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WVE-004, <a href="https://wavelifesciences.com/">Wave Life Sciences</a>&#8216; investigational treatment for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), significantly reduces toxic proteins associated with C9orf72 genetic mutations, but that doesn&#8217;t seem to translate into functional status gains in patients.
Based on findings from the <a href="https://clinicaltrials.gov/ct2/show/NCT04931862">Phase 1b/2a FOCUS-C9 trial (NCT04931862)</a>, the company has decided to discontinue developing WVE-004 for C9orf72-associated ALS.
&#8220;We are deeply disappointed that we were not able to see any evidence of potential benefits that would be expected to drive meaningful outcomes for these patients,&#8221; Paul Bolno, MD, president and CEO of Wave, said in a <a href="https://www.globenewswire.com/news-release/2023/05/23/2674200/0/en/Wave-Life-Sciences-Announces-Topline-Results-from-Phase-1b-2a-FOCUS-C9-Study-of-WVE-004-for-C9orf72-associated-Amyotrophic-Lateral-Sclerosis-and-Frontotemporal-Dementia.html">company press release</a>.
C9orf72 mutations are the most common genetic cause of ALS and frontotemporal dementia (FTD), a related neurodegenerative condition. They are marked by the excessive repetition of six nucleotides, or DNA building blocks, in the gene&#8217;s code.
Normally, these six nucleotides — GGGGCC — are repeated up to a couple dozen times, but in ALS- or FTD-associated mutations, they are repeated hundreds or thousands of times. This results in abnormal proteins being produced, including poly(GP), that form toxic clumps inside cells.
WVE-004 is a type of therapy called an antisense oligonucleotide, which works to prevent the production of these toxic proteins by interfering with the gene&#8217;s messenger RNA (mRNA), an intermediate molecule produced from DNA that acts as a template for making protein.
The FOCUS-C9 study evaluated the safety and pharmacological properties of WVE-004 in people with ALS or FTD who carry C9orf72 mutations.
In its first part, participants were given a single dose of WVE-004 (10, 30, or 60 mg) or a placebo via an intrathecal injection (into the spinal canal) and were observed for three months.
<a href="https://alsnewstoday.com/news/wve-004-reduces-toxic-proteins-early-focus-c9-study-data/">Interim data</a> indicated the therapy reduced poly(GP) levels in the cerebrospinal fluid, which surrounds the brain and spinal cord, at all tested doses, indicating it was engaging its intended biological target.
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<h3>Reductions in poly(GP), but no clinical gains</h3>
Wave extended the observation period to six months to see if poly(GP) would continue to decline and added a single 20 mg dosing group.
In another part of the trial, participants were assigned to receive multiple doses of 10 mg WVE-004 — either every four or 12 weeks — and were compared with a placebo group.
Top-line results concerning all dosing groups indicate single and multiple doses were generally well tolerated, with most side effects being mild and related to the disease progression or intrathecal injections. No new safety signals were identified since the interim analysis.
Strong reductions in poly(GP) were observed, with patients on a single 20 mg dose and those in the multiple dose groups all having a roughly 50% decrease in poly(GP) levels over the start of the study.
Still, no significant clinical benefits were observed after six months on any efficacy measure, including the ALS Functional Rating Scale-Revised (ALSFRS-R), a standard measure of functional status in ALS clinical trials.
[quote align=&#8221;center&#8221;]Following our initial positive single dose data last year, we advanced WVE-004 with the hope that its potency and differentiated pharmacology may deliver a better result than C9orf72-targeting oligonucleotides discontinued by others in the field.[/quote]
While those treated with WVE-004 every four weeks did see a significant reduction in ALSFRS-R declines relative to a placebo, the scores were not significantly different from the decline in a natural history control group from an ALS database and weren&#8217;t deemed clinically meaningful. Reductions in poly(GP) didn&#8217;t correlate with stabilizations or improvements in ALSFRS-R scores or other clinical measures.
Based on the data, Wave will discontinue developing the therapy, FOCUS-C9 and its open-label extension study will be stopped, and the latest results will be presented at a future medical congress.
&#8220;Following our initial positive single dose data last year, we advanced WVE-004 with the hope that its potency and differentiated pharmacology may deliver a better result than C9orf72-targeting oligonucleotides discontinued by others in the field,&#8221; Bolno said. &#8220;Our hope is that these data can help advance future research &#8230; On behalf of everyone at Wave, I wish to sincerely thank the participants, their families, the clinical sites, and our study advisory committees for their participation and support.&#8221;

Development of WVE-004 to cease after Phase 1/2 trial failure

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: Phase 1/2 clinical trial

Development of WVE-004 to cease after Phase 1/2 trial failure

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