First COVID-19 Trial Success For Roche’s Actemra, But No Sign It Saves Lives
Trial Focused On Hispanic, Black And Native Americans
Executive Summary
A composite endpoint conceals Actemra’s lack of mortality benefit – while life-saving dexamethasone gets EMA endorsement.
Roche Holding AG’s Actemra (tocilizumab) has hit its primary endpoint in a pivotal trial of patients with severe COVID-19 associated pneumonia - but the results are however far from clear-cut.
The EMPACTA (Evaluating Minority Patients with Actemra) trial found the IL-6 inhibitor more effective than placebo in reducing the risk of these patients progressing to mechanical ventilation or death, and produced no new safety concerns.
It represents the first Phase III success for the immunosuppressive therapy in COVID-19 after several earlier trials failed, including Roche’s own COVACTA study in July. (Also see "Coronavirus Update: Roche's Actemra Fails In Phase III COVID Study" - Scrip, 29 Jul, 2020.)
However, the new results come with a major caveat: the data did not show the treatment reduced the risk of death compared with placebo.
This apparent contradiction is because the primary endpoint was a composite, encompassing both progression to mechanical ventilation and death – and the trial hit this endpoint thanks to fewer patients requiring mechanical ventilation, and not on the overall number of deaths.
While the results give the first glimmer of hope that Actemra might have a role against COVID-19, Roche is not getting carried away.
It told Scrip: “We plan to share these results with health authorities including the US Food and Drug Administration,” but added: “It is premature to speculate on filing an EUA [Emergency Use Authorization] at this time.”
The trial is also significant because Roche focused on recruiting people from minority racial and ethnic groups, who have been shown to have higher mortality rates from COVID-19 than white patients.
The trial was conducted in the US, South Africa, Kenya, Brazil, Mexico and Peru and around 85% of the 389 patients enrolled were Hispanic, with significant representation of Native American and Black populations.
Jamie Freedman, Head of Genentech US Medical Affairs
“We have been striving to improve inclusion and diversity in our trials,” said Jamie Freedman, Roche’s head of US medical affairs. “During the COVID-19 pandemic, we saw how high the stakes were for many communities of color and made diversity the centerpiece of this trial.”
EMPACTA Results
The results from the placebo-controlled trial of 389 patients with COVID-19 associated pneumonia show that those who received Actemra plus standard of care were 44% less likely to progress to mechanical ventilation or death compared to patients who received placebo plus standard of care (log-rank p-value = 0.0348; HR [95% CI] = 0.56 [0.32, 0.97]).
The cumulative proportion of patients who progressed to mechanical ventilation or death by day 28 was 12.2% in the Actemra arm versus 19.3% in the placebo arm.
However, while these results do achieve statistical significance, they do not provide evidence that the drug saves the lives of hospitalized COVID-19 patients whose condition is deteriorating.
The study also hit none of its secondary endpoints, including a separate measure of mortality between patients who received Actemra or placebo by day 28 (Actemra = 10.4%; placebo = 8.6%, p-value = 0.5146, Difference [95% CI]: 2.0% [-5.2%, 7.8%].
Roche nevertheless said that it was “working to analyze this data in conjunction with other studies to better understand the potential benefit/risk of Actemra in COVID-19 pneumonia.”
Roche is also conducting MARIPOSA, a Phase II trial of two doses of Actemra in patients with moderate to severe (rather than severe) COVID-19 pneumonia.
Another major ongoing study of the drug is REMDACTA, in which it is combined with Gilead’s Veklury (remdesivir), the only drug to gain an EUA in the US and conditional approval in Europe for hospitalized coronavirus patients.
Dexamethasone Endorsed
Roche’s update comes just days after Eli Lilly announced results from its study of Olumiant (baricitinib) with Veklury, and results from its monoclonal antibody therapy LY-CoV555. Early datasets from both studies showed signs of safety and efficacy for the therapies, but look likely to fall well short of "gamechanger" status. (Also see "Lilly Claims Proof Of Concept For Neutralizing Antibodies In COVID-19 Therapy" - Scrip, 16 Sep, 2020.)
The one therapy which has demonstrated significant impact on COVID-19 mortality is the off-patent steroid dexamethasone. The UK-led RECOVERY trial showed that 6mg once daily for up to 10 days reduced 28-day mortality in patients receiving respiratory support.
The European Medicines Agency (EMA) has just endorsed its use in this setting, and said in a statement that companies that market dexamethasone medicines can request this new use to be added to their product license by submitting an application to national medicines agencies or to the EMA.