The potent immunosuppressive action of Jak inhibitors raised the prospect that these agents might play a valuable role in treating the sickest Covid-19 patients. The failure of Incyte’s Ruxcovid study is a big disappointment, therefore, and shows that much still has to be learned about the best way to treat this disease, even with relatively well-understood mechanisms.
This is not to say that Jak inhibition is over in Covid-19. Several trials have yet to read out, and the mechanism can boast one of the few emergency use authorisations granted so far, albeit for a different drug and in a different setting to that tested in Ruxcovid. The unequivocal failure of this trial is not encouraging, however.
Ruxcovid tested Incyte’s Jakafi in patients with Covid-19-associated cytokine storm. The drug was found to bestow no benefit over standard of care in terms of survival, respiratory failure or admission to intensive care (p=0.769), with all secondary endpoints also missing.
The idea behind testing Jakafi, a Jak 1&2 inhibitor, in this setting was evidence suggesting that overactive signalling through the Jak-Stat pathway might drive the cytokine storm seen in some Covid-19 cases. What drives the systemic inflammatory state in these patients is poorly understood, however, so it is hard to say whether the drug or the way it was used is to blame for the study’s failure.
Even beyond Covid-19, cytokine release syndrome is ill-defined, being caused by a wide range of illnesses or interventions with various manifestations. There is even disagreement over whether the inflammatory state seen in Covid-19 should be referred to as “cytokine storm”.
A recent NEJM article attempted to define the condition when it is caused by the pandemic viral strain. Clotting events are seen more commonly, for instance, as well as lymphopenia (low white blood cells), while levels of certain cytokines, such as IL-6, appear less severely elevated in Covid-19 than in some other cytokine disorders, the authors wrote.
They stressed, however, that the timing of treatment and selection of subgroups of patients will most likely have an effect on outcomes, something that the Ruxcovid investigators will no doubt now be pondering. An answer might be found in the next big test for Jakafi, the Ruxcovid-Devent trial, which enrols an even sicker patient group, those already on a ventilator.
Still, another failure might raise questions about Olumiant's emergency use authorisation. This Jak – also originated at Incyte but this time sold by Lilly – won emergency authorisation in November. Again, several trials with this agent are ongoing.
The crucial question that all are trying to answer here is which biological pathways are best targeted in these very sick Covid-19 patients. IL-6 was an early target, but trials have been largely unsupportive, and it is probably fair to say that the jury is still out on Jak inhibitors.
Anti-GM-CSF antibodies look like the next big immunosuppressive mechanism to yield results, with at least three companies undertaking major trials. Another pro-inflammatory cytokine, GM-CSF has been found in some severely ill Covid-19 patients.
Many other repurposed drugs and experimental agents are being pitted at the problem, and the table below being only a small snapshot of the pipeline. Over the coming months questions will hopefully start to be answered.
|Suppressing the immune system: a selection of studies in Covid-19|
|Product (company)||Mechanism||Trial setting etc||Trial ID|
|Jakafi (Novartis/Incyte)||Jak 1&2 inhibitor||To reduce mortality and complications in patients with Covid-19 cytokine storm: failed Dec 2020||NCT04362137|
|Jakafi (Novartis/Incyte)||Jak 1&2 inhibitor||To reduce mortality in ventilated patients, Incyte sponsored||NCT04377620|
|Otilimab (Glaxosmithkline)||Anti-GM-CSF MAb||Survival of severe Covid-19 patients; primary completion Dec 2020||NCT04376684|
|Mavrilimumab (Kiniksa)||Anti-GM-CSF MAb||Mortality in severe Covid-19 patients with pneumonia and hyper-inflammation; data due from phase II portion||NCT04447469|
|Lenzilumab (Humanigen)||Anti-GM-CSF MAb||Time to recovery in severe or critical patients; readout by YE 2020||NCT04351152|
|Ultomiris (Alexion); Olumiant (Lilly)||Anti-C5 MAb; Jak 1&2 inhibitor||To reduce disease severity in hospitalised patients; academic study, TACTIC-R||NCT04390464|
|Olumiant (Lilly)||Jak 1&2 inhibitor||To reduce disease severity in hospitalised patients, Lilly study||NCT04421027|
|Tavalisse (Rigel); Jakafi (Novartis)||Syk inhibitor; Jak 1&2 inhibitor||To reduce progression to severe pneumonia, academic study||NCT04581954|
|RG7880 & RG6149 (Roche)||Anti-IL 22 & anti-IL33 MAbs||Disease progression in patients with severe Covid-19 pneumonia; primary completion Jan 2021||NCT04386616|
|Otezla (Amgen); Firazyr (Takeda); cenicriviroc (Abbvie); razuprotafib (Aerpio)||PDE4 inhibitor; bradykinin B2 receptor antagonist; CCR2 & CCR5 receptor agonist; VE-PTP inhibitor.||Adaptive I-Spy Covid trial recruiting critically ill patients, agents tested + and vs remdesivir||NCT04488081|
|Source: EvaluatePharma & clinicaltrials.gov.|