Redhill Biopharma — Rapid progress with COVID-19 programme

RedHill has identified its anti-cancer/anti-inflammatory candidate opaganib (Yeliva, formerly ABC294640) as a potential treatment for COVID-19. The company was able to make rapid progress with this programme because opaganib is already being investigated in Phase II clinical trials. It has also completed a Phase I study, as well as safety and pharmacokinetics studies in healthy volunteers and had been given to over 130 subjects.

Opaganib is a sphingosine kinase-2 (SK2) inhibitor. Sphingomyelin is not only a building block for cellular membranes but also acts as a precursor for lipid messengers for the potent bioactive lipid ceramide and the pro-inflammatory lipid sphingosine 1-phosphate (S1P) that have profound cellular effects. During one of the downstream processes, sphingosine kinases (there are two isoforms SK1 and SK2) promote rapid production of S1P from sphingosine. S1P in turn promotes cancer growth, proliferation and inflammation processes. Opaganib is a specific SK2 inhibitor that decreases S1P synthesis. This approach has been demonstrated to have an effect on a broad range of fundamental biological processes and has potential in oncology, inflammatory diseases and as an anti-viral agent.

Prior pre-clinical studies with opaganib support the potential role of SK2 in the replication-transcription complex of positive-strand single-stranded RNA viruses, which includes coronavirus, and its inhibition may potentially stop viral replication. In vivo studies have demonstrated that opaganib decreased fatality rates from influenza-virus infection (Exhibit 1A and 1B). In vivo studies with bacterial-induced lung injury models (Pseudomonas aeruginosa in mice) also showed that the damage is ameliorated (Exhibit 1C).

It is the combination of the anti-inflammatory and anti-viral effects that makes this drug a unique potential treatment for SARS-CoV-2 infections. Theoretically, it should not only treat the cause of the disease, the virus, but also alleviate the inflammation, which triggers severe acute respiratory syndrome (SARS). SARS is a known severe, life threatening condition, but it also increases the risk of pulmonary fibrosis. There is growing concern that pulmonary fibrosis could be a long-term negative consequence for many individuals affected by COVID-19, even for those who avoided the most severe form of the disease with the need for admission to intensive care units. It is fair to say that we are still in an acute phase of the COVID-19 pandemic. At this point, it is impossible to predict what the longer-term public health consequences will be, but if COVID-19 infection is proven to increase the risk of pulmonary fibrosis in the wider affected population, we believe this will be a major public health issue in addition to the acute phase, as the patients who are recovering currently may start experiencing disabling complications years later. In this scenario, drugs with a mechanism of action like opaganib’s could be of major interest.

Opaganib has been given to a total of 131 subjects to date (cancer patients and healthy volunteers in the previous Phase I and Phase II studies and participants in expanded access programmes). Currently opaganib is being investigated in a Phase I/IIa study for cholangiocarcinoma and in another Phase II study in prostate cancer.

In early April, RedHill announced compassionate use programmes in Israel, but it is also working with other countries. Later that month, the company reported findings from the first evaluable patients, who were hospitalised in Israel at one of the tertiary academic hospitals (the preprint article was made available in June).

Before the treatment with opaganib, all patients had severe disease requiring oxygen support via high-flow nasal cannula. The investigators reported findings from five evaluable patients treated with opaganib versus matched case controls:

One patient, who received hydroxychloroquine and azithromycin (macrolide class antibiotic) on top of opaganib, developed diarrhoea after two doses of opaganib and the treating physicians decided to discontinue all his medications. This patient was not included in the results analysis. We believe, it is difficult to say whether this was a side effect of opaganib, as both hydroxychloroquine and azithromycin (macrolide class antibiotic) can cause diarrhoea. No other side effects that were deemed opaganib-related were reported.

As a control group, the investigators selected similar group of patients (n=18, same sex, same severity and similar age group), who met the inclusion and exclusion criteria at the same hospital. The descriptive baseline characteristics of both groups of patients were largely similar, but the key difference, in our view, was the fact that a third of control patients received methylprednisolone and no opaganib group patients received it.

In mid-June, the preliminary results from a separate study conducted in the UK to test a range of potential treatments for COVID-19 patients were published (the RECOVERY study – Randomised Evaluation of COVid-19 thERapY). This study was unrelated to RedHill and opaganib. The key new finding was that for patients on ventilators, low-dose dexamethasone treatment was shown to reduce mortality by about one-third, and for patients requiring oxygen therapy mortality was cut by about one-fifth. In total 2,104 patients were randomised to receive dexamethasone. Because of this large sample size, the fact that synthetic corticosteroids are a very well-established class of drugs, easily available and cheap, the use of dexamethasone for severe COVID-19 patients immediately became widespread in the UK.

Both methylprednisolone and dexamethasone are synthetic corticosteroids, and while there are some pharmacokinetic and pharmacodynamic differences, these drugs can be interchangeable in certain cases if the correct dosing is chosen (eg, in chronic obstructive pulmonary disease exacerbation). The authors of the of RedHill’s opaganib article were not aware of the benefit of corticosteroids, as the article was submitted for publication before the UK study results were published. We believe it is possible that the use of methylprednisolone in the control arm increased the hurdle for opaganib. If corticosteroids had not been administered to patients in the control arm, the benefit of opaganib might have been even more pronounced.

In our view, the first compassion use results are interesting, but the patient sample is small and a controlled trial is still needed for regulatory approval. RedHill filed for an IND with the FDA, which was approved in May. This will be a randomized, double-blind, placebo-controlled Phase IIa study with the goal of enrolling up to 40 COVID-19 patients with severe-to-critical infection requiring hospitalisation and high-flow supplemental oxygenation. Patients randomized at a 1:1 ratio will receive either opaganib or placebo in combination with standard-of-care. The primary endpoint is to evaluate the reduction in total oxygen requirement over the course of treatment (up to 14 days). Secondary endpoints include time to 50% reduction in oxygen requirements, the proportion of patients without fever at day 14 and the proportion with negative nasal swabs at day 14. By mid-July more than 25% of patients were enrolled in the study and RedHill expects to complete enrolment in August.

In July, RedHill plans to initiate a Phase II/III multi-centre, randomized, double-blind, parallel-arm, placebo-controlled study with opaganib and aims to enrol 270 severe COVID-19 patients in up to 40 clinical sites across the UK, Italy, Russia, Mexico and Brazil. The patients will be randomized at a 1:1 ratio. The primary endpoint will be the proportion of patients requiring intubation and mechanical ventilation by day 14.

If these studies are successful, RedHill plans to submit opaganib for emergency use approval as early as Q420.

RedHill also has another potential asset against COVID-19, RHB-107 (upamostat). RHB-107 is an inhibitor of the S1 family of trypsin-like serine proteases with potential for use in the treatment of cancer, inflammatory lung diseases and irritable bowel syndrome. Inhibition of serine proteases, including trypsins, may inhibit viral attachment and replication, and alleviate lung damage in viral pneumonia. Based on its possible mechanism of action, RHB-107 was selected for in vitro testing by the US National Institute of Allergy and Infectious Diseases (NIAID).