by Reynald Castaneda in London and Nancy Jaser in New York.
Despite Abivax’s ABX464 having an attractive triple mechanism for Covid-19, there is uncertainty if the drug’s efficacy promise would pan out in its Phase IIb/III trial. Gaps in fully understanding the drug’s mechanism for SARS-CoV-2, ulcerative colitis data lacking clear extrapolation potential and some trial design elements weigh against ABX464, though the trial is focusing on patients typically underrepresented in investigations.
ABX464 as a microRNA upregulator to inhibit SARS-CoV-2 entry into the human cell and reduce inflammation may be too broad, risking unintended knock-on effects. The drug boosting interleukin-22 (IL-22) may be beneficial in limiting long-term lung injury via tissue repair, the third part of its triple-action mechanism. However, patients having high levels of interferon, a biomarker not monitored in the trial, may increase risk of IL-22’s potential inflammatory effect.
While ulcerative colitis (UC) physicians noted ABX464’s efficacy data in moderate-to-severe UC are in-line with available therapies, extrapolating such data to Covid-19 is dubious. Oral ABX464, under investigation in both indications as a once-daily 50mg drug, may require different dosing for Covid-19 but the 28-day treatment period is better than other experimental treatments. Similarly, the Phase IIb/III MiR-AGE trial’s (NCT04393038) concentration on patients over 65 years old and those with comorbidities is welcome as they are at more risk of severe disease with their weaker immune systems.
The placebo-controlled study may, however, suffer due to the lack of standardized guidelines for standard of care (SOC) therapies and clinical practice. The trial allows SOC use in both arms and is primarily investigating how many patients are prevented from progressing to requiring oxygen support. Also, the trial includes hospitalised and nonhospitalised patients, but there is no standard approach in treating and monitoring the latter group, which would make it challenging to run a uniform trial.
On 2 July, Abivax announced topline results are expected YE and that the first patient had been treated. Abivax, which has a $ 307.3m market cap, did not respond by press time.
Efficacy may be limited by too broad a mechanism
A drug like ABX464 that has a three-pronged approach to treat Covid-19 by inhibiting viral replication, assuaging hyperinflammation and promoting tissue repair is attractive, said a critical care physician treating Covid-19 patients. However, he noted uncertainty about whether a single drug will able to do all three things effectively. ABX464’s anti-viral mechanism works through the upregulation of the microRNA miR-124, with the drug also upping IL-22 levels, which helps lung tissue repair and triggers an anti-inflammatory effect.
In vitro data in reconstituted human respiratory epithelium models showed ABX464 inhibited replication of SARS-CoV-2, a 14 May media release states. Yet, the value of such preclinical models hinges on the materials used, said a microbiologist physician treating Covid-19 patients. For example, studies that use freshly collected human airway epithelial cells may be more informative, he said.
There is some rationale for ABX464’s anti-viral mechanism, since upregulating miR-124 inhibits dynamin-2, said Stephen Barr, PhD, associate professor of molecular virology, Western University, Ontario, Canada. SARS-CoV-2 replication requires dynamin-2, a GTPase necessary for viral entry, according to the aforementioned media release. Any drug that targets a human cellular protein required by the virus to survive could have merit, noted Barr.
But inhibiting dynamin-2 could be counterproductive, as it has other important roles, Barr added. Dynamin-2 helps regulate cellular organelle structure and function as well as cellular cytoskeletal integrity.
Another caveat with upregulating microRNAs such as miR-124 is that it can target many genes, which heightens the risk of off-target impact, noted John Alcorn, PhD, associate professor, Division of Pulmonary Medicine, UPMC Children’s Hospital of Pittsburgh, Pennsylvania.
According to the May media release, ABX464 promotes tissue repair and decreases pulmonary fibrosis. And based on preclinical data in UC, the drug leads to an increased expression of IL-22, a January 2019 presentation shows. IL-22 can limit acute inflammation via its epithelial protective effects, Alcorn explained. Preserving barrier function in the lung limits tissue injury, accumulation of inflammatory cells in the lung airspace, swelling and alveolar haemorrhage, he added.
While company statements have described ABX464 as limiting long-term injury via tissue repair, the aim of the Phase IIb/III on ClinicalTrials.gov is described as treating inflammation and preventing acute respiratory failure. At enrolment, patients have to have a pulse oximetry arterial saturation ≥92% on room air, and the primary endpoint assesses the rate of patients on intermittent mandatory ventilation (IMV) or noninvasive ventilation (NIV)—excluding nasal/mask oxygen supplementation—and who are alive.
However, IL-22 can become an inflammatory risk when there are high interleukin levels in the blood, Alcorn added. ABX464 may hence be more ideal in Covid-19 patients who are about a week into their infection when interferon levels are likely lower compared with earlier in the course of infection, he said. MiR-AGE is treating patients at the point of diagnosis, and a 2 July company presentation notes that the time between infection to a PCR diagnosis is estimated to be 2–10 days. While recruitment is based on measuring certain laboratory parameters, obtained within seven days prior to trial start, interleukin levels are not measured.
UC efficacy data dubious predictor for Covid-19
While Abivax has said that ABX464’s anti-inflammatory and tissue repair MOAs are bolstered by observations in UC patients, experts were not convinced. ABX464’s safety profile in UC is so far encouraging, added Dr Andres Jose Yarur, assistant professor, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee. Most adverse events were mild-to-moderate and ABX464 was not associated with increased opportunistic infection risk.
But while UC efficacy data are also encouraging, as there is inflammation improvement, this is only an early efficacy signal, said Dr Russell Cohen, director, Inflammatory Bowel Disease Center, UChicago Medicine, Illinois. In the Phase IIa induction UC trial (NCT03093259), 30% of the 23 intention-to-treat patients reached clinical remission versus 11% of patients receiving placebo (p=0.16), according to the July company presentation.
Furthermore, the inflammation cascade between UC and Covid-19 is likely to be different, said Yarur and the critical care physician. In fact, for example, despite UC and Crohn’s disease both being inflammatory bowel diseases, a drug that works in the former may not work in the latter, Yarur added. The dosing required for UC and Covid-19 could be different, Yarur added, but the Covid-19 trial is using the same 50mg once-daily dose as was tested in the Phase IIa UC study.
However, MiR-AGE’s 28-day treatment period is logical compared to other therapies of shorter durations, said the critical care physician. There are patients who were admitted to the intensive care unit (ICU) in March who are yet to recover, he noted. But perhaps even a longer treatment may be needed, and the timeframe may have been an empirical choice with regards to lung damage improvements, he added. After the 28-day treatment, patients are followed for 14 days for safety assessments.
Trial design may fall victim to country heterogeneity
On top of ABX464’s mechanism gaps, MiR-AGE’s trial design had experts cautioning that the study may lack uniformity in execution though some patient inclusion criteria drew favour.
MiR-AGE combines ABX464 with SOC, but the critical care physician cautioned SOC is different in various countries. Abivax plans to run the trial in Europe and in Latin American countries like Brazil. There are no clear guidelines on how to treat Covid-19 patients, said a Brazil-based physician treating Covid-19 patients. Corticosteroids and hydroxychloroquine are used, but the latter has recently waned, he added. Gilead Sciences’ Veklury (remdesivir) is not available in Brazil, he noted.
Clinical practice is also heterogeneous across countries, said the critical care physician, who is based in France. For example, transitioning hospitalised patients to more advanced forms of oxygen support is increasingly being delayed, he noted. Yet, the Brazil-based physician was not as concerned, noting journal publications based on the experience in countries first hit are used as a guide.
Still, the critical care physician noted, with regards to nonhospitalised patients, clinicians err towards keeping patients at home. Patients are typically called at least every other day to check if there is evidence of deterioration, he explained.
In Brazil, however, public healthcare system Sistema Único de Saúde utilizes community agents, so patient follow-up can be more inconsistent, whereas patients in private health plans are monitored directly by their doctor, explained a second Brazil-based infectious disease physician.
Abivax has yet to detail how many nonhospitalised and hospitalised patients would be enrolled in the 1,034-patient MiR-AGE, with the trial having a 2:1 trial design. According to the company presentation, Abivax expects a 75% response rate in the placebo group, versus 83% in the ABX464 arm. Conflating both groups for data analysis is not logical, as hospitalised patients are at a higher risk of disease progression, the critical care physician said.
Yet, the trial’s inclusion of patients 65 and older and those with risk factors is welcome, as they can be underrepresented in Covid-19 trials, the microbiologist physician said. Younger patients with at least one risk factor can also be recruited. There is an overlap between these two cohorts considering their weaker immune systems make them sensitive to disease progression, the critical care physician added.
Reynald Castaneda is Associate Editor and Nancy Jaser is Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.