Iclaprim

Unassigned

New Medicines

Acute bacterial skin and skin structure infections and hospital acquired bacterial pneumonia

Information

New molecular entity
Motif Bio
Motif Bio

Development and Regulatory status

None
Phase III Clinical Trials
Pre-registration (Filed)
01. Company hope to file in US 2007; it has fast track status (1). Positive results from ASSIST-2 (2).
02. Filed in US for skin and soft tissue infections Dec 07 (3)
03. PII trials in nosocomial pneumonia in US (Dec 07) (3)
04. PI clinical trials in nosocomial infections in EU (Oct 03) (3)
05. US FDA accepted NDA for complicated skin and skin structure infections (may 08 ) (4)
06. Filed in EU for complicated skin and soft tissue infections Aug 08 (5).
07. Nov 08: FDA panel voted 17-2 against recommending approval for the treatment of complicated skin and skin structure infections. It failed to demonstrate equivalent cure rates vs linezolid and there were safety concerns (8).
08. FDA Complete Response letter states that they cannot approve the application for iclaprim in its current form and that further data is necessary to show efficacy to gain approval. The FDA letter stated that the NDA did not show the efficacy of iclaprim for cSSSI within an acceptable non-inferiority margin. The FDA requires further data to evaluate the benefits and risks of iclaprim for cSSSI. Jan 09 (9)
09. Filed in Canada
10. Oct 09: Arpida has withdrawn the marketing application iclaprim and terminated further development plans after the CHMP reached a negative opinion for its use in the treatment of complicated skin and soft tissue infections [11]
11. Dec 10: Development appears to be continuing (see below) [12].
12. Jul 15: The FDA has designated Motif Bio’s novel antibiotic iclaprim as a Qualified Infectious Diseases Product (QIDP). QIDP designation is used to help incentivise production of new antibiotics, and makes icalrpim eligible for priority review and fast track designation, as well as 10 years of market exclusivity. Motif, which specialises in novel antibiotics, says it believes iclaprim is the first drug in the dihydrofolate reductase inhibitor class to receive QIDP designation. The new designation covers the indications of acute bacterial skin and skin structure infections (ABSSSI) and hospital acquired bacterial pneumonia (HABP), two of the most common and serious forms of bacterial infection. This includes illnesses caused by prevalent resistant strains such as MRSA (methicillin-resistant Staphylococcus aureus) and MDRSP (multi-drug resistant Streptococcus pneumoniae) [13].
13. Feb 18: Company pipeline states; PIII trials in ABSSSI completed; NDA submission planned for Q1 2018.[21]
14. Jun 18: Filed NDA in US for ABSSSI. [22]
15. Aug 18: Granted priority review in US [23]

Category

Dihydrofolate reductase inhibitor; broad-spectrum antibiotic designed to be effective against multi-drug resistant bacteria.
Data published in 2009 showed that ABSSSI accounted for almost 870,000 hospital admissions in the US in 2004, an increase of ~30% over 4-years (Ther Adv Infect Dis. 2017 Sep; 4(5): 143–161).
Acute bacterial skin and skin structure infections and hospital acquired bacterial pneumonia
Intravenous

Trial or other data

01. ASSIST-1 trial directly compared iclaprim with linezolid and demonstrated equivalent efficacy. ASSIST-2 results due 2007 (1). ASSIST-2 (iclaprim vs. linezolid) has met primary endpoint of statistical non-inferiority in the clinical cure rate; the safety profile that was demonstrated in ASSIST-1 was confirmed (2).
02. Results from ASSIST trials (n=991): iclaprim showed high clinical cure rate similar to those of linezolid in complicated skin and skin structure infections caused by G+ve bacteria, including MRSA. In a combined efficacy analysis, the clinical cure rate at the test-of-cure visit was 82.2 % for iclaprim vs. 85.3 % for linezolid in the intent-to-treat population and cure rates were 92.3 % and 97.8 %, respectively, in the per protocol population. Data from the studies also show that iclaprim showed a high eradication rate for MRSA (76.4 %), which was comparable to that of linezolid (78.7 %). Adverse events were found to be less frequent among patients treated with iclaprim vs. linezolid. (5)
03. Oct 08: Data from a combined analysis of ASSIST-1 and ASSIST-2 were presented at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy)/Infectious Diseases Society of America 46th annual meeting. 991 adults with cSSSIs were treated for 10 to 14 days with either 0.8 mg/kg iclaprim or 600 mg linezolid twice daily. The clinical cure rate at the test of cure visit was 82.2% and 85.3% respectively in the ITT population. The pre-specified non-inferiority margin was -12.5%, and this was met in in both trials. The MRSA eradication rate was 76.4% and 78.7%, respectively (7).
04. Dec 10: Subsequent to the complete response letter issued in the US in Jan 2009, the FDA has issued updated draft guidance (August 2010) recommending new clinical endpoints and study populations in a newly defined indication, Acute Bacterial Skin and Skin Structure Infections ABSSSI. The FDA has agreed that pooled data from the two existing PIII studies together with further analysis and conditions was basically acceptable for a resubmission under the new guidance. This indicates that one additional study may be sufficient to gain approval. The company is planning further trials in the US and the EU [12].
05. Sep 15: FDA granted Fast Track designation for iclaprim IV [14].
06. Nov 15: PIII study (REVIVE-1; NCT02600611) to assess the efficacy and safety of iclaprim compared to vancomycin for treatment of skin and skin structure infections begins. 600 adults will be recruited in the US. Primary outcome is ≥20% reduction in lesion size at 48 to 72 hours; data collection should complete Aug 17 [15].
07. Nov 15: second PIII study (REVIVE-II, NCT02607618) begins [16]
08. Mar 16: Motif Bio announce first patient dosed in the REVIVE trial programme; they expect that both studies will be complete by 2H17. Both REVIVE-I & REVIVE-II are multi-centre, multi-national trials of similar design: if successful, they are expected to satisfy requirements for approval by both the EMA and the FDA [17].
09. Jan 17: PIII REVIVE-1 study (NCT02600611) has completed recruitment. Collection of primary outcome data was expected to complete Dec 16. PIII REVIVE-2 study (NCT02607618) is still recruiting and expected to complete collecting primary outcome data in Aug 17 [18].
10. Apr 17: in PIII REVIVE-1 trial, iclaprim was used in acute bacterial skin and skin structure infections and achieved non-inferiority (10% margin) compared to vancomycin at both early time point (48 to 72 hours after the start of treatment) 80.9% and 81% and at the test of cure endpoint, 7 to 14 days after study drug discontinuation, 84.2% vs 87% respectively [19].
11. Oct 17: In PIII Revive-2 study, iclaprim achieved primary endpoint of non-inferiority against vancomycin (current standard of care), with clinical cure in 78% (vancomycin result not stated). Resolution/ near resolution at end of therapy was achieved in 54.6% and 55.4%, respectively [20].