with each asset in the pipeline to treat Hunter syndrome. As IDS enzyme through enzyme replacement therapy didn’t cross the blood-brain barrier, all hope is on next-generation gene therapy to treat the patient with Hunter syndrome.