Respiratory complications caused by COVID-19 can propel a patient from a mild cough one day to a ventilator and an ICU only 10 days later.
As countries around the world work to stockpile ventilators and citizens continue social distancing measures, biopharma companies are tackling the development of fast-acting therapeutics to disrupt a dire disease trajectory in hospitalized patients.
An industry-wide frantic race has ensued. On March 5, BioWorld reported that there were approximately 30 therapeutics and vaccines in development for COVID-19. As of April 28, there were 343 total: 249 therapeutics and 94 vaccines. Of the therapeutics, several are targeting respiratory complications that can quickly cascade into severe inflammatory responses, primarily driven by T cells, in the lung.
Also known as a cytokine storm, these inflammatory responses arrest breathing, cause severe pneumonia, hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS), making it difficult for oxygen to reach vital organs. For survivors, it can lead to life-long compromised pulmonary function.
“What we’ve learned from the experts is that once you go into the hospital there are two pathways here,” said Sanjay Shukla, president and CEO of San Diego-based Atyr Pharma Inc. Some patients with severe pneumonia recover, but a smaller segment of those infected become worse and need help in down-regulating the inflammatory response. “That’s also where hospitals are struggling right now with regards to how much capacity they have for those kinds of patients.”
Atyr’s neuropilin-2 modulator
Atyr announced April 21 that the FDA accepted its investigational new drug (IND) application for a phase II trial of ATYR-1923 in COVID-19 patients with severe respiratory complications.
“The drug works by engaging immune cells that are involved in an inflammatory response,” Shukla told BioWorld.
In January, the company signed a $175 million deal with Tokyo-based Kyorin Pharmaceutical Co. Ltd. to develop the product for interstitial lung diseases in Japan, with plans to move into a registrational trial in pulmonary sarcoidosis (PS) pending phase Ib/IIa data expected later in the year. At that time, little was known outside of China about the SARS-CoV-2 infection.
Now, the data from the PS trial, along with the expected timelines for about 300 other clinical trials, have been delayed as a result of the pandemic. Shukla said a restart in the next month or two of the PS trial will result in “about a quarter delay” in the final readouts, originally expected for the third quarter of 2020.
When the initial reports of COVID-19 began to emerge from China in late January and medical literature described the lung injury and inflammatory damage, Atyr executives took notice.
“That’s when it started to occur to us we may have a hyperacute environment going on here,” Shukla said.
ATYR-1923, a modulator of neuropilin-2, down-regulates T-cell responses and disrupts the inflammatory cytokine and chemokine signaling found in severe COVID-19 patients. In several animal models of immune-mediated acute lung injury, it has improved lung function and reduced inflammation and fibrosis.
“One key differentiator of our product is it interfaces directly with the immune cells and not the immune markers,” Shukla said, adding that a number of monoclonal antibodies currently tested focus solely on either interleukin-6, interleukin-2, tumor necrosis factor (TNF) or granulocyte macrophage colony-stimulating factor (GM-CSF), but all are “very important inflammatory biomarkers” and “by turning them down, we reset the immune balance.”
The randomized, double-blind, placebo-controlled phase II trial will enroll 30 confirmed COVID-19 patients at up to 10 centers in the U.S. They will receive either a placebo or a single intravenous dose (1 mg/kg or 3 mg/kg) with the aim of demonstrating safety and preliminary efficacy.
Calcimedica’s CRAC channel inhibitor
Another company focused on severe respiratory complications of COVID-19 is La Jolla, Calif.-based Calcimedica Inc., which started a phase IIa study with its small-molecule calcium release-activated calcium (CRAC) channel inhibitor, CM-4620-injectable emulsion (IE), in patients with severe pneumonia who are at risk for ARDS. The company received a “Study May Proceed” letter from the FDA earlier this month and the trial began April 8.
The four-person company was in the process of starting a phase IIb study in acute pancreatitis, the mortality of which is due to lung injury and ARDS.
“When the pandemic started,” said Sudarshan Hebbar, privately held Calcimedica’s chief medical officer, “we obviously shifted focus immediately to try to put the IND through to the FDA. We had an IND in at the pulmonary division and were told to submit an IND to the antiviral division.”
The phase IIb in acute pancreatitis was put on hold and the COVID-19 trial is expected to be completed in July. Data thus far has shown CM-4620-IE to be safe with potential efficacy in patients with hypoxemia secondary to systemic inflammatory response syndrome from acute pancreatitis.
“Our goal when we talked to the FDA was we wanted to prevent people from going on ventilators,” Hebbar told BioWorld. “That’s where we see the real need is.”
CM-4620-IE prevents the increase of intracellular calcium from CRAC channel overactivation and alleviates pulmonary endothelial damage and the cytokine storm in COVID-19 patients. It inhibits the Icrac pathway in human T cells, blocking IL-2 and TNFa, and has been shown to reduce neutrophil activation. Having three different integrated mechanisms of action differentiates the candidate from other agents, as does its lack of long-term immunosuppression, Hebbar said.
“We know that once you stop the infusion of our drug, within 24 or 36 hours the immune system returns back to normal,” he added.
An open-label phase II trial will enroll 60 patients on low-flow oxygen with severe COVID-19 pneumonia, 40 of whom will receive CM-4620-IE plus standard of care, while 20 receive standard of care alone. The trial was expanded to include a second arm of 60 patients on high-flow oxygen. The first patients enrolled were at Regions Hospital in St. Paul, Minn., with additional patients enrolled at Henry Ford Hospital in Detroit and seven other sites.
Next steps, other options
Both Shukla and Hebbar credited the FDA for its swift pace in helping the companies get their internally funded trials set to begin. The agency has shown enthusiasm for new therapies, while it continues to provide the emergency use authorization pathway for approved and repurposed drugs. Assuming positive results in the phase II trials, both Atyr’s and Calcimedica’s candidates would then move to pivotal trials.
Other candidates for COVID-19 respiratory complications include La Jolla, Calif.-based Inmune Bio Inc.’s dominant-negative TNF inhibitor; Cambridge, U.K.-based Astrazeneca plc’s BTK inhibitor Calquence (acalabrutinib); Vancouver, Wash.-based Cytodyn Inc.’s CCR5 antagonist PRO-140 (leronlimab); Hemel Hempstead, U.K.-based Eusa Pharma Inc.’s siltuximab; and Foster City, Calif.-based Gilead Sciences Inc.’s antiviral remdesivir.
Inmune announced its phase II trial on April 20 and said it was working with regulatory authorities and clinical sites to get started quickly. As of April 15, the first of about 390 patients with severe infection were dosed in a phase IIb/III study with PRO-140. A phase II study with siltuximab began April 15 in 200 patients with COVID-19 pneumonia in an effort to prevent progression and admission to an ICU. Remdesivir, which is in several phase III trials, showed cumulative incidence of clinical improvement of 84% in 53 hospitalized patients with severe complications who were treated on a compassionate use basis. And Astrazeneca’s acalabrutinib began the Calavi phase II trial in 428 patients in mid-April.
“This is the fastest launch of any clinical trial in the history of Astrazeneca,” said Jose Baselga, the company’s executive vice president of oncology R&D.
Also working on therapies for respiratory complications are Tel Aviv, Israel-based Redhill Biopharma Ltd., which filed an IND to start a U.S. clinical trial for opaganib, its oral small-molecule sphingosine kinase-2 selective inhibitor, and El Segundo, Calif.-based Nantkwest Inc. and Culver City, Calif.-based Immunitybio Inc., which are developing a mesenchymal stem cell therapy specifically for patients with ARDS due to severe COVID-19.
The World Health Organization reported a total of 2.95 million confirmed infections and 202,597 deaths on April 28. While that puts the death rate at about 6.9%, a true figure is expected to be much lower, assuming that a more accurate count of asymptomatic individuals and others infected will eventually be made.
“I think we’re in some desperate need for some help here until we get a good vaccine,” Shukla said, adding that no single solution will be enough to beat COVID-19. “We’re going to need a toolkit.”