Alnylam launches Phase 1 trial of ALN-HTT02 for Huntington’s
Trial to test safety, pharmacological properties of injection therapy
Alnylam Pharmaceuticals has launched a Phase 1 clinical trial to test the safety and pharmacological properties of its treatment candidate ALN-HTT02 in adults with Huntington’s disease, the company announced as part of a financial update.
“We [have] made great strides with our pipeline, … initiating a Phase 1 study for ALN-HTT02 in adult patients with Huntington’s,” said Yvonne Greenstreet, Alnylam’s CEO.
The Phase 1 trial (NCT06585449) is expected to enroll up to 54 adults, ages 25-70, with stage 2 or early stage 3 Huntington’s. The study’s starting in the U.K. and Canada, with additional sites planned for other countries, according to a company presentation in late September.
Huntington’s disease is caused by mutations in the HTT gene that result in the production of an abnormal version of huntingtin that’s prone to toxically clumping up in nerve cells, damaging them.
These mutations occur within the first protein-coding portion of HTT, called exon 1, and result in the formation of two types of mutant huntingtin protein — one that’s full-length and another that’s shorter — both of which may contribute to disease processes.
Adults in Phase 1 trial to be monitored for up to 1 year
In development by Alnylam in collaboration with Regeneron Pharmaceuticals, ALN-HTT02 is a type of molecule called a small interfering RNA (siRNA). It’s designed to lower the production of all forms of HTT, including the mutant versions that cause disease.
The experimental therapy specifically targets a section on exon 1 that’s conserved across all versions of the HTT gene’s messenger RNA (mRNA), promoting their breakdown. mRNA is an intermediate molecule derived from DNA that guides protein production.
By preventing the production of all versions of the huntingtin protein, ALN-HTT02 — administered directly into the spinal canal, which is called an intrathecal injection — is expected to help slow Huntington’s. The therapy is also linked to a fatty molecule known as C16 that helps it be taken up by cells in the brain.
Preclinical data showed that a single dose of ALN-HTT02 led to reductions in both full-length and shortened versions of HTT mRNA in the brains of mice.
Additionally, data from nonhuman primates showed that ALN-HTT02 was widely distributed in the brain and spinal cord, and led to sustained dose-dependent reductions in huntingtin levels with a single dose.
The therapy also showed a good safety profile, with multiple doses of the treatment over a six-month period being well tolerated by the primates, with no neurological abnormalities observed.
In the first part of the Phase 1 trial, participants will be randomly assigned to receive a single intrathecal injection of either one of several doses of ALN-HTT02 or a placebo, and will be monitored for up to a year.
The main goal is to evaluate the therapy’s safety and tolerability. Levels of ALN-HTT02 in blood, urine, and cerebrospinal fluid (CSF), or the liquid surrounding the brain and spinal cord, as well as huntingtin levels in the CSF, will be evaluated as secondary outcome measures.
Exploratory measures may include changes in clinical, imaging, and biomarker measures of disease progression.
Those assigned to the placebo and completing the one-year follow-up period may choose to enter the study’s open-label extension, during which they will receive ALN-HTT02 and be monitored for up to another year.
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