Recent Anti-Infective Trials Reviewed at ID Week 2017

Clinical trials are a linchpin of clinical science. They are designed to evaluate the prowess of an antibacterial, antifungal, and antiviral compounds. The busy clinical trial terrain results in a barrage of data. Sifting through all this information to discover studies that describe drugs that are practice-changing can be challenging for a busy clinician.

A session at the year’s ID Week in San Diego, California came to the rescue. The speakers were tasked with summarizing recent important clinical trials involving viruses, bacteria, and fungi. Francisco Marty, MD, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, reviewed recent antiviral trials, excepting those involving HIV. His focus was the herpes zoster subunit vaccine, intravenous (IV) influenza drugs, and letermovir for prevention of post-transplant cytomegalovirus (CMV) infection.

An adjuvanted herpes zoster vaccine that targets the viral glycoprotein E subunit was evaluated in 2 large (over 17,700 subjects total) ZOE-50 and ZOE-70 randomized, placebo-controlled trials (RCTs). The glycoprotein is necessary for viral replication and cell-to-cell spread, and so is a good target. Vaccine efficacy and safety was demonstrated. The prowess of the same vaccine following autologous hematopoietic cell transplantation was evaluated in a phase 1/2 trial of 121 patients. Efficacy and safety were also evident.

Two other trials evaluated IV zanamivir versus oral oseltamivir for the treatment of severe influenza. These trials have been sorely needed. Approved antivirals for influenza have been limited to mild disease or the outpatient setting. There is a pressing need for an IV option for severe disease. In an open-label phase 2 trial, zanamivir demonstrated tolerable efficacy and safety, and has been used for thousands of emergency responses to influenza. All these reasons have made zanamivir an attractive potential option for oseltamivir-resistant influenza.

Both trials were positive. However, frustratingly, because these are pioneering trials, there is no basis for comparison with other data, which has become a roadblock to those at the US Food and Drug Administration who wield the power of drug approval.

The final antiviral RCT assessed the use of letermovir in preventing CMV infections in high-risk allogeneic hematopoietic stem cell transplant recipients. Letermovir blocks the activity of a viral complex that is essential for replication. Positive phase 2 results spurred a phase 3 RCT featuring a 14-week treatment with letermovir (n=373) or placebo (n=192) and follow-up to 48 weeks. The drug significantly reduced the incidence of CMV infections with comparable safety to the placebo. Approval of the drug is expected in the coming months.

Shifting gears, recent trials in antibacterials were discussed by Susan Rehm, Cleveland Clinic, Cleveland, Ohio. Her task was formidable, given the huge number of trials in the past several years. The trials presented were by no means exhaustive. Investigational antibiotics and abstracts presented at ID Week 2017 were not presented.

The IGNITE 1 trial evaluated the efficacy and safety of eravacycline in 512 patients with complicated intra-abdominal infection. Eravacycline is a synthetic fluorocycline antibiotic similar in structure to tigecycline, which inhibits bacterial protein synthesis and which has broad-spectrum activity. A high rate of cure was achieved, similar to the comparator (ertapenem).

Iclaprim, a bactericidal diaminopyrimidine that is active against gram-positive bacteria and which has orphan drug designation for Staphylococcus aureus respiratory tract infections in people with cystic fibrosis. It is also being evaluated for acute bacterial skin and skin structure (ABSSI) infections in the recently closed REVIVE I and II trials and was compared to vancomycin in a randomized phase 2 trial of nosocomial pneumonia involving 70 patients. Significantly better cure rates were evident for 2 dosing regimens compared to vancomycin in the phase 2 setting.

Other trials of note involved the demonstration of protective activity against Clostridium difficile infection of the human monoclonal antibodies actoxumab and bezlotoxumab in 3 trials, the efficacy of omadacycline against ABSSI and against pneumonia in the community setting in the OASIS-2 and OPTIC trials, respectively, and the prowess of meropenem-vaborbactam in TANGO-I and -II. Still, other trials are recruiting or will be shortly. These include RESTORE-IMI 1 (NCT02452047), RESTORE-IM 2 (NCT02493764), LEAP 1 (NCT02559310), LEAP 2 (NCT02813694), PERIFOS (NCT03235947), and PROOF (NCT03260010).

Shifting gears one last time, recent notable trials in mycology were discussed by Thomas Patterson, MD, University of Texas Health Science Center at San Antonio and South Texas Veterans Health Care System, San Antonio, Texas. The gamut of trials included new agents for aspergillosis and mucormycosis (single-arm, open-label VITAL trial), Aspergillus and mold treatment strategies including combination therapy and prophylaxis (isavuconazole versus voriconazole; phase 3 SECURE trial), cryptococcal meningitis in HIV infection (fluconazole in combination with flucytosine or amphotericin B; adjuvant dexamethasone; adjuvant corticosteroid) and endemic fungi, candidiasis (isavuconazole versus caspofungin; ACTIVE trial), and monitoring and management of toxicity of therapeutic drugs.

A novel development is the formulation of itraconazole using a proprietary technology dubbed SUBA (SUperBioAvailable) in which spray drying creates nanoparticle of itraconazole in a polymer matrix. Delayed released posaconazole has been studied in patients at high risk of fungal infections.

These and other trial results are available at www.msgercdoctorfungus.com.

DISCLOSURES

Francisco Marty: Astellas Pharma US: Consultant and Grant Investigator, Consulting fee and Grant recipient Chimerix: Consultant and Grant Investigator, Consulting fee and Grant recipient

Fate Therapeutics: Scientific Advisor, Consulting fee Gilead Sciences: Consultant and Grant Investigator, Consulting fee and Grant recipient LFB: Consultant, Consulting fee

Merck: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient Roche Molecular Systems: Consultant, Consulting fee Shire: Consultant and Grant Investigator, Consulting fee and Grant recipient

Susan J. Rehm: Amgen: Shareholder, dividend Merck: Shareholder, dividend Pfizer: Consultant and Shareholder, Consulting fee and dividend

Thomas Patterson: Astellas: Consultant, Consulting fee Basilea: Consultant, Consulting fee Gilead: Consultant, Consulting fee Merck: Consultant, Consulting fee Scynexis: Consultant, Consulting fee Toyama: Consultant, Consulting fee

PRESENTATION

SYMPOSIUM New Anti-Infective Clinical Trials that Will Change Your Practice

Recent Trials in Non-HIV Antivirals

Francisco M. Marty, MD, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA

Recent Trials in Antibacterials

Susan J. Rehm, MD, Cleveland Clinic, Cleveland, OH

Recent Trials in Antifungals

Thomas Patterson, MD, University of Texas Health Science Center At San Antonio and South Texas Veterans Health Care System, San Antonio, TX

Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at hoyle@square-rainbow.com.