According to Centers for Disease Control and Prevention (CDC) data published in Morbidity and Mortality Weekly Report, CDAD has been a cause of some mortality and significant morbidity in hospitalized patients. More recent and less commonly encountered strains of CDAD are exhibiting significantly higher rates of mortality and have been less responsive to current treatments, such as metronidazole.
According to Sherwood L. Gorbach, MD, of Tufts University School of Medicine, "New strains of CDAD have emerged which are not responding to certain commonly used antibacterials. PAR-101 may provide healthcare professionals with a new tool to treat this potentially deadly bacterial illness. CDAD is highly contagious and has recurrence rates ranging from 20 percent to 25 percent after existing therapies. It is important that healthcare professionals have additional agents to treat this illness."
The Phase 1B study was a randomized, double-blind, multiple-dose, placebo-controlled study to evaluate pharmacokinetics, tolerance, and safety of PAR-101 in healthy volunteers. Oral doses of PAR-101 150 mg, 300 mg, and 450 mg were administered once-daily for 10 days. PAR-101 was well tolerated by all subjects at all doses; no adverse events were considered to be drug related. The absorption of PAR-101 was minimal, with the majority of drug being eliminated in the feces.
In the proof-principle Phase 2A study, PAR-101 was evaluated in 45 CDAD patients in order to select an appropriate dose for subsequent trials. Subjects were randomized to receive either 50 mg, 100 mg, or 200 mg of treatment every 12 hours followed by clinical evaluation.
The clinical evaluation included relief of symptoms of CDAD, time to resolution of diarrhea, and clinical recurrence. Plasma and fecal samples were collected to investigate the relationship among dose, concentration, and excretion of PAR-101 in CDAD patients. PAR-101 was well tolerated by all subjects at all doses. Clinical response was as follows: only two patients in each of the two lower dose groups and none in the top dosing group were transferred to conventional therapy for apparent treatment failure
(41/45, >91 percent cured overall). Of the subjects that completed therapy, 2/41 (<5 percent) patients had recurrence of symptoms within the six weeks of follow-up, one
each in the low and high dose groups. After multiple dose oral administrations, plasma concentrations of PAR-101 were typically less than or equal to 5 ng/mL (0.005 mcg/mL) across the dose range, while fecal concentrations were high, averaging over 10,000 times the MIC90 for C. difficile at the top dose.
"PAR-101 has the potential to address an emerging health problem for both patients in hospitals and patients living in healthcare related environments. We are looking forward to the development of PAR-101 for this marketplace," said John MacPhee, president of the Branded Products Division at Par Pharmaceutical Companies, Inc.
CDAD, a potentially deadly bacterial illness, is the most common cause of nosocomial diarrhea in developed countries. CDAD is usually acquired in a hospital setting; almost all patients who develop this illness are taking, or have recently received, antibiotic therapy. The organism accounts for approximately 20 percent of cases of antibiotic-associated diarrhea as well as the majority of cases of antibiotic-associated colitis. Patients with diarrhea, especially if severe or accompanied by incontinence, may unintentionally spread the infection to other patients, and large outbreaks of CDAD have been observed in hospitals. Other symptoms may include abdominal pain and fever.
While there are commonly used therapies for the treatment of CDAD, including vancomycin (FDA-approved for this indication) and metronidazole, both have limitations in treating this illness. Based on clinical data, both agents are capable of inducing CDAD, and some patients do not respond to therapy with these agents and are at risk of developing more severe disease.
Source: Par Pharmaceutical Companies, Inc.