Candidate: Actemra® (tocilizumab)
Type: Interleukin-6 (IL-6) receptor antagonist approved by the FDA in 2010, with indications in rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome.
2021 Status: FDA AUTHORIZES EMERGENCY USE—The FDA on June 24 granted emergency use authorization (EUA) to Genentech, a member of the Roche Group, for intravenous Actemra (tocilizumab) for the treatment of COVID-19 in hospitalized adults and pediatric patients (2 years of age and older) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).
The FDA based its EUA on data from four randomized, controlled studies that assessed Actemra as a COVID-19 treatment in more than 5,500 hospitalized patients. The studies suggested that Actemra may improve outcomes in patients receiving corticosteroids and requiring supplemental oxygen or breathing support.
The Phase II/III Randomised Evaluation of COVID-19 Therapy (RECOVERY; NCT04381936) Actemra study was led by researchers in the U.K. and included more than 4,000 hospitalized COVID-19 patients. Genentech-sponsored global Phase III trials included the placebo-controlled EMPACTA (NCT04372186), COVACTA (NCT04320615), and REMDACTA (NCT04409262) studies. There have been no new safety signals identified for Actemra in any of these studies, Genentech said. The most common adverse reactions seen (incidence ≥ 3%) are constipation, anxiety, diarrhea, insomnia, hypertension and nausea.
Researchers from the University of Oxford posted a preprint study on bioRxiv February 11 with data from the RECOVERY trial showing that Actemra reduced the risk of death when given to hospitalized patients with severe COVID-19. Within 28 days, 596 patients (29%) in the tocilizumab group died within 28 days compared with 694 patients (33%) in the usual care group.
The study also showed that Actemra increased the probability of discharge alive within 28 days from 47% to 54%. And among patients not on invasive mechanical ventilation upon entering the trial, Actemra significantly reduced the chance of progressing to invasive mechanical ventilation or death from 38% to 33%.
2020 Status: Genentech, a Member of the Roche Group, on September 18 announced results from the Phase III EMPACTA trial (NCT04372186) showing Actemra® (tocilizumab) plus standard of care to have met the study’s primary endpoint. Patients with COVID-19 associated pneumonia who received Actemra were 44% less likely to progress to mechanical ventilation or death compared to patients who received placebo plus standard of care alone. 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, Genentech acknowledged that at day 28, Actemra showed no significant difference over placebo in two key secondary endpoints: Difference in time to hospital discharge or “ready for discharge,” and difference in time to improvement in ordinal clinical status. Actemra also did not show a statistically significant difference over placebo in mortality, and time to clinical failure.
EMPACTA enrolled 389 patients in the U.S, Brazil, Kenya, Mexico, Peru, and South Africa. Genentech said about 85% of those patients were from minority racial and ethnic groups. Most of those patients were Latinx, with significant representation of Native American and Black populations.
In July, Roche acknowledged that Actemra failed the Phase III COVACTA trial (NCT04320615) by missing its primary endpoint of improved clinical status in hospitalized adult patients with severe COVID-19 associated pneumonia. Key secondary endpoints, which included the difference in patient mortality at week four, were also not met—though Roche said it found “a positive trend” in time to hospital discharge in patients treated with Actemra/RoActemra. COVACTA results will be published in a peer-reviewed journal. That time was 20 days for Actemra patients and 28 days for placebo patients—but the difference cannot be considered statistically significant since the primary endpoint was not met.
COVACTA was a randomized, double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of intravenous Actemra plus standard of care in hospitalized adults with severe COVID-19 pneumonia, compared to placebo plus standard of care. The trial enrolled 450 patients worldwide, including the U.S. COVACTA results will be published in a peer-reviewed journal.
The trial’s primary and secondary endpoints include clinical status, mortality, mechanical ventilation and intensive care unit (ICU) variables. Patients were followed for 60 days post-randomization. Genentech, a Member of the Roche Group, won FDA approval for COVACTA in collaboration with the Biomedical Advanced Research and Development Authority (BARDA) in March.
Roche said the difference in clinical status between Actemra and placebo in patients assessed using a 7-category ordinal scale at week four was not statistically significant. There was no difference between Actemra/RoActemra and placebo in the percentage of patients that died by week four (19.7% for Actemra, 19.4% for placebo).
In June, the Italian Medicines Agency (Aifa) said June 17 that the first randomized clinical trial assessing Actemra as a COVID-19 treatment was halted after the drug “showed no benefit in treated patients neither in terms of aggravation (entry into intensive care) nor in terms of survival.”
The Phase II trial (NCT04346355) enrolled 126 patients—one-third of the expected number—including 19 who recently came to need hospital care, but not invasive or semi-invasive mechanical ventilation procedures. An analysis of 123 of the patients (the other three withdrew their consent) showed similar percentages of aggravations in the first two weeks in patients randomized to receive tocilizumab and in patients randomized to receive standard therapy (28.3% vs. 27.0%). No significant difference was seen in the total number of accesses to Intensive Care (10.0% versus 7.9%) or in 30-day mortality (3.3% vs. 3.2%).
Results could be considered significant conclusive for patients with less advanced COVID-19, but not in patients with greater severity of disease, for whom the results of other studies still in progress are expected, Aifa said. Profs. Carlo Salvarani, MD, PhD, and Massimo Costantini, MD, were principal investigators for the study, conducted by Local Health Unit-Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) of Reggio Emilia, with collaboration from 24 centers.
In Italy, Actemra remains the subject of an up-to-330-patient trial Phase II trial recruiting patients as of July 13 (TOCIVID-19; NCT04317092) and an up-to-30-patient Phase II trial active but no longer recruiting patients (NCT04315480) designed to study the drug as a single 8mg/Kg dose in patients affected by severe pneumonia correlated to SARS-CoV2.
Genentech CEO Alexander Hardy told reporters at a Pharmaceutical Researchers & Manufacturers of America (PhRMA) at a June 16 briefing that his company has ramped up production of Actemra from hundreds of thousands to millions of doses at its own risk, since clinical results have yet to fully emerge on the drug: “We want to make sure we aren’t in a situation where there is going to be difficult trade-off decisions because demand will far exceed supply. That is why we are all doing this.”
In April, a team of Chinese researchers published a study in PNAS, concluding from preliminary data that Actemra improved clinical outcomes immediately in 20 patients with severe or critical COVID-19, and thus “is an effective treatment to reduce mortality.” Five days after treatment, 15 of the 20 patients (75%) lowered their oxygen intake, and 1 patient needed no oxygen therapy. The percentage of lymphocytes in peripheral blood, which decreased in 17 of 20 patients (85%) before treatment, returned to normal in 10 of 19 patients (52.6%) on the fifth day after treatment.
Two days earlier, Actemra met its primary endpoint—a combination of the need for ventilation (mechanical or non-invasive) or death on day 14 after treatment—in the CORIMUNO-TOCI open-label randomized controlled trial conducted at the Assistance Publique-Hôpitaux de Paris (APHP), the hospital stated. A total of 129 patients were randomized: 65 for usual treatment + tocilizumab and 64 for usual treatment. The primary efficacy endpoint was achieved in a significantly lower proportion of patients in the tocilizumab arm, APHP said, adding that results will be submitted for publication in a peer-reviewed journal.
Actemra sales during Q1 jumped 25% (30% at constant exchange rates) from a year earlier, to CHF 666 million ($683 million) from CHF 534 million ($548 million)—a possible result of the drug being studied for COVID-19 in several Chinese cohort studies, plus reports of effective treatment from Italy, Antoine Grey, Senior Healthcare Analyst at GlobalData, said in April.
In March, Genentech said it will provide 10,000 vials of Actemra to the U.S. Strategic National Stockpile for potential future use at the direction of the U.S. Department of Health and Human Services (HHS).
Also that month, a Chinese research team published a study showing positive results for Actemra: 19 of 20 severe COVID-19 patients were discharged from hospital an average 13.5 days after treatment.
China’s National Health Commission earlier this month included Actemra in its 7th updated diagnosis and treatment plan for COVID-19, to treat patients with high levels of IL-6 and serious lung damage. Actemra is also under study as a COVID-19 treatment in three active Chinese clinical trials, according to the Chinese Clinical Trials Registry: A 188-patient study (ChiCTR2000029765), a 150-patient trial assessing Actemra in combination with favipiravir (ChiCTR2000030894); a 120-patient trial in combination with continuous renal replacement therapy (CRRT) (NCT04306705); a 100-patient trial in combination with intravenous immunoglobulin and CRRT (ChiCTR2000030442 ); and a 60-patient trial with JinYu Bio-Technology Co., which markets the drug as CMAB806 (ChiCTR2000030196).
COVID-19: 200 Candidates and Counting
To navigate through the >200 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: