A pair of good-news items from Chimerix Inc. pushed the Durham, N.C.-based company’s stock (NASDAQ:CMRX) to $2.15, closing up 64 cents, or 42%, higher as backers reacted to near-term NDA plans for smallpox countermeasure brincidofovir (BCV) and the start of a phase II/III trial with dociparstat sodium (DSTAT) in COVID-19 patients with acute lung injury (ALI).
CEO Mike Sherman said the COVID-19 outbreak brought about “an interesting confluence of events” for Chimerix, placing the spotlight on viral outbreaks. “This, in fact, has been at the core of our purpose for more than a decade,” he said, referring to the work with BCV in smallpox, a more contagious and much more deadly disease than the virus now making headlines. “The value of this kind of preparation has never been clearer,” he said.
Chimerix gained clearance from the FDA to start a rolling NDA for BCV, an oral antiviral, and the submission will start in May, with completion targeted for the middle of the year. BCV is designed to improve treatment of infections by enhancing drug delivery to the intracellular site of viral replication. The treatment penetrates cells via its lipid conjugate, releasing the nucleotide analogue cidofovir, which then acts to inhibit the bug. Allowing the NDA was “not a controversial decision” for the FDA, Sherman said during a conference call with investors.
DSTAT, a glycosaminoglycan derivative of heparin with strong anti-inflammatory properties, already was in the late-stage works for acute myeloid leukemia (AML). In exploring drugs that might work against COVID-19, Sherman said, “it was going to require a truly promising opportunity to take any of our focus away from our focus on delivering [BCV] for smallpox and launching our phase III trial in AML.” DSTAT turned out to be just that opportunity in ALI related to COVID-19. Chimerix had aimed to kick off such work “down the road, but the pandemic has accelerated those plans,” he said, especially once the company established “a truly compelling case” for DSTAT’s mechanism of action “in the context of this unique disease.”
The mechanism is complicated. A primary anti-inflammatory effect of DSTAT is mediated by inhibition of HMGB1 activity, Chimerix noted. HMGB1 induces downstream pro-inflammatory cytokines, including but not limited to, interleukin-6 (IL-6), TNF-alpha, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha, all of which are elevated in COVID-19. Infiltration of monocytes and other immune cells into inflamed lung tissue is known as a key pathogenic driver of ALI, and DSTAT reduces lung infiltration, probably by blocking of MCP-1 and other ligands involved in migration of monocytes, neutrophils and other effector cells.
DSTAT may also attack the underlying causes of coagulation disorders by inhibiting HMGB1 and platelet factor 4 (PF4) activities. Two studies have identified a high neutrophil/lymphocyte ratio and low platelet counts as clinically relevant indicators of disease severity and mortality in COVID-19. Neutrophils are early responders to infection capable of extruding granular and nuclear contents to produce neutrophil extracellular traps (NETs); the latter may be beneficial by trapping pathogens, though too many neutrophils and NET release can be pathogenic. HMGB1 promotes NETs, which may drive hypercoagulation by providing a substrate for platelet aggregation and up-regulating tissue factor on endothelial cells. Activated platelets in turn release PF4, which makes inflammation worse. DSTAT to the rescue, investigators hope, by blocking PF4 and HMGB1.
AML launch still seen in 2024
The phase II/III study is a 1-to-1 randomized, double-blind, placebo-controlled experiment to determine the safety and efficacy of DSTAT in adults with severe COVID-19 at high risk of respiratory failure. Eligible subjects will be those with confirmed COVID-19 who need hospitalization and supplemental oxygen therapy. The primary endpoint is the proportion of subjects who survive and do not require mechanical ventilation through day 28. Other measures include time to improvement as assessed by the National Institute of Allergy and Infectious Diseases ordinal scale, time to hospital discharge, time to resolution of fever, number of ventilator-free days, all-cause mortality, and changes in key biomarkers such as IL-6, TNF-alpha, HMGB1, C-reactive protein and d-dimer.
Enrolled in the phase II portion will be 24 subjects to confirm the maximum safe dose. This will expand by 50 more patients at the selected dose. A formal analysis of all endpoints, including supportive biomarkers, will be performed at the conclusion of the phase II part. If the results are positive, the phase III portion of the study will enroll about 450 subjects.
DSTAT came to Chimerix by way of Weston, Fla.-based Cantex Pharmaceuticals Inc. The licensing deal in late July 2019 for the compound then known as CX-01 gave Chimerix exclusive worldwide rights. CX-01 already had gained fast track and orphan drug designations for the treatment of AML.
Wainwright analyst Edward White found what “appears to be a convincing rationale for the [COVID-19] trial.” He pointed out that the phase III with DSTAT in AML has been delayed because of the pandemic and the new study related to it, but “we believe there could be upside with COVID-19 data to validate the mechanism,” and findings may “lead to more excitement and awareness for the AML study.” The latter is expected to enroll about 570 newly diagnosed adult patients who are fit for intensive chemotherapy. Patients would receive DSTAT in combination with standard chemo or placebo in combination with standard chemo. The trial is designed for overall survival (OS) as the primary endpoint. An early efficacy analysis is planned for the first 80 evaluable patients. At 250 OS events, there is a proposed interim efficacy peek, and then at 308 OS events the full analysis. White did not change his estimated 2024 launch date and said the product “could address two-thirds of the newly diagnosed AML patient population that is eligible for intensive therapy.” He pegged sales in 2027 at about $201 million.