A Noninvasive Treatment Against Degenerating Brain Cells

Huntington’s Disease: OCCT-HTT siRNA

Ophidion is developing a first-in-class, systemically administered, disease-modifying treatment for Huntington’s disease (HD) that utilizes OCCT- delivered siRNA to suppress synthesis of both normal and mutant Huntingtin protein in the brain, an approach that has shown disease modifying benefit in HD animal models. Ophidion’s preclinical proof-of-concept studies have demonstrated suppression of wild-type and mutant human Huntingtin mRNA levels in several regions of the mouse brain.

Ophidion’s proprietary OCCT-linked siRNA’s/ASO’s targeting both the mutant and wild-type Huntingtin allelles have successfully reduced gene expression by a therapeutically relevant and important 30-50% in the striatum and hippocampus of humanized mice in a time-dependent manner following single i.v. administration (Figure 1) which could translate into a 2-3 month dose interval in humans (once monthly as a worst case). The targeted ~30-50% Huntingtin gene knockdown is designed to avoid possible detrimental effects from reducing wild-type Huntingtin protein to deleterious levels.

Two leading oligonucleotide-based Huntington’s Disease competitors, Ionis/Roche and Wave Life Sciences/Takeda, have recently halted and curtailed their Phase 3 and Phase 1a/2b clinical development programs, respectively. Ionis/Roche targeting both mutant and wild-type Huntingtin genes observed lack of efficacy, CSF biomarkers suggestive of neuronal damage, and worsening symptoms with their highest dose. Wave Life Sciences/Takeda selectively targeting two patient-specific mutant alleles failed to achieve sufficient knock-down of targeted protein in CSF but still intend to advance a third patient-specific ASO into preclinical development. Ophidion’s program differs fundamentally from these two competitors by virtue of leveraging 4,000 miles of capillaries in the human blood-brain barrier to ensure the delivery of various therapeutics throughout the brain structure following intravenous administration versus the competitors’ invasive, localized spinal injection into the cerebrospinal fluid (CSF) with secondary diffusion-based spread throughout the brain, requiring initial localized injection of highly concentrated ASOs.

In summary, Ophidion’s first-in-class proprietary i.v. injectable OCCT-linked siRNA’s/ASO’s targeting the mutant and wild-type Huntingtin allelles have achieved preclinical proof of concept in humanized mouse models achieving ~30%-50% gene knockdown that could translate to disease-modifying efficacy in Huntington’s Disease patients.

Figure 1. Proof of Concept Study in Humanized Transgenic BACHD Mice: Sustained knockdown of 49% demonstrated for our lead formulation.

About Huntington Disease

Huntington’s disease is an autosomal dominant disorder, characterized by chorea (jerky involuntary movements especially affecting the shoulders, hips, and face), psychiatric illness, and cognitive decline. HD affects over 30,000 patients in the U.S. and 83,000-130,000 globally.

Because mutations in the Huntingtin gene (HTT) are causative, gene-silencing siRNA therapeutics should be disease-modifying, as has been established in HD mouse models. Intrathecal injection of ASO’s have been shown to lower the disease-causing Huntingtin protein in patients but less invasive intravenous or subcutaneous administration is precluded by the BBB. Ophidion’s OCCT-HTT siRNA therefore represents a first-in-class non-invasive HTT gene silencing approach which would be developed for intravenous use via the orphan disease designation (ODD) pathway.