Iclaprim

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.

Highlights

  • Phase 3 trials in acute bacterial skin and skin structure infections (ABSSSI) completed; NDA submission planned for Q1 2018
  • 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
  • Continued acceptable safety profile: studied in over 1,300 patients and healthy volunteers and, unlike current standard of care antibiotics, no evidence of kidney toxicity in clinical trials to date
  • Administered intravenously at a fixed dose with no dosage adjustment required in renally impaired or obese patients
  • Concentrates in the skin and lung following intravenous administration
  • Commercial potential in at least three hospitalized patient segments with serious MRSA infections and unmet medical needs – ABSSSI, hospital-acquired bacterial pneumonia (HABP), including ventilator-associated bacterial pneumonia (VABP), and Staphylococcus aureus lung infections in cystic fibrosis patients
  • 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 US upon approval

Overview

Iclaprim is a novel investigational antibiotic that has a different and underutilized mechanism of action compared to other antibiotics. Iclaprim exhibits potent in vitro activity against Gram-positive clinical isolates of many genera of staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA). Iclaprim is rapidly bactericidal in vitro. To date, iclaprim has been studied in over 1,300 patients and healthy volunteers. In clinical studies iclaprim has been 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 and overall hospital treatment costs may be lower, especially in patients with renal impairment.

Iclaprim is a diaminopyrimidine antibiotic that inhibits an essential bacterial enzyme called dihydrofolate reductase (DHFR). Diaminopyrimidines are a class of chemical compounds that inhibit different enzymes in the production of tetrahydrofolate, a form of folic acid, which is required for the production of bacterial DNA and RNA. The inhibition of DHFR represents an underutilized mechanism of action compared with other antibiotics.

Iclaprim has been administered to more than 1,300 patients and healthy volunteers and in contrast to vancomycin, a standard of care antibiotic in hospitalized patients with Gram-positive infections, no evidence of kidney toxicity has been observed with iclaprim. Thus, therapeutic monitoring or dosage adjustment in renally impaired patients is not required. Iclaprim has also demonstrated rapid bactericidal activity – achieving 99.9% in vitro kill against MRSA within 4 to 6 hours of drug exposure versus 8 to 10 hours for vancomycin, the standard of care – and has a low in vitro propensity for resistance development.

Iclaprim is being developed to treat hospitalized patients with serious MRSA infections. The first proposed indication is acute bacterial skin and skin structure infections (ABSSSI), serious skin infections covering 75 cm2 or more of the skin surface, including infected surgical wounds, abscesses and cellulitis. We believe that iclaprim is an attractive potential candidate for use as a first-line empiric monotherapy (the first therapy administered before identifying the pathogen), in hospitalized patients with ABSSSI and who have comorbidities (suffer from other health issues), such as renal impairment, which affects up to 26% of ABSSSI patients. Other potential indications for iclaprim include hospital acquired bacterial pneumonia (HABP), including ventilator-associated bacterial pneumonia (VABP), and Staphylococcus aureus lung infections in people with cystic fibrosis.

The US Food and Drug Administration (FDA) designated iclaprim as a Qualified Infectious Disease Product (QIDP) for ABSSSI and HABP. QIDP status grants iclaprim regulatory Fast Track designation, Priority Review following submission of an NDA, and, if approved, a five-year extension to the statutory market exclusivity period in the United States, resulting in 10 years of market exclusivity from the date of approval. If approved by the European Medicines Agency (EMA), we expect that iclaprim will qualify for eight years of data exclusivity and an additional two years of market exclusivity in the EU.

Key Clinical Results

During 2017, we announced 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. These trials had identical protocols but were conducted at different clinical sites in the US, Europe and South America.

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. Treatments were administered every 12 hours for 5 to 14 days. The trial involved clinical centers in Europe, South America and the US.

Iclaprim: REVIVE-1 and -2 Phase 3 ABSSSI Trials Study Design

Double-blinded, active-controlled, global non-inferiority trials with approximately 80 trial sites across REVIVE 1 & 2.

In April 2017, we announced positive topline results from 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. Detailed information from this study were presented at Motif’s Investor & Analyst Event in September 2017.

Iclaprim Achieves Primary Endpoint in REVIVE-1 Phase 3 Trial

Time point Endpoint Iclaprim

N=298

Vancomycin

N=300

% Difference

(95% CI)

ETP Early Clinical Response (ECR)* 241 (80.9%) 243 (81.0%) -0.13

(-6.42, 6.17)

*≥20% reduction of lesion area at 48-72 hours

In October 2017, we announced positive topline results from 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. More details about the REVIVE-2 results are available here.

Iclaprim Achieves Primary Endpoint in REVIVE-2 Phase 3 Trial

Timepoint Endpoint Iclaprim

N=295

Vancomycin

N=305

% Difference

(95% CI)

ETP

(primary endpoint)

Early Clinical Response (ECR)* 231 (78.3%) 234 (76.7%) 1.58

(-5.10, 8.26)

*>20% reduction of lesion area at 48-72 hours

We also plan 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. Additionally, in a Phase 1 healthy volunteer trial, concentrations of iclaprim at the site of infection in the lungs were considerably higher than concentrations in plasma. 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 lung infections in patients with cystic fibrosis. Formulation work for this indication is ongoing.

Commercial Opportunity

Worldwide antibiotic sales totaled US$26bn in 2015, and are projected to grow at 9% annually to US$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 US, 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 US 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.

ABSSSI

The market opportunity for treating hospitalized ABSSSI patients with renal impairment is estimated at US$2.8 billion in the US, with 3.6 million patients hospitalized with ABSSSI annually, 26% of whom also suffer from renal impairment. 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 no observed kidney toxicity and no requirement for therapeutic monitoring or dosage adjustment in patients with renal impairment, iclaprim could offer advantages over current standard of care Gram-positive antibiotics for ABSSSI in high-risk patients, including renal impaired, diabetic, and 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. Vancomycin-associated acute kidney injury 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 mean cost per patient to treat nephrotoxicity associated with vancomycin treatment is $11,233.

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 offers compelling potential advantages, including potential pharmacoeconomic advantages, in this patient population over the standard of care Gram-positive antibiotics.

HABP/VABP

In the US alone, there are approximately 1.4 million hospitalized patients each year with nosocomial pneumonias, including ventilator-associated bacterial pneumonia (VABP), representing a total market of approximately US$1.7 billion.

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. If Phase 3 testing confirms these early indications, iclaprim could become a standard of care for these dangerously ill patients.

Staphylococcus aureus pulmonary infections among cystic fibrosis (CF) patients

There are an estimated 30,000 patients with CF in the US 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 US FDA for or the treatment of Staphylococcus aureus lung infections in patients with cystic fibrosis.

References

  1. 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