Developing Drugs for Difficult-to-treat Diseases
Industry Insight May 21, 2020 | By Laura Elizabeth Lansdowne, Senior Science Writer, Technology Networks
Technology Networks recently spoke with Mike Sherman, Chief Executive Officer at Chimerix to learn more about the company’s oncology, biodefense and COVID-19 therapeutic efforts. Mike elaborates on the two lead candidates featured in their R&D pipeline and highlights the recent initiation of a Phase 2/3 study investigating the safety and efficacy of dociparstat sodium (DSTAT,) as a treatment for acute lung injury in patients with severe COVID-19.
Laura Lansdowne (LL): For our readers that may not be familiar with Chimerix, could you tell us a little more about the company, your mission and values?
Mike Sherman (MS): Chimerix is a biopharmaceutical company based in Durham, North Carolina. We are focused on developing medicines that have a substantial impact on the lives of patients with cancer and other deadly diseases. We like to think we do this by taking a differentiated approach to addressing difficult-to-treat diseases.
Although we have been concentrating our efforts on oncology and biodefense, we recently started working with the US Food and Drug Administration (FDA) on a Phase 2/3 clinical trial to help in the fight against COVID-19 with one of our lead drug candidates. This demonstrates our commitment to filling gaps in the treatment paradigm where there is a critical need.
Led by an experienced antiviral drug development team, we consider ourselves entrepreneurs who leverage both scientific ingenuity and business experience to develop creative solutions that transform the healthcare industry. We approach this important work with humility and we hold ourselves to the highest standards of ethical behavior, honesty, fairness, and professionalism in every project we embark on. We embrace unique talents, honor diverse life and work styles, value the contributions of others and empower individuals to take ownership and harness the agility of our company to deliver quality solutions to today’s deadly diseases. Over the past year we have worked together as a team to execute and accomplish our goals and we continue to foster a sense of execution throughout the organization.
LL: What drug candidates are currently featured in your development pipeline and what indications are they being evaluated for?
MS: As our work on COVID-related conditions demonstrates, we are continuously evaluating new ways to overcome deadly diseases and currently we have two lead drug candidates in the pipeline, that have the potential to address current and possible future pandemics or threats.
The first one is called dociparstat sodium, also known as DSTAT. DSTAT is a glycosaminoglycan derivative of the common heparin with known anti-inflammatory properties. However, DSTAT has a substantially reduced risk of bleeding complications compared to commercially available forms of heparin. DSTAT is now in development for the firstline treatment of a complicated type of cancer known as acute yyeloid leukemia or AML. We received Orphan Drug and Fast Track designations from the FDA for this purpose.
However, we are now evaluating the use of DSTAT for the treatment of acute lung injury (ALI) in COVID-19 patients, as it has demonstrated potential in preclinical studies to address the key inflammatory and coagulation disorders observed in patients with severe COVID-19.
The second lead drug candidate we are developing at the moment is called brincidofovir or BCV. BCV is an oral antiviral designed for the treatment of smallpox that acts by enhancing drug delivery to the intracellular site of viral replication as BCV effectively penetrates cells via its lipid conjugate, releasing the nucleotide analog cidofovir, which in turn acts to inhibit virus replication.
LL: Could you tell us more about the Phase 2/3 study of DSTAT in acute lung injury (ALI) for patients with severe COVID-19 that you recently initiated?
MS: We very recently started looking at the potential for this drug to be used in COVID-19 patients. So working with some key physicians that have been involved in treating COVID-19 patients, very experienced researchers and the FDA, it was a matter of weeks to move from our first evaluation of DSTAT’s potential to obtain the FDA’s clearance to move ahead with this Phase 2/3 trial.
This is a randomized, double-blind, placebo-controlled Phase 2/3 study designed to evaluate the safety and efficacy of DSTAT in patients with ALI due to COVID-19 who are at high risk of respiratory failure. This study will aim to determine if DSTAT can accelerate the recovery,prevent the progression of the disease and reduce the need for mechanical ventilation, in patients severely affected by COVID-19 who require hospitalization and supplemental oxygen therapy.
In this study, the primary endpoint we are evaluating is the proportion of subjects who survive and do not require mechanical ventilation through day 28. Additionally, we are looking at the time it takes to improve, as assessed by the National Institute of Allergy and Infectious Disease ordinal scale, and the time to hospital discharge, the time to resolution of fever, the number of ventilator-free days, all-cause mortality, and any changes in key biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), high mobility group box 1 (HMGB1) or C-reactive protein and d-dimer.
For the Phase 2 portion of the study, we expect to enroll 24 subjects to confirm the maximum safe dose and will then expand it by an additional 50 patients (74 total) at the selected dose. We expect to have data from the first safety cohort available in the second half of this year. The Phase 3 portion of the study will enroll approximately 450 subjects.
LL: Could you elaborate on the underlying basis for exploring DSTAT as a treatment for COVID-19?
MS: In severe cases, COVID-19 leads to an excessive reaction by the body’s immune system. This inflammatory response can cause damage to multiple organs and is particularly harmful to the lungs, and can also cause clotting disorders. We have seen how the mortality in cases of severe COVID-19 has been often associated with ALI which then progresses to acute respiratory distress syndrome (ARDS).
The respiratory distress that these patients experience is likely to be the result of high concentrations of inflammatory cytokines that form what it is known as a “cytokine storm” as well as other immune cell aberrations and coagulation disorders such as disseminated intravascular coagulation (DIC) and pulmonary embolisms. Here is where we believe that DSTAT has the potential to help with both the inflammatory response and the clotting disorders by inhibiting this hyperactive immune response and resulting inflammation, as well as addressing the underlying mechanisms of the coagulation disorders seen in these patients. The key difference is that DSTAT may interrupt this immune response before it gets too severe and it may do this with substantially reduced risk of bleeding complications, compared to commercially available forms of heparin.
It is hard not to be motivated to pursue these programs when you know you have the potential to help patients worldwide, so we continue to work tirelessly to bring this solution to patients as soon as possible. If it proves safe and effective in COVID-19, it may also provide hope to the many more patients who suffer from ALI or ARDS from other causes.
LL: Your candidate brincidofovir is being developed for the treatment of smallpox under the FDA’s Animal Rule. What is the purpose of this rule and how does this impact the drug development process?
MS: The development of this treatment is being done under the FDA’s Animal Efficacy Rule. This allows for testing of investigational drugs in animal models to support effectiveness in diseases that are not ethical or feasible to study in humans due to the nature of the disease. We believe that preparing BCV for the US Strategic National Stockpile (SNS) is a critical element to protect the world population from this deadly virus, whether a potential outbreak occurs naturally or through a bioterrorist attack. We are looking forward to finalizing our submission mid-year and to a potential procurement contract with the government to enable the addition of BCV to the SNS as well as the countermeasure stockpiles of other countries globally.
Mike Sherman was speaking with Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.