Highlights
Israel’s RedHill Biopharma is developing an experimental drug, opaganib, focusing on the treatment of COVID-19 infection caused by SARS-CoV-2 coronavirus and occurring severely in hospitalized patients.
Oral opaganib has been successfully evaluated clinically, confirming reduced mortality and accelerated recovery.
It should be understood that opaganib has proven its therapeutic efficacy in a population of hospitalized critically ill patients whose COVID-19 symptoms took an average of 11 days from manifestation to treatment initiation. This population differs sharply from outpatients with mild-to-moderate COVID-19, for whom oral medications such as Paxlovid (nirmatrelvir + ritonavir) and molnupiravir, prescribed within 5 days of the onset of symptoms and signs of COVID-19, have been proposed for treatment.
The mechanism of action of opaganib targets the human body rather than the virus, and therefore coronavirus variants, including Omicron, will not affect the effectiveness of this medication.
RedHill, which began submitting the drug’s application to regulators in the fourth quarter of 2021, anticipates that the commercial availability of opaganib, including in the United States, Europe, and the United Kingdom, will occur in the first half of 2022.
The brand name for opaganib is Yeliva.
In parallel, RedHill is developing an experimental drug, upamostat (RHB-107, WX-671), to treat outpatients with symptomatic COVID-19 infection, which is mild-to-moderate and which manifests symptoms within 5 days. Oral upamostat, formerly known as Mesupron and licensed from Germany’s Heidelberg Pharma, is an inhibitor of serine proteases.
Upamostat: Oral Medication for COVID-19
Upamostat by RedHill Biopharma prevents COVID-19 complications from developing followed by hospitalization or death.
Yeliva: Efficacy of Opaganib in Severe COVID-19 Treatment
The NCT04467840 phase 2/3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial invited adult patients (n=463) hospitalized with severe COVID-19 infection.
Among the main inclusion criteria for the trial were radiographically confirmed pneumonia and the need for supplemental oxygen (high-flow oxygen, positive pressure ventilation, or oxygen delivery via face mask).
Patients received standard COVID-19 therapy (including remdesivir and corticosteroids) or the same therapy in combination with opaganib (500 mg daily every 12 hours).
The opaganib group demonstrated a 62% reduction in mortality relative to the control group among patients with moderately severe COVID-19, those requiring a fraction of inspired oxygen (FiO2) of up to 60%. 6.0% of subjects (n=7/117) died — versus 15.7% of patients (n=21/134): relative risk (RR) 2.6 (p=0.019).
Opaganib increased the likelihood of avoiding supplemental oxygen: By day 14 of treatment, 77.0% of patients receiving Yeliva were in status without oxygen therapy — vs. 63.5% in the control group (p=0.033).
Opaganib accelerated hospital discharge by 4 days: a median of 10 days in hospital — vs. 14 days (p=0.0195).
The addition of Yeliva to severe COVID-19 standard treatment, which included the use of remdesivir and corticosteroids, provided an even greater reduction in mortality by 70.2%. Thus, by day 42 of therapy, the mortality rate in the opaganib group was 7.0% (n=3/43) — vs. 23.4% (n=11/47) in the control group (p=0.034).
The inclusion of Yeliva to standard COVID-19 therapy resulted in a one-third (34%) reduction in time to recovery among the entire patient population. While 37.4% of patients in the opaganib group (n=86/230) recovered by day 14 of treatment, 27.9% of subjects in the comparison group (n=65/233) did so: hazard ratio (HR) 1.49 (p=0.013).
Opaganib accelerated viral RNA clearance by at least 4 days: after 14 days, the corresponding time to rid the body of the viral load in the Yeliva group reached the median of 10 days, while the median was not reached in the control group: HR 1.34 (p=0.043).
Yeliva: Mechanism of Action of Opaganib
Opaganib (ABC294640) is an oral small-molecule sphingosine kinase-2 (SK2) inhibitor with anti-inflammatory and antiviral actions.
Stimulation of sphingolipid metabolism is a critical step in the mechanism of action of inflammatory cytokines. Sphingomyelin, as a structural component of cell membranes, serves as a precursor of the potent bioactive lipid ceramide and the proinflammatory lipid sphingosine-1-phosphate (S1P).
Ceramide is formed as a result of hydrolysis of sphingomyelin in response to inflammatory stress, including tumor necrosis factor alpha (TNF) [1] [2], and can induce apoptosis in proliferating cells. Ceramide is further hydrolyzed by ceramidase, converting into sphingosine, which is phosphorylated by sphingosine kinase (SK), giving rise to S1P.
S1P regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and is also involved in immunomodulation and suppression of T-cell innate immune responses.
Increasing intracellular levels of S1P and depleting ceramide levels promotes cell proliferation and suppresses apoptosis. S1P protects neutrophils and macrophages from apoptosis [3] [4], and has several other important effects on cells mediating immune functions. Platelets, monocytes, and mast cells release S1P upon activation, promoting inflammatory cascades at the site of tissue damage. [5] [6]
SK activation is required for signaling responses to TNF. [2] Moreover, S1P mimics the ability of TNF to induce cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) synthesis. [7] S1P mediates Ca2+ influx during neutrophil activation by TNF, which leads to the production of superoxide and other toxic radicals. [8] [9]
Inhibition of SK2 by opaganib results in blocking S1P synthesis, which is reflected in the inhibition of pathological inflammation including TNF signaling and production of other inflammatory cytokines.
The specificity of opaganib toward SK2 rather than sphingosine kinase-1 (SK1) gives the molecule a better therapeutic index than non-specific sphingosine kinase inhibitors or inhibitors targeting SK1 alone. In addition, SK2 inhibition differs from SK1 inhibition in that the effect is localized more intracellularly because it does not depend on the receptor-mediated extracellular action of S1P.
Modeling in rodents with intestinal inflammation, Crohn’s disease, and arthritis confirmed the anti-inflammatory activity of opaganib. [10] [11 ][12] Genetic deletion of SK2 in mice resulted in attenuation of Pseudomonas aeruginosa-induced lung damage. [13]
Decreased expression or pharmacological inhibition of SK2 was reflected in the suppression of Chikungunya virus replication. [14] Opaganib reduced the fatality rates of mice from influenza A infection. [15] Opaganib inhibited the replication of Ebola and Marburg viruses. [16]
The antiviral effect of opaganib evaluated in vitro on a three-dimensional human lung bronchial tissue model (EpiAirway) found that the drug inhibited SARS-CoV-2 replication in a dose-dependent manner. Complete inhibition began at a concentration of 1 μg/ml, with no apparent cytotoxicity or disruption of cell membrane integrity. The test was performed on coronavirus variants Alpha, Beta, Gamma, and Delta. The antiviral activity of opaganib is explained by the fact that SK2 is a critical component of the viral replication–transcription complex.
Opaganib is said to retain its activity in the presence of various variants of SARS-CoV-2, including highly pathogenic Delta and aggressively spreading Omicron, because the mechanism of action of the drug is independent of the mutational features of the coronavirus. Opaganib is claimed to work against Omicron subvariants, including the original Omicron variant (BA.1, or B.1.1.529.1), BA.2 (B.1.1.529.2), and XE (recombination of BA.1 and BA.2).
Preclinical data have validated the antithrombotic activity of opaganib: A reduction in the length, weight, and total number of clots has been demonstrated in an animal model of acute respiratory distress syndrome (ARDS). ARDS is one of the most dangerous complications of COVID-19 entailing potentially fatal venous thrombosis and pulmonary embolism.
A preclinical study showed that opaganib significantly reduced renal fibrosis in an animal model of unilateral ureteral obstruction caused by renal interstitial fibrosis. Over 20% of patients hospitalized with COVID-19 are thought to experience acute renal failure, putting them at increased risk of developing renal fibrosis.
In parallel, opaganib is being tested in cancer therapy, including metastatic castration-resistant prostate cancer (in combination with abiraterone or enzalutamide) and unresectable advanced cholangiocarcinoma (in combination with hydroxychloroquine).
Opaganib, which competitively binds SK2 and inhibits the activity of this enzyme, prevents phosphorylation of S1P, which promotes cell survival and is critical for immunomodulation. This leads to induction of apoptosis and inhibition of proliferation of tumor cells overexpressing SK2. SK2 and its isoenzyme SK1 are overexpressed in numerous types of cancer cells.
Apogee Biotechnology, the company behind the discovery of opaganib, licensed it to RedHill in March 2015. The latter paid $1.5 million up front and promised $4 million as the project developed, as well as royalties from sales of the finished drug.
Extras
RedHill Biopharma. Corporate presentation. June 2022. [PDF]
RedHill Biopharma. Corporate presentation. February 2022. [PDF]
Compassionate use of opaganib for patients with severe COVID-19. J Emerg Dis Virol. 2020 Nov;5(3). [source]
Comparative MD study of inhibitory activity of opaganib and adamantane-isothiourea derivatives toward COVID‐19 main protease Mpro. ChemistrySelect. 2021 Sep 7; 6(33): 8603–8610. [source]
Opaganib in COVID-19 pneumonia: Results of a randomized, placebo-controlled phase 2a trial. bioRxiv, January 12, 2022. [source]