Huntington’s disease is a fatal hereditary disease that results in the progressive breakdown of nerve cells in the brain. It erodes a person’s physical and mental abilities, usually beginning in their 30s and 40s, and to date has no cure. Now Austin-based Asuragen Inc. is joining forces with Wave Life Sciences USA Inc., of Cambridge, Mass., to change Huntington’s fatal trajectory with plans to develop companion diagnostics (CDx) for Wave’s investigative allele-selective therapeutic programs targeting the underlying genetic cause of the devastating disease.
Huntington’s is one of several trinucleotide disorders that result when the length of a repeated section of a gene exceeds normal range. In this case, the repeats involve a sequence of three DNA bases, cytosine-adenine9-quanine (CAG), on the huntingtin (HTT) gene. While most people without the HTT mutation that causes the disease have between 17 and 20 CAG repeats, affected individuals can have 36 or more repeats.
“Wave is developing oligonucleotide therapies that specifically target only the expanded HTT gene by targeting nearby polymorphisms (SNPs) on the same chromosome as the expanded allele,” Bernard Andruss, senior vice president of operations and regulatory affairs at Asuragen, told BioWorld MedTech. “Building on work done previously by Wave, Asuragen will be using our Amplidex technology to build a diagnostic test that can rapidly, efficiently and accurately measure HTT CAG repeat length and determine whether the expanded allele is on the same chromosome with the SNP targeted by the Wave therapeutics.”
Targeting two SNPs
Specifically, Asuragen will be developing CDx tests for two SNPs targeted by Wave’s WVE-120101 and WVE-120102 candidates, which are seen alone or together in up to 70% of Huntington’s patients. Wave is currently assessing the safety, tolerability, pharmacokinetics and pharmacodynamics of the companion treatments in coordinated Phase 1b/2a multicenter, randomized, double-blind, placebo-controlled studies in adults with early manifestation of Huntington’s who carry targeted SNPs. The PRECISION-HD1 trial is evaluating WVE-120101 in patients with rs362307 (SNP1), while the PRECISION-HD2 study is assessing WVE-120102 in patients with rs362331 (SNP2). The therapies are designed to lower the mutant HTT mRNA transcript by targeting these SNPs while leaving not altering healthy, or wild-type, transcript. Wave expects to report results from the PRECISION-HD1 and PRECISION HD-2 trials by the end of this year or early 2020.
“We’re pleased to be a part of this new category of potential therapies and to have a positive impact on such a devastating disease,” said Matthew McManus, Asuragen’s president and CEO. “Developing a companion diagnostic for Wave’s novel allele-selective silencing program in HD is a great example of how our products will continue to advance personalized medicine.”
Enhanced amplification, scalability
Andruss said that Asuragen’s Amplidex technology is designed to overcome the challenges of standard polymerase chain reaction technology by increasing the fidelity of PCR amplification of sequences where polymerases “frequently slip or stall,” such as those with large numbers of guanidine and cytosine bases. This enables more accurate measurement of the repeats.
The partnership plans to use Asuragen’s technology and expertise in repetitive sequence diagnostics to deliver scalable SNP phasing to support global phase III development and commercialization of WVE-120101 and WVE-120102. The Amplidex-based assay will be evaluated alongside the treatments as a potential CDx in determining which patients stand to benefit.
“The potential for developing treatments that could provide dramatic improvement in the symptoms of HD is a very exciting development,” Andruss said. “Asuragen’s approach to making challenging assays available and accessible to laboratories in an efficient and standardized workflow with analytical software, combined with our manufacturing and regulatory capabilities, will enhance the availability of the test when and where needed.”
Jaya Goyal, vice president of bioanalytics, pharmacology and biomarker development at Wave Life Sciences, expressed his enthusiasm about the collaboration. “Our partnership with Asuragen for companion diagnostic development was a natural fit in light of their deep knowledge and expertise with challenging molecular targets, diagnostic regulatory experience and their growing presence in the neurogenetics testing market,” he said.
Asuragen first applied its Amplidex technology to provide PCR-based testing for expansions of the CGG triplet repeat in the FMR1 gene responsible for fragile X syndrome and associated genetic disorders. In results presented at the Association of Molecular Pathology annual meeting in Baltimore earlier this month, a deep learning system applied to Amplidex-processed fragile X specimens classified short tandem repeat (STR) alleles with ≥ 96% sensitivity and ≥ 97% positive predictive value, for overall accuracy of ≥ 97%.
Expanding search for a cure
Beyond Huntington’s human toll, its economic impact is substantial. A retrospective database analysis found that the mean total annualized cost per patient with private insurance increased from $4,947 in the early stages to $22,582 in late stages of the disease. Per patient costs to Medicaid ranged from $3,257 to $37,495. With about 30,000 symptomatic Americans and more than 200,000 at risk of inheriting the disease, finding ways to control its progress has health care cost as well as patient outcome implications.
While there are no treatments to cure or reverse Huntington’s, there are some medications that help to control the symptoms. And more efforts are underway to alter the course of the disease. A Chinese study has identified small molecule compounds that can lower levels of the HTT protein involved in development of the disease. Vaccinex Inc., of Rochester, N.Y., also has its eye on the space. The company recently raised $13.8 million in a stock purchase agreement with new and existing investors aimed at advancing development of its lead drug candidate, pepinemab, in Huntington’s disease and cancer.