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I had to laugh when you posted the CDYD volume chart; since it is down about 50% from its high YTD. Most of the volume spike was bailing out after its catastrophic FDA Covid study.
You are trying too hard. We will find out what the truth is when the Brilacidin for Covid trial is soon completed.
Good luck,relax and be happy,
Farrell
I disagree, the IBD trial has the potential to be very successful.
The early trials have been successful and it is a unique treatment with a very large market. See CallmeCrazy's post353005
Ipix rightfully postponed it due to Covid16, but it will be restarted soon. IPIX has the funds to begin the first phase 2 trials of oral Brilacidin for Ulcerative Colitis and we will see that whether Brilacidin is successful against Covid19 or not.
Another point is clear to those paying attention; Leo's frugal management is the only reason we may benefit from Brilacin for Covid19 and IBD.
JMO, Farrell
BTW ... The capitalization key is on the left side of the keyboard.
Great post.
I agree IPIX prioritized Brilacidin for Covid19. As you pointed out with the market size as well as the critical need for a good anti Covid antiviral plus the outstanding pre clinical studies it is the right path for the company.
Glta,Farrell
IPIX first announced the pancoronavirus research in 06/2020:
"Innovation Pharmaceuticals (OTCQB:IPIX) (“the Company”), a clinical stage biopharmaceutical company, announces today the Company and researchers at a U.S. Regional Biocontainment Laboratory (RBL) are collaborating on a federal grant application to be submitted this week"
"The proposed research aims to evaluate Brilacidin as a potential pan-coronavirus therapeutic, for treating SARS-CoV-2, SARS-CoV-1 and MERS-CoV, including extending the current in vitro testing of Brilacidin to in vivo testing. Longer-term objectives include potentially performing additional research to develop Brilacidin as a broad-spectrum antiviral, with possible application beyond coronaviruses, e.g., treating other viruses, such as encephalitic alphaviruses and filoviruses."
"The ongoing Brilacidin anti-SARS-CoV-2 research being conducted at the RBL is separate from the ongoing research being performed at a Public Health Research Institute (PHRI). The lead researchers at both the RBL and at the PHRI have informed the Company they plan to submit their findings, separately, upon completion of in vitro testing, for peer-review publication."
WAKEFIELD, Mass., Nov. 30, 2020 (GLOBE NEWSWIRE) -- Innovation Pharmaceuticals (OTCQB:IPIX) (“the Company”), a clinical stage biopharmaceutical company, today announces additional independent preliminary laboratory research suggests Brilacidin, the Company’s flagship defensin mimetic, has the potential to treat other endemic human coronaviruses (H-CoVs), such as those causing common colds, and not just SARS-CoV-2, the novel coronavirus responsible for the ongoing global COVID-19 pandemic.
Research shows Brilacidin exerted potent in vitro inhibition of multiple strains of H-CoVs. On completion of testing, the H-CoV findings are expected to be submitted for peer-review publication. The Company is evaluating these data alongside previously obtained SARS-CoV-2 data, strategizing with its scientific advisors and consultants, to develop Brilacidin as a “pan-coronavirus” therapeutic...
The Company is planning to conduct additional in vitro and in vivo Brilacidin studies on multiple coronaviruses, to further inform the drug’s anti-coronavirus properties and prepare for potential future clinical testing.
My guess is this in vitro studies should be done soon. The in vivo animal studies may take longer. I would expect the labs would also be studying the coronavirus mutations. I am looking forward to seeing another Brilacidin publication.
GLTA'
Farrell
https://www.globenewswire.com/news-release/2020/11/30/2136611/0/en/Innovation-Pharmaceuticals-COVID-19-Clinical-Trial-to-Support-Additional-Development-of-Brilacidin-as-a-Pan-Coronavirus-Therapeutic.html
https://www.globenewswire.com/news-release/2020/06/11/2046799/0/en/Innovation-Pharmaceuticals-Collaborating-with-Regional-Biocontainment-Lab-on-Grant-Application-to-Research-Brilacidin-as-a-Pan-Coronavirus-Therapeutic.html
If I am seriously ill with Covid19 and go elsewhere there is almost a 100% chance of receiving Remdesivir which has been shown to have next to no effect on mortality or Covid complications.
Plus, we know Rememdesivir has been shown to have the potential to have hepatotoxicity since the current dose is close to the safe theraputic index...a ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective.
The hepatotoxicity was first described in the Ebola studies and is now being reported in Covid 19 patients being treated with Remdesivir.
Below are several recent reports of Covid19 patients suffering liver damage due to Remdesivir.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386240/
"Our observation supports previous findings obtained in healthy volunteers (Gilead Sciences, data on file) and COVID-19 patients treated with RDV [4, 5], suggesting this antiviral may cause hepatocellular injury."
In addition Remdesivir has many drug interactions which can limit treatment of other life threatening conditions:
https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa883/5864408
https://www.uptodate.com/contents/image/print?imageKey=EM%2F73326&topicKey=RHEUM%2F1666&source=see_link
Your contention that Brilacidin may have "known Serious Adverse Events" pales to the risk of Remdesivir. If a patients on Brilacidins blood pressure increases it is easily treatable and serious elevations of blood pressure were not demonstrated at the Brilacidin.6mg/kg dose. The tingling sensation has not been shown to be associated with neurologic or other long term complications.
The real question is would you rather have a drug with the potential to have profound effect against the Covid19 or a drug we know has little effect.
I will stand by my post.
My bet is after Brilacidins Phase2 trial there will be many requests across the country for compassionate use of Brilacidin for Covid 19 for the reasons I have outlined.
GLTA Farrell
A few points are undeniable:
-oil price is trending up
-demand for oil is up
-value of oil reserves is up
-ERHC's volume is up
-ERHC's share price is up
Even hedge funds are investing in oil:
https://www.reuters.com/article/us-global-oil-hedgefunds-focus-idUSKBN2A70IM
Good luck,
Farrell
If I get Covid19, I am heading to DuPage co NorthWestern hospital ASAP. I had some family that lived in Carol Stream, but they moved some time ago. I have visited there a number of times, but never to the hospital.
Keep your eyes and ears open.
Good luck to all,
Farrell
Inching up at close ??? may be green today.
GLTA, Farrell
The Northwestern hospital system is participating in a number of Covid 19 studies, but the webpage has not been updated yet to include Brilacidin for Covid19 at the west NW hospital.
Brilacidin continues to progress!
https://www.feinberg.northwestern.edu/sites/covid-19/covid-19-clinical-trials.html
Here is the hospital in the western Chicago suburbs:
https://www.nm.org/locations/central-dupage-hospital?utm_source=yext&utm_medium=gmb+location&utm_campaign=online+listings&y_source=1_ODIyOTgyMi03MTUtbG9jYXRpb24uZ29vZ2xlX3dlYnNpdGVfb3ZlcnJpZGU%3D
Good luck to all,
Farrell
You sound concerned; as if IPIX will not be fairly rewarded if the clinical trial is a big success.
Many would agree an excellent treatment for Covid19 is virtually impossible to value, in fact invaluable.
Earlier you threw $50 million; which is absolutely laughable.
The only context we have is the 1.9 billion Remdesivir brought in last quarter.
If Brilacidin proves to be safe and effective it will make more than Remdesivir.
JMO
GLTA,Farrell
PS do the math...it is astounding
One of the reason health care workers are refusing the vaccine is many have already had Covid 19. They feel they have developed immunity and feel vaccination is unnecessary. I have heard of hospitals where as many as 70% of the interns and resident doctors have already contracted Covid19 and 35-40% of the nurses.
https://khn.org/news/nurses-and-doctors-sick-with-covid-feel-pressured-to-get-back-to-work/
http://publichealth.lacounty.gov/acd/docs/COVID19HCWReport.pdf
GLTA Farrell
Good post.
I am trying to think of something to add to your post and this thread, but the subject seems to have been beaten to death this morning. With that background I think the most constructive point I can make is I am looking forward to seeing positive posts regarding IPIX, Brilacidin and the clinical trials.
GLTA,Farrell
If the phase 2 trials are positive you can expect an expanded compassionate use to be granted like it was for Remdesivir after their phase 2 trial. Many sick Covid patients are still not responding well to current standard of care.
Glta,
Farrell
One fact is undeniable, every dollar the price of oil increases the value of Erhc assets in the EEZ and JDZ . Most analysis are expecting $80 oil in a few mos as the demand continues to rise.
Glta, Farrell
Commanders Palace is one of our favorites. Great food followed by a nice walk on Magazine st and the Garden district. Enjoy
Controversy regarding Molnupiravir formerly EIDD-2801 now MK-4482
continues:
"This brings us to the controversy around the drug as explained by C&EN (emphasis ours):
" EIDD-2801 has been viewed as a potential competitor to remdesivir, although a contentious one, because similar compounds are mutagenic in animal studies, meaning they produce birth defects. Rick Bright, who was removed from his position as head of the US Biomedical Advanced Research and Development Authority (BARDA) in April, was reluctant to provide funding for the drug for this reason, according to an 89-page whistleblower complaint Bright filed after being fired. Merck’s investment in EIDD-2801 can be seen as a vote of confidence in the compound.
Bright’s concerns began in November 2019, more than one month before China disclosed the first COVID-19 cases in Wuhan — ScienceMag has that story:
Raymond Schinazi, an Emory University chemist who has extensively studied the active ingredient in EIDD-2801 but has no connection to DRIVE, notes that his former pharmaceutical company, Pharmasset, abandoned it in 2003 after discovering its mutagenic properties. Schinazi says the small chemical tweaks made to increase the ingredient’s bioavailability and transform it into EIDD-2801 are unlikely to change its mutagenicity. “Thank goodness someone is raising the red flag,” about EIDD-2801, Schinazi says. “You don’t develop a drug that’s mutagenic. Period.”
" Merck’s Research Labs President Roger Perlmutter addressed the lingering questions about the drug’s mutagenic side-effects during the earnings call and explained what the company is doing to address safety concerns, a transcript of which is available at this link.
First of all, for the MK-4482, as you know, the compound is Ames positive. That’s, in a way, not unexpected given its mechanism of action. It is a cytosine analog so that — one could expect to see those kinds of things. The question is, does the compound have mutagenic activity that’s meaningful in mammalian cells and what do we want to do about this. Ordinarily, of course, we don’t want to take mutagens forward into clinical practice, although it has been done where the benefit/risk profile makes sense"
What does it mean to be Ames positive?:
The Ames test is a widely employed method... it is a biological assay to assess the mutagenic potential of chemical compounds.[1] A positive test indicates that the chemical is mutagenic and therefore may act as a carcinogen, because cancer is often linked to mutation. The test serves as a quick and convenient assay to estimate the carcinogenic potential of a compound...
THe positive Ames test and documented birth defects in similar compounds as document by Dr Bright must be thoroughly addressed.
GLTA, Farrell
https://bgr.com/2020/07/31/coronavirus-cure-merck-mk-4482-eidd-2801-rick-bright-controversy/
https://en.wikipedia.org/wiki/Ames_test
Wow what a list. That's a Roladex of Phds It is helplful to have friends in high places.
Go IPIX!
GLTA,Farrell
Strong close on good volume bodes well for the rest of the week.
GTA,Farrell
It is important to remember that many mild BP elevations do not require treatment and the higher levels can be treated easily.
Hypertension was addressed in the Brilacidin clinical trial eligibility criteria:
"-Hypertensive urgency (e.g., SBP >220 mmHg or DBP >120 mmHg) or hypertensive emergency within the last 72 hours, as assessed by the investigator following local guidelines.
-If has a history of hypertension in the last 3 months, must have been receiving appropriate anti-hypertensive therapy in accordance with local guidelines."
GLTA,
Farrell
It has been my observation the hedge fund managers are never shy.
Of course, it reflected badly on him and Ridgeback when Dr Bright stood up to him when his political contacts tried to help him score funds from Barda.
Even though Merck bought a position in Ridgeback, it is Ridgeback controlling the phase 1 and 2 trials, not Merck. How much credibility does Ridgeback have?
Stuart Varney"s and Dr Siegel"s phones must be ringing constantly to tell them the rest of the story. Mr Hedge fund has made a lot of enemies.
Remember. Dr Rick Bright is now on the Biden Coronavirus Advisory Committee
The other point is Dr Rick Bright spent several years early in his career at Emory then the CDC which works closely with Emory. I doubt many at Emory were happy to see Molnupiravir sold to a hedge fund.
Which brings up the question,why the hell would they do that?
The truth is often stranger than fiction.
GLTA Farrell
I have a better question. The oil bull market is on the up slope.
Many credible sources are projecting $80 a barrel oil by this summer.
When is ERHE going to participate?
ERHE's JDZ assets are increasing in value daily. Is anyone home to answer the phone?
Best wishes to all,
Farrell
Love the FDA pictures. Reminiscent of Sienfeld's Kramer going to the taking vet medicine for a cough.
Who said the stiffs at the FDA had no sense of humor?
https://www.google.com/search?client=firefox-b-1-d&q=you+tube+Kramer+taking+vet+medicine
GLTA, Farrell
Additional background about Molnupiravir:
- its mechanism of action is similar to Remdesivir and Favipiravir as a nucleoside analogue
- it has only completed a phase 1 study in healthy volunteers
- its large phase 2 trials are still recruiting patients
-it is was purchased from Emory University by a hedge fund
- the hedge fund owner,Rick Holman, is listed as an author of the Phase 1 study publication
-The hedge fund company's Ridgeback Biotherapeutics has been accused of improper influence in seeking Barda funds
-Former Barda chief Dr Rick Bright stated, "similar experimental drugs in this class had been shown to cause reproductive toxicity in animals, and offspring from treated animals had been born without teeth and without parts of their skulls."
-Bright also stated,"illegally retaliated against him for objecting to what he saw as improper and unscientific efforts to steer taxpayer dollars to certain firms run by "cronies" or "for political purposes"
-in the end Dr Bright filed a whistleblower lawsuit which result in his removal from Barda.
- Dr Rick Bright is now a Biden Transition COVID-19 Advisory Board member
-Ridgeback has licensed Molnupipiravir to Merck,but still has a substantial interest in the drug including being responsible for the Phase 1 and 2 clinical trials.
"Ridgeback will continue to fund and conduct multiple Ridgeback-sponsored Phase 1 and 2 trials and fund manufacturing campaigns for clinical supply. Going forward, the parties will collaborate on clinical development for COVID-19 and manufacturing..."
https://www.businesswire.com/news/home/20200701005928/en/Merck-and-Ridgeback-Bio-Announce-Closing-of-Collaboration-and-Licensing-Transaction
From Wikipedia
"In his complaint, Bright also noted the dangers in pursuing EIDD-2801, an oral antiviral candidate previously supported by NIAID led by Dr. Anthony Fauci and DOD...In February, 2021, Bright co-authored an opinion editorial in the Washington Post claiming "efforts to develop a therapeutics were slow and limited.]"
https://www.businesswire.com/news/home/20200701005928/en/Merck-and-Ridgeback-Bio-Announce-Closing-of-Collaboration-and-Licensing-Transaction
https://www.washingtonpost.com/business/2020/06/11/coronavirus-drug-
ridgeback-biotherapeutics/
https://pulitzercenter.org/stories/emails-offer-look-whistleblower-charges-cronyism-behind-potential-covid-19-drug
https://aac.asm.org/content/aac/early/2021/02/24/AAC.02428-20.full.pdf
https://www.clinicaltrials.gov/ct2/results?recrs=&cond=&term=Molnupiravir&cntry=&state=&city=&dist=
https://en.wikipedia.org/wiki/Rick_Bright
Glta,Farrell
© 2021 InvestorsHub.com, Inc.
There are many things DR Siegal left out about Molnupiravir:
- its mechanism of action is similar to Remdesivir and Favipiravir as a nucleoside analogue
- it has only completed a phase 1 study in healthy volunteers
- its large phase 2 trials are still recruiting patients
-it is was purchased from Emory University by a hedge fund
- the hedge fund owner,Rick Holman, is listed as an author of the Phase 1 study publication
-The hedge fund company's Ridgeback Biotherapeutics has been accused of improper influence in seeking Barda funds
-Former Barda chief Dr Rick Bright stated, "similar experimental drugs in this class had been shown to cause reproductive toxicity in animals, and offspring from treated animals had been born without teeth and without parts of their skulls."
-Bright also stated,"illegally retaliated against him for objecting to what he saw as improper and unscientific efforts to steer taxpayer dollars to certain firms run by "cronies" or "for political purposes"
-in the end Dr Bright filed a whistleblower lawsuit which result in his removal from Barda.
- Dr Rick Bright is now a Biden Transition COVID-19 Advisory Board member
-Ridgeback has licensed Molnupipiravir to Merck,but still has a substantial interest in the drug including being responsible for the Phase 1 and 2 clinical trials.
"Ridgeback will continue to fund and conduct multiple Ridgeback-sponsored Phase 1 and 2 trials and fund manufacturing campaigns for clinical supply. Going forward, the parties will collaborate on clinical development for COVID-19 and manufacturing..."
https://www.businesswire.com/news/home/20200701005928/en/Merck-and-Ridgeback-Bio-Announce-Closing-of-Collaboration-and-Licensing-Transaction
From Wikipedia
"In his complaint, Bright also noted the dangers in pursuing EIDD-2801, an oral antiviral candidate previously supported by NIAID led by Dr. Anthony Fauci and DOD...In February, 2021, Bright co-authored an opinion editorial in the Washington Post claiming "efforts to develop a therapeutics were slow and limited.]"
https://www.businesswire.com/news/home/20200701005928/en/Merck-and-Ridgeback-Bio-Announce-Closing-of-Collaboration-and-Licensing-Transaction
https://www.washingtonpost.com/business/2020/06/11/coronavirus-drug-
ridgeback-biotherapeutics/
https://pulitzercenter.org/stories/emails-offer-look-whistleblower-charges-cronyism-behind-potential-covid-19-drug
https://aac.asm.org/content/aac/early/2021/02/24/AAC.02428-20.full.pdf
https://www.clinicaltrials.gov/ct2/results?recrs=&cond=&term=Molnupiravir&cntry=&state=&city=&dist=
https://en.wikipedia.org/wiki/Rick_Bright
Glta,Farrell
Great post.
In the NHS dexamethasone trial its anti-inflammatory effect was judged by the clinical response. Inflammatory markers are only briefly mentioned.
https://www.nejm.org/doi/full/10.1056/NEJMoa2021436
Now we have Brilacidin with 3 possible antiviral MOA's plus being a proven broad spectrum antibiotic and with anti-inflammatory properties.
It seems it would be difficult to tell which MOA was primarily improving clinical response except as you outlined by correlating the time from the first infectious symptoms and following inflammatory markers serially.
The other question I have is the 3 or 5 day dosing. Obviously the current planned dosing is for the antiviral effect. The long half life of Brilacidin will extend its biologic effects several days.
If the Brilacidin's primary MOA is anti inflammatory and not anti viral should the dosing be adjusted for that effect? In the NHS study Dexamethasone was given for up to 10 days. Will monitoring inflammatory markers as planned be helpful in adjusting the Brilacidin treatment course from 3 to 5 days?
In this short Phase 2 trial it is not likely additional adjustments will be made in the trial parameters. If the inflammatory markers show a response to Brilacidin, how would you design the Phase 3 trial?
TIA
GLTA Farrell
You are correct it is not clear. It is clear the DMC will review the results after its interim analysis safety review. So about half of the patients will receive the 3 day treatment, whatever dose that is.
The other half could receive the 3 day or the 5 day course. It is possible sub groups or even individual patients could receive different treatment lengths based on their response to treatment ,but I think that would complicate the statistical analysis and make the"quadruple blinding" more complex.
I had the same thought that it was a compromise between IPIX and the FDA.
Hopefully the interim report will be more revealing.
Good luck,Farrell
Leronlimab is an anti-inflammatory medication; its primary competitor for Covid 19 is Dexamethasone.
If Brilacidin proves to be an effective antiviral for Covid 19 its primary competitor will be Remdesivir.
Even if Leronolib becomes the primary Covid19 anti-inflammatory drug it does not, "raise the bar" for Brilacidin one millimeter.
Dexamethasone has become widely used for Covid19. It has a long history as an inexpensive synthetic corticosteroid with multiple indications.
Dexamethasone was shown to significantly reduce mortality against Covid19 in an extremely well done 11,000 patient British study published in the NEJM.
https://www.nejm.org/doi/full/10.1056/NEJMoa2021436
"Dexamethasone reduced deaths by one-third in ventilated patients and by one fifth in other patients receiving oxygen only.There was no benefit among those patients who did not require respiratory support."
https://www.gmmh.nhs.uk/download.cfm?doc=docm93jijm4n7645.pdf&ver=10221
It is Leronlimab, even with its potentially promising study, which still has a significant bar to overcome.
GLTA, Farrell
Ridgeback Biotherapeutics has an interesting as well as colorful history in its efforts to profit from Molnupiravir :
https://www.washingtonpost.com/business/2020/06/11/coronavirus-drug-
ridgeback-biotherapeutics/
https://pulitzercenter.org/stories/emails-offer-look-whistleblower-charges-cronyism-behind-potential-covid-19-drug
Molnupiravir is an oral drug with a mechanism of action similar to Remedesivir and Favipiravir. The phase 1 study is linked below:
https://aac.asm.org/content/aac/early/2021/02/24/AAC.02428-20.full.pdf
Interesting the hedge fund manager,Wayne Holman, is listed as a lead author of the Phase1 report.
Glta,Farrell
I agree since it was found to be safe in the ABSSSI trial, it makes sense to use the .6mg/kg Brilacidin dose even if it later proves to be effective at a lower dose. The lower possible dose was suggested in the RBL studies and was reported in the Virus journal article:
"Recently released in vitro data showed Brilacidin exhibited a potent inhibitory effect on SARS-CoV-2, the novel coronavirus responsible for COVID-19, in a human lung epithelial cell line—reducing viral load by 95 percent and 97 percent at two efficacious concentrations tested, compared to control (DMSO)."
"The new data, using the same assay method, reveal Brilacidin exhibited a similarly potent inhibitory effect against SARS-CoV-2 at an even lower concentration in the same human lung epithelial cell line. Brilacidin achieved approximately 90 percent inhibition of SARS-CoV-2 at a drug concentration that was one-half lower than previously tested. The lowest concentration of Brilacidin used in RBL testing to date is well below the clinically-achievable concentration based on the pharmacokinetics observed in the Company’s Phase 2b clinical trial of Brilacidin in Acute Bacterial Skin and Skin Structure Infections"
http://www.ipharminc.com/press-release/2020/7/20/innovation-pharmaceuticals-brilacidin-inhibits-novel-coronavirus-covid-19-by-almost-90-at-the-lowest-concentration-tested-to-date-in-a-human-lung-cell-line
The journal article also gave some additional information regarding Brilacidin dosing which I summarized in post 346149 It also allows comparison with Remdesivir:
The Discussion on page 10 outlines the results of the study:
1. "All experiments conducted in Vero and Calu-3 cell line models were supportive of an early inhibition exerted by brilacidin on SARS-CoV-2, indicating the drug’s impact on viral integrity. The idea that brilacidin directly interferes with the integrity of the virion is further supported by the observation that when drug treatment was limited to the virus alone (Figure 2E), with no treatment of host cells, a robust decrease of viral load was still observed in both the Washington strain and the Italian strain of SARS-CoV-2."
This is consistent with claims Brilacidin is virucidal. It quickly attacks the virus before it enters the cell.
2. "The high CC50 (a measure of cytotoxicity) and low IC50 (a measure of potency) values observed for brilacidin in Calu-3 cells—{ human lung epithelial cells}yielding a Selectivity Index (SI) for brilacidin of 426 (CC50 = 241µM/IC50 = 0.565µM)—strongly support brilacidin’s treatment potential to possibly achieve positive antiviral outcomes in humans clinical trials."
This statement reflects the low toxicity and high potency of Brilacidin against Covid 19. The high SI number supports positive outcomes in human clinical trials
3. In the combination studies Brilacidin and Remdesivir 2.5 um demonstrated synergy in vitro
https://www.mdpi.com/1999-4915/13/2/271
The reality is the 2.5 um dose is easiy achievable in vivo by Brilacidin which obtained a median C-max in the ABSSSI study of 7.67 um and is well above its IC 50 of .565um.
https://www.biorxiv.org/content/10.1101/2020.10.29.352450v1.full
Remdesivir IC 50 in vitro is .77um, but it has to enter the host cells to prevent intracellular viral reproduction. Remdesivir is a prodrug and is converted inside the cell to its active metabolite, Nuc-TP, which is estimated to have an IC 50 of 38um to 231um or 7.7um in other studies, well below that of Brilacidin's IC 50 of .565um.
Its pharmacology explains Remdesivir's poor clinical performance in spite of a relatively good in vitro IC 50.
In addition Remdesivir's hepatotoxicity limits higher dosing.
"Assuming similar distribution and accumulation ratios of remdesivir and Nuc-TP in the lung between humans and monkeys, an optimistic estimation of Nuc-TP in the human lung tissues is 2 to 3-fold higher at a steady state than that observed in the monkey lung tissues [1]. This suggests that an IV dose of 200 mg remdesivir in a human may only achieve a suboptimal concentration of active form of Nuc-TP of <?2–5 µM in the human lung tissues (TableIII). Given that the intracellular volume (0.54 l) is 46% of the total volume of the lung (1.17 l) [17], the intracellular concentration of Nuc-TP in the human lung may be only at 4–10 µM (TableIII), which may be below the estimated intracellular IC50 and IC90 of Nuc-TP. Unfortunately, systemic adverse effects such as hepatotoxicity preclude escalation of the remdesivir dose to more than 200 mg/day."
The following article demonstrates these findings in great detail.
https://link.springer.com/article/10.1208/s12248-020-00459-8
GLTA Farrell
Thanks for sharing your insight and experience.
How do you expect the SOC drugs will be used? If SOC includes Remdesivir do you expect it will be used in either the control or treatment arm?
If Redesivir is used in the treatment arm it may make it difficult to determine Brilacidin's effect in such a small trial.
In Russia it seems Favipiravir will be used as the SOC.
I was surprised the Brilacidin for Covid phase 2 clinical trial did not include any dosage information. The best guess seems to be it will follow the .6mg/kg x first day then .3mg/kg the final 2 days as in the ABSSSI trial followed by IV placebo x 3 days:
" Subjects randomized to brilacidin will receive either a single intravenous infusion (0.6 mg/kg or 0.8 mg/kg) followed by six days of once daily placebo, or a three day regimen (0.6 mg/kg on Day 1 followed by 0.3 mg/kg on Days 2 and 3) followed by 4 days of once daily placebo. Subjects randomized to daptomycin will receive 7 days of treatment. Subjects will be assessed for both clinical and microbiologic efficacy 48-72 hours after the first dose of study drug. After an assessment at Day 7-8, subjects will be again be evaluated for efficacy at Day 10-14 and via a phone contact at Day 21-28."
https://clinicaltrials.gov/ct2/show/NCT02052388
Thanks again,
Farrell
Experts fear a new surge of coronavirus infections in the US due to new mutations.
"The fear is that just as humanity appears to be finally turning the corner in the battle against the virus, the variants could give the pathogen the upper hand once again. They could trigger a new surge. And new, even more worrisome variants could emerge because the virus is still spreading so widely."
New therapeutics are more important than ever before.
GLTA,
Farrell
https://www.npr.org/sections/health-shots/2021/03/03/971327204/worried-about-coronavirus-variants-heres-what-you-need-to-know
I reviewed the Brilacidin clinical trials .gov site again this AM and found this:
"The study will start with 3 days of study drug administration. After an interim analysis safety review, by an independent Data Monitoring Committee (DMC), dosing may be extended to 5 days."
My interpretation is if the drug is working well they will maintain the 3 day dosing. If after the interim review ,which should be mid trial, they can increase the dosing to 5 days if they feel additional benefit can be safely achieved from 2 additional days of treatment.
So that answers a lot of questions. The DMC will only raise the dose for the whole trial based on the analysis at the interim review. Individual patients will not be given 2 extra days based on their individual responses.
Sorry for the oversight.
GLTA Farrell
That is a good question which brings up more questions:
What criteria will the DMC use to extend treatment, will the 5 day course be given to patients who are struggling; patients with more risk factors who are otherwise improving; will the doctors have to request the extension; how will the extension affect the data interpretation as well as the "blinding of the trial"?
Another good point: the DMC must be working around the clock in order to be able to make the call to extend a patient from 3 day to 5 day.
DMC responsibilities and meetings can vary. Below are some reviews of DMCs.
https://www.ctti-clinicaltrials.org/files/recommendations/dmc-recommendations.pdf
https://www.jclinepi.com/article/S0895-4356(20)30612-0/pdf
GLTA Farrell
The trial is not adaptive as I thought it might be. The only variation allowed is the possible extension of dosing to 5 days as previously PRed.
Ordinal scale for staging at onset and quantifying results as previously reported.
I read it twice and could not find the dosing.
Nothing surprising on the exclusions.
The primary and secondary outcomes were well explained and reasonable. I thought they were more challenging than other therapeutic trials.
Bottom line if it works it works. We should know soon.
With the slow roll out I hope theywill do an interim report as mentioned previously.
GLTA Farrell
Agree...Excellent review:
Thanks for posting, Farrell
Brilacidin COVID-19 Antiviral News
March 2, 2021 - Innovation Pharmaceuticals announced the publication of a peer-reviewed scientific article—Brilacidin Demonstrates Inhibition of SARS-CoV-2 in Cell Culture—in the journal Viruses. Leo Ehrlich, Chief Executive Officer of Innovation Pharmaceuticals, commented, “Infectious disease experts have noted the next phase in the global fight against COVID-19 will be in developing potent antivirals that directly act on the SARS-CoV-2 virus—which is what Brilacidin has been shown to do in pre-clinical studies.
February 26, 2021 - Innovation Pharmaceuticals provided additional study details for its ongoing Phase 2 clinical trial assessing Brilacidin as a novel therapeutic in hospitalized patients with COVID-19. Patients are being treated, with recruitment and enrollment progressing at trial sites.
January 14, 2021 - Innovation Pharmaceuticals’ Brilacidin for the Treatment of COVID-19 Receives FDA Fast Track Designation. Laboratory testing at independent laboratories supports Brilacidin’s antiviral ability to safely and potently inhibit SARS-CoV-2 and multiple strains of human coronaviruses. In a human lung cell line against SARS-CoV-2, Brilacidin achieved a Selectivity Index of 426. A molecular screening study of 11,552 compounds also supports Brilacidin as a promising novel coronavirus treatment. Brilacidin antiviral research to date has been limited to laboratory-based experiments.
December 21, 2020 - The U.S. FDA Granted IND Approval for Phase 2 Clinical Trial of Innovation Pharmaceuticals’ Brilacidin for Treating COVID-19. Brilacidin’s potent in vitro inhibition of the Washington and Italian strains of SARS-CoV-2 supports its potential to inhibit emerging coronavirus mutations (variants), such as those in the United Kingdom, Denmark, and South Africa.
November 30, 2020 - Innovation Pharmaceuticals COVID-19 Clinical Trial to Support Additional Development of Brilacidin as a “Pan-Coronavirus” Therapeutic. Additional independent preliminary laboratory research suggests Brilacidin, the Company’s flagship defensin mimetic, can treat other endemic human coronaviruses (H-CoVs), such as those causing common colds, and not just SARS-CoV-2, the novel coronavirus responsible for the ongoing global COVID-19 pandemic.
November 16, 2020 - Innovation Pharmaceuticals announced that an overseas Clinical Trial Application (CTA) had been submitted to the governing health agency, with a U.S. Investigational New Drug (IND) application also to be submitted this week to the FDA. Both these submissions are part of final preparations for the Company’s multinational Phase 2 clinical trial of Brilacidin for COVID-19, which is on track to commence in 2020 upon gaining required approvals.
October 30, 2020 - Innovation Pharmaceuticals and George Mason University’s (Mason’s) National Center for Biodefense and Infectious Diseases (NCBID) jointly announced the completion of extensive laboratory testing supporting the anti-SARS-CoV-2 activity of Brilacidin, a defensin-mimetic drug candidate, which is being developed as a potential COVID-19 treatment. “In testing at GMU’s BSL-3 lab, we showed that Brilacidin potently inhibits SARS-CoV-2 in vitro against the live virus. Beyond exhibiting treatment potential for those already infected by COVID-19, Brilacidin’s ability to disrupt viral integrity and block viral entry indicates it has the added potential to prevent infection, upon appropriate formulation, as a prophylactic. I look forward to working with Innovation to investigate further Brilacidin’s antiviral properties,” said Aarthi Narayanan, Ph.D., Associate Professor of Systems Biology in Mason’s College of Science.
Brilacidin COVID-19 Antiviral Clinical Trial
The Phase 2 clinical trial will be a randomized, double-blind, placebo-controlled, multi-national, multi-center study that is expected to enroll approximately 120 patients with moderate-to-severe COVID-19. The trial’s primary endpoint is time to sustained recovery through Day 29 based on the National Institute of Allergy and Infectious Diseases Adaptive COVID-19 Treatment Trial clinical status ordinal scale.
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reserach lab
Fact checked by Robert Carlson, MD
3 in 1 Combination COVID-19 Therapeutic Launches Late-Stage Study
Innovation Pharmaceuticals Brilacidin is a combination antiviral, immuno/anti-inflammatory, and antimicrobial COVID-19 therapeutic candidate
https://www.precisionvaccinations.com/vaccines/brilacidin-covid-19-therapeutic
Vaccine Data
Condition:
COVID-19
Drug Class:
Antiviral
Name
Brand:
Brilacidin
Generic:
PMX-30063
Manufacturer
Innovation Pharmaceuticals Inc
Country ID:
US
Code
ChEMBL ID:
25023695
Accession Number:
DB12997
UNII:
I1679X069H
Status
Status:
Candidate
FDA First In Class:
Yes
Availability:
Pending
Clinical Trials
Clinical Trial Phase II:
Study of the Effects of Brilacidin Oral Rinse on Radiation-induced Oral Mucositis in Patients With Head and Neck Cancer (Brilaci
External Data
VIS:
PDF
New Vax Data
VIR-7831 Antibody
Janssen COVID-19 Vaccine (Ad26.COV2-S)
Herpes Vaccine Candidates
Plaquenil Antiviral Medication
Pfizer-BioNTech COVID-19 Vaccine
Moderna COVID-19 Vaccine
Sputnik V Vaccine
Sci-B-Vac Hepatitis B Vaccine
Brilacidin COVID-19 Therapeutic
VBI-1901 Glioblastoma (GBM) Cancer Vaccine
VBI-2601 Hepatitis B Vaccine
VGX-3100 HPV Cancer Vaccine
Thanks for pointing that out. I should have said it is likely to be an adaptive trial as I explained in the post below:
"We will not know for sure until the Brilacidin for Covid19 protocol is released {? tomorrow} but the last PR is suggestive of a plan similar to NIAID's ACTT plan which tested Remdesivir and other Covid drugs.
Plus the most of the recent Covid therapeutic studies have been done through one of the 6 ACTT plans.
https://www.nih.gov/research-training/medical-research-initiatives/activ/covid-19-therapeutics-prioritized-testing-clinical-trials#activ6
"After an interim review, by an independent Data Monitoring Committee (DMC), dosing may be extended to 5 days.
The trial’s primary endpoint is time to sustained recovery through Day 29, using a clinical status ordinal scale based on that used in the series of National Institute of Allergy and Infectious Diseases (NIAID) Adaptive COVID-19 Treatment Trials (ACTTs). Additional endpoints include: in-hospital outcomes (e.g., duration of hospitalization, time to discharge), all-cause mortality, measurement of disease biomarkers (e.g., CRP, ferritin) and inflammation-related biomarkers (e.g., IL-1ß, IL-6, IL-10, total IL-18, TNF-a), changes to SARS-CoV-2 viral load, as well as other key measures."
http://www.ipharminc.com/press-release/2021/2/26/innovation-pharma-provides-study-details-for-ongoing-phase-2-clinical-trial-of-brilacidin-in-hospitalized-covid-19-patients"
Glta, Farrell
Good luck, Farrell
We will not know for sure until the Brilacidin for Covid19 protocol is released {? tomorrow} but the last PR is suggestive of a plan similar to NIAID's ACTT plan which tested Remdesivir and other Covid drugs.
Plus the most of the recent Covid therapeutic studies have been done through one of the 6 ACTT plans.
https://www.nih.gov/research-training/medical-research-initiatives/activ/covid-19-therapeutics-prioritized-testing-clinical-trials#activ6
"After an interim review, by an independent Data Monitoring Committee (DMC), dosing may be extended to 5 days.
The trial’s primary endpoint is time to sustained recovery through Day 29, using a clinical status ordinal scale based on that used in the series of National Institute of Allergy and Infectious Diseases (NIAID) Adaptive COVID-19 Treatment Trials (ACTTs). Additional endpoints include: in-hospital outcomes (e.g., duration of hospitalization, time to discharge), all-cause mortality, measurement of disease biomarkers (e.g., CRP, ferritin) and inflammation-related biomarkers (e.g., IL-1ß, IL-6, IL-10, total IL-18, TNF-a), changes to SARS-CoV-2 viral load, as well as other key measures."
http://www.ipharminc.com/press-release/2021/2/26/innovation-pharma-provides-study-details-for-ongoing-phase-2-clinical-trial-of-brilacidin-in-hospitalized-covid-19-patients
Glta, Farrell
Some of key points:
-The Merck/Oncoimmune drug, CD24Fc now MK-7710, is an immunmomodulating drug developed for treatment of Graft vs Host disease seen as a complication of bone marrow transplants.
-Its phase 3 clinical trial for Covid19 showed good results even in the sickest patients.
-As an anti-inflammatory it will compete against dexamethasone. If I was advising the FDA what I would want to know is this really better than dexamethasone and would require a head to head trial.
-Neither Dexamethosone or CD24Fc now MK-7710 will compete directly against Brilacidin which is being studied as an antiviral.
Unless ,of course, Brilacidin immmunomodulating effects are so effective it makes anti-inflammatory medications unnecessary.
GLTA, Farrell
Most of what concerns you and Mr Locke about the Brilacidin Phase 2 trials ignores the fact that this is an adaptive trial and has the ability to add additional patients and even extend the trial to a Phase 3 seamlessly if Brilacidin is found to be safe and effective.
Below the FDA describes different scenarios describing current clinical trials for Covid 19. Brilacidin's protocol will likely have elements of these trials
From the FDA update:
https://www.nih.gov/research-training/medical-research-initiatives/activ/covid-19-therapeutics-prioritized-testing-clinical-trials
"The Adaptive COVID-19 Treatment Trial (ACTT) is evaluating the safety and efficacy of the investigational antiviral Veklury® (remdesivir), developed by Gilead Sciences Inc., alone and in combination with other therapeutics. The patient population is hospitalized adults with COVID-19 and evidence of lung involvement, including rattling sounds when breathing (rales) with a need for supplemental oxygen or abnormal chest X-rays, or illness requiring mechanical ventilation."
"The ACTIV-2 master protocol(link is external) is designed as a Phase 2 trial that can expand seamlessly to Phase 3. The trial will enroll adults with COVID-19 who are not hospitalized and aims to evaluate safety, to understand if the investigational treatment can reduce the duration of symptoms, and to test if the treatment can increase the proportion of participants with undetectable virus. It will perform testing using nasopharyngeal swabs at specific time points. Multiple therapies, beginning with a monoclonal antibody but including other types of therapeutics, will be tested in ACTIV-2."
"Working in an unprecedented timeframe, the ACTIV public-private partnership has evaluated hundreds of available therapeutic agents with potential application for COVID-19, prioritized the most promising candidates, designed and harmonized five adaptive master protocols for ACTIV clinical trials, and selected numerous NIH-supported networks to launch these clinical trials to test prioritized therapeutic candidates.
"Master protocols allow coordinated and efficient evaluation of multiple investigational agents as they become available, but within the same clinical trial structure, across multiple study sites. Adaptive protocols swiftly weed out experimental drugs that do not demonstrate effectiveness and identify those that do. Adaptive master protocols reduce administrative burden and cost, provide a flexible framework to rapidly identify drugs that work, and rapidly move additional experimental agents into the trial."
GLTA Farrell
Why GSK? If phase 2 Brilacidin for Covid 19 is solidly positive IPIX should have its choice of suitors.
Good luck to all,
Farrell