Current therapies for the rare genetic disorder Hurler syndrome can alleviate physical symptoms but don't do much to tackle the effects of the disease on the brain. Now, California biotech ArmaGen has the first data showing its new drug may resolve that problem.
Hurler syndrome—a severe form of the lysosomal storage disease mucopolysaccharidosis type I (MPS I)—is caused by a deficiency or absence of the enzyme iduronidase, causing complex sugars to accumulate in the body and leading to organ damage.
Thankfully, enzyme replacement therapy (ERT) is available for MPS I in the form of Sanofi/Genzyme's $200-million-a-year Aldurazyme (laronidase), which can help with somatic symptoms such as lung function and physical disability. There's no evidence yet, however, that Aldurazyme can help with the central nervous system effects of MPS I, such as neurological impairment. Right now the only therapy for that is a stem cell transplant, which has been shown to have some activity in preserving brain function.
Enter ArmaGen, which has just reported data from the first five patients in a Brazilian phase 2 trial of AGT-181, a drug that fuses the missing enzyme with an antibody targeting the insulin receptor that is designed to help it pass the blood-brain barrier and penetrate the central nervous system.
Preliminary results from the six-month study showed that four of five patients showed significant neurological and cognitive improvements on AGT-181, with the fifth child showing signs that the cognitive decline has been halted.
The effects on somatic manifestations of MPS I, such as liver and spleen enlargement, as well as tolerability seemed to be in line with standard ERT, and there was also a trend toward an improvement in shoulder range of motion with the experimental drug.
"Reports from the patients often tell us much more than mathematical scores," ArmaGen CEO Matthias Schmidt, Ph.D., told FierceBiotech. "For instance, we had one severely affected nine-year-old Hurler child who was not able to use his hands at all. After 26 weeks he could reach out to hold a cup. We heard from one mother that her child is doing more things and getting more curious," he added, noting that even stopping a trajectory of losing once-accomplished skills goes a long way and is meaningful for both patients and their parents.
ArmaGen completed enrollment of the study in January and should have final results in around August, according to Schmidt, who said the biotech is already planning the pivotal trials necessary to seek and obtain approval from regulatory authorities and hopes to get these underway before the end of the year.
And while the results are exciting for Hurler syndrome, the data supporting ArmaGen's "Trojan horse" delivery technology for biologics into the CNS opens up a whole new vista of opportunities for the company, including other lysosomal storage diseases such as metachromatic leukodystrophy, MPS IIIA and MPS IIIB as well as therapies for more common indications like Alzheimer's disease, Parkinson's disease or multiple sclerosis.
"The biotechnology industry has struggled for decades to bring large molecules across the blood-brain barrier, [and] solving this challenge will open a floodgate of treatments for many serious brain diseases that affect millions of patients," said Schmidt.
A number of competitors have been looking at using receptors to shuttle large molecules across the blood-brain barrier, but some have encountered preclinical safety challenges and so far none have achieved success in the clinic, he added.
ArmaGen is also hoping that the phase 2 proof-of-concept data will flush out potential partners for AGT-181 and its other programs which could help it accelerate the development timeline for its programs.
Shire could be one option, as the two companies are already collaborating on ArmaGen's AGT-182 candidate for Hunter syndrome, and it also has a neuroscience-focused partnership in place with Janssen that for now is being kept under wraps. Meanwhile, the biotech is also looking to raise some additional cash via a series B financing round.
"We have a rich preclinical pipeline and we are eager to make these medicines available to the patients who cannot afford to wait," said Schmidt. "They just want something that many of us took for granted—to live a normal childhood."