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Enrollment is complete in a Phase 2 trial testing <a href="https://inflectisbioscience.com/">InFlectis BioScience</a>’s oral candidate IFB-088 (icerguastat) in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), the company has announced.
The <a href="https://clinicaltrials.gov/study/NCT05508074">trial (NCT05508074)</a> enrolled a total of 50 adults with bulbar-onset ALS, a form of the disease that first affects the muscles in the head and neck, leading to swallowing, chewing, and speech difficulties.
Participants were randomly assigned to receive IFB-088 or a placebo, given as an add-on to <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">riluzole</a>, an approved ALS therapy sold as Rilutek, Tiglutik, or Exservan. Treatment will be given twice a daily for six months, and early results might be presented later this year.
“We dosed the first patient in December 2022 and randomized the last patient on January 30, 2024,” Anne Visbecq, MD, InFlectis’ chief medical officer, said in a <a href="https://inflectisbioscience.reportablenews.com/pr/inflectis-completes-enrollment-phase-2-trial-of-ifb-088-in-als">company press release</a>. “Following the six-month treatment period, we look forward to reporting our initial findings as early as the end of this year.”
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<h3>Phase 2 trial results will determine timing, scope of potential global study</h3>
“These results will determine the timing and scope of a potential global registration study in the overall ALS population,” Visbecq added.
ALS is characterized by the progressive dysfunction and death of motor neurons, the nerve cells that control voluntary movements. About one-third of patients have <a href="https://alsnewstoday.com/forms-of-als/">bulbar-onset ALS</a>, which is more aggressive and has a shorter life expectancy than limb-onset ALS, in which first symptoms are associated with weakness in the muscles of the arms and hands, or legs and feet.
IFB-088 is an orally available small molecule capable of crossing the blood-brain barrier, a cell layer that protects the brain from disease-causing agents and toxins that may be present in the blood.
The medication inhibits the PPP1R15A/PP1c protein complex to keep a natural cellular stress-response mechanism active. This is thought to give stressed cells additional time to correct their protein imbalances and eliminate protein clumps, a hallmark of ALS that contributes to neurodegeneration.
IFB-088 also serves as an inhibitor of certain glutamate receptors. These receptors are involved in a process called excitotoxicity, in which neurons are over-stimulated and fire much more than needed, leading to nerve damage.
An earlier <a href="https://clinicaltrials.gov/study/NCT03610334">Phase 1 trial (NCT03610334)</a> involving healthy volunteers showed the investigational therapy is generally safe and well tolerated. The therapy was given at doses ranging from 2.5 mg to 60 mg daily, and no reports of serious adverse events or dose-limiting toxicities were reported.
The ongoing Phase 2 trial enrolled 50 patients at sites in France and Italy who are receiving 50 mg daily of IFB-088 — given as two oral 25 mg capsules 12 hours apart and 30 minutes before a meal — or a placebo, for 26 weeks. All are also taking riluzole in the form of tablets (Rilutek and generics) or a suspension formulation (<a href="https://alsnewstoday.com/tiglutik-for-als/">Tiglutik</a>) at a daily dose of 100 mg, given as two 50 mg doses every 12 hours.
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<h3>Trial to examine IFB-088&#8217;s safety, ability to slow functional decline in patients</h3>
The trial’s main goal is to assess the treatment&#8217;s safety and tolerability, but researchers will also examine if the therapy can slow patients’ functional decline, reflected by changes in the ALS Functional Rating Scale-Revised.
Two <a href="https://alsnewstoday.com/stages-of-als/">staging systems</a> — the King’s College and the Milano-Torino systems — will also be used to assess changes in patients&#8217; clinical progression and treatment response. The therapy’s effect on the patient&#8217;s quality of life and disease-related blood biomarkers will also be assessed.
“This trial reflects our commitment to bring a novel molecule with a unique mode of action to ALS patients, starting with patients suffering from bulbar-onset ALS, the most aggressive form of the disease,” Visbecq said.
IFB-088&#8217;s development and the Phase 2 trial were financially supported by the <a href="https://www.als.org/">ALS Association</a>, AFM-Téléthon (a French patient organization fighting rare neuromuscular diseases), and Bpifrance (the French public bank of investment). The <a href="https://alsnewstoday.com/news/inflectis-okd-to-start-phase-2-trial-of-ifb-088-for-bulbar-onset-als/">trial was approved</a> in 2022 by the French health authority ANSM.
Also in 2022, IFB-088 was granted <a href="https://alsnewstoday.com/news/inflectis-ifb-088-orphan-drug-status-fda-als-treatment/">orphan drug designation</a> by the U.S. Food and Drug Administration. The designation is meant to accelerate IFB-088’s clinical development and review by providing regulatory support and financial benefits, and a seven-year marketing exclusivity if the therapy is ultimately approved.

Phase 2 trial of oral IFB-088 for bulbar-onset ALS now fully enrolled

Genetic and clinical factors that can influence how <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) progresses were identified in a recent analysis of data from <a href="https://www.precisionals.ie/">PRECISION-ALS</a>, a large European research project.
Consistent with known risk factors for <a href="https://alsnewstoday.com/stages-of-als/">ALS progression</a>, C9ORF72 genetic mutations, <a href="https://alsnewstoday.com/forms-of-als/#Clinical_onset">bulbar-onset disease</a>, and faster functional declines were linked to a shorter survival time, as was older age at disease onset.
However, differences were seen among the project&#8217;s centers in the time it took for interventions like feeding tube placement (gastrostomy) or noninvasive ventilation to be needed, and the reasons require further study, according to the scientists.
Harry McDonough, a clinical researcher at the University of Sheffield in England, and Alejandro Caravaca Puchades, a clinician at the Hospital of Bellvitge in Spain, discussed findings in the oral presentation &#8220;<a href="https://www.tandfonline.com/doi/pdf/10.1080/21678421.2023.2260189" rel="nofollow">Mapping the natural history of ALS in Europe</a>,&#8221; given at the 34th International Symposium on ALS/MND held last week in Basel, Switzerland, and virtually. It was supported by <a href="https://www.biogen.com/" rel="nofollow">Biogen</a>, which also supports the PRECISION-ALS study.
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<h3>Likely ALS progression via factors like speed of diagnosis, disease type at onset</h3>
PRECISION-ALS, launched last year, is a European collaboration with the broad goal of <a href="https://alsnewstoday.com/news/e10m-european-collaborative-project-hopes-use-ai-als-precision-medicine/">better understanding the natural history of ALS</a> and the factors that influence differences in <a href="https://alsnewstoday.com/symptoms-of-als/">disease symptoms</a> and progression among patients.
&#8220;We know that ALS is a condition with lots of variation between individuals,&#8221; McDonough said in the presentation. &#8220;By studying the natural history we hope to be able to understand the factors that impact this variation, and hopefully, in turn, that helps us clinically to improve outcomes for our patients &#8230; [and] hopefully directing them towards trials that are most likely to benefit them.&#8221;
Nine clinical sites across eight countries are involved in the project, which brings together clinical researchers, data scientists, and industry partners.
The recent analysis concerned PRECISION-ALS&#8217; extant data study, meaning it was an analysis of previously collected and existing clinical data. All nine sites contributed information from patients in their individual databases, which were combined for a population-based assessment of ALS progression from symptom onset, to diagnosis, clinical interventions, and death.
Data covered 21,571 ALS patients, mostly male (57.2%). Across the entire group, the median age at symptom onset was 63.9, with a delay of about one year between symptom onset and an <a href="https://alsnewstoday.com/als-diagnosis/">ALS diagnosis</a>.
Disease onset tended to be earlier in men, patients with spinal-onset ALS — where symptoms of limb weakness are the first to emerge — and those with mutations in the ALS-associated genes FUS or SOD1.
Individuals with bulbar-onset ALS — where symptoms initially affect muscles in the head and neck needed for speech, swallowing, and breathing — and those with mutations in the C9ORF72 gene experienced a shorter diagnostic delay.
An earlier symptom onset tended to link with a slower functional decline — indicated by a less than 0.3 point monthly decline in a patient&#8217;s ALS Functional Rating Scale-Revised (ALSFRS-R) scores — compared with patients with intermediate or quickly progressing disease. In turn, a faster functional decline, defined as a monthly change in ALSFRS-R scores of more than 1.06, was associated with a shorter diagnostic delay.
<h3>Earlier need for gastrostomy seen with bulbar onset, C9ORF7 mutations</h3>
Overall median survival among these patients was 2.59 years. Bulbar-onset ALS, fast disease progression, older age at onset (ages 70 and older), and FUS and C9ORF7 mutations all were seen as independent predictors of poorer survival in a final analysis. Better lung function and a slower arrival at a definitive ALS diagnosis linked with longer survival times.
The time to reach certain clinical interventions — namely, gastrostomy and noninvasive ventilation — also were influenced by these factors, with bulbar-onset ALS and C9ORF7 mutations linked to an earlier need for a gastrostomy.
In adjusted statistical analyses, the start of noninvasive ventilation was significantly associated with respiratory-onset ALS and male sex, whereas better lung function and a longer diagnostic delay again were seen to protect against a need for such ventilation.
Notably, significant differences among clinical sites were seen in the time from ALS diagnosis to a gastrostomy or noninvasive ventilation, as well as in patients&#8217; average lung function when ventilation started.
Analyses taking these factors into account indicated that centers with less ready use of noninvasive ventilation had poorer survival outcomes, but these differences were not statistically significant.
&#8220;It&#8217;s important to note that given the significant amount of missing data that we have, it is difficult to draw conclusions on this alone,&#8221; McDonough said.
Currently, it&#8217;s not clear whether differences among clinical sites are &#8220;due to differences in clinical practice, differences in the cohorts between these clinical centers, or data collection or a combination of these factors,&#8221; the scientists noted.
PRECISION-ALS is working on a prospective study, where data will be collected across its nine sites using a specific data platform, to help improve uniformity.

Tag: bulbar-onset ALS

Phase 2 trial of oral IFB-088 for bulbar-onset ALS now fully enrolled

ALS/MND 2023: European study spotting factors that affect progression