by Manasi Vaidya in New York and Reynald Castaneda in London.
Gilead Sciences’ remdesivir has potential for use in a combination approach in Covid-19, but there is uncertainty about whether Roche’s Actemra / RoActemra (tocilizumab) or Eli Lilly’s Olumiant (baricitinib) would be its ideal partner due to limited immunomodulator monotherapy data.
Combining remdesivir, which interferes with SARS-CoV-2’s ribonucleic acid (RNA) polymerase, with immunomodulators like Actemra and Olumiant could offer a two-pronged approach in Covid-19. However, immunomodulator monotherapy data has been underwhelming. While Janus kinase (JAK) inhibitor use may interfere with the immune system to fight the viral attack if used too early, inhibiting specific JAKs could blunt such a challenge.
Experts preferred to wait for clinical data before choosing between Actemra or Olumiant as a remdesivir partner, but Olumiant may carry dosing and safety advantages. Ongoing studies include the National Institute of Allergy and Infectious Diseases’ (NIAID’s) 1,032-patient Phase III ACTT-II study (NCT04401579) evaluating remdesivir and 14-day orally-administered Olumiant. Additionally, Roche is conducting the 450-patient Phase III (NCT04409262) REMDACTA study with remdesivir and a single administration of intravenous Actemra in a 10-day treatment schedule.
Remdesivir is also being combined with ViralClear Pharmaceuticals’ merimepodib, a broad-spectrum antiviral, in a Phase II study. ViralClear is a subsidiary of BioSig Technologies. While it is attractive to use two antivirals for an additive effect, their utility may be limited to before patients undergo mechanical ventilation, as the viral load becomes less relevant the more severe a patient is. While remdesivir use has been authorised for a broad range of hospitalised patients, it is envisioned its monotherapy and combination use to be early, before a patient requires mechanical ventilation.
Following results from the Phase II / III RECOVERY (NCT04381936), which showed mortality benefit with generic steroid dexamethasone in certain subgroups, this data may negatively impact any potential use of immunomodulators like Actemra or Olumiant in combination with remdesivir given their similar mechanisms.
Remdesivir and Actemra and Olumiant combinations logical but more monotherapy data desired
A combination of an anti-interleukin (IL)-6 or a JAK inhibitor with remdesivir targets two different pathways, said Dr Christopher Tignanelli, assistant professor, Division of Critical Care / Acute Care Surgery, University of Minnesota, Minneapolis. By adding an anti-inflammatory or immune modulator drug, the exuberant inflammatory response seen in Covid-19 can be modulated to prevent the development of acute respiratory distress syndrome (ARDS) and the need for ventilator support, said Dr Susan Kline, professor of Medicine, Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis.
However, it may be counterintuitive to combine remdesivir with a JAK inhibitor like Olumiant in the early Covid-19 phase of hospitalised patients, said Dr Thomas Marron, assistant director, Early Phase and Immunotherapy Trials, The Tisch Cancer Institute, New York. Remdesivir targets viral mechanisms and aims to stimulate an immune response, but a JAK inhibitor like Olumiant can incapacitate T cells, impairing an immune system attack on the virus if used too early, Marron said. However, if a JAK inhibitor is selective to JAK2, it may be specific and avoid interfering with the interferon-alfa or beta antiviral pathways linked to the TYK2 / JAK1 pathway, said Tignanelli. JAK1 / JAK2 inhibitors like Olumiant and Eli Lilly’s Jakafi (ruxolitinib) may have a mechanistic edge over Pfizer’s JAK 1 / 3 inhibitor Xeljanz (tofacitinib) in Covid-19, as the former two therapies may have a clearer link in downregulating IL-6, this news service reported on 27 April.
Actemra monotherapy has not had strong positive data yet in Covid-19, said Marron. Among 123 Covid-19 patients in Phase II investigator-led study (NCT04346355), no significant difference was seen with Actemra compared to standard of care (SOC) without Actemra for entry into intensive care (10% versus 7.9%) and 30-day mortality (3.3% versus 3.2%), as according to an Italian Medical Agency (AIFA) 17 June press release. SOC was not defined in the press release. There may be a need to find further subpopulations of patients who are likely to benefit, an infectious disease clinician said on the AIFA Actemra data. It is possible the repurposing strategy for an anti-IL-6 may not be ideal at all, as Covid-19 could have a different disease pathology compared with other diseases such therapies are approved for, Marron noted.
There are no robust, well-controlled studies showing the safety and efficacy of Actemra alone or in combination with antiviral therapy in the treatment of patients with Covid-19 pneumonia, said a Roche spokesperson. REMDACTA is the first global study to evaluate the remdesivir / Actemra combination. Olumiant monotherapy is being evaluated in Lilly’s Phase III trial (NCT04421027), which has a 1 September primary completion date.
While it is not clear whether Actemra or Olumiant would be a better combination partner with remdesivir, Olumiant has an edge since it is an orally-administered therapy versus intravenously-administered Actemra, said a virologist clinician. Olumiant has a short half-life, so it has one potential benefit of being stopped if necessary, and it would not have a prolonged effect, said Kline. If antibodies are longer acting and a patient develops serious infections, it is harder to reverse their effects, she said, adding safety data with Actemra and Olumiant combinations will have to be compared closely. In both studies, a loading dose of remdesivir is followed by a maintenance remdesivir dose for ten days and then combined with either 4mg Olumiant daily for the duration of the hospitalisation up to a 14-day total course, or one infusion of Actemra on day one, respectively.
Apart from Olumiant and Actemra, remdesivir is also being studied in combination with merimepodib in a ViralClear-sponsored Phase II study (NCT04410354). The virologist clinician supported a dual antiviral combination in theory, as has been useful in other viral diseases like human immunodeficiency virus (HIV) and hepatitis C, but said it should be limited to earlier stages of the disease up to the noninvasive ventilation stage. The merimepodib study includes advanced Covid-19 patients but excludes those in later stages of the disease needing invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO).
In vitro data indicates merimepodib in combination with remdesivir is more effective than remdesivir alone, said investigator Dr Eric Whitman, medical director, Atlantic Health System Cancer Care, Morristown, New Jersey. The SARS-CoV2 virus titer was reduced to undetectable levels at different time points when remdesivir and merimepodib was used in combination at seven different dose combinations (p<0.001) in Vero cells (Bukreya et al., epub: https://f1000research.com/articles/9-361).
Merimepodib is a pan-antiviral affecting the host cell’s synthesis of guanidine, a nucleotide making up a part of RNA and DNA, said Jerome Zeldis, executive chairman of ViralClear Pharmaceuticals, adding there is a synergy between merimepodib and remdesivir. Eli Lilly did not respond to a request for comment.
Remdesivir utility window related to mechanism
Remdesivir monotherapy is indicated for Covid-19 patients with severe disease, defined as oxygen saturation (SpO2) ≤94% on room air, requiring supplemental oxygen, mechanical ventilation, or ECMO, as per its FDA Emergency Use Authorization (EUA). However, patients in the early stages of Covid-19 disease are currently being prioritised for remdesivir monotherapy before the need for mechanical ventilation arises, said Whitman and the infectious disease clinician.
The REMDACTA study includes the proportion of patients requiring mechanical ventilation as a secondary endpoint and is enrolling patients requiring more than 6L / min supplemental oxygen to maintain SpO2 >93%. However, the ACTT-II study is enrolling patients who may need supplemental oxygen, mechanical ventilation or ECMO.
Experts placed remdesivir use as monotherapy or a combination in the early stages of hospitalisation. If a patient gets admitted and has signs of pneumonia, remdesivir can easily be given to them since it is readily available in the pharmacy, said Whitman. Moreover, remdesivir seems to benefit patients before they get to the stage of requiring mechanical ventilation, and most hospitals are currently administering it early in this manner, said Dr Richard Novak, chief, Division of Infectious Diseases, University of Illinois College of Medicine, Chicago. Once a patient suffers from cytokine storm syndrome (CSS), antiviral agents may not make too much of a difference, said Whitman.
There is no clear line on transitioning from an antiviral to anti-inflammatory treatment, said the virologist clinician. There is an overlap between when an antiviral and anti-inflammatory approach may be effective in Covid-19, but it could be a short window, said the virologist. In the ACTT-II study, a high loading dose would allow remdesivir to inhibit the virus and simultaneously suppress the inflammation with Olumiant, said Novak. Roche’s Actemra trial also uses a loading dose and maintenance dose schedule for remdesivir.
Dexamethasone intriguing with remdesivir
There is an interest for adding dexamethasone to standard treatments like remdesivir, similar to the combinations with Olumiant and Actemra, but more data is needed, said Kline. In Phase II / III RECOVERY study (NCT04381936), dexamethasone showed a mortality benefit in ventilated patients (rate ratio=0.65; p=0.0003) and those receiving oxygen (rate ratio=0.80; p=0.0021), but not in those not on respiratory support, as per a 16 June University of Oxford press release. The virologist clinician described the positive anecdotal experience of using remdesivir plus dexamethasone in an elderly patient with comorbidities who required supplementary oxygen for five days. The combination was effective enough to prevent the need for ventilator support. However, he emphasised there is still a need for randomised data on the combination.
Given the mortality benefit, dexamethasone will likely be incorporated into standard practise soon, said Novak, adding clinicians are waiting for National Institutes of Health guidance on the use of dexamethasone. While RECOVERY may have had limitations, its mortality benefit was impressive enough for it to be included in his institute’s Covid-19 treatment guidelines as SOC, said Whitman.
Pharma companies will now have to see if dexamethasone is acceptable in ongoing trials as SOC in the same way they had to decide whether remdesivir use would be allowed in trials once it got an EUA, said Whitman. Since dexamethasone is now considered a SOC for hospitalised patients, it will be allowed on the remdesivir / merimepodib study, said Zeldis. There may be an interference of mechanisms if dexamethasone is used in trials also using an anti-IL-6 or other immunomodulator, Whitman added. However, a more specific approach like JAK1 / 2 inhibition may be better than the broadly immunosuppressive dexamethasone, said Novak.
Manasi Vaidya is a Senior Reporter and Reynald Castaneda is an Associate Editor 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.