Innovation Pharmaceuticals Inc (IPIX)

[BooDog]

Kevetrin and Brilacidin Abstract info...


GregChase Monday, 04/20/15 05:01:52 PM
Re: None
Post # of 98436

Is this CTIX at ASCO from the Iplanner...

Abstract #TPS2613

A phase 1, dose-escalation, safety, pharmacokinetic, pharmacodynamic study of thioureidobutyronitrile, a novel p53 targeted therapy, in patients with advanced solid tumors.

Geoffrey Shapiro, MD, PhD

Dana-Farber Cancer Institute


Saturday, May 30 | 8:00 AM - 11:30 AM


https://iplanner.asco.org/am2015/AM2015.aspx/Search
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ABSTRACTS Title Brilacidin, host defence peptide mimetic, one of a new class of immunomodulatory agents that can target multiple disease indications

Poster No: EV0201
Author(s): Scott Richard W., Sonis Stephen T., Kroczak Bozena, Freeman Katie B., DeGrado William F, Holden Sylvia A., Kumar Ashok, Chafai-Fadela Karima, Ram Siya, Menon Krishna
Affiliation(s): Fox Chase Chemical Diversity Center, Doylestown PA, USA, Fox Chase Chemical Diversity Center, Doylestown PA, USA, NewMed, Wayne PA, USA, Fox Chase Chemical Diversity Center, Doylestown PA, USA, University of California, San Francisco CA, USA, Fox Chase Chemical Diversity Center, Doylestown PA, USA, Fox Chase Chemical Diversity Center, Doylestown PA, USA, Fox Chase Chemical Diversity Center, Doylestown PA, USA, Fox Chase Chemical Diversity Center, Doylestown PA, USA, Fox Chase Chemical Diversity Center, Doylestown PA, USA
Session: EV06 Antimicrobials: new antimicrobials
Date: Saturday - April 25, 2015 08:00 - 18:00
Location: ePoster Area
Subtopic: Antimicrobials: new antimicrobials
Topic: ePoster Viewing

Objective

Brilacidin, a synthetic mimic of Host Defence Proteins (HDP), is a promising immunomodulatory compound with both immunomodulatory and antimicrobial properties that possesses clinical potential beyond the treatment of antibiotic-resistant infections. Non-peptide HDP mimics were designed which maintain the structural and biological properties of HDPs and have improved pharmacological properties. HDPs are short cationic molecules produced by most multicellular organisms and serve as the first line of defence against microbial infection. HDPs have immunomodulatory functions, as well as antimicrobial activity, that can target both inflammatory diseases and multi-antibiotic-resistant infections. Cellceutix's leading HDP mimetic, brilacidin, is undergoing clinical evaluation as an immunomodulator (Phase 2 trial for Oral Mucositis) and as an anti-microbial agent (Phase 3 trial for Acute Bacterial Skin and Skin Structure Infection [ABSSSI]).

Methods

In vivo efficacy was assessed using acute and fractionated radiation-induced oral mucositis (OM) models in hamsters. Brilacidin was applied topically 3 times daily at 1, 3 or 10 mg/ml over 28 days, following a single 40 Gy radiation dose to the buccal cheek pouch. The brilacidin topical dose with fractionated radiation (7.5 Gy/day, 8 times over 10 days) was 3 mg/ml, 3 times daily over 35 days. OM was scored clinically. Anti-bacterial activity was assessed by the microbroth dilution assay, recommended by the Clinical and Laboratory Standards Institute, for determining in vitro antimicrobial activity.

Results


In the acute OM model, brilacidin reduced the number of animal days with ulceration from 43% in vehicle-treated hamsters to <5% (?2 test p<0.001). In the fractionated model, brilacidin significantly reduced the daily mucositis scores (Mann-Whitney Rank-Sum analysis, p<0.001) and reduced the number of animal-days with ulceration from 55% in vehicle-treated hamsters to 3.3% in brilacidin treated animals (?2 test p<0.001).

Brilacidin also demonstrated potent anti-bacterial activity against both Gram-positive and Gram-negative bacteria. Brilacidin was effective against Staphylococci (MIC90 1 µg/mL) and maintained a consistent activity profile against methicillin-resistant isolates relative to methicillin susceptible isolates. Among Gram-negative isolates, brilacidin was more potent against Enterobacter cloacae and Citrobacter spp. (MIC90 4 µg/mL) than Pseudomonas aeruginosa and Acinetobacter spp. (MIC90 16 µg/mL). Overall, brilacidin was potent against staphylococci and other gram-positive cocci including beta-hemolytic streptococci and Enterococcus faecium.

Conclusion
Oral ulcerative mucositis is a common, painful, dose-limiting toxicity of cancer therapy with minimal treatment options. The well-tolerated and efficacious HDP mimetic, brilacidin, in the animal model supports its further development as a topical therapeutic for OM. While we believe the efficacy in the OM model is primarily the result of brilacidin’s immunomodulatory activities, its antimicrobial function can also play a role in treating the lesions. Based on these promising studies, a Phase 2 trial in radiation induced OM is ongoing.


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Title A randomized, double-blind study comparing single-dose and short-course brilacidin to daptomycin in the treatment of acute bacterial skin & skin structure infections (ABSSSI)

Poster No: O195
Speaker: Jorgensen, Daniel
Author(s): Jorgensen Daniel M, Scott Richard W, O'Riordan William A, Tack Kenneth J
Affiliation(s): Cellceutix Corp. Beverly MA, USA, Cellceutix Corp. Beverly MA, USA, eStudySite, San Diego CA, USA, Cellceutix Corp. Beverly MA, USA
Session: OS28 New antibacterial agents - phase 2 and phase 3 clinical trials
Date: Monday - April 27, 2015 16:48 - 17:00
Location: Hall J

Background: Brilacidin (BRI), a small-molecule synthetic mimic of host defense proteins, has in vitro activity vs. multi-drug resistant Staphylococcus aureus (SA), including methicillin-resistant strains (MRSA), and Streptococcus pyogenes (SP). In a previous phase 2a study exploring multi-day dosing regimens, BRI was considered safe and efficacious, relative to daptomycin (DAP), but required dose optimization. Through PK/PD modeling, three dosing regimens were selected to optimize efficacy and minimize risk of adverse events. This phase 2b trial is the first efficacy study exploring single-dose (SD) and short-course (SC) therapy for this novel class of antibiotics, the defensin-mimetics.

Methods: Patients meeting the definition of ABSSSI were randomized 1:1:1:1 into three groups receiving BRI followed by placebo or 7d DAP. BRI groups differed in total dose (SD Low-0.6 mg/kg; SD High-0.8 mg/kg; SC 3 day-0.6 mg/kg on d1, then 0.3 mg/kg on d2 and d3). All treatment was administered via IV infusion. Assessments occurred on treatment (48-72 hours), end of treatment (d7-8), short-term follow-up (d10-14) and long-term follow-up (d21-28). The primary endpoint, Early Clinical Response at 48-72 hours, was defined as: > 20% reduction in lesion size in alive patients who did not receive rescue therapy (FDA, 2013).

Results: A total of 215 patients were randomized at several U.S. sites. Analysis populations included: ITT (N=215); All Treated (N=209); Micro-ITT (N=133); Safety (N=209). Clinical response rates in the All Treated population are shown.








Study Visit

BRI SD-Low (N=53)

BRI SD-High (N=53)

BRI SC-3 day (N=53)

DAP-7 day (N=50)


48-72 hrs1 47/51 (92.2%) 46/48 (95.8%) 51/52 (98.1%) 45/48 (93.8%)
Day 7-82 45/49 (91.8%) 42/49 (85.7%) 48/52 (92.3%) 47/50 (94.0%)
Day 10-142 44/50 (88.0%) 39/47 (83.0%) 44/47 (93.6%) 46/48 (95.8%)
Day 21-282,3 42/43 (97.7%) 39/40 (97.5%) 40/42 (95.2%) 46/47 (97.9%)

1per FDA definition; 2per Investigator; 3 Day 21-28= Sustained Clinical Response

Efficacy results were similar in the other analysis populations. The most common isolated pathogen was SA, including MRSA. Numbness/tingling (N/T) was the most frequently reported adverse event (AE), occurring in 58.5%, 62.3%, 73.6%, and 8.0%, respectively, in the SD-Low, SD-High, SC-3day and DAP groups. These events were transient, mild, and did not lead to any discontinuations. Excluding N/T, related AE rates were lower across all groups (SD-Low-7.5%, SD-High-7.5%, SC-3day-15.1%, DAP-26.0%). There were no deaths and no treatment-related Serious Adverse Events

Conclusions: Clinical efficacy was high across all BRI treatment groups, including the two single-dose regimens, and similar to the active control, DAP. BRI was safe and well tolerated. As the first-ever defensin-mimetic to advance through phase 2, BRI may be a promising alternative to other ABSSSI compounds. A phase 3 program is planned, using a single-dose regimen.

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Title Synthetic novel host defense protein mimetics for the treatment of Gram-negative bacterial infections

Poster No: O082
Speaker: Ram, Siya
Author(s): Ram Siya, Menon Krishna, Scott Richard W., Weaver Damian, Freeman Katie B., Tew Gregory N., Weiss William, DeGrado William F., Chafai-Fadela Karima, Kumar Ashok, Brennan David, Holden Sylvia A.
Affiliation(s): Cellceutix Corporation, Beverly MA, USA, Cellceutix Corporation, Beverly MA, USA, Cellceutix Corporation, Beverly MA, USA, Cellceutix Corporation, Beverly MA, USA, Cellceutix Corporation, Beverly MA, USA, University of Massachusetts, Amherst MA, USA, Cellceutix Corporation, Beverly MA, USA, University of California at San Francisco, San Francisco CA, USA, Cellceutix Corporation, Beverly MA, USA, Cellceutix Corporation, Beverly MA, USA, Cellceutix Corporation, Beverly MA, USA, Cellceutix Corporation, Beverly MA, USA
Session: OS11 Drug discovery
Date: Sunday - April 26, 2015 14:42 - 14:54
Location: Hall C

Objectives:

Synthetic Host Defense Protein mimetics are being developed by Cellceutix for treating Gram-negative organisms. The innate immune system is the first line of defense against microbial infection, and a significant part of this system consists of the activities of Host Defense peptides. These naturally producing antimicrobial peptides directly disrupt bacterial cell membranes. At Cellceutix, synthetic Host Defense Proteins (HDP) mimetics are being explored as a new class of antimicrobial agents, which are less likely to develop resistance. Brilacidin has emerged as a novel small molecule for the treatment of bacterial infections. A successful Phase IIb clinical trial for ABSSSI has been completed and a Phase III application will be submitted.

Methods:

A library of approximately 1800 compounds in 12 distinct chemical classes has been developed. Antimicrobial activity was assessed by the standard microbroth dilution assay. In vivo efficacy was evaluated in neutropenic mice inoculated in their thigh muscle with K. pneumoniae 13883 (4.9 log10 CFUs/thigh).

Results:

Antimicrobial biological screening of this library identified compounds with broad or narrow-spectra of activity, which are being optimized for different pathogens, including Gram (-) and Gram (+) bacteria, fungi and other pathogens. CC-1278, CC-1741 and CC-1807 were active against Gram (-) organisms, specifically K. pneumoniae and its multi-drug-resistant (MDR) isolates, and retained activity in the presence of mouse serum (Table 1). These leads also possess low mammalian cell cytotoxicity (EC50, µM) against HepG2 and NIH3T3 cells; CC-1278 (192 & >1000), CC-1741 (463 & 697) and CC-1807 (181 & 472), respectively. The in vitro profile and PK data encouraged us to further evaluate these leads for their efficacy against the Gram (-) pathogens, E.coli and K. pneumoniae in a mouse thigh burden model. At 24 h post infection, CC-1807 showed a superior reduction of bacterial burden (-5.21 log10 CFUs) than meropenem (-3.05 log10 CFUs) at dose 32 mg/kg and 25 mg/kg, respectively.

Table 1: MIC Profiles







MIC(µg/ml)
Bacterial strains CC-1278 CC-1741 CC-1807
E.coli 25922 0.78 0.78 0.39
EC + 40% mouse serum 12.5 3.13 0.78
K. pneumonia 13883 0.78 0.2 0.39
K. pneumonia + 40% mouse serum 12.5 6.26 1.56
MDR Kpn UNT180-1-MHB 4 2 2
UNT180-1-MHB + 40% mouse serum 16 2 2
MDR Kpn UNT127-1-MHB >16 4 1
UNT127-1-MHB + 40% mouse serum 2 4 4

Conclusion:

These lead compounds can be easily synthesized from commercially available starting materials using standard synthetic methodologies. Results from the above studies suggest that CC-1807 may be a potential candidate for the treatment of K. pneumoniae and other Gram (-) bacterial infections.




Quote:
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Brilacidin Abstracts; Don't forget about the time difference. Denmark is 6 hours ahead. smile

Abstracts will be visible starting 15 April 2015

Brilacidin, host defence peptide mimetic, one of a new class of immunomodulatory agents that can target multiple disease indications

http://eccmid.meetingexpert.net/ECCMID_546/poster_124310/program.aspx




A randomized, double-blind study comparing single-dose and short-course brilacidin to daptomycin in the treatment of acute bacterial skin & skin structure infections (ABSSSI)

http://eccmid.meetingexpert.net/ECCMID_546/poster_122533/program.aspx/anchor122533

Synthetic novel host defense protein mimetics for the treatment of Gram-negative bacterial infections

http://eccmid.meetingexpert.net/ECCMID_546/poster_122353/program.aspx
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