Transposon’s TPN-101 selected for testing in HEALEY ALS trial
Inclusion follows final data from Phase 2 trial
Oral small molecule TPN-101 has been selected for testing in amyotrophic lateral sclerosis (ALS) as part of the HEALEY ALS platform trial.
The decision to include TPN-101 in the platform trial (NCT04297683) was based on the treatment’s unique mechanism of action and final data from a Phase 2 clinical trial (NCT04993755) in adults with ALS or frontotemporal dementia (FTD) related to C9orf72 mutations, developer Transposon Therapeutics said.
The company said it expects dosing in the TPN-101 Phase 2/3 arm of the trial to begin in the fourth quarter.
“We appreciate the endorsement of the HEALEY Therapy Evaluation Committee for inclusion of TPN-101 into the platform trial based on its novel target and Phase 2 clinical data, and look forward to working with the HEALEY group to advance the development of TPN-101 in ALS,” Andrew Satlin, MD, Transposon’s chief medical officer, said in a company press release.
The HEALEY ALS platform trial is testing multiple medications simultaneously under a shared protocol. This reduces costs and shortens time to development. By using a shared placebo, it also gives more people with ALS the opportunity to join and potentially receive an effective treatment.
Enzyme blocking to stop immune response, slow disease progression
In ALS and FTD, a related condition, abnormal clumps of the TDP-43 protein cause genetic elements known as retrotransposons to become active. Retrotransposons are leftover pieces of viral DNA from the human evolutionary past that normally stay silent.
When activated, retrotransposons produce DNA products that the body mistakes for viruses. This can set off an immune response, leading to inflammation and damage to nerve cells. Over time, this may contribute to the progression of conditions such as ALS and FTD.
TPN-101 is designed to block the LINE-1 reverse transcriptase enzyme, which helps activate DNA products from LINE-1 retrotransposons. By doing so, TPN-101 is expected to stop the immune response and protect nerve cells from damage, slowing disease progression.
The Phase 2 clinical trial involved 42 adults with ALS or FTD related to C9orf72 mutations, which are generally linked to a more active LINE-1 reverse transcriptase enzyme.
Patients were randomly assigned to receive daily doses of either TPN-101 (400 mg) or a placebo for 24 weeks, or about six months. They could then enter an open-label extension in which all received TPN-101 for an additional 24 weeks.
After the initial six months, patients on TPN-101 experienced 50% less decline in respiratory function than those on the placebo (8.4% vs. 16.5%). When patients on the placebo switched to TPN-101 in the extension, their decline slowed down and became similar (7.2%) to those on the treatment from the start.
TPN-101 also slowed disease progression over the full 48 weeks, as measured by the ALS Functional Rating Scale-Revised, and was associated with reductions in biomarkers of inflammation and neurodegeneration.
“We look forward to collaborating with the Transposon team to develop their regimen for investigating TPN-101 in people with ALS,” said Merit Cudkowicz, MD, principal investigator and sponsor of the HEALEY ALS platform trial. “We are grateful to our patient advisory committee and all the people who participate in the Platform Trial to help discover new treatments for ALS.”
Cudkowicz is the director of the Sean M. Healey & AMG Center for ALS and executive director of the Neuroscience Institute at Mass General Brigham.
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