FDA OKs Launch of Phase III Tocilizumab Trial for COVID-19 Pneumonia

The FDA has approved the initiation of a double-blind, randomized phase III clinical trial of the oncology supportive care drug tocilizumab (Actemra) for use in combination with standard of care for the treatment of hospitalized adult patients with severe COVID-19 pneumonia, according to Genentech (Roche), the manufacturer of the interleukin-6 receptor antagonist.¹

Genentech is collaborating with the Biomedical Advanced Research and Development Authority (BARDA), a part of the US Health and Human Services Office of the Assistant Secretary for Preparedness and Response (ASPR), to evaluate tocilizumab combined with standard of care versus placebo plus standard of care.

Genentech also announced in a press release that the company is providing 10,000 vials of tocilizumab to the United States Strategic national stockpile for potential future use as determined by the US Department of Health and Human Services.

“We thank the FDA for rapidly expediting the approval of this clinical trial to evaluate Actemra in critically ill patients suffering from pneumonia following coronavirus infection and we’re moving forward to enroll as quickly as possible,” Alexander Hardy, chief executive officer of Genentech, said in the press release.

“Conducting this clinical trial in partnership with BARDA and providing Actemra to support the national stockpile, through the efforts of Secretary Azar and HHS, are important examples of how the US government the biotechnology industry and healthcare communities are working together in response to this public health crisis,” added Hardy.

According to Genentech, the phase III study is the first global trial in this setting. Enrollment is expected to start as early as April 2020, with a target accrual of 330 patients across the United States and other countries. Investigators will follow patients for 60 days after randomization and early proof of efficacy will be assessed at an interim analysis. Key study endpoints will be clinical status, mortality, mechanical ventilation, and intensive care unit variables.

Genentech explained in the press release that there are already multiple independent clinical trials evaluating tocilizumab as a potential therapy for patients with COVID-19 pneumonia; however, none of these trials is well-controlled and there have been limited published results regarding the efficacy and safety of tocilizumab in patients with COVID-19.

As the CAR T-cell therapy revolution has spread across the treatment paradigm for patients with hematologic malignancies, tocilizumab has become critical to ensuring that patients are able to receive this type of therapy. Specifically, tocilizumab is approved by the FDA for the treatment of cytokine release syndrome (CRS) that is severe or life-threatening. CRS is the most severe toxicity associated with CAR T-cell therapy. Tocilizumab is used in adults and children aged 2 years and older who have CRS caused by CAR T-cell therapy.

Tocilizumab has been a critical component to ensuring the success of several pivotal clinical trial of CAR T-cell therapy. For example, the FDA is currently reviewing a biologics license application for the anti-CD19 CAR T-cell therapy lisocabtagene maraleucel for the treatment of adult patients with relapsed/refractory large B-cell lymphoma after at least 2 prior therapies, based on data from the multicenter phase I TRANSCEND NHL 001 study.² In this pivotal trial, the incidence of any grade CRS was 42%, which occurred at a median onset of 5 days. Nineteen percent of patients received tocilizumab to manage CRS. Nearly all cases of CRS were entirely reversible.

The FDA is also currently reviewing a biologics license application for the investigational CAR T-cell therapy KTE-X19 as a treatment for adult patients with relapsed/refractory mantle cell lymphoma. The designation is based on findings from the phase II ZUMA-2 trial, in which grade ≥3 CRS and occurred in 15% of patients and no grade 5 CRS events occurred.³ Tocilizumab was used for CRS management in 59% of patients. Overall, the median time to onset of CRS was 2 days and the median duration was 11 days. All events resolved.

Beyond CRS, tocilizumab also has FDA-approved indications for rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis.

References

1. Genentech Announces FDA Approval of Clinical Trial for Actemra to Treat Hospitalized Patients With Severe COVID-19 Pneumonia. Posted March 23, 2020. https://www.gene.com/media/press-releases/14843/2020-03-23/genentech-announces-fda-approval-of-clin. Accessed March 23, 2020.
2. U.S. Food and Drug Administration (FDA) Accepts for Priority Review Bristol-Myers Squibb’s Biologics License Application (BLA) for Lisocabtagene Maraleucel (liso-cel) for Adult Patients with Relapsed or Refractory Large B-Cell Lymphoma. Published February 13, 2020. https://bit.ly/39uYC0l. Accessed February 13, 2020.
3. Wang ML, Munoz J, Goy A, et al. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in patients (pts) with relapsed/refractory (r/r) mantle cell lymphoma (MCL): results of the phase 2 zuma-2 study. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 754.