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A first healthy volunteer has been dosed in a Phase 1 clinical study evaluating how safe and well tolerated is CVN293, a treatment candidate for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer’s disease</a>, the therapy&#8217;s developer, <a href="https://www.cerevance.com" rel="nofollow">Cerevance</a>, announced.
The treatment, given orally, is designed to block a protein called KCNK13 on microglia, a type of immune cell that resides in the brain and is thought to play a role in ALS and other diseases.
Single ascending doses (SAD) and multiple ascending doses (MAD) are being tested in the study, with ascending doses of CVN293 administered once or repeatedly and compared with a placebo.
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<h3>Problems in microglia function may promote brain inflammation in ALS</h3>
A total of 64 healthy men and women, ages 18 to 55, will be randomly assigned in a 6:2 ratio to either CVN293 or a placebo. Five groups of eight people will be in the study&#8217;s SAD part; three groups of eight will enter its MAD portion.
In addition to therapy safety and tolerability, the study will evaluate CVN293&#8217;s pharmacokinetics, or how the drug moves into, through, and out of the body.
“We are very pleased to advance CVN293, a selective small-molecule inhibitor of the novel target KCNK13 into Phase 1 clinical development,” Craig Thompson, Cerevance’s CEO, said in a <a href="https://www.globenewswire.com/news-release/2023/09/19/2745619/0/en/Cerevance-Doses-First-Subject-in-Phase-1-Clinical-Study-of-CVN293-a-Selective-Inhibitor-of-KCNK13-Designed-to-Selectively-Modulate-Neuroinflammation-for-the-Treatment-of-ALS-and-Al.html">company press release</a>.
ALS occurs when motor neurons — the nerve cells that control muscle movement — become damaged and die over time. This results in <a href="https://alsnewstoday.com/symptoms-of-als/">muscle weakness</a>, leading to problems that include breathing, speaking, and eating.
What exactly <a href="https://alsnewstoday.com/causes-of-als/">causes ALS</a> is not known, but immune cells like microglia are believed to be involved. Like macrophages, the pathogen-engulfing immune cells that reside in tissues outside the brain, microglia eat bacteria, viruses, and debris.
It is thought that microglia, which normally protect the brain from harmful invaders, may go awry in ALS and allow a long-lasting cycle of inflammation that further damages motor neurons.
CVN293 was developed using the company’s proprietary <a href="https://www.cerevance.com/netsseq" rel="nofollow">Nuclear Enriched Transcript Sort sequencing (NETSseq) platform</a>, which lets researchers scan the molecular signature of specific types of cells within the brain and identify potential targets for neurological conditions.
It is designed to block KCNK13, also known as THIK-1, a channel protein that allows potassium ions to flow out of microglia. Earlier <a href="https://www.pnas.org/doi/10.1073/pnas.2106294118">work in mice</a> found that ion efflux (outflow) regulates the release of inflammatory signals from microglia, limiting communication between nerve cells.
By targeting the ion channel and preventing potassium release by microglia, CVN293 aims to lower inflammation in the brain without dampening immune cells working outside the central nervous system (brain and spinal cord).
Unlike other proteins, KCNK13 is almost exclusive to microglia and present only at very low levels in macrophages. As such, CVN293 may target microglia while leaving macrophages — needed for a healthy immune response — unharmed.
“KCNK13, an important modulator of neuroinflammation, was selectively identified using NETSseq and represents the power of the Cerevance platform in discovering precision neuroscience targets,” Thompson said.
“This [trial] is an important milestone as we continue to translate scientific discoveries into potential therapeutic options to address neuroinflammatory conditions,” he added.

Dosing of healthy adults begins in Phase 1 study of oral CVN293

A Phase 1/2 clinical trial testing the investigational imaging agent 18F-OP-801 in healthy volunteers and people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) has enrolled its first patient.
<a href="https://avttx.com/" rel="nofollow">Ashvattha Therapeutics</a>&#8216; agent is designed to detect inflammation in imaging exams like positron emission tomography (PET) or MRI scans. This is possible because the agent is able to cross the protective brain-blood barrier, and it aims specifically to be taken up by reactive macrophages and microglia, the cells that primarily drive neuroinflammation in ALS.
The tracer, made of a hydroxyl dendrimer (HD), could also help researchers understand how certain investigational therapeutic compounds in the company&#8217;s pipeline, made of similar hydroxyl dendrimer molecules, might be taken up by these target cells.
“An obstacle to the treatment of neurodegenerative diseases like ALS is ensuring that treatment reaches areas of disease in the brain,&#8221; Farshad Moaradi, MD, PhD, a diagnostic radiology specialist and professor at Stanford Medicine, said in a <a href="https://www.globenewswire.com/news-release/2023/02/06/2602080/0/en/Ashvattha-Therapeutics-Announces-First-Patient-Enrolled-in-a-Phase-1-Study-of-18F-OP-801-for-Use-as-Imaging-Agent.html">company press release</a>.
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<h3>Tracer that might make &#8216;precision medicine even more precise&#8217;</h3>
&#8220;This study will determine if visualizing [18F-OP-801] uptake can pinpoint regions of inflammation and disease with enough specificity to provide insights into future patient selection, potentially making precision medicine even more precise,” Moaradi added.
Ashvattha is working on developing <a href="https://avttx.com/technology/" rel="nofollow">hydroxyl dendrimer therapeutics</a>, or HDTs. HDs are tiny molecules with properties that enable them to be taken up selectively by diseased cells in areas of inflammation, including in the brain.
With HDTs, disease-modifying treatments are attached to a hydroxyl dendrimer to facilitate their uptake by target cells. Because of an HD&#8217;s selectivity, these therapies have the potential to be low cost and safe at high doses, according to Ashvattha.
The company expects that this precision medicine approach could be applied to a range of inflammatory indications, including certain cancers, eye diseases, and neurodegenerative diseases like ALS.
18F-OP-801 is essentially an HD molecule with a radioactive element — a form of fluorine called 18F — attached that enables it to be detected by imaging scanners.
It&#8217;s designed to cross the blood-brain barrier — a selective membrane that helps keep foreign substances out of the brain — and to be taken up by inflammatory cells there.
In preclinical studies, the tracer effectively entered the brain, and its <a href="https://alsnewstoday.com/news/pet-tracer-capature-microglia-related-brain-inflammation-in-als/?cn-reloaded=1">uptake correlated with the level of inflammation</a> in mice with induced sepsis, an extreme response to infection. The tracer only entered organs that were expected to exhibit activated microglia and macrophages, highlighting its specificity for those cell types.
18F-OP-801 can be used to track neuroinflammation&#8217;s progression in people with ALS and other neurodegenerative diseases, Ashvattha reported, as well as help to identify how well therapeutic HD agents are taken up in these target areas.
“With [18F-OP-801], we will be able to estimate HDT uptake in the diseased part of the brain prior to treating patients with the HDT,&#8221; said Jeffrey Cleland, PhD, chairman, CEO and president of Ashvattha. &#8220;This approach, if successful, will reduce clinical risk by ensuring the correct amount of drug reaches the target to treat the neurological disease.”
<h3>Trial enrolling up to 26 healthy adults, ALS patients at Stanford site</h3>
The ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT05395624?term=OP-801&amp;draw=2&amp;rank=1">Phase 1/2 trial (NCT05395624)</a> is enrolling up to 26 healthy adults and ALS patients, ages 18-80, who will receive a single into-the-vein injection of 18F-OP-801 at Stanford University. <a href="https://clinicaltrials.gov/ct2/show/NCT05395624?term=OP-801&amp;draw=2&amp;rank=1#contactlocation">Contact and other information</a> is available.
In addition to monitoring for safety, the trial aims to assess the molecule&#8217;s pharmacokinetics — its movement into, through, and out of the body — as well as its biodistribution, or where it travels to and is absorbed in the body.
The study will also look at whether 18F-OP-801 is found selectively in areas of neuroinflammation compared with non-inflamed brain tissue in ALS patients. This will be done using PET/MRI or PET/CT scans.
“The initiation of the clinical trial evaluating [18F]OP-801 as an imaging agent is a significant step to unlocking the potential of our proprietary HD technology for treatment of neurological diseases,” Cleland said.
One such investigational HDT, called OP-101, was shown to target microglia in people with severe COVID-19 and block pro-inflammatory pathways.
The company previously noted plans to test OP-101 in ALS patients, using the 18F-OP-801 tracer as a companion tool to track treatment-related changes in neuroinflammation.

Tag: neuroinflammation

Dosing of healthy adults begins in Phase 1 study of oral CVN293

Phase 1/2 trial of imaging agent for inflammation enrolls 1st ALS patient