{"id":1693,"date":"2015-07-10T07:12:57","date_gmt":"2015-07-10T11:12:57","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1693"},"modified":"2015-10-07T03:34:46","modified_gmt":"2015-10-07T07:34:46","slug":"brilacidin-qidp-drug-at-a-critical-juncture","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/07\/10\/1693\/brilacidin-qidp-drug-at-a-critical-juncture\/","title":{"rendered":"Brilacidin – QIDP Drug At a Critical Juncture"},"content":{"rendered":"

\"brilacidin<\/a>
\n<\/a>At around this time (July 2015), Cellceutix is\u00a0expected to hammer out a Phase 3 program for brilacidin, its defensin-mimetic and host-defense protein (HDP) mimic structurally similar to magainin, with FDA.<\/p>\n

Brilacidin is certainly an interesting novel compound, coming from a new class, with a unique mode of action.\u00a0 It has great activity against Staph aureus and other Gram-positive pathogen (usually MIC90<\/sub>\u00a0\u22641 \u00b5g\/mL) and has some very favorable characteristics.\u00a0 Nonetheless, it had a difficult clinical gestation period. In the hands of PolyMedix, its prior owner, a standard Phase 1 was executed followed by a very large\u00a0Phase 2 program consisting of 2 (sic!) dose-finding programs in ABSSSI patients.<\/p>\n

Here some details which were not easy to piece together as full-fledged publications for brilacidin studies are unavailable:\u00a0 Either Phase 2 trial enrolled 215 patients and had a 4-arm parallel design comparing 3 brilacidin dose regimens against daptomycin. Between the 2 trials, a total of 6 different dosing regimens of brilacidin were tested:\"brilacidin\"<\/a><\/p>\n

Phase 2a:<\/u>
\nBrilacidin arms<\/strong>[1]<\/sup><\/a>:
\n0.4 mg\/kg on Day 1, then 0.30 mg\/kg qd x 4 Days;
\n0.75 mg\/kg on Day 1, then 0.35 mg\/kg qd x 4 Days;
\n1.0 mg\/kg on Day 1, then 0.35 mg\/kg qd x 4 Days;
\nComparator arm<\/strong>:\u00a0 Daptomycin: 4 mg\/kg IV qd x 7 Days<\/p>\n

In this trial, significant blood pressure changes were noted, with systolic spikes >180 mmHg in 6 brilacidin recipients.\u00a0 While efficacy was shown similar to daptomycin, the doses selected were clearly\u00a0too high and proved toxic. Based on PK\/PD modeling, lower and less frequent dosing was used in the subsequent study:<\/p>\n

Phase 2b:<\/u>
\nBrilacidin arms<\/strong>:
\n0.6 mg\/kg single dose;
\n0.8 mg\/kg single-dose;
\n0.6mg\/kg Brilacidin IV on Day 1, then 0.3mg\/kg Brilacidin IV on Days 2 and 3;
\nComparator arm<\/strong>:\u00a0 Daptomycin: 4 mg\/kg IV qd x 7 Days<\/p>\n

The company informs us that the single dose brilacidin regimen was numerically non-inferior to the daptomycin comparator regimen administered for 7 days.[2]<\/a>\u00a0 This is not all that surprising given brilacidin\u2019s long half-life (approx. 20 hrs) and should be good news for the company.\u00a0 But how about the AE profile?

A\u00a0total of 6 (six!) brilacidin dosing regimens were tested in Phase 2<\/span><\/p>\n<\/div><\/p>\n

Good news here too: At the lowest dose level (0.6 mg\/kg\u00a0single dose), very few cases of hypertension were seen.\u00a0 However, there was a steep dose response as both higher dose arms were clearly associated with hypertensive events, much more so than in the daptomycin arm.<\/p>\n

There were 4 SAEs in the brilacidin arms, all related to \u2018cellulitis\u2019, none in the daptomycin group.\u00a0 It is hard to evaluate these cases without the benefit of full clinical information but by protocol definition these outcomes qualify as clinical failures and as such are probably already captured in the efficacy assessments.<\/p>\n

More important and of concern is the fact that numbness and tingling are still extremely frequent AEs (58-74%) in the Phase 2b trial despite the dose reduction.\u00a0 The syndrome has been described as \u201cparesthesias, usually beginning in the oral area, and often with subsequent extension to one or more of the following areas: face, scalp, extremities, upper thorax, and\/or perineum (groin and buttocks)\u201d; the company refers to it as an \u2018ion channel effect\u2019 of short duration and reversible. [3]<\/a><\/p>\n

In the context of the blood pressure changes observed in Phases 1 and 2, this \u2018ion channel effect\u2019 may be anything but trivial.\u00a0 Electrophysiologic studies on human cell lines published in abstract form found that even low concentrations of brilacidin (1\u00b5M) block ion channels to a significant degree: 43.2% (ASIC1a), 56.3% (hNav1.7) and 45.8% (hKv1.6).[4]<\/a>\u00a0 \u00a0In case you are interested, ASIC1a stands for acid-sensing ion channel, and hNav1.7 and hKv1.for the sodium and the potassium channel, respectively.

Adverse Events like\u00a0hypertension, numbness and paresthesia seem to be caused by inhibition of Na, K and other ion\u00a0channels <\/span><\/p>\n<\/div><\/p>\n

This Kv1.6 channel is expressed not only in neurons, but also in cardiac and other muscle tissue where it affects membrane potential and cellular response to stimuli\u00a0[5]<\/a>.\u00a0 While ion-channel blockers are an area of considerable interest for drug therapy, we are not convinced such off-target effects are desirable for an antibiotic.\u00a0 Even if it is a QIDP drug.<\/p>\n

Clearly, a Thorough QT study with brilacidin showing no major QTc prolongation would go a long way to set everyone at ease.\u00a0 Such a study has not been done yet. \u00a0However, we were surprised to find a trial of brilacidin ORAL RINSE listed on clinicaltrials.gov. Interestingly, patients with EKG abnormalities, hypertension, and QT prolongation are specifically excluded from participation in this trial, although brilacidin is only given topically.<\/p>\n

What do we really know about brilacidin \/ PMX-30063?\u00a0 Given the dearth of published information, and the total lack of peer-reviewed publications, \u00a0the answer is: Really not much.\u00a0 Abstracts and presentations by PolyMedix and Cellceutix, the new owner of brilacidin, from various conferences are uniformly selective, redacted\u00a0and incomplete. [6,7]<\/a>,\u00a0<\/span><\/p>\n

We look forward to the next press release from Cellceutix detailing the outcome of their FDA interaction and plans for Phase 3.<\/p>\n

\n

PS: \u00a0Immunomodulatory and anti-biofilm effects were not substantiated in the clinical study program as of yet.<\/p>\n

ABSSSI \u00a0 acute bacterial skin\/skin structure infections<\/p>\n

References:
\n<\/strong>[1]<\/a>\u00a0http:\/\/globenewswire.com\/news-release\/2012\/04\/23\/473929\/252858\/en\/PolyMedix-Announces-Positive-Results-From-Phase-2-Clinical-Trial-With-PMX-30063-First-in-Class-Defensin-Mimetic-Antibiotic.html
\n[2]<\/a> http:\/\/finance.yahoo.com\/news\/cellceutix-provides-uplist-application-115823200.html
\n[3]<\/a> http:\/\/www.thefreelibrary.com\/PolyMedix+Announces+Positive+Phase+I+Clinical+Data+with+PMX-30063…-a0190569376
\n[4]<\/a> http:\/\/registration.akm.ch\/einsicht.php?XNABSTRACT_ID=128728&XNSPRACHE_ID=2&XNKONGRESS_ID=136&XNMASKEN_ID=900
\n[5]<\/a> http:\/\/www.alomone.com\/p\/anti-kv1.6\/apc-003\/55
\n[6]<\/a> http:\/\/eccmidlive.org\/resources\/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–2
\n[7]<\/a> http:\/\/cellceutix.com\/wp-content\/uploads\/2014\/06\/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.pdf<\/p>\n","protected":false},"excerpt":{"rendered":"

At around this time (July 2015), Cellceutix is\u00a0expected to hammer out a Phase 3 program for brilacidin, its defensin-mimetic and host-defense protein (HDP) mimic structurally similar to magainin, with FDA. Brilacidin is certainly an interesting novel compound, coming from a new class, with a unique mode of action.\u00a0 It has Continue reading Brilacidin – QIDP Drug At a Critical Juncture<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1713,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[19,227,3,18],"tags":[360,1130,403,1136,874,876,56,229,228,875,428,1137,1138,5,1134,1131,1133,1129,1132,39,1127,1128,1371,222,1135],"class_list":["post-1693","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-recent_literature","category-the_news","category-the_viewpoint","tag-adverse-events","tag-anti-biofilm","tag-antibiotic-blog","tag-arrhythmia","tag-brilacidin","tag-cellceutix","tag-clinicaltrials-gov","tag-cubicin","tag-daptomycin","tag-defensin-mimetic","tag-dose-finding","tag-ekg-abnormalities","tag-electrophysiology","tag-fda","tag-hypertension","tag-immunomodulator","tag-ion-channel-blocker","tag-magainin","tag-paresthesia","tag-pkpd","tag-pmx-30083","tag-polymedix","tag-qidp","tag-qt-prolongation","tag-thorough-qtc-study"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/brilacidin-slider2-copy1.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-rj","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":1028,"url":"https:\/\/allphasepharma.com\/dir\/2014\/10\/05\/1028\/qidp-drugs-here-they-are-all-of-them\/","url_meta":{"origin":1693,"position":0},"title":"QIDP Drugs: Here They Are, All of Them","author":"Harald","date":"October 5, 2014","format":false,"excerpt":"For the latest QIDP listing, please click HERE As of Oct. 9, 2014, there were by my accounting 30 compounds with QIDP designation. 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