Chimerix Phase II/III DSTAT potential in Covid-19 needs clinical validation, although has preclinical rationale and ideal trial population

GlobalData Healthcare 12th November 2020 (Last Updated November 12th, 2020 16:05)

Chimerix’s dociparstat sodium’s (DSTAT) Phase II/III clinical potential in Covid-19 is undetermined, as its mechanistic rationale in the disease is primarily driven by preclinical data.

Chimerix Phase II/III DSTAT potential in Covid-19 needs clinical validation, although has preclinical rationale and ideal trial population

by Manasi Vaidya in New York

Chimerix’s dociparstat sodium’s (DSTAT) Phase II/III clinical potential in Covid-19 is undetermined, as its mechanistic rationale in the disease is primarily driven by preclinical data. That said, given DSTAT’s aim to curb the inflammatory cascades, the focus on hospitalised patients at risk of progressing to intensive care is rational.

While heparin’s anti-inflammatory activities can be isolated in glycosaminoglycan derivatives like DSTAT, evidence for efficacy with such approaches is still largely preclinical, evoking caution. Moreso, the risk for off-target side effects due to the inclusion of any other complex polysaccharides may be a factor to consider.

However, given the potentially likely need for use of anticoagulant therapy in Covid-19 patients, experts did not foresee any conflict in the use of DSTAT and heparin, if needed. Targeting inflammation at the stage when patients are hospitalised and at risk of progressing further, DSTAT’s focus, makes sense given the disease pathogenesis.

The 524-patient Phase II/III study (NCT04389840) is focused on Covid-19 patients with acute lung injury (ALI) and assesses success based on the proportion of patients alive and free of mechanical ventilation in a 28-day time frame. The company expects enrollment of the Phase II portion to complete in 4Q, as per its 2Q results.

One analyst said positive data in Covid-19 patients with ALI could lead to the study of DSTAT in acute respiratory distress syndrome (ARDS) arising from other illnesses. DSTAT’s revenues are estimated to be $168m in 2026, as per GlobalData consensus forecasts. Chimerix did not comment for this article.

Mechanism could be adapted in Covid-19, but evidence is early

Experts agreed there is preclinical rationale for DSTAT’s purported anti-inflammatory properties since an impact on inflammatory cascades has also been studied with heparin and its other analogs. If heparin derivatives are developed with different structural characteristics, then they can block different phenomena, like the inflammatory responses triggered by a SARS-CoV-2 infection, said Antonella Bisio, PhD, researcher, Carbohydrate Sciences Group, Ronzoni Institute, Milan, Italy.

The goal of the derivative would be to enrich a specific sequence in heparin to lead to an intended effect, said Dr Joseph Hippensteel, Pulmonary Disease and Critical Care Medicine, University of Colorado, Aurora. However, the pharmacology on specific derivatives like DSTAT is complex which makes it hard to establish its activity, said a pharmacology expert, but did not dismiss the potential for DSTAT to be effective.

While preclinical data is scientifically interesting, it may be inadequate in understanding the clinical efficacy or toxicity potential in humans in Covid-19, said the expert. In mice, DSTAT was shown to inhibit neutrophil elastase, an inflammatory mediator, and its induced airway inflammation (Griffin et al; Am J Respir Cell Mol Biol. 2014 Apr;50(4):684-9). In particular, more preclinical data with DSTAT is needed since there have been adverse effects with derivatized polysaccharides treatments, said the expert, referring to a previous heparin contamination episode. In 2008, Baxter (ETR:BTL) recalled its heparin products due to reported adverse events and deaths and a later investigation revealed the heparin was contaminated with a semisynthetic polysaccharide oversulfated chondroitin sulfate (OSCS).

The technique for isolating glycosaminoglycans isn’t perfect, so there is the risk of the derivative containing other components of heparin, said Hippensteel. The heparin contamination episode is a good example of this challenge, and hence it is important to ensure there are no untoward events or off-target side effects with derivatives since heparin is a bioactive molecule, he added. The expert agreed, adding while heparin has been studied for more than 80 years, its complex mixture of different polysaccharides is still not fully understood. The complexity of DSTAT and other heparin derivatives is more challenging given the rapid time in which they are being repurposed for Covid-19, the expert added.

Currently, in the hospitalised setting, many patients get heparin because of a thrombosis risk associated with Covid-19, said Ritesh Tandon, PhD, associate professor of Microbiology (Virology), The University of Mississippi Medical Center. At the point of hospitalisation, diffused coagulation in different organs has already started and the use of heparin as an anticoagulant is then important, said Bisio. Moreover, when patients are in the hospital bed for a long time it is better to actively maintain anticoagulant usage since they are at risk for developing clots, she added.

DSTAT has minimal anticoagulant activity, according to the aforementioned paper, and the trial is excluding patients who are receiving or anticipated to require anticoagulants at a therapeutic intensity, according to ClinicalTrials.gov. More clinical evidence is required to support the notion but the simultaneous administration of heparin and its derivative without strong anticoagulant properties could be potentially possible, said Bisio. Heparin use after DSTAT could also be explored, experts said.

While DSTAT has been studied clinically in HMA-refractory acute myeloid leukemia (AML) or myelodysplastic syndrome, in that indication its mechanism is focused on inhibiting certain proteins, including HMGB1, that are involved in leukemic blast adhesion, survival and proliferation.

Ideal time of intervention

The Phase II/III trial is recruiting patients requiring supplemental oxygen or noninvasive ventilation. If the goal is to block inflammation before the condition worsens and to avoid the ICU, then a heparin derivative can be explored before that happens, Bisio said.

It would make sense in using a derivative with an anti-inflammatory mechanism between seven to 14 days after infection, said Hippensteel. Hippensteel suggested looking at data of patients who benefited from the dexamethasone in the Phase II/III RECOVERY (NCT04381936) study as a surrogate for an anti-inflammatory effect. Patients on supplemental oxygen were shown to have a shorter hospital stay in the RECOVERY study and are now put on dexamethasone, said Hippensteel. However, if the disease is in advanced stages, it remains to be seen if a heparin derivative can sufficiently block the outstanding inflammatory response, said Bisio. Nonetheless, in Covid-19, there is a good argument to be made to decrease the severity of illness since overcrowded ICUs at the height of the pandemic make patient care challenging, said Hippensteel.

Manasi Vaidya is an Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.