At around this time (July 2015), Cellceutix is expected 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. It has great activity against Staph aureus and other Gram-positive pathogen (usually MIC90 ≤1 µg/mL) and has some very favorable characteristics. 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 Phase 2 program consisting of 2 (sic!) dose-finding programs in ABSSSI patients.
Here some details which were not easy to piece together as full-fledged publications for brilacidin studies are unavailable: 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:
Phase 2a:
Brilacidin arms[1]:
0.4 mg/kg on Day 1, then 0.30 mg/kg qd x 4 Days;
0.75 mg/kg on Day 1, then 0.35 mg/kg qd x 4 Days;
1.0 mg/kg on Day 1, then 0.35 mg/kg qd x 4 Days;
Comparator arm: Daptomycin: 4 mg/kg IV qd x 7 Days
In this trial, significant blood pressure changes were noted, with systolic spikes >180 mmHg in 6 brilacidin recipients. While efficacy was shown similar to daptomycin, the doses selected were clearly too high and proved toxic. Based on PK/PD modeling, lower and less frequent dosing was used in the subsequent study:
Phase 2b:
Brilacidin arms:
0.6 mg/kg single dose;
0.8 mg/kg single-dose;
0.6mg/kg Brilacidin IV on Day 1, then 0.3mg/kg Brilacidin IV on Days 2 and 3;
Comparator arm: Daptomycin: 4 mg/kg IV qd x 7 Days
The company informs us that the single dose brilacidin regimen was numerically non-inferior to the daptomycin comparator regimen administered for 7 days.[2] This is not all that surprising given brilacidin’s long half-life (approx. 20 hrs) and should be good news for the company. But how about the AE profile?
A total of 6 (six!) brilacidin dosing regimens were tested in Phase 2
Good news here too: At the lowest dose level (0.6 mg/kg single dose), very few cases of hypertension were seen. 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.
There were 4 SAEs in the brilacidin arms, all related to ‘cellulitis’, none in the daptomycin group. 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.
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. The syndrome has been described as “paresthesias, 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)”; the company refers to it as an ‘ion channel effect’ of short duration and reversible. [3]
In the context of the blood pressure changes observed in Phases 1 and 2, this ‘ion channel effect’ may be anything but trivial. Electrophysiologic studies on human cell lines published in abstract form found that even low concentrations of brilacidin (1µM) block ion channels to a significant degree: 43.2% (ASIC1a), 56.3% (hNav1.7) and 45.8% (hKv1.6).[4] In 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 hypertension, numbness and paresthesia seem to be caused by inhibition of Na, K and other ion channels
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 [5]. 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. Even if it is a QIDP drug.
Clearly, a Thorough QT study with brilacidin showing no major QTc prolongation would go a long way to set everyone at ease. Such a study has not been done yet. However, 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.
What do we really know about brilacidin / PMX-30063? Given the dearth of published information, and the total lack of peer-reviewed publications, the answer is: Really not much. Abstracts and presentations by PolyMedix and Cellceutix, the new owner of brilacidin, from various conferences are uniformly selective, redacted and incomplete. [6,7],
We look forward to the next press release from Cellceutix detailing the outcome of their FDA interaction and plans for Phase 3.
PS: Immunomodulatory and anti-biofilm effects were not substantiated in the clinical study program as of yet.
ABSSSI acute bacterial skin/skin structure infections
References:
[1] http://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
[2] http://finance.yahoo.com/news/cellceutix-provides-uplist-application-115823200.html
[3] http://www.thefreelibrary.com/PolyMedix+Announces+Positive+Phase+I+Clinical+Data+with+PMX-30063…-a0190569376
[4] http://registration.akm.ch/einsicht.php?XNABSTRACT_ID=128728&XNSPRACHE_ID=2&XNKONGRESS_ID=136&XNMASKEN_ID=900
[5] http://www.alomone.com/p/anti-kv1.6/apc-003/55
[6] 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
[7] 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
Please review this paragraph:
“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. The syndrome has been described as “paresthesias, 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)”; the company refers to it as an ‘ion channel effect’ of short duration and reversible. [3]”
The Phase 2b reference suggests that the AEs are from the Cellceutix trial while the footnote I believe correctly attributes them to Polymedix.
I know this is an old blog but people are still referring to it.
Hi Bob, just to clarify: the blog states that Polymedix’s brilacidin was taken over by Cellceutix but it does not state that “the AEs are from the Cellceutix trial”. Indeed, when the blog was written, all brilacidin news came from Polymedix press releases; hence one would reasonably assume that Polymedix was the sponsor of the Phase 2 program.
On PubMed search no publication of the Phase 2 brilacidin studies can be found. The large 215 patient trial was finished in 2014, Cellceutix (!) was listed as the sponsor of NCT02052388 in 2015. No trial results are provided on the Clinicaltrials.gov website either. It seems that Cellceutix (now called Innovation Pharmaceuticals Inc) has fallen behind in publication efforts or has lost interest in brilacidin as an anti-infective agent.
I know it’s a long time in coming but since Innovation Pharmaceuticals has now published the results of the Oral Rinse trial…https://clinicaltrials.gov/ct2/show/results/NCT02324335?term=brilacidin&draw=2&rank=1
I wonder if you have anything to add and whether you still feel that the Company has lost interest in brilacidin as an anti-infective agent.
The blog was very helpful.