Redhill Biopharma Ltd.’s chief operating officer, Gilead Raday, told BioWorld that the firm will build on positive results in severe COVID-19 patients with oral opaganib, a first-in-class sphingosine kinase-2 inhibitor that the company has branded Yeliva, and could seek emergency use authorization based on data due by year-end.

He pointed to “relatively confirmed successes” with the antiviral remdesivir in mid to early stage patients and with the anti-inflammatory agent dexamethasone, more helpful in later-stage disease.

“Both pathways seem to be relevant and have a role in providing a benefit to patients,” Raday said. “The combination of these two mechanisms is probably the most promising,” and opaganib deploys both.

Published in the online journal Medrxiv, the favorable outcomes involved seven patients treated via compassionate use at a hospital in Israel. The findings, which related to five patients included in the final analysis of the active arm, turned up substantial benefit to patients in clinical outcomes and inflammatory markers as compared to a matched case-control group. Tel Aviv, Israel-based Redhill recently started a phase IIa study under an IND. There’s a phase II/III study due to begin shortly in Europe. Meanwhile, pandemic watchers were sorting through the just-published results.

Prior to starting treatment, patients were hospitalized and required treatment with supplemental oxygen via high-flow nasal cannula while being treated with standard of care, on top of which opaganib was given. An investigator-selected matched case-control group of patients with similar baseline characteristics at the same hospital was identified for comparison (n=18).

All patients in the opaganib-treated group were discharged from the hospital on room air without having required mechanical ventilation, whereas 33% of patients in the control group needed it. Median time to weaning from high-flow nasal cannula was reduced to 10 days in the opaganib-treated arm, as compared to 15 days in the control group. Improvement in lymphocyte counts was faster in opaganib-treated patients as compared to control, too, and C-reactive protein showed faster improvement in the opaganib arm. Opaganib proved safe and well-tolerated. Improvement in clinical and laboratory parameters also was shown for opaganib-treated patients compared to matched case-controls, Redhill said.

Gilead Raday, chief operating officer, Redhill

A randomized, double-blind, placebo-controlled phase IIa experiment with opaganib in the U.S. is open for recruitment. It’s set to enroll up to 40 patients with severe COVID-19 pneumonia requiring hospitalization and supplemental oxygen. The effort is not powered for statistical significance. At the same time, the company has submitted clinical trial applications in Russia, Italy and the U.K. for a multicenter, randomized, double-blind, parallel-arm, placebo-controlled phase II/III study with opaganib in patients hospitalized with severe COVID-19. The study will sign up as many as 270 subjects across up to 40 sites.

Redhill also has opaganib in midstage testing for cholangiocarcinoma, or bile duct cancer. “We historically selected oncology as the primary indication to pursue, and started phase II study in bile duct cancer,” Raday said, but the drug, which targets the replication transcription complex in cells, had been previously investigated in such viruses as influenza and, with the NIH, Ebola. Opaganib looked feasible in in vitro cell lines “but then the [Ebola] pandemic subsided, and there was no further development. When COVID-19 came, we had [those] data in our dossier.” The first arm of the phase II bile duct experiment was completed in 39 evaluable patients, with data showing a signal that “invoked us to expand the study [and] add an arm” where opaganib is combined, interestingly, with a drug that also crops up during COVID-19 talks: hydroxychloroquine.

Potential is intact

Redhill has another dual oncology/COVID-19 prospect in the works: RHB-107 (upamostat, formerly known as Mesupron) is a first-in-class, orally administered protease inhibitor. The compound has been granted orphan drug designation in pancreatic cancer, but that indication is not being pursued at the moment. Some work was done by licensor Heidelberg Pharma AG (formerly known as Wilex AG), of Ladenburg, Germany, and upamostat showed “some activity, but we want to go back and define what population specifically would be most likely to benefit from the drug,” Raday said. It’s being explored in the bile duct indication when combined with opaganib. At the recent virtual annual meeting of the American Association for Cancer Research, Redhill showed both candidates active in xenograft models, but the pairing of them was more potent than either individually.

In late 2019, the company gained approval of Talicia (omeprazole magnesium, amoxicillin and rifabutin) delayed-release capsules for Helicobacter pylori infection in adults. Talicia combines two antibiotics and a proton pump inhibitor to dodge the resistance challenge presented by H. pylori. Aemcolo (rifamycin), a broad-spectrum, orally non-absorbable antibiotic for the treatment of traveler’s diarrhea caused by noninvasive strains of Escherichia coli, was cleared by the FDA in late 2018 and launched in December 2019. Redhill has a U.S. licensing deal for Aemcolo with Dublin-based Cosmo Pharmaceuticals NV.

Redhill in February acquired for $67.5 million the global rights to Movantik (naloxegol), excluding Europe, Canada and Israel, from Astrazeneca plc. The drug is a peripherally acting mu-opioid receptor antagonist indicated for the treatment of opioid-induced constipation in adults with chronic noncancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent opioid dosage escalation. Wainwright analyst Swayampakula Ramakanth in a March 5 report said he was “cautiously optimistic” about Movantik’s performance. Approved in September 2014, the drug reaped U.S. net sales of $122 million, $109 million and $96 million in 2017, 2018 and 2019, respectively. “We are generally encouraged by this acquisition, and believe that Movantik could help the company build its GI franchise,” he wrote. “However, considering the declining sales over the last two years and the backdrop of decline in opioid prescriptions, we are conservative at this time and expect current Movantik sales trajectory to continue in 2020 and 2021,” with only “nominal growth” in 2022. Raday called sales fairly stable and said Redhill could grow the product, given its 100-person sales force, significantly larger than the team devoted to the drug by Cambridge, U.K.-based Astrazeneca. During April, Redhill’s first month of promotion, the company chalked $7.3 million in revenues from Movantik, he said. Edison analyst Jonas Peciulis said in a report that the intake “seems a good result, given this was the peak month of the COVID-19 pandemic.” Efforts with Aemcolo and Talicia were affected “but we believe the potential of these drugs is intact,” he added.

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