Cincinnati Children’s researchers initially developed a transgenic mouse to model HLH (hemophagocytic lymphohistiocytosis), a deadly childhood immune disease but as it now turns out this effort may end up saving lives during the COVID-19 pandemic. Cincinnati Children’s Gang Huang, PhD, one of the genetical mouse strain’s inventors, served as co-investigator on a small clinical trial that successfully tested a drug to treat to HLH (ruxolitinib) to dramatically reverse respiratory and multi-system inflammation in severely ill COVID-19 patients. The results from this study were recently published in the Journal of Allergy and Clinical Immunology and led to a bigger Phase III clinical trial called the RUXCOVID Study. Could ruxolitinib be the answer to the COVID-19 deadly cytokine storm?
The Cincinnati Children’s Connection to COVID-19 China Study
Gang Huang and team at Cincinnati Children’s have been studying HLH and made an important connection. They uncovered that the so-called cytokine storm that inundates the bodies of severely ill COVID-19 patients with inflammatory cells produced by the immune system is a common feature of children battling secondary HLH, which occurs in patients where initial HLH treatment hasn’t worked. Since the start of the COVID-19 pandemic, Huang and team have been working around-the-clock to study and find solutions to COVID-19; and at one point, the lightbulb came on and Huang and team noticed this common clinical feature of both illnesses.
Huang observed that severe COVID-19 disease clinical manifestations are eerily similar to those seen in transgenic laboratory mice created to faithfully mimic human secondary HLH in the lab. That preclinical laboratory research, some of it in collaboration with a research team in China, helped identify the drug ruxolitinib for treating secondary HLH. The anti-inflammatory drug is also used to treat other blood diseases including leukemia. This influenced a first clinical trial in China with incredible results.
Cincinnati Children’s Huang Reached out to Chinese Investigators to Share Critical Information
Huang connected with colleagues in Wuhan—as it turns out, Huang was a research colleague of Janfeng Zhou, MD, PhD Department of Hematology at Tongji Hospital, Tongji Medical College and Huazhong University of Science in Wuhan—and informed them of these observations connecting the HLH information to COVID-19.
At this point, it was a dire situation—“The disease was spreading very rapidly and many people were dying. We believed the existing clinical drug would help save lives. So we worked to push it forward before there is an effective vaccine for everyone,” commented Huang. Doctors in China needed to move fast.
Important Information Comes out of Pandemic & Crisis
As colleagues were working frantically—on high alert to battle the pandemic in January—including studies with compressed timelines—the investigators found other clinical studies involving other diseases where ruxolitinib also had worked well at quieting inflammation and testing on COVID-19 patients proceeded. The Cincinnati Children’s investigator has successfully ensured that the Chinese team would use ruxolitinib.
The First Study in China: In the Middle of the Pandemic
Titled “Severe novel coronavirus pneumonia (COVID-19) patients treated with ruxolitinib in combination with mesenchymal stem cells: a prospective, single blind, randomized controlled clinical trial”, the study was designed to test the safety and efficacy of the novel treatment strategy. As reported in a recent Cincinnati Children’s press release, the study involved 43 hospitalized patients diagnosed with severe COVID-19 between February 9 and February 28, in Wuhan, China, believed to be ground zero for the pandemic.
The multi-center study was led by Janfeng Zhou, MD, PhD, Department of Hematology at Tongji Hospital, Tongji Medical College and Huazhong University of Science in Wuhan. Again, Dr. Zhou is a longtime collaborator of Huang and colleagues at the Cincinnati Children’s HLH Center of Excellence, part of the Cancer and Blood Disease Institute.
Patients taking ruxolitinib were randomly selected to receive two daily 5mg oral doses of the anti-inflammatory drug, plus the standard of care treatment for COVID-19. A randomly selected control group of 21 patients received a placebo along with the standard of care treatment.
As it turns out those patients that were part of the ruxolitinib arm “had a numerically faster clinical improvement” reported the study authors. They wrote, “Significant chest CT improvement, a faster recovery from lymphopenia and favorable side-effect profile in ruxolitinib group were encouraging and informative to future trials to test efficacy of ruxolitinib in a larger population.”
Moreover, those patients in the ruxolitinib arm experienced shorter median time to clinical improvement compared to the control group. The investigators noted that 90% of the ruxolitinib patients evidenced CT scan improvement within 14 days, compared with 9% of patients from the control group. The patients in the control group eventually died of respiratory failure. All of the severely ill patients who received ruxolitinib survived!
The JACI study funding originated from an Emergency Research Project of Tongji Hospital Huazhong University of Science and Technology, an Emergency Research Project of Hubei Province.
RUXCOVID Study: Does Ruxolitinib Stop the Cytokine Storm?
Again, this larger study was the result of the connections Cincinnati Children’s Gang Huang made in regards to his research with the transgenic laboratory mice to mimic secondary HLH in the lab. He found connections between HLH and the COVID-19 cytokine storm and helped contribute to the first study in Wuhan.
The larger Phase III clinical trial RUXCOVID trial is now testing up to 402 severely ill COVID-19 patients with the drug reported by Huang. Preliminary clinical data is expected this summer.
The study is a randomized, double-blind, placebo-controlled, 29 -day, multicenter study to assess the efficacy and safety of ruxolitinib plus the standard of care (SoC) therapy, compared with placebo and standard of care therapy in patients 12 and above with COVID-19 pneumonia. Currently enrolling patients, sponsors Novartis and Incyte Corporation are recruiting up to 402 patients in the United States, United Kingdom, Spain and Germany. The study started in May and is planned through July 2020.
Quieting the ‘Cytokine Storm’
Huang commented, “This is the first therapy we know of that appears to work effectively to quiet the cytokine storm and inflammation in severe COVID-19 disease, and there is no significant toxicities to patients who take the drug by two pills a day.” This could be a critical approach until a vaccine is ready, Huang noted.
What is Ruxolitinib?
Known under the trade names Jakafi or Jakavi, it is a drug for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative disorder that affects the bone marrow and for polycythemia vera (PCV) when there has been an inadequate response to or intolerance of hydroxyurea. It has also been used to improve cases of chronic graft versus host disease in patients following a bone marrow transplant. It was developed and is currently marketed by Incyte Corporation as Jakafi and by Novartis as Jakavi.
The drug is under investigation for plaque psoriasis, alopecia areata, relapsed diffuse large B-cell lymphoma, peripheral T-cell lymphoma and, of course, now COVID-19.
Gang Huang, PhD, Member, Division of Experimental Hematology & Cancer Biology, Associate Professor, UC Department of Pathology and Laboratory Medicine
Janfeng Zhou, MD, PhD Department of Hematology at Tongji Hospital, Tongji Medical College and Huazhong University of Science in Wuhan
Call to Action. TrialSite News will monitor the RUXCOVID study as an effective counter to the COVID-19 cytokine storm asa key treatment moving forward to beat back the pathogen. Sign up for the newsletter for updates.