British drug giant AstraZeneca is rushing forward a big clinical trial for its blood cancer drug Calquence because it has shown early promising results in later-stage COVID-19 patients—those in intensive care units and on ventilators. Calquence and top-selling leukemia drug Imbruvica are the latest hopes in getting coronavirus patients off ventilators, where there is a 50% mortality rate.
The federal government’s National Cancer Institute has given Calquence to a small number of hospitalized COVID-19 patients at the Walter Reed Army Medical Center. This effort has been expanded to other sites, partially through McKesson’s U.S. Oncology, the large cancer services company. Some of the severely ill COVID-19 patients who received Calquence, which is also known by its generic name acalabrutinib, were materially helped by the drug, people familiar with the matter say.
“NCI is involved with administration of off-label use of acalabrutinib in a small number of selected patients with severe COVID-19,” the National Cancer Institute said in a statement to Forbes, being careful to dampen speculation. “While some clinical benefit has been observed in select patients with advanced lung disease caused by COVID-19, it is premature to conclude that it will provide benefit across patients with advanced lung disease due to the very early and limited use of this agent in COVID-19 at this time.”
As Calquence enters into a randomized, controlled clinical trial, the NCI noted that while the drug is already approved in the U.S. for some blood cancers, it is not approved by the Food and Drug Administration as a treatment for COVID-19.
One of the most serious medical issues of the current pandemic is how the immune system of people infected with SARS-CoV-2 fights off the virus. Some COVID-19 patients have become critically ill or died after cytokine molecules in their bodies sparked an out-of-control immune response (or cytokine storm) that damaged the lungs or caused acute respiratory distress syndrome (ARDS), which floods the lungs with fluid.
Calquence and Imbruvica are known as Bruton’s tyrosine kinase (BTK) inhibitors because they block the BTK protein that is key to the signaling of white blood B cells of the human immune system into action. These drugs have proven to be especially effective in patients with chronic lymphocytic leukemia, but they also have an anti-inflammatory benefit like arthritis drugs.
“The science of acalabrutinib and, I think more than that, of Bruton’s tyrosine kinase situation, is pretty strong. The mechanism is very clear,” said José Baselga, the head of oncology research and development at AstraZeneca.
“The cytokine storm that occurs in the pneumonia of these patients is heavily mediated by Bruton’s kinase and, unlike approaches that are trying to deal with one cytokine at a time, I see this more as a truncal intervention, in which you are basically hitting the central key pathway that regulates many of these cytokines so the rationale is incredibly strong . . . it gives us the opportunity to address the whole problem.”
Early last week, AstraZeneca formed a COVID-19 task force after receiving early data regarding patients given Calquence by the NCI. Baselga said that within 72 hours the company had completed drafting a COVID-19 clinical trial and submitted it to the FDA, the fastest study he has ever seen put together in his 30-year career. Such an effort would normally take more than three months.
AstraZeneca’s two-arm, 400-patient trial is designed to give Calquence to patients on ventilators and includes a control group consisting of patients at high risk of going on ventilators, some of whom will be given the drug while others will not. Baselga said the decision to not give the drug to some patients was difficult but necessary.
Senior medical leadership at AstraZeneca also reached out for guidance to Jeff Sharman, the medical director of hematology research for the U.S. Oncology network, who led pivotal clinical trials of Calquence. Sharman requested a supply of Calquene to give to COVID-19 patients through U.S. Oncology’s network under compassionate-use rules, expanding the use of Calquence among COVID-19 patients in the U.S. in recent days.
“This is not a moment where continuing the status quo is acceptable. With a mortality rate of 50% among critically ill patients, every rational idea needs to be evaluated quickly,” said Sharman. “Many of the things being done for patients suffering from COVID-19 are done off label with far less scientific rationale.”
One tricky issue AstraZeneca has had to work through is how to give Calquence, which is a capsule, to patients who are on ventilators. AstraZeneca is advising doctors to give the drug through a tube in a solution made up of Coca-Cola, which due to its acidity properly liquefies the powder. The drug has already been administered in such a fashion.
Imbruvica and Calquence are two of the most lucrative drugs on the planet. Imbruvica generated $8.1 billion of global sales in 2019 for AbbVie and Johnson & Johnson. Calquence, which was approved in the U.S. for chronic lymphocytic leukemia patients in November, was the only product of Acerta, which was acquired by AstraZeneca in a $7 billion deal in 2016. A third BTK inhibitor, Beigene’s Brukinsa, received U.S. approval in November.
“I think a small molecule BTK inhibitor is one of the most exciting anti-inflammatory targets for cytokine storm, or potentially ARDS, particularly given this class of drug's clean safety profile and mechanism of action, as evidenced in preclinical models for lung injury," says Wayne Rothbaum, the former executive chairman of Acerta and a driving force behind the development of Calquence, who emphasized the BTK protein must be irreversibly inhibited for maximum potency.
“There is no question in my mind that a selective BTK inhibitor will be highly effective in a subpopulation of COVID-19 patients where this mechanism should work.”
The Ohio State University’s cancer center is also working to file with the Food & Drug Administration a randomized controlled study of a different BTK inhibitor drug in later-stage COVID-19 patients.
“We have received and reviewed proposals to conduct exploratory research studies to evaluate ibrutinib [Imbruvica] for the treatment of patients with moderate or severe COVID-19 requiring hospitalization,” J&J’s Janssen said in a statement. “The investigators and institutions sponsoring the studies are in the process of registering the trials with the U.S. Food and Drug Administration.”
John Byrd, a hematologist and chair of leukemia research at the Ohio State University’s cancer center in Columbus, played a leading role in the development and approval of both Imbruvica and Calquence. He felt helpless as the pandemic descended on the U.S. in February. First, he stopped taking work trips because he was worried about infecting his cancer patients. He also started to read about the novel coronavirus, learning about the cytokine storm and other associated issues that made him think a BTK inhibitor might be applicable for some COVID-19 patients.
As his cancer center closed down due to the pandemic, Byrd instructed the 70 or so people on his hematology oncology team to read as much as they could about SARS-CoV-2. “I told them, ‘Let’s come up with something we can do, something impactful, and if we don’t find something, at least we have read about it, and we are going to try,’” Byrd said. “Our priority, I told the group, is ibrutinib [Imbruvica] because it reduces the inflammatory response.”
Byrd also heard an anecdotal report from a doctor in northern Italy, where the healthcare system was overwhelmed by COVID-19 patients, that most of his elderly chronic lymphocytic leukemia patients who were taking Imbruvica as part of their normal course of treatment were not showing symptoms of COVID-19. Being immunocompromised, those patients were under strict orders to self-isolate, but there was a chance that there was something else going on related to the medications they were taking.
Indeed, while BTK inhibitors work in blood cancer through cell trafficking, they also have an anti-inflammatory synergistic benefit. Rheumatoid arthritis drugs that inhibit pro-inflammatory cytokines, like Roche’s Actemra, are being tested in later-stage COVID-19 patients. Incyte’s Jakafi and Olumiant are two other treatments that are high on the list of drugs that some observers believe can tamp down the immune system’s cytokine storm in COVID-19 patients.
Scrounging through the scientific literature in March, Byrd and his team came across several relevant papers they never under normal circumstances would have bothered to find. One discovery they made soon made the rounds among blood cancer doctors. It described preclinical work conducted in 2018 at the University of Texas Health Science Center at Tyler. In the trial, mice were infected with a lethal dose of influenza virus. Three days later, a randomly chosen group of the mice started to receive daily doses of Imbruvica. The mice that did not receive Imbruvica suffered lung damage and died, while the mice that got the drug recovered.
“Our innovative findings suggest that BTK may be a new drug target for influenza-induced lung injury, and, in general, that immunomodulatory treatment may be key in treating lung dysfunction driven by excessive inflammation,” the authors of the study concluded.
Byrd noted that the pathology of the mice in the study resembled what he had read about in the autopsies of people who died due to lung failure associated with COVID-19. He says the preclinical data on Imbruvica and what is known about how it works in patients with graft-versus-host disease show that not only do BTK inhibitors decrease inflammation, but they may do so without compromising the ability of a patient’s immune system to respond to the virus.
Byrd emphasized that it’s early, and it will be crucial to properly conduct clinical trials of BTK inhibitors in COVID-19 patients to see if they work properly. In the meantime, he is exceptionally concerned about the limited supply of BTK inhibitors for chronic lymphocytic leukemia patients who need these drugs to survive.
“The science here is right,” says Byrd. “This is a horrible virus and to make a difference with COVID-19 you need a drug available right away that will prevent patients from getting to the point of being intubated.”
The federal government’s National Cancer Institute has given Calquence to a small number of hospitalized COVID-19 patients at the Walter Reed Army Medical Center. This effort has been expanded to other sites, partially through McKesson’s U.S. Oncology, the large cancer services company. Some of the severely ill COVID-19 patients who received Calquence, which is also known by its generic name acalabrutinib, were materially helped by the drug, people familiar with the matter say.
“NCI is involved with administration of off-label use of acalabrutinib in a small number of selected patients with severe COVID-19,” the National Cancer Institute said in a statement to Forbes, being careful to dampen speculation. “While some clinical benefit has been observed in select patients with advanced lung disease caused by COVID-19, it is premature to conclude that it will provide benefit across patients with advanced lung disease due to the very early and limited use of this agent in COVID-19 at this time.”
As Calquence enters into a randomized, controlled clinical trial, the NCI noted that while the drug is already approved in the U.S. for some blood cancers, it is not approved by the Food and Drug Administration as a treatment for COVID-19.
One of the most serious medical issues of the current pandemic is how the immune system of people infected with SARS-CoV-2 fights off the virus. Some COVID-19 patients have become critically ill or died after cytokine molecules in their bodies sparked an out-of-control immune response (or cytokine storm) that damaged the lungs or caused acute respiratory distress syndrome (ARDS), which floods the lungs with fluid.
Calquence and Imbruvica are known as Bruton’s tyrosine kinase (BTK) inhibitors because they block the BTK protein that is key to the signaling of white blood B cells of the human immune system into action. These drugs have proven to be especially effective in patients with chronic lymphocytic leukemia, but they also have an anti-inflammatory benefit like arthritis drugs.
“The science of acalabrutinib and, I think more than that, of Bruton’s tyrosine kinase situation, is pretty strong. The mechanism is very clear,” said José Baselga, the head of oncology research and development at AstraZeneca.
“The cytokine storm that occurs in the pneumonia of these patients is heavily mediated by Bruton’s kinase and, unlike approaches that are trying to deal with one cytokine at a time, I see this more as a truncal intervention, in which you are basically hitting the central key pathway that regulates many of these cytokines so the rationale is incredibly strong . . . it gives us the opportunity to address the whole problem.”
Early last week, AstraZeneca formed a COVID-19 task force after receiving early data regarding patients given Calquence by the NCI. Baselga said that within 72 hours the company had completed drafting a COVID-19 clinical trial and submitted it to the FDA, the fastest study he has ever seen put together in his 30-year career. Such an effort would normally take more than three months.
AstraZeneca’s two-arm, 400-patient trial is designed to give Calquence to patients on ventilators and includes a control group consisting of patients at high risk of going on ventilators, some of whom will be given the drug while others will not. Baselga said the decision to not give the drug to some patients was difficult but necessary.
Senior medical leadership at AstraZeneca also reached out for guidance to Jeff Sharman, the medical director of hematology research for the U.S. Oncology network, who led pivotal clinical trials of Calquence. Sharman requested a supply of Calquene to give to COVID-19 patients through U.S. Oncology’s network under compassionate-use rules, expanding the use of Calquence among COVID-19 patients in the U.S. in recent days.
“This is not a moment where continuing the status quo is acceptable. With a mortality rate of 50% among critically ill patients, every rational idea needs to be evaluated quickly,” said Sharman. “Many of the things being done for patients suffering from COVID-19 are done off label with far less scientific rationale.”
One tricky issue AstraZeneca has had to work through is how to give Calquence, which is a capsule, to patients who are on ventilators. AstraZeneca is advising doctors to give the drug through a tube in a solution made up of Coca-Cola, which due to its acidity properly liquefies the powder. The drug has already been administered in such a fashion.
Imbruvica and Calquence are two of the most lucrative drugs on the planet. Imbruvica generated $8.1 billion of global sales in 2019 for AbbVie and Johnson & Johnson. Calquence, which was approved in the U.S. for chronic lymphocytic leukemia patients in November, was the only product of Acerta, which was acquired by AstraZeneca in a $7 billion deal in 2016. A third BTK inhibitor, Beigene’s Brukinsa, received U.S. approval in November.
“I think a small molecule BTK inhibitor is one of the most exciting anti-inflammatory targets for cytokine storm, or potentially ARDS, particularly given this class of drug's clean safety profile and mechanism of action, as evidenced in preclinical models for lung injury," says Wayne Rothbaum, the former executive chairman of Acerta and a driving force behind the development of Calquence, who emphasized the BTK protein must be irreversibly inhibited for maximum potency.
“There is no question in my mind that a selective BTK inhibitor will be highly effective in a subpopulation of COVID-19 patients where this mechanism should work.”
The Ohio State University’s cancer center is also working to file with the Food & Drug Administration a randomized controlled study of a different BTK inhibitor drug in later-stage COVID-19 patients.
“We have received and reviewed proposals to conduct exploratory research studies to evaluate ibrutinib [Imbruvica] for the treatment of patients with moderate or severe COVID-19 requiring hospitalization,” J&J’s Janssen said in a statement. “The investigators and institutions sponsoring the studies are in the process of registering the trials with the U.S. Food and Drug Administration.”
John Byrd, a hematologist and chair of leukemia research at the Ohio State University’s cancer center in Columbus, played a leading role in the development and approval of both Imbruvica and Calquence. He felt helpless as the pandemic descended on the U.S. in February. First, he stopped taking work trips because he was worried about infecting his cancer patients. He also started to read about the novel coronavirus, learning about the cytokine storm and other associated issues that made him think a BTK inhibitor might be applicable for some COVID-19 patients.
As his cancer center closed down due to the pandemic, Byrd instructed the 70 or so people on his hematology oncology team to read as much as they could about SARS-CoV-2. “I told them, ‘Let’s come up with something we can do, something impactful, and if we don’t find something, at least we have read about it, and we are going to try,’” Byrd said. “Our priority, I told the group, is ibrutinib [Imbruvica] because it reduces the inflammatory response.”
Byrd also heard an anecdotal report from a doctor in northern Italy, where the healthcare system was overwhelmed by COVID-19 patients, that most of his elderly chronic lymphocytic leukemia patients who were taking Imbruvica as part of their normal course of treatment were not showing symptoms of COVID-19. Being immunocompromised, those patients were under strict orders to self-isolate, but there was a chance that there was something else going on related to the medications they were taking.
Indeed, while BTK inhibitors work in blood cancer through cell trafficking, they also have an anti-inflammatory synergistic benefit. Rheumatoid arthritis drugs that inhibit pro-inflammatory cytokines, like Roche’s Actemra, are being tested in later-stage COVID-19 patients. Incyte’s Jakafi and Olumiant are two other treatments that are high on the list of drugs that some observers believe can tamp down the immune system’s cytokine storm in COVID-19 patients.
Scrounging through the scientific literature in March, Byrd and his team came across several relevant papers they never under normal circumstances would have bothered to find. One discovery they made soon made the rounds among blood cancer doctors. It described preclinical work conducted in 2018 at the University of Texas Health Science Center at Tyler. In the trial, mice were infected with a lethal dose of influenza virus. Three days later, a randomly chosen group of the mice started to receive daily doses of Imbruvica. The mice that did not receive Imbruvica suffered lung damage and died, while the mice that got the drug recovered.
“Our innovative findings suggest that BTK may be a new drug target for influenza-induced lung injury, and, in general, that immunomodulatory treatment may be key in treating lung dysfunction driven by excessive inflammation,” the authors of the study concluded.
Byrd noted that the pathology of the mice in the study resembled what he had read about in the autopsies of people who died due to lung failure associated with COVID-19. He says the preclinical data on Imbruvica and what is known about how it works in patients with graft-versus-host disease show that not only do BTK inhibitors decrease inflammation, but they may do so without compromising the ability of a patient’s immune system to respond to the virus.
Byrd emphasized that it’s early, and it will be crucial to properly conduct clinical trials of BTK inhibitors in COVID-19 patients to see if they work properly. In the meantime, he is exceptionally concerned about the limited supply of BTK inhibitors for chronic lymphocytic leukemia patients who need these drugs to survive.
“The science here is right,” says Byrd. “This is a horrible virus and to make a difference with COVID-19 you need a drug available right away that will prevent patients from getting to the point of being intubated.”
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