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Top 5 New Antibiotics Advance to Fight Resistant Infections

SAN FRANCISCO — Five standout antibiotics were featured during a pipeline session here at IDWeek 2018.

The application process was open to all companies and the agents selected had the most novel data and are likely to have to most impact, said Cesar Arias, MD, PhD, from the University of Texas School of Public Health in Houston, who is a vice chair of the program committee for the meeting.

The new drugs in development are welcomed because rates of antibiotic-resistant infections have roughly doubled since 2002, as reported by Medscape Medical News..

Last year at IDWeek, 10 standouts were presented after many years of a development drought.

TP-6076 is a novel, synthetic, broad-spectrum tetracycline for the treatment of infections such as those caused by two of the most dangerous organisms: carbapenem-resistant Enterobacteriaceae and multidrug-resistant Acinetobacter baumannii.

It works by binding to the 30S ribosomal subunit.

TP-6076, Tetraphase Pharmaceuticals

Researchers have completed phase 1 single-ascending-dose and multiple-ascending-dose clinical studies.

TP-6076 was well tolerated when given in a single dose up to 60 mg, said Larry Tsai, MD, from Tetraphase.

No deaths or serious or severe adverse events were reported, and no study participant withdrew as a result of an adverse event. The most common adverse effect was nausea, Tsai reported, and the rate of gastrointestinal adverse events increased as the dose increased.

TP-6076 shows low minimum inhibitory concentrations (MICs) against multidrug-resistant Gram-negative organisms. For Enterobacteriaceae, MIC is 0.5 μg/mL, and for multidrug-resistant A  baumannii, MIC is 0.06 μg/mL.

The clinical development plan for TP-6076 is to target patients with serious infections caused by A baumannii, Tsai said.

Of the many Gram-negative drugs in development, few are effective against Acinetobacter, he noted.

CF-301 (Exebacase, ContraFect)

CF-301 is a phage-derived first-in-class lysin with a mechanism of action that is distinct from traditional antibiotics.

Its bactericidal effect is rapid against all Staphylococcus strains and some Streptococcus species, and its propensity to resistance is low, said Cara Cassino, MD, chief medical officer for ContraFect.

The agent also eradicates biofilms, which harbor bacteria and protect them from immune defenses, making them very difficult for conventional antibiotics to kill.

The US Food and Drug Administration (FDA) has fast-tracked its development as a treatment for Staphylococcus aureus bacteremia and endocarditis.

In a phase 1 trial, it was well tolerated and there were no clinical adverse safety signals.

In a phase 2 multinational superiority study, CF-301 in combination with conventional antibiotics is being compared with conventional antibiotics alone to test the potential for the agent to improve outcomes in people with bacteremia, including endocarditis, caused by S aureus.

Topline data are expected in the fourth quarter of this year, Cassino said. It is the first lysin to reach phase 2 in the United States.

Tebipenem Pivoxil (SPR994), Spero Therapeutics

SPR994 aims to provide a highly bioavailable oral carbapenem prodrug to treat serious infections caused by cephalosporin- and fluoroquinolone-resistant Enterobacteriaceae. It has the potential to become the first oral carbapenem for use in adults.

“The ultimate goal is to decrease the need for intravenous antibiotic therapy and help shift the focus of care for patients with serious infection from the inpatient to the outpatient arena,” said David Melnick, MD, chief medical officer of Spero.

The target population includes adults with complicated urinary tract infection and acute pyelonephritis. It is also intended for step-down use in the hospital to speed transition to outpatient care.

Phase 1 single-ascending-dose and multiple-ascending-dose studies have shown that the safety profile of SPR994 is similar to that of the carbapenems, Melnick reported. There were no serious or severe adverse events. Gastrointestinal events were the most common and there were no cases of Clostridium difficile infection.

A phase 3 trial of patients with complicated urinary tract infection will compare the efficacy of oral SPR994 with that of an intravenously administered carbapenem.

Ibrexafungerp (Formerly SCY-078) SCYNEXIS, Inc.

Ibrexafungerp is the first in a novel class of structurally distinct glucan synthase inhibitors called triterpenoid antifungals, which are active against Candida species, including multidrug-resistant Candida auris, Aspergillus, and Pneumocystis.

It is active against azole-resistant strains and most echinocandin-resistant strains. An oral formulation is being used in clinical trials and intravenous formulations are in development. The flexibility of both formulations broadens its potential in inpatient and outpatient settings.

It has a low risk for drugdrug interactions and is well tolerated, said David Angulo, MD, chief medical officer of SCYNEXIS.

Phase 2 and 3 trials are being developed to look at multiple indications for ibrexafungerp, including vulvovaginal candidiasis, invasive candidiasis, invasive aspergillosis, and refractory invasive fungal infections.

The FDA has fast-tracked both formulations of Ibrexafungerp for the treatment of candidiasis (including candidemia), aspergillosis, and vulvovaginal, and has granted orphan drug status for the treatment of candidiasis and aspergillosis.

ETX2514 and Sulbactam, Entasis Therapeutics

ETX2514SUL — the combination of ETX2514 and sulbactam — is a novel beta-lactam–beta-lactamase inhibitor combination being developed as a fixed-dose intravenous treatment for Acinetobacter infections.

“There is a desperate unmet medical need for new agents in this area,” said Robin Isaacs, MD, chief medical officer of Entasis, citing the growing prevalence of Acinetobacter and its association with high mortality rates.

Infections with carbapenem-resistant baumannii have been linked with mortality rates as high as 52%, according to the Centers for Disease Control and Prevention.

The broad-spectrum inhibitor was well tolerated and safe in phase 1 and 2 trials. A phase 3 trial testing ETX2514SUL against carbapenem-resistant A baumannii infections is set to begin in the first quarter of 2019.

ETX2514SUL has shown strong in vivo activity in both thigh and lung models.

The FDA has granted the agent fast-track status for the treatment of hospital-acquired and ventilator-acquired bacterial pneumonia and bloodstream infections caused by A baumannii.

Tsai is employed by Tetraphase, and research funding was provided by CARB-X. Cassino is chief medical officer for ContraFect. Melnick reports support from the Biomedical Advanced Research and Development Authority and Meiji Seika Pharma. Angulo is chief medical officer at SCYNEXIS. Isaacs is chief medical officer at Entasis.

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