Iclaprim is a targeted Gram-positive1 antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA). Iclaprim works in a different way than most other antibiotics and rapidly kills bacteria in vitro.
- PDUFA (Prescription Drug User Fee Act) decision date by FDA regarding marketing approval of iclaprim for treatment of acute bacterial skin and skin structure infections (ABSSSI): February 13, 2019.
- Two positive Phase 3 trials in ABSSSI completed.
- Iclaprim may have the potential to provide avoidance of costs related to vancomycin-associated acute kidney Injury (VA-AKI) (est. ~$17,000 per patient) in hospitalized ABSSSI patients at risk or with existing moderate to severe renal impairment. It is estimated that the incidence of AKI in hospitalized patients with skin infections is as high as 9%.
- A dihydrofolate reductase Inhibitor with a low propensity for resistance development and rapidly bactericidal in vitro.
- Targeted spectrum of activity against Gram-positive bacteria, including MRSA; aligned with antibiotic stewardship principles.
- An established safety profile: studied in over 1,400 patients and healthy volunteers and no evidence of kidney toxicity in REVIVE Phase 3 trials.
- Administered intravenously at a fixed dose with no dosage adjustment required in renally impaired or obese patients. Iclaprim fixed dose may, if approved, help reduce the resources required in hospitals since dosage adjustment by health care professionals is avoided, no therapeutic drug monitoring is needed, and overall hospital treatment costs may be lower, especially in patients with renal impairment.
- Concentrates in the skin and lung following intravenous administration; less than 2% excreted unchanged through kidneys; no clinically relevant drug-drug interactions.
- Commercial potential in at least three hospitalized patient segments with serious MRSA infections and unmet medical needs – ABSSSI (including patients at risk of VA-AKI), hospital-acquired bacterial pneumonia (HABP), including ventilator-associated bacterial pneumonia (VABP), and Staphylococcus aureus lung infections in patients with cystic fibrosis.
- Qualified Infectious Disease Product (QIDP) designation granted by FDA, and, if approved as a New Chemical Entity, will be eligible for 10 years of market exclusivity in the U.S. upon approval.
- Notices of Allowance from the United States Patent and Trademark Office for two method of use patents that will expire in 2037.
Iclaprim is a novel investigational antibiotic with a targeted Gram-positive spectrum of activity. In contrast to commonly used broad-spectrum antibiotics, this “precision medicine approach” is consistent with antibiotic stewardship principles which, among other things, seek to reduce the inappropriate use of broad-spectrum products to avoid antimicrobial resistance and to lessen the impact on the microbiome of the patient.
Iclaprim has a different and underutilized mechanism of action compared to most other antibiotics. Following positive results from two Phase 3 trials (REVIVE-1 and REVIVE-2), a New Drug Application (NDA) was submitted to the U.S. Food & Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and is now under review, with a PDUFA date of February 13, 2019. To date, iclaprim has been studied in over 1,400 patients and healthy volunteers. Clinical and microbiological data indicate that iclaprim has a targeted Gram-positive spectrum of activity, low propensity for resistance development and an established safety profile. In the REVIVE clinical studies, iclaprim was administered intravenously at a fixed dose with no dosage adjustment required in patients with renal impairment or in obese patients. The iclaprim fixed dose may, if approved, help reduce the resources required in hospitals since dosage adjustment by health care professionals is avoided, therapeutic drug monitoring is not needed, and overall hospital treatment costs may be lower, especially in patients with renal impairment. Many standard of care Gram-positive antibiotics are not suitable for hospitalized ABSSSI patients with renal impairment due to efficacy and/or safety issues.
Key Clinical Results
Positive results from two Phase 3 trials with iclaprim in acute bacterial skin and skin structure infections (ABSSSI) – the REVIVE-1 and REVIVE-2 trials – were announced in 2017. These trials had identical protocols but were conducted at different clinical sites in the U.S., Europe and South America. Data from both trials, as well as pooled results, have been published in peer-reviewed medical journals. Highlights from the individual trials are outlined below.
REVIVE: two global double-blinded, active-controlled, Phase 3 clinical trials each with 600 patients with ABSSSI that compared the safety and efficacy of an 80mg intravenous dose of iclaprim with a 15mg/kg intravenous dose of vancomycin. Both treatments were administered every 12 hours for 5 to 14 days.
REVIVE-1: Iclaprim achieved the primary endpoint of non-inferiority (10% margin) compared to vancomycin at the early time point (ETP), 48 to 72 hours after the start of administration of the study drug, in the intent-to-treat (ITT) patient population.
Iclaprim was well tolerated in the study, with most adverse events categorized as mild or moderate. Detailed results from this study were published in Clinical Infectious Diseases.
REVIVE-2: Iclaprim achieved the primary endpoint of non-inferiority (10% margin) compared to vancomycin, the current standard of care, at the ETP, 48 to 72 hours after the start of administration of the study drug, in the ITT patient population.
Iclaprim was well tolerated in the study, with most adverse events categorized as mild or moderate. The results of the REVIVE-2 trial have been published in Antimicrobial Agents and Chemotherapy.
The pooled results from the REVIVE trials have been published in the Journal of Antimicrobial Agents. In the pooled analysis, iclaprim was well tolerated in the study, with most adverse events categorized as mild or moderate. Of note, no patients in the iclaprim group had clinically significant creatinine increases compared to seven cases reported in the vancomycin group.
Motif also plans to develop iclaprim for the treatment of hospital-acquired bacteria pneumonia (HABP) including ventilator-associated bacteria pneumonia (VABP), based on results from a Phase 2 trial in this indication in which iclaprim achieved high clinical cure rates and demonstrated a good safety profile compared to the comparator vancomycin. The results of this Phase 2 trial were published in Clinical Therapeutics. Additionally, in a Phase 1 healthy volunteer trial, iclaprim concentrated in lung compartments (epithelial lining fluid and alveolar macrophages) considerably higher than concentrations in plasma. These data were published in the Journal of Antimicrobial Chemotherapy. A Phase 3 trial in this indication is planned; trial initiation is subject to additional funding.
The ability of iclaprim to concentrate in the lungs is also supportive of its potential use to treat S. aureus lung infections in patients with cystic fibrosis. Formulation work for this indication is ongoing.
Worldwide antibiotic sales totaled U.S. $26bn in 2015 and are projected to grow at 9% annually to U.S. $40bn by 2020. Dramatically rising levels of antibiotic resistance, safety issues and a need for improved clinical and pharmacoeconomic outcomes have created an urgent need for new treatment options. More than 10 million people globally are expected to die from drug-resistant infections by 2050, approximately 20% more deaths than those attributable to cancer. Approximately 23,000 deaths annually in the U.S., and a comparable number in Europe, are directly attributable to antibiotic-resistant infections. Infections are becoming more severe and complicated to treat due to an aging, obese population who are more likely to have diabetes and kidney disease. In fact, baby boomers in the U.S. are 55 percent more likely to have diabetes and 25 percent more likely to be obese than previous generations – signaling a higher risk for developing related chronic conditions and increased medical expenses.
In response to the global antibiotic resistance crisis, government and other agencies are offering incentives for new drug development including shorter development and review timelines, extended market exclusivity periods, and higher price reimbursement for clinically differentiated antibiotics.
The market opportunity for treating hospitalized ABSSSI patients with renal impairment is estimated at $2.8 billion in the U.S., with 3.6 million patients hospitalized with ABSSSI annually, 26% of whom also suffer from renal impairment. The ABSSSI patient population at highest risk for vancomycin-associated acute kidney injury (VA-AKI) is estimated to represent a market opportunity of >$800 million. This population is expected to grow due to the increasing prevalence of diabetes and aging of the population, as renal function declines with age and poorly controlled diabetes.
With iclaprim, no kidney toxicity was observed in the REVIVE Phase 3 trials and there is no requirement for therapeutic monitoring or dosage adjustment in patients with renal impairment or in obese patients.
Vancomycin, the current standard of care for the treatment of ABSSSI, is a generic antibiotic that must be dose-titrated against body mass and is nephrotoxic. Patients with renal impairment must therefore be carefully monitored during treatment, and there is risk of nephrotoxicity associated with vancomycin treatment. VA-AKI, estimated to occur in approximately 9% of hospitalized ABSSSI patients, leads to poor clinical outcomes, including a higher rate of death, longer total length of hospital stay and longer duration of hospital stay post-initiation of vancomycin therapy. The incremental cost per patient to treat nephrotoxicity associated with vancomycin treatment is estimated to be over $17,000.
A review of the scientific literature shows that there is a high unmet need for an alternative to treat the renally impaired ABSSSI sub-population. Hospitalized ABSSSI patients with MRSA infections plus renal impairment and/or diabetes have higher hospital costs and longer length of hospital stay.
Primary market research conducted with hospital-based clinicians found that iclaprim’s fixed dose administration and safe clearance through the kidneys offer compelling potential advantages, including potential pharmacoeconomic advantages, in this patient population over the standard of care Gram-positive antibiotics.The iclaprim fixed dose may, if approved, help reduce the resources required in hospitals since dosage adjustment by health care professionals is avoided and overall hospital treatment costs may be lower, especially in patients with renal impairment. Less than 2% of iclaprim is excreted unchanged through the kidneys, and no nephrotoxicity was observed in the two REVIVE Phase 3 trials.
In the U.S. alone, there are approximately 1.4 million hospitalized patients each year with nosocomial pneumonias, including ventilator-associated bacterial pneumonia (VABP), 40% with Gram-positive pathogens, including MRSA.
Despite existing antibiotic therapies, the all-cause mortality rate associated with nosocomial pneumonia is 13-47%. Iclaprim penetrates and concentrates in lung tissue and has shown evidence of efficacy in a Phase 2 clinical trial. Subject to additional funding, Motif plans to conduct a Phase 3 trial in this indication.
Staphylococcus aureus pulmonary infections among cystic fibrosis (CF) patients
There are an estimated 30,000 patients with CF in the U.S. and over 70,000 worldwide. An estimated 80% or more of patients with CF die due to respiratory infections caused by various bacteria, with the number of MRSA infections growing in recent years. Motif believes that there are currently no products indicated to treat Staphylococcus aureus lung infections in this patient population. In September 2017, iclaprim was granted Orphan Drug Designation by the U.S. FDA for or the treatment of Staphylococcus aureus lung infections in patients with cystic fibrosis.
- Gram-positive and Gram-negative refer to how bacteria react to the Gram stain test based on the outer casing of the bacteria and the bacteria’s cell wall structure. Each type of bacteria may be associated with different diseases