We are pleased that we reached agreement with the U.S. Food and Drug Administration (FDA) for the immediate initiation of the pilot portion of the Phase 3 Open-label Brincidofovir Trial for the treatment of adenovirus infections in immunocompromised patients. Josh Hardy’s story brought to public attention the often-devastating impact of adenovirus infection, and helped accelerate an ongoing discussion between the FDA and Chimerix regarding the need for additional clinical development to assess brincidofovir’s potential in adenovirus infection so that many patients may be able to benefit in the future.
Over the past several years Chimerix has received hundreds of requests for the compassionate use of brincidofovir. Words are inadequate to express our empathy and concern for what individuals with life-threatening viral infections, and their families, are experiencing. This is why we are dedicated to demonstrating the safety and efficacy of brincidofovir in our ongoing Phase 3 SUPPRESS clinical trial in cytomegalovirus and now in our new Phase 3 clinical trial in adenovirus - so that we can make brincidofovir available as soon as possible to the thousands of patients each year who might benefit from it.
Chimerix, Inc. (Nasdaq:CMRX), a biopharmaceutical company developing novel, oral antivirals in areas of high unmet medical need, today announced the extension of its contract with the Biomedical Advanced Research and Development Authority (BARDA) for the continued development of CMX001 as a potential medical countermeasure against smallpox, which is classified as a Category A bioterror agent by the U.S. Centers for Disease Control and Prevention. The extension of the contract provides $5 million in funding over 12 months for Chimerix to conduct animal studies that are necessary for an approval of CMX001 for treatment of smallpox infection under the U.S. Food and Drug Administration's (FDA) Animal Efficacy Rule.
CMX001 is being developed as a treatment or preventive therapeutic for multiple viral diseases based on its antiviral activity against all five families of double-stranded DNA (dsDNA) viruses that cause disease in humans, including smallpox. Data from cell culture and animal models of smallpox have shown CMX001 to be highly effective against viruses in the poxvirus family. There is no antiviral agent approved for the treatment of smallpox. An antiviral is needed, in particular, for patients who cannot be vaccinated due to medical conditions that prevent them from mounting an appropriate immune response to a smallpox vaccine.
"CMX001 continues to show progress as a potential medical countermeasure against smallpox, including recent data generated in a highly relevant rabbitpox model," said Kenneth I. Moch, President and CEO of Chimerix. "We look forward to continuing our work with BARDA and the FDA to advance CMX001 as a medical countermeasure for smallpox. Simultaneously, we are also continuing the development of CMX001 for the prevention, preemption or treatment of other dsDNA viruses, including herpesviruses, polyomaviruses, and adenoviruses, that cause morbidity and mortality in immunocompromised individuals."
Since smallpox has been declared eradicated in humans, development of CMX001 for the treatment of smallpox is occurring under the FDA's Animal Efficacy Rule, pursuant to which the FDA uses data from animal studies to support the effectiveness of products that cannot be studied in humans. In February 2011, BARDA awarded Chimerix an Advanced Research and Development Contract for the development of CMX001 as a medical countermeasure in the event of an accidental or intentional release of smallpox, such as a bioterrorist attack, which could trigger a global health emergency (Contract Number HHSO100201100013C). The current extension represents continuation of work under this contract.
The contract with BARDA supports research and development of CMX001 as a treatment for smallpox infections, but does not include a purchase option for the Strategic National Stockpile. Information regarding BARDA can be found online at: http://www.phe.gov/about/barda/Pages/default.aspx.
Chimerix's lead product candidate, brincidofovir (CMX001), is an oral nucleotide analog that has shown broad-spectrum antiviral activity against all five families of double-stranded DNA (dsDNA) viruses that affect humans, including cytomegalovirus (CMV), adenovirus (AdV), BK virus (BKV) and herpes simplex viruses. Brincidofovir has a favorable safety and tolerability profile, with no evidence of kidney or bone marrow toxicity in nearly 900 patients dosed with brincidofovir to date. Chimerix believes that brincidofovir has the potential to be the first broad-spectrum antiviral for the prevention and treatment of clinically significant infections and diseases caused by dsDNA viruses.
Following positive Phase 2 results, in the third quarter of 2013 Chimerix initiated the Phase 3 SUPPRESS trial which will support Chimerix's initial regulatory submission for prevention of CMV infection in adult hematopoietic cell transplant (HCT) recipients. Chimerix recently presented results from its Phase 2 trial in AdV, an often-fatal infection with no approved treatment. A brincidofovir dose of 100 mg twice weekly demonstrated a potent antiviral effect on levels of AdV in the blood, and a numeric decrease in overall mortality. Chimerix continues to work with the Biomedical Advanced Research and Development Authority (BARDA) to develop brincidofovir as a medical countermeasure against smallpox.
About Cytomegalovirus (CMV) and Double-Stranded DNA (dsDNA) Viruses
CMV is a member of the herpesvirus family and is the most common infectious pathogen in transplant recipients. A majority of adults in the US have been exposed to CMV, generally in childhood, with lifelong viral latency established following resolution. In healthy individuals with a functioning immune system, CMV remains dormant throughout life. A functioning immune system protects an infected individual against future exposure to CMV but does not clear the virus from their body. In immunocompromised individuals with weakened immune systems, such as transplant recipients, CMV often reactivates during the post-transplant period when the immune system is rebuilding itself. No therapies are approved for the prevention of CMV in HCT recipients. Currently available systemic anti-CMV agents can be effective against CMV; however, their use is limited by significant toxicities, including bone marrow suppression and renal impairment, and these therapies are only approved for certain solid organ transplant patient populations. CMV infection is known to correlate with progression to CMV disease and death. CMV itself is immunosuppressive and reactivation of the virus can predispose a patient to other opportunistic viral infections in addition to fungal and bacterial infections.
Chimerix Announces Publication of Positive Phase 2 Results of Brincidofovir (CMX001) in the New England Journal of Medicine
Phase 2 Trial Evaluated Brincidofovir for the Prevention of Cytomegalovirus (CMV) Infection in Hematopoietic Cell Transplant Recipients
DURHAM, N.C., Sept. 26, 2013 (GLOBE NEWSWIRE) -- Chimerix, Inc. (Nasdaq:CMRX), a biopharmaceutical company developing novel, oral antivirals in areas of high unmet medical need, today announced the publication of results from its Phase 2 Study CMX001-201 evaluating brincidofovir (CMX001) for the prevention of cytomegalovirus (CMV) infection in hematopoietic cell transplant (HCT) recipients. The article, entitled "CMX001 to Prevent Cytomegalovirus Disease in Hematopoietic-Cell Transplantation," appears in the September 26th issue of the New England Journal of Medicine (N Engl J Med 369:1227-36).
Brincidofovir, Chimerix's lead product candidate, is an investigational oral nucleotide analog lipid-conjugate that has shown broad-spectrum antiviral activity against double-stranded DNA (dsDNA) viruses including CMV. Study CMX001-201, a 230-subject, randomized, placebo-controlled, double-blind, dose-escalation study, met the primary endpoint of reduction in CMV viremia and/or CMV disease for brincidofovir 100 mg twice weekly versus placebo (p=0.002). Based on these positive Phase 2 results, Chimerix recently initiated the Phase 3 SUPPRESS trial of brincidofovir 100 mg twice weekly for the prevention of CMV infection in HCT recipients.
"Although prevention of CMV infection has been recognized as a superior approach to decrease CMV-related morbidity and mortality in the months following hematopoietic cell transplantation, the side effects of available antivirals have precluded their approval and use in this setting," said M. Michelle Berrey, MD, MPH, Chief Medical Officer of Chimerix. "The significant decrease in CMV events and lack of hematologic and renal toxicity shown in Study CMX001-201 provided the supportive data to allow us to progress brincidofovir into the Phase 3 SUPPRESS trial."
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SUPPRESS is designed to demonstrate the efficacy and safety of brincidofovir for the prevention of CMV infection versus a placebo control, as no therapy is currently approved for the prevention of CMV in HCT recipients. The primary endpoint for SUPPRESS is the rate of clinically significant CMV infection through the first 24 weeks post-transplant. The trial is powered to detect a relative 50% decrease in clinically significant CMV infection in subjects receiving brincidofovir versus those receiving placebo. Secondary endpoints in the SUPPRESS trial include clinical and virologic evidence of dsDNA viral infections, including AdV, BKV and other herpesviruses such as HHV-6 and varicella zoster virus that contribute to morbidity and mortality in the first year following HCT.
SUPPRESS is anticipated to enroll approximately 450 HCT recipients who are at increased risk of CMV infection, with approximately 300 subjects receiving 100 mg twice weekly brincidofovir and 150 receiving placebo (2-to-1 ratio). Approximately 40 transplant centers will participate in SUPPRESS. Dosing of study drug will begin shortly after subjects receive their transplant, and will not require evidence of stem cell "engraftment" (evidence of production of blood cells by the new transplant), a safety precaution incorporated in the Phase 2 trial of brincidofovir and other recent trials of investigational antivirals for CMV prevention. Enrolled subjects will continue on brincidofovir or placebo through Week 14 post-transplant, the period of highest risk for viral reactivation. Subjects will continue to be monitored for evidence of CMV and other dsDNA viral infections through Week 24 post-transplant.
Data from SUPPRESS are anticipated in mid-2015 and, if positive, may support Accelerated Approval of brincidofovir for the prevention of CMV infection.
Chimerix Presents Brincidofovir (CMX001) Adenovirus Phase 2 Results
DURHAM, NC, September 11, 2013 – Chimerix, Inc. (NASDAQ: CMRX), a biopharmaceutical company developing novel, oral antivirals in areas of high unmet medical need, today announced the results from its exploratory Phase 2 Study 202 evaluating brincidofovir (CMX001) in hematopoietic cell transplant (HCT) recipients with early adenovirus (AdV) infection. Study 202 was the first trial of an antiviral agent in AdV infection. Brincidofovir (CMX001) is an investigational oral nucleotide analog lipid-conjugate that has demonstrated activity against all pathogenic families of double-stranded DNA (dsDNA) viruses, including herpesviruses, adenoviruses, and polyomaviruses.
Michael Grimley, MD, Associate Professor of Clinical Pediatrics in the Division of Bone Marrow Transplant and Immune Deficiency at Cincinnati Children’s Hospital Medical Center, and the lead investigator in Chimerix’s Phase 2 AdV study, presented the trial results during the “Viral Infections in Immunosuppressed Hosts” session at the 53rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting on September 10, 2013 in Denver, CO.
“These data strongly support the continued development of CMX001 as a global prevention for dsDNA viruses, a leading cause of non-relapse mortality in the months following a transplant,” said Dr. Grimley.
Although AdV in HCT recipients has been recognized as a severe and often-fatal infection in pediatric and adult patients who have undergone recent HCT, there are no approved antiviral treatments. Potential risk factors associated with an increased risk of rapid progression to AdV infection have been identified in the scientific literature, but the frequency of AdV in the blood or AdV disease was unknown prior to this trial. Early data from patients who had received CMX001 for AdV infection through Emergency Investigational New Drug (EIND) regulations had provided anecdotal evidence of improved outcomes compared with historic data. This exploratory Phase 2 trial was designed to initiate CMX001 or placebo during early AdV infection, prior to symptomatic disease, and to evaluate the potential to decrease AdV viral load or prevent progression to AdV disease.
Results: Safety and tolerability data from this 48-subject trial confirmed the lack of hematologic and renal toxicity for once-weekly (QW) or twice-weekly (BIW) CMX001 dosed for 6-12 weeks, and showed the successful implementation of the Safety Monitoring and Management Plan (SMMP) to address gastrointestinal side effects reported in earlier trials. Temporary dose interruptions for grade 3 diarrhea were successfully utilized in the trial, with one permanent discontinuation for diarrhea in the CMX001 QW cohort. Three additional discontinuations in the trial were reported for abdominal pain (CMX001 BIW cohort), lower GI hemorrhage (CMX001 BIW cohort), and severe rash (placebo cohort). No new serious safety issues were identified in this trial, and no changes were necessary in the safety monitoring in the recently initiated Phase 3 SUPPRESS trial for prevention of CMV.
Efficacy outcomes for Study 202 were progression to possible or probable AdV disease or significant changes in AdV viremia. Although statistical significance was not achieved, numerical benefit was demonstrated for CMX001 100 mg BIW for multiple endpoints:
Adenovirus in the blood was chosen as a potential early indicator of AdV disease based on the accepted clinical utility of viremia as an early trigger for initiation of antiviral therapy for CMV in these patients. Results from this study bring into question whether AdV viremia is an indicator of early AdV disease. For low-level AdV viremia (< 3.0 log10 copies/mL), a significant proportion of subjects spontaneously cleared viremia prior to initiation of therapy or during placebo therapy. These data indicate that low level AdV viremia may be a transient phenomenon in some subjects. In contrast, high level AdV viremia (> 3.0 log10 copies/mL) at screening was often associated with rapid development of symptoms and end-organ disease even before therapy could be started. Further research is needed to identify clinical indicators of early AdV disease which could be used for early intervention, but prevention of AdV continues to be the preferred strategy through which diseases caused by dsDNA viruses can be avoided.
“The acceptable safety and tolerability of CMX001, and successful incorporation of the Safety Monitoring and Management Plan in this study, were important milestones for the brincidofovir program as we initiate dosing in the Phase 3 SUPPRESS trial for CMV prevention in HCT recipients,” said M. Michelle Berrey, MD, MPH, Chief Medical Officer of Chimerix. “Additionally, consistent trends toward decreased progression of AdV disease and a decrease in overall mortality for subjects randomized to CMX001 BIW reaffirm our belief that earlier intervention in viral disease is the preferred strategy to decrease morbidity and mortality from AdV and other dsDNA viral diseases. Ultimately, we believe that broad use of CMX001 as a prevention for CMV, AdV, and other viral diseases that impact immunocompromised patients will prove to be the best approach.”
Summary of CMX001 Study 202 Results Presented at ICAAC
CMX001 BIW initiated at the time of detection of AdV viremia showed potential clinical benefit in reducing progression to AdV disease and all-cause mortality. Subset analyses of disease progression and all-cause mortality were consistent in trends favoring the CMX001 BIW regimen over placebo or CMX001 QW. A greater proportion of subjects randomized to CMX001 BIW achieved undetectable levels of AdV viremia during randomized therapy and a lower proportion of subjects on the BIW regimen progressed to symptomatic disease compared to placebo or CMX001 QW.
CMX001 Study 202 Design
Study 202 was a randomized, blinded, placebo-controlled proof-of-concept trial assessing the use of CMX001 as a preemptive therapy for AdV infection. HCT recipients were randomized into the study upon appearance of detectable AdV viremia but before the appearance of symptoms of AdV disease. Subjects were randomized to one of three dosing regimens: CMX001 BIW, CMX001 QW or placebo. Forty-eight pediatric and adult subjects were randomized into the trial beginning in June 2011.
The design of the study was based on the limited information available on the natural history of AdV infection in immunocompromised subjects, preliminary and uncontrolled data available on the activity of CMX001 against AdV, ethical considerations due to the placebo-controlled design and high mortality associated with AdV disease in HCT recipients and epidemiologic data indicating a low incidence of AdV viremia in subjects post-HCT.
Our core scientific assets, the Lipid-Antiviral-Conjugate Technology and the Chimerix Chemical Library, provide us with a rich source for new drug leads. The Chimerix Chemical Library is especially well-suited to discovering novel inhibitors of viral polymerases and helicases. Screening is ongoing for antivirals to treat CMV, BKV, dengue, influenza A and B, respiratory syncytia virus and hepatitis B virus.
HIV therapies have advanced substantially in recent years, yet HIV can develop resistance to all current agents and significant drug side effects remain an issue for many patients. Tenofovir (marketed in a prodrug form by Gilead as Viread®) is one of the most widely used antiretrovirals and is part of the Truvada® and Atripla® fixed-dose combinations. Tenofovir has also been associated with renal toxicity and resistance can be conferred by a single mutation.
CMX157, a nucleotide analog, is being developed as an antiviral therapy against HIV. We believe CMX157 has the potential to be less nephrotoxic than tenofovir based on in vitro data showing CMX157 is not a substrate for the membrane pumps that secrete tenofovir into kidney cells. Combined with high in vitro potency against all common NRTI-resistant HIV genotypes, this suggests CMX157 could be a best-in-class antiretroviral with the potential to address an estimated worldwide market of $1 billion.
CMX001 is in development for the treatment of double stranded DNA (dsDNA) viruses in transplant recipients, representing an estimated market in excess of $1 billion. The compound has the potential to become a standard of care for "universal prophylaxis" for dsDNA viruses in immunocompromised patients due to its broad-spectrum antiviral activity.
Human cytomegalovirus (CMV) is a member of the herpesvirus family of dsDNA viruses that typically causes mild or subclinical disease, but can cause severe systemic or localized disease in immunocompromised individuals. CMV is a common virus that infects most people worldwide. In most developed countries, 40-80 percent of children are infected with CMV before puberty and exposure to the virus increases with age in the general population. Like other members of the herpesvirus group, CMV rests in the host in a latent state following primary infection. The virus can emerge from latency when the immune system becomes compromised, causing significant morbidity and mortality. Organ involvement manifestations of CMV disease include hepatitis, pneumonitis, pancreatitis, colitis, erosive gastrointestinal bleeding, meningoencephalitis, myocarditis, and chorioretinitis.
Historically, CMV-induced disease has been most frequently observed in HIV/AIDS patients, immunosuppressed transplant recipients and cancer patients receiving chemotherapy. We are initially developing CMX001 for use in transplant patients where there is a significant unmet medical need. Cytomegalovirus is present in more than two-thirds of donors and recipients prior to transplantation. In a study of transplant patients who did not receive induction therapy or CMV prophylaxis, the relative risk of overall mortality was 2.5 to 2.9 times higher than those without CMV for CMV disease and CMV infection, respectively. The burden of CMV disease in the transplant population has increased as the frequency of organ transplantation has increased. Each year more than 60,000 transplants are performed in the U.S. and Europe. Over 75 percent of these transplant recipients are at moderate-to-high risk of CMV a dsDNA viral infection adn a sizable proportion are co-infected with multiple dsDNA viruses. Organ loss and other morbidities due to CMV remain a large and costly issue.
Therapy for CMV in transplant patients may be prophylactic, preemptive or treatment of disease. Despite prophylaxis with existing drugs, often continued for 100 days, disease prevalence at six months is estimated to be from 12 to 22 percent.
The in vitro activity of CMX001 against CMV has been assessed in MRC-5 cells (a human lung fibroblast-derived cell line) and human foreskin fibroblast (HFF) cells. Depending on cell type, virus strain, and method of assay (DNA or plaque reduction), EC50 values ranged from 2 x 10-6 µM to 2.5 x 10-2 µM. In all cases, CMX001 was 2 to 5 logs more potent than cidofovir.
CMX001 is expected to have a decided advantage over current treatments for prophylaxis of CMV infection in solid organ and bone marrow transplant recipients and in cancer patients receiving myelosuppressive chemotherapy or radiation therapy based on its potential for increased potency, decreased toxicity, broader spectrum antiviral activity and favorable cross resistance profile.
Like CMV, BK virus is widespread but rarely causes disease, except in immunosuppressed or immunocompromised patients. A member of the polyomavirus family, BK virus remains latent in the kidney and urinary tract where it persists throughout a patient's lifetime. In renal transplant patients, because of treatment with immunosuppressive agents, BK viruria is a serious complication that is growing in prevalence. BK viruria may eventually lead to loss of the kidney graft, or to uncontrolled bleeding in the bladder.
Chimerix Signs Worldwide License Agreement with Merck for CMX157, A Novel Candidate for the Treatment of HIV
RESEARCH TRIANGLE PARK, NC – July 24, 2012 – Chimerix, Inc. today announced the execution of a license agreement granting Merck, known as MSD outside the United States and Canada, exclusive worldwide rights to CMX157, Chimerix's novel lipid acyclic nucleoside phosphonate currently being evaluated to treat HIV infection.
Under the terms of the agreement, Merck receives an exclusive worldwide license and will be responsible for development and commercialization of CMX157, an investigational oral nucleoside reverse transcriptase inhibitor (NRTI). Chimerix will receive a $17.5 million upfront payment and will be eligible to receive up to $151 million in milestones, as well as royalties on future sales.
"This agreement is a significant milestone in Chimerix's mission of developing best-in-class therapies for major unmet medical needs based on our lipid technology platform," said Kenneth I. Moch, President and CEO of Chimerix. "Merck is the ideal collaborator to develop this drug and help us to maximize the potential of CMX157, given its commitment to its HIV franchise. The value created through the licensure of CMX157 will help us continue to advance our lead compound, CMX001, through its critical Phase 3 trial, for which we currently plan to begin enrolling patients early next year."
"Merck is committed to bringing forward new treatment options for patients with HIV/AIDs," said Daria Hazuda, Vice President and Worldwide Discovery Head for Infectious Diseases, Merck Research Laboratories. "We look forward to working closely with Chimerix to advance development of this NRTI candidate."
CMX157 is a novel lipid acyclic nucleoside phosphonate that delivers high intracellular concentrations of the active antiviral agent tenofovir diphosphate. CMX157 is more than 200-fold more potent in vitro versus tenofovir against all major HIV subtypes resistant to current therapies, which may allow activity against tenofovir-resistant viruses (e.g., K65R), and against HBV. CMX157's novel structure results in decreased circulating levels of tenofovir, lowering systemic exposure and thereby reducing the potential for renal side effects. CMX157 has completed a Phase 1 clinical trial in healthy volunteers, demonstrating a favorable safety, tolerability and drug distribution profile.
Following positive Phase 2 results, in the third quarter of 2013 Chimerix initiated the Phase 3 SUPPRESS trial which will support Chimerix's initial regulatory submission for prevention of CMV infection in adult hematopoietic cell transplant (HCT) recipients. Chimerix recently presented results from its Phase 2 trial in AdV, an often-fatal infection with no approved treatment. A brincidofovir dose of 100 mg twice weekly demonstrated a potent antiviral effect on levels of AdV in the blood, and a numeric decrease in overall mortality. Chimerix continues to work with the Biomedical Advanced Research and Development Authority (BARDA) to develop brincidofovir as a medical countermeasure against smallpox.. Read More
Chimerix has amassed an unusual breadth of assets with considerable potential in antiviral innovation, including our Lipid Conjugation Technology and the Chimerix Chemical Library. The combination of our team’s internal antiviral product expertise with a number of internally-generated leads against several important viruses allows us the flexibility to pursue out-licensing or co-development partners for our emergent antiviral medicines. Read More