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MTFB: REVIVE-1 Results Published in Clinical Infectious Diseases

02/01/2018
By David Bautz, PhD

NASDAQ:MTFB

Motif Bio Plc (NASDAQ:MTFB) is a biopharmaceutical company focused on the development of antibiotic compounds for difficult to treat bacterial infections. The company’s lead asset, iclaprim, is a novel diaminopyrimidine molecule that has completed Phase 3 testing for the treatment of acute bacterial skin and skin structure infections (ABSSSI), with the company announcing positive results from the two studies earlier in 2017. We anticipate a New Drug Application (NDA) to be submitted for iclaprim in first quarter of 2018 and a regulatory submission in Europe in the second quarter of 2018. In addition, the U.S. Food and Drug Administration (FDA) has granted iclaprim orphan drug designation (ODD) for the treatment of bacterial infections in patients with cystic fibrosis caused by Staphylococcus aureus. 

REVIVE-1 Results Published

On December 21, 2017, Motif announced the publication of results from the Phase 3 REVIVE-1 study in the journal Clinical Infectious Diseases (Huang et al., 2017). The company had previously announced positive topline results from the study in April 2017.

The REVIVE-1 study was a multicenter, double blind, randomized trial where suffering from acute bacterial skin and skin structure infections (ABSSSI) received either 80 mg iclaprim or 15 mg/kg vancomycin intravenously (IV) every 12 hours. The study design followed both the U.S. FDA and European Medicines Agency guidance. The primary endpoint was an analysis of early clinical response (ECR) at the early time point (ETP, 48-72 hours after the first infusion of drug) comparing response to iclaprim with response to vancomycin. Secondary analyses included response to treatment at the end of therapy (EOT), at test of cure (TOC, 7-14 days after the last dose of study drug), and safety and tolerability. The following chart shows the schedule of visits for study subjects.

 

A total of 598 patients were randomized into the study to receive either iclaprim (n=298) or vancomycin (n=300) and the baseline and demographic characteristics were comparable between the two groups. The baseline mean lesion sizes of iclaprim and vancomycin groups were 333 cm2 and 337 cm2, respectively. In the intent-to-treat (ITT) population, which consisted of all randomized subjects, an ECR was reported for 80.9% (241/298) of iclaprim-treated patients and 81.0% (243/300) of vancomycin-treated patients (% difference, -0.13; 95% CI, -6.42, 6.17), thus iclaprim demonstrated non-inferiority (within 10% margin) compared to vancomycin. The clinical cure rates at the EOT were 92.3% (275/298) and 90.7% (272/300) for the iclaprim and vancomycin groups, respectively. Clinical cure at the TOC was 83% (248/298) and 87% (262/300) for the iclaprim and vancomycin groups, respectively. Lastly, the ECR at ETP was comparable between iclaprim and vancomycin groups when stratifying by lesion type, pathogen, diabetes, and renal impairment. The results are summarized in the following table. 

 

Iclaprim was safe and well tolerated as drug-related treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (SAEs) were similar between treatment groups. There were slight increases in the incidence of headache (10.2% and 2.4%), nausea (9.9% and 5.7%), and fatigue (6.1% and 3.0%) in the iclaprim group compared to the vancomycin group. Importantly, there were no drug-related TEAEs related to nephrotoxicity reported for iclaprim compared to 3 (1.0%) for vancomycin. TEAEs led to discontinuation in 2.7% and 4.4% of patients in the iclaprim and vancomycin groups, respectively. A summary of the safety findings is shown in the following table. 

 

In summary, REVIVE-1 met the primary endpoint of demonstrating non-inferiority between iclaprim and vancomycin for the treatment of ABSSSI with respect to ECR at the ETP 48-72 hours after the first dose of drug. In addition, TEAEs were similar between the two treatments. As shown in the results table above, approximately 20-25% of patients in each treatment group had infections caused by methicillin-resistant Staphylococcus aureus (MRSA), with the ECR at ETP almost identical to the result for the treatment group as a whole. The International Disease Society of America (IDSA) guidelines for the treatment of ABSSSI include the use of vancomycin, linezolid, or daptomycin in patients with risk factors for MRSA (Stevens et al., 2014). However, both safety issues and resistance have been reported for these drugs (Hanai et al., 2016; Nannini et al., 2010). Thus, iclaprim may be an appropriate treatment option for ABSSSI caused by or suspected to be caused by MRSA given its efficacy, lack of nephrotoxicity, and no need for therapeutic drug monitoring or renal dosing adjustments. 

NDA Filing in 1Q18

We continue to anticipate an NDA being filed for iclaprim for the treatment of ABSSSI before the end of the first quarter of 2018. The FDA then has up to two months to determine whether or not to accept the application for review. If accepted, we anticipate iclaprim will receive a priority review (the FDA has designated it a Qualified Infectious Disease Product, QIDP), which will result in a PDUFA date six months following acceptance of the NDA as opposed to the usual 10-month review time period. Thus, iclaprim could be approved before the end of 2018, with a commercial launch likely in the beginning of 2019. Upon approval, iclaprim would be eligible to receive 10 years of market exclusivity (five years for new molecular entity status and 5 years for QIDP). 

Valuation

There are an estimated 3.6 million people hospitalized with ABSSSI every year. We conservatively estimate that 20% of patients have renal insufficiency, based on published data (Halilovic et al., 2012). We believe iclaprim could attain peak market share among these patients of 20%. We model for a full course of treatment costing $3000 and an inflation rate of 2%, which leads to peak sales of approximately $500 million in the U.S. Outside the U.S., we believe Motif will sign a commercialization agreement that will result in an average 15% royalty on net sales, which we estimate will peak at approximately $225 million. Using a 90% probability of approval and a 15% discount rate leads to a net present value for iclaprim in ABSSSI of $475 million. After factoring in the company’s cash position, potential cash from the exercise of outstanding warrants, and dividing by the fully diluted ADS share count of 16.9 million leads to a valuation of $31 per share. The stock continues to trade at a significant discount to our valuation, thus offering investors plenty of upside at the current price.

READ THE FULL RESEARCH REPORT HERE

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