In a virtual presentation at the CHDI Foundation’s 16th Annual Huntington’s Disease (HD) Therapeutics Conference, Triplet Therapeutics presented preclinical data on the therapeutic target and route of administration of its first clinical candidate, an antisense oligonucleotide, TTX-3360. This is the first therapeutic candidate with the potential to modify the course of HD and other repeat expansion disorders (REDs).

Triplet Therapeutics also pledged to place 1% of its equity into an independently managed trust fund that will monetize the equity to benefit RED patients and their families. “I think this is really important. It’s the first time this has ever been done in the biotech industry. I hope the industry looks at this and uses it as a template across other indications,” said Nessan Bermingham, PhD, Triplet Therapeutics CEO, president and founder (former CEO of Intellia).

Nessan Bermingham, PhD, Triplet Therapeutics CEO, president and founder

HD is a genetic disorder where triplet repeats (CAG) within the gene Huntingtin (HTT) expand with age, particularly in neurons, and beyond a threshold wreak havoc on a variety of brain functions including motor skills and cognition, ultimately leading to death.

More than 50 known genetic diseases, currently categorized as REDs, are associated with DNA nucleotide repeats. Studies including patient genome-wide association studies (GWAS) across multiple indications indicate the DNA Damage Response (DDR) pathway plays a central role in driving the repeat expansion process.

“TTX-3360 targets MSH3, a component of the DDR pathway that sits upstream of mutant HTT to drive disease onset and progression,” said presenter Irina Antonijevic, MD, PhD, chief medical officer at Triplet.

Zofia Miedzybrodzka, PhD, who is professor of Medical Genetics at the Institute of Medical Sciences at the University of Aberdeen, U.K. and is unrelated to Triplet Therapeutics or the study said, “Targeting MSH3 is a logical approach towards developing treatments for the devastating neurological condition of Huntington disease, and offers affected families new hope.”

“One thing to note,” said Bermingham, “When you think about it from an efficacy standpoint, a 50–60% knockdown [of MSH3] is enough to stop expansion. In autopsied samples you can identify neurons where there are a 1000 plus repeats when they were born with 40. It’s the expansion that is driving the onset and progression of disease. This is probably one of the first examples we have where human genetics has shown us a whole new pathway that is relevant across a broad number of diseases.”

This approach that involves preventing the expansion of genomic repeats is fundamentally different from targeting an inherited mutant protein. “What we are targeting is not a process that is present at birth,” said Antonijevic. Post-mortem data indicates somatic expansion can start nearly two decades before the manifestation of motor deficits. “Depending on the inherited repeat, they can be in their 20s, 30s, or 40s. This is the patient population we are targeting once they start to show very subtle changes.”

Irina Antonijevic, MD, PhD, chief medical officer at Triplet Therapeutics

Patients at very early stages of the expansion process can be detected by CAP and PIN scores. “These are enrichment scores for patients who show somatic expansion but have still enough neurons left so that when we stop expansion, they should have a very mild disease or no further progression,” said Antonijevic. “We have identified a patient population that is interested and eager to participate.”

The process of repeat expansion is cell autonomous with HTT repeats in each cell expanding at a different rate. “In autopsied samples we see some cells are at 1000 repeats when others are still at 40 or 50. When you are stopping it, you are stopping it across the board but they are at different stages,” said Bermingham. “Our view is, the earlier we can go the more cells we can get that are under the toxic threshold. This is why earlier genetic diagnoses that we are seeing in the population is good because it allows you to intervene earlier.”

Based on the safety profile in earlier knockdown and knockout studies, Triplet selected MSH3 as its initial DDR target. They showed Msh3 knockdown in normal mice, two mouse models of HD and non-human primates was safe and well-tolerated with no adverse effects. Knocking down the expression of MSH3 by half with TTX-3360 in HD patient-derived cell lines and in the HD mouse model slowed or stopped the expansion of mutant HTT repeats.

The company has not disclosed the dosing paradigm yet, but Bermingham says, “The duration of action is quite long. In the NHP [non-human primate] studies we evaluated the drug at 12 weeks.  With a single injection and no loading dose, we still were able to achieve significant knockdown of our target within the deep brain regions and other regions like the cortex.”

The presentation showed that a single dose of TTX-3360 delivered directly into the ventricles on the brain (via intracerebroventricular, ICV injection) knocked down MSH3 by ~50–80% in the caudate and cortex in both hemispheres of the brain, in non-human primates (NHP) for at least 12 weeks.

“ICV injection is critical to our goal of slowing or stopping the onset and progression of HD and other REDs,” said Bermingham. “We use ICV injection to reach the caudate, putamen and other deep brain structures, in addition to the cortex, that are affected early on in Huntington’s disease.”

Pain-free ICV injections through an implanted device have been used safely for the delivery of several therapeutic modalities whereas intrathecal (IT) delivery requires repeated painful lumbar punctures (spinal taps) in a clinical setting and primarily delivers therapies to the spinal column and cortex.

“A reservoir is put underneath the scalp and a catheter goes right into the brain. You put the drug into the reservoir, and is picked up in the deeper reaches of the brain, very similar to what is being used for Brineura, BioMarin’s drug for Batten’s disease. The difference is that Brineura is a 4.5 hour infusion, whereas this is a 1–2 minute injection and it opens the potential of treating patients at home which is unprecedented when we think about this therapeutic paradigm,” says Bermingham.

Triplet is preparing to submit an IND/CTA for TTX-3360 by the end of 2021 with an initial focus on symptomatic pre-manifest and early manifest HD patients, and is planning a Phase 1/2a for TTX-3360 in these stages of HD. The company then plans to expand TTX-3360 into additional indications, including spinocerebellar ataxias (SCAs) and myotonic dystrophy type 1 (DM1).

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