BOSTON & MORRISTOWN, N.J.—In early February, Paratek Pharmaceuticals Inc. announced that The New England Journal of Medicine (NEJM) had published detailed results from the OPTIC and OASIS-1 Phase 3 clinical trials of Nuzyra (omadacycline). Both studies met all primary and secondary endpoints, and showed that Nuzyra was safe and well tolerated.
Nuzyra is a modernized tetracycline administered in once-daily intravenous (IV) and oral formulations for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI). Nuzyra is specifically designed to overcome tetracycline resistance and exhibits activity across a spectrum of bacteria, including gram-positive, gram-negative, atypicals and other drug-resistant strains.
“In both pneumonia and skin settings, Nuzyra’s demonstrated efficacy against common pathogens, including pathogens resistant to other antibiotic classes, suggests that it has an important role for doctors in need of effective and safe IV and oral agents for their patients,” said Dr. Keith Kaye, director of research in the Division of Infectious Diseases at the University of Michigan Medical Center.
OPTIC (Omadacycline for Pneumonia Treatment In the Community) was a global, pivotal Phase 3 clinical study that compared the safety and efficacy of once-daily IV-to-oral Nuzyra to IV-to-oral moxifloxacin for treating adults with CABP. OPTIC demonstrated that Nuzyra was non-inferior to moxifloxacin for the treatment of adults with CABP, and was safe and well tolerated. In the intent-to-treat population, Nuzyra (n=386) was non-inferior to moxifloxacin (n=388) for early clinical response (ECR) (81.1 percent vs. 82.7 percent), and investigator assessment of clinical response (IACR) at post-treatment evaluation (PTE) was 87.6 percent vs. 85.1 percent. Efficacy results were consistent across study populations, PORT Risk Class and causative pathogen.
The rate of serious treatment-emergent adverse events (TEAEs) was 6 percent in the Nuzyra-treated group and 6.7 percent in the moxifloxacin-treated group. The most common adverse events were gastrointestinal events (Nuzyra, 10.2 percent; moxifloxacin 18 percent) and included vomiting (2.6 percent vs. 1.5 percent), nausea (2.4 percent vs. 5.4 percent) and diarrhea (1 percent vs. 8 percent), respectively. There were no cases of Clostridium difficile colitis or infection in patients treated with Nuzyra, compared with eight cases (2.1 percent) in patients treated with moxifloxacin. The mortality rate was 2.1 percent with Nuzyra and 1 percent with moxifloxacin.
“The publication of two of our global Phase 3 trials in a journal as prestigious as The New England Journal of Medicine is an affirmation of the clinical impact to the practice of medicine in an era of growing resistance to older antibiotic agents, and will help inform physicians’ decisions as they treat these serious, often life-threatening, community-acquired infections,” noted Dr. Evan Loh, president, chief operating officer and chief medical officer of Paratek. “These pivotal clinical trials demonstrated that Nuzyra is an effective, well-tolerated monotherapy option for patients with activity across an appropriate spectrum of bacteria, including gram-positive, gram-negative, atypicals and drug-resistant strains, and we believe Nuzyra can play an important role in winning the battle against the growing health challenge of antibiotic resistance.”
The global pivotal Phase 3 registration study known as OASIS-1 evaluated the efficacy and safety of an IV to oral once-daily Nuzyra against twice-daily linezolid over a seven- to 14-day course of therapy in 645 adult patients. OASIS-1 demonstrated that Nuzyra was non-inferior to linezolid for treating ABSSSI, with a similar safety profile. Efficacy results were consistent across study populations and sub-populations, type of skin infection and causative pathogen, including MRSA.
In the modified intent-to-treat population (mITT), Nuzyra (n=316) was non-inferior to linezolid (n=311) for ECR (84.8 percent vs. 85.5 percent). Nuzyra also was non-inferior to linezolid for IACR at PTE in the mITT (86.1 percent vs. 83.6 percent) and clinically evaluable (96.3 percent vs. 93.5 percent) populations. In both groups efficacy was comparable for methicillin-susceptible and methicillin-resistant Staphylococcus aureus infections, which account for nearly half of all ABSSSI isolates in the U.S.
Serious TEAEs occurred in 3.7 percent of Nuzyra patients and 2.5 percent of linezolid patients, none of which were considered related to study drug. Among TEAEs, gastrointestinal events were most common in both treatment groups (18 percent for Nuzyra; 15.8 percent for linezolid) and included nausea (12.4 percent vs. 9.9 percent), vomiting (5.3 percent vs. 5 percent) and diarrhea (2.2 percent vs. 3.1 percent).
The mortality rate was 0.3 percent with Nuzyra and 0.6 percent with linezolid.
In other pneumonia-related clinical trial news, BioAegis Therapeutics Inc. announced recently that patient enrollment is underway in a Phase 1b/2a study of recombinant plasma gelsolin (rhu-pGSN) in community-acquired pneumonia (CAP) in the Republic of Georgia. Plasma gelsolin (pGSN) is an abundant circulating protein that enhances macrophage antimicrobial activity, limits the excessive spread of inflammation and neutralizes actin exposed by damaged cells.
The Data Safety Monitoring Board (DSMB) met on Jan. 25, 2019, to review the safety data for the 6 mg/kg multiple dose level (cohort 2). Review of the safety data did not reveal any safety concerns, and accordingly the DSMB recommended starting enrollment into the 12 mg/kg multiple ascending dose level (cohort 3).
BioAegis, together with scientists at Vanderbilt University, Northwestern University and the CDC, had previously demonstrated in human samples that patients admitted to the hospital with CAP have depressed levels of plasma gelsolin at presentation, and that the extent of this depression predicts subsequent adverse outcomes.
Therapeutic efficacy of rhu-pGSN supplementation has been consistently demonstrated in more than 25 infectious and non-infectious disease animal models. Due to its host-based mechanism, rhu-pGSN has further demonstrated effectiveness against both gram-positive and gram-negative infection, including pathogens resistant to multiple antibiotics.
“Harnessing the body’s immune system offers a safe, powerful approach that can lead to more effective therapies for serious infectious and non-infectious inflammatory diseases,” commented Dr. Mark DiNubile, BioAegis’ chief medical officer. “We eagerly look forward to successfully completing the remaining two cohorts in our dose-finding safety trial.”