GSK's Otilimab Misses Primary Endpoint in Phase 2 COVID-19 Trial but Shows Promise in Patients Aged 70+

Compiled by Fan Dongdong

Recently, GSK’s otolimab failed to meet the primary endpoint in a Phase 2 clinical trial conducted among hospitalized patients with coronavirus disease 2019 (COVID-19). However, as pre-specified analysis results indicated that otolimab holds therapeutic potential for elderly patients aged 70 years and older, GSK has decided to expand the study population to further validate the efficacy data.

The primary endpoint of this Phase II OSCAR clinical trial was to compare the proportion of patients with COVID-19 who were alive and free from respiratory failure at 28 days between those receiving standard of care (including antiviral therapy and glucocorticoids) and those receiving otilimab plus standard of care. The trial primarily enrolled 806 patients with severe COVID-19-associated pulmonary disease who required substantial oxygen support or early invasive mechanical ventilation. The results showed that, across all age groups, the proportion of patients alive and free from respiratory failure at 28 days post-treatment was 5.3 percentage points higher in the group receiving GSK’s otilimab compared to the standard-of-care group (95% CI = -0.8%, 11.4%). However, this difference was not statistically significant, resulting in the study missing its primary endpoint.

However, the results of a pre-specified analysis in patients aged 70 years and older were encouraging. An efficacy analysis of COVID-19 patients aged 70 years and older (n=180) showed that 28 days after treatment with otilimab plus standard care, 65.1% of patients remained alive without respiratory failure, compared with 45.9% of patients receiving standard care alone (95% CI = 5.2%, 33.1%; p=0.009), representing an absolute improvement of 19.1%. Furthermore, mortality rates differed between the treatment and control groups among patients aged 70 years and older. In the 60-day post-treatment mortality analysis, the mortality rate was 40.4% in the control group versus 26% in the otilimab group (95% CI = 0.9%, 27.9%; p=0.040), corresponding to a 14.4% reduction in the risk of death.

In view of the potential significant clinical benefits of otilimab in the elderly subgroup of high-risk patients and public health needs, GlaxoSmithKline has decided to amend the OSCAR study to expand recruitment for this cohort in order to confirm these potentially important findings. Christopher Corsico, Senior Vice President of Development at GlaxoSmithKline, stated, “Patients aged 70 years and older account for 70% of all COVID-related deaths and 40% of hospitalizations. Given the profound impact of the pandemic on the elderly population and the positive results from the OSCAR trial, we aim to further advance the development of otilimab.”

In the OSCAR trial, the most commonly observed serious adverse event was respiratory failure (5% in the control group and 4% in the otilimab group). Overall, all adverse events and serious adverse events observed were typical symptoms in patients with severe COVID-19. In the subgroup aged over 70 years, the incidence of adverse events associated with otilimab was lower than that in the placebo group.

This drug was not originally developed by GlaxoSmithKline. In 2013, GlaxoSmithKline obtained the exclusive global rights to develop and commercialize otilimab across all therapeutic areas from MorphoSys AG. Previously designated as GSK3196165, this fully human monoclonal antibody inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF), a protein that plays a central role in a wide range of immune-mediated diseases, including rheumatoid arthritis. GM-CSF acts on cells, including macrophages (a type of immune cell that plays a key role in the inflammatory process), leading to inflammation, joint damage, and pain. Otilimab neutralizes the biological function of GM-CSF by blocking its interaction with cell surface receptors, thereby achieving therapeutic effects.

GlaxoSmithKline was interested in the efficacy of otilimab in patients aged 70 years and older, partly due to evidence suggesting that GM-CSF may play a more significant role in the immune response of elderly individuals. According to a paper published in 2020, unlike younger patients, those aged 70 years and older with COVID-19 exhibited elevated levels of D-dimer, CXCL10, and GM-CSF. GM-CSF is associated with disease severity, and elderly patients have a poorer prognosis from COVID-19. Since otilimab inhibits GM-CSF, there is rationale to believe that this drug could benefit a large population of COVID-19 patients who lack therapeutic options.

Although this subgroup yielded positive research results, the relatively small sample size inevitably raises questions about whether the subgroup analysis can accurately reflect the impact of otilimab on elderly patients. In response, GSK believes that the findings demonstrate sufficient potential and promise to warrant further in-depth investigation. Currently, GSK is recruiting an additional 350 patients aged over 70 years to participate in a trial aimed at validating the therapeutic efficacy of otilimab in the elderly population, with results expected in the second half of the year.

In addition to COVID-19, GlaxoSmithKline is also actively researching breakthroughs in the treatment of rheumatoid arthritis with this drug. According to positive results from a Phase 2b, multicenter, controlled trial published last year, otilimab treatment rapidly reduced joint pain and swelling, with significant improvements in patient-reported pain scores.

Reference Source:

1.GSK announces results evaluating its investigational monoclonal antibody, otilimab, for the treatment of hospitalised adult patients with COVID-19

2.GSK fails COVID-19 phase 2, subgroup finding fuels further work