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Did you miss this headline?
Cellceutix Brilacidin ABSSSI Trial Gets Positive Review By Data Safety
Monitoring Board; Best Possible Outcome, No Treatment-Related Serious
Adverse Events (SAEs)
"Independent experts did not observe any concerning safety signals in the study. In addition, the Company reports there are no treatment-related Serious Adverse Events (SAEs), and none classified as cardiovascular or neurological, thus far in the study."
https://www.biospace.com/article/releases/cellceutix-brilacidin-absssi-trial-gets-positive-review-by-data-safety-monitoring-board-best-possible-outcome-no-treatment-related-serious-adverse-e/
GLTA Farrell
The in vitro studies suggest Brilacidin is effective at a low dose and cell toxicity occurs at a relatively high dose, thus the excellent Selectivity Index of 426.
We will have a better idea about future dosing when the Phase 2 study reports.
GLTA, Farrell
Great point. Many short of breath "long haulers" actually have pulmonary fibrosis as a complication from pulmonary Covid.
Wonder if Brilacidin would be helpful for idiopathic pulmonary fibrosis?
I have a feeling we may see a clinical trial some day.
GLTA, Farrell
The obvious answer is because pharma has not offered IPIX enough money yet. As the clinical studies evolve a valuation will be easier to assess;at that time I would expect partnership offers to occur.
Glta, Farrell
New information at AVS :
Brilacidin is effective against all Covid 19 strains tested including the Delta variant.
Brilacidin has a biologic effect against Alpha viruses {encephalitis} and Bunyaviris {Rift Valley Fever}
Brilacidin inhibits pulmonary fibroblasts
Brilacidin's anti-inflammatory effects are confirmed
" Inhibition appears to impact viral integrity in a manner that interferes with entry and/or early
post-entry steps
• Inhibition extends to different strains of SARS-CoV-2 (alpha, beta, gamma and delta strain
assessments are planned)
• Synergistic activity with remdesivir without any apparent increase in toxicity
• Cell type independent inhibition of SARS-CoV-2 (Calu-3, Caco-2, primary lung fibroblasts)"
GLTA Farrel
Another reason we need Brilacidin.
Corona virus enhancing antibodies found. These antibodies enhance corona virus entry into cells and are associated with more severe disease.
Enhancing antibodies have been induced by vaccines in the past
{Vaccine antibody dependent enhancement]. Enhancing antibody levels may be responsible for the inconsistent results with Convalescent serum therapies since serum with higher levels of enhancing antibodies would be less effective.
The authors point out different corona virus mutations have variations in the S protein antibody binding sites which may be responsible for different viral levels and disease severity.
GLTA Farrell
https://www.cell.com/cell/fulltext/S0092-8674(21)00662-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867421006620%3Fshowall%3Dtrue
https://www.nature.com/articles/s41579-020-00462-y
Herd immunity may not be possible
Researchers are now postulating that too many hurtles to herd immuntity exist. The concept of vaccinating the population to end the Covid epidemic may not be possible. It is obvious to everyone that vaccinating high risk individuals markedly reduces the chances of severe illness,but it does not completely eliminate the possibility of fatal and severe illness since deaths in fully vaccinated occur.
The Yankee's baseball quarantine due to the spread of Covid from the fully vaccinated, as pointed out by Hungry_Ghost and JFM, is one of the prime reasons herd immunity may not be possible.
Other factors include Covid variants may be resistant to vaccines; the reduction of risks in the vaccinated has opened up the country,but paradoxically has contributed to the spread of Covid;vaccine side effects such as myocarditis and now Guillain-Barre are further impediments to vaccination in the the large part of the population hesitant to be immunized.
https://www.nature.com/articles/d41586-021-00728-2
Some counties which are highly immunized such as Israel are continuing to have Covid outbreaks.
https://www.reuters.com/world/middle-east/living-with-covid-19-israel-changes-strategy-delta-variant-hits-2021-07-13/
Many posters here have come to realize the situation we are in and have reached the same conclusion as Dr Flasche quoted below
" The vaccine is “an absolutely astonishing development”, but it’s unlikely to completely halt the spread, so we need to think of how we can live with the virus, Flasche says. This isn’t as grim as it might sound. Even without herd immunity, the ability to vaccinate vulnerable people seems to be reducing hospitalizations and deaths from COVID-19."
It seems to be futile to expect vaccinating healthy children to have a role in curbing the epidemic just as it is obvious vaccinating the elderly and ill has become vital.
The Covid infection seems destined to become an on going endemic infection which means effective therapeutics, eg Brilacidin should have a prominent role in reducing death and morbidity from Covid in the future
GLTA Farrell
Lambda variant spreading in South America. Death rate in Peru almost 10%.
M RNA vaccines may be effective; others may not be effective.
https://www.cnbc.com/2021/07/09/covid-heres-what-you-need-to-know-the-lambda-variant.html
https://www.forbes.com/sites/brucelee/2021/07/10/lambda-variant-of-covid-19-coronavirus-is-spreading-what-you-need-to-know/
https://www.news-medical.net/news/20210705/Study-says-mRNA-COVID-vaccines-are-effective-against-Lambda-variant.aspx
GLTA, Farrell
There is a lot of speculation about the causes of the persistent post Covid19 symptoms.The symptoms vary widely,but the cause is uncertain. Some patients may have residual lung and kidney damage.The Covid heart inflammation,myocarditis, is being more widely reported now and can produce effects which can be long lasting or even permanent. Many patients report neurologic and psychiatric symptoms including "brain fog" whose underlying causes are not well understood.
It has been postulated some long haulers could have an immunologic basis, but some have a suspected persistent viremia.Studies have shown patients can demonstrate signs of the Covid virus for several weeks after the onset of Covid 19.
"The estimated time until loss of virus RNA detection ranged from 45.6 days for nasopharyngeal swab samples to 46.3 days for feces samples in mild cases and from 48.9 days for nasopharyngeal swab samples to 49.4 days for feces samples in severe cases, which was longer than those of SARS-CoV and MERS-CoV (10,11). Lan et al. reported positive rRT-PCR results in throat swab sampless from patients who recovered from mild COVID-19 for 50 days at maximum (8)"
https://wwwnc.cdc.gov/eid/article/26/8/20-1097_article
As Biodoc stated earlier administration of the vaccine seems to help some of the long haulers which IMO may be an indication of a low grade chronic viremia.
Since Brilacidin is both an antiviral and an anti-inflammatory it is possible it could possibly be beneficial in both proposed causes.
I am looking forward to the clinical studies of Brilacidin for Covid19. Hopefully Brilacidin will relieve this plague.
GLTA Farrell
https://www.yalemedicine.org/news/vaccines-long-covid
https://www.nature.com/articles/s41591-021-01283-z
In addition to the Covid19 results, the upcoming ASV conference should shed more light on new Covid variants as well as the additional viral in vitro studies.
Brilacidin has been reported to show activity against coronaviruses, alphaviruses and bunyaviruses (with lab testing against other viruses also underway)
The August militay symposium presentation will focus on non Covid viral disorders:
“Development of New Front Line Therapies to Prevent and Treat Non-SARS-CoV-2 Endemic Viral Diseases”
Although testing on specific viruses has not been announced below is a list of some of the diseases reported with each family of viruses.
Alpha viruses:
eastern equine encephalitis
Western equine encephalitis
Chikungunya fever
bunyaviruses diseases
-nephritis
-hemorrhagic fever
-California encephalitis
-Rift Valley fever
-Lassa fever
Coronavirus
-common cold
-bronchitis and pneumonia
-diarrhea
-MERS
-SARS
-Covid19
plus possible other viruses TBA...
GLTA, Farrell
Thanks again for sharing your experience with the board. The long-haul Covid patients outcomes are not widely known and are particularly discouraging.
GLTA Farrell
Another terrific post. Thanks for posting.
GLTA Farrell
I spent some time looking for a better reference. It appears Merck and Ridgeway were not proud of the result.
GLTA, Farrell
Molnupiravir (also known as MK-4482 and previously as EIDD-2801) clinical trial for moderate to severe Covid19 was discontinued due to poor results. Merck is continuing study of molunpiravir in outpatient covid patients witn mild disease and risk factors for progression.
"But in April, Merck and Ridgeback announced that it would end their trial of molnupiravir in hospitalized patients because the data showed it was unlikely to help. They will continue the trial in non-hospitalized patients, however."
https://www.nytimes.com/interactive/2020/science/coronavirus-drugs-treatments.html
GLTA Farrell
Molunpiravir's safety concerns still have not been satisfactorily addressed in spite of the fact it is Ames positive. Dr Bright had serious concerns regarding molunpiravir being mutagenic and the political pressure being placed to approve the drug.
Mr Perlmutter's comments below are less than reassuring
" 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"
https://bgr.com/2020/07/31/coronavirus-cure-merck-mk-4482-eidd-2801-rick-bright-controversy/
Below is a copy of my post 351726 from 3/11/2021which highlights some of the points made in the above article
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
Thanks for posting. The lack of veracity is going to continue to fuel speculation until the truth is revealed.
GLTA,
Farrell
FDA guidelines for unblinding or terminating a study for good results.
This has been posted before, but a timely review is helpful
https://www.fda.gov/media/75398/download
4.4.1.1. Monitoring for EffectivenessIn studies with serious outcomes, all parties would wish that any major treatment advance be identified and made available as soon as possible. It is critical, however, that the study yield a valid and definitive result. Thus, tensions between ethical and scientific considerations may arise. Consider, for example, a placebo-controlled trial of a new product for a serious illness or condition for which there is no standard treatment. If the emerging data suggest that those receiving the treatment are doing better, one might expect that a DMC would consider whether the study should be terminated earlier than planned. Estimates of treatment effect, however, will be unstable at early points in a study, and the chance is substantial of observing a nominally statistically significant benefit (e.g., p<0.05) at one of multiple interim analyses during a study of an ineffective product (see Section 4.4.2). A DMC, guided by a pre-specified statistical monitoring plan acceptable to both the DMC and the study leadership, will generally be charged with recommending early termination on the basis of a positive result only when the data are truly compelling and the risk of a false positive conclusion is acceptably low.
7.2.1
In almost all cases, a DMC is advisory to the sponsor; the sponsor decides whether to accept recommendations to discontinue a trial. FDA will rarely, if ever, tell a sponsor which decision to make. For trials that may be terminated early because a substantial benefit has been observed, however, consideration may still need to be given to the adequacy of data with regard to other issues such as safety, duration of benefit, outcomes in important subgroups and important secondary endpoints. We recommend that sponsors of trials that could potentially be terminated early for efficacy reasons discuss these issues with FDA prior to implementing the trial, when the statistical monitoring plan and early stopping boundaries are being developed. In these settings, consultation with FDA may provide the sponsor with important information regarding the regulatory and scientific implications of a decision and may lead to better decisions. Sponsors are encouraged to revisit these issues with FDA when considering DMC recommendations for early termination if new issues have arisen and/or if the regulatory implications of early termination were not adequately clarified at the outset of the trial.
"To others, it was the perfect example of the unnecessary dangers of gain-of-function science. “The only impact of this work is the creation, in a lab, of a new, non-natural risk,” the Rutgers microbiologist Richard Ebright, a longtime critic of such research,"
Ebbright summarizes the risk. The purpose of the gain in function research was to develop vaccines and therapeutics against viruses which were constantly mutating naturally. The fallacy is, as far as I can tell, no vaccines or therapeutics were studied or developed. I have not been able to find any funding allocated for treatment of these viral threats which makes the risks of studying these viruses untenable.
While Baric,Daszak and Yi were facilitating the gain in function research no one seemed to limit the risks in studying the viruses in the Chinese level 2 BSL lab which the article stated had the infection control precautions of a dental office.
Senator Paul was right in shining a light on these practices.
GLTA Farrell
Nice summary article thanks for posting
The Brilacidin Phase 2 studies will not have to be "good" to be successful because the present antivirals studied have not shown efficacy in treating Covid 19 patients with moderate to severe disease.
Any trend pointing to possible lower mortality, reduced complications, lower numbers needing Ventilators,ECMO,and reduced oxygen usage, shorter recovery times, shorter hospitalization rates, will all send Brilacidin to a stage 3 trial.
The inflammatoy markers, viral tests and immunological tests should confirm the biologic effect of Brilacidin
Of course I expect the trial to confirm the safety of Brilacidin shown in the previous studies.
The study guidelines for measuring success are list below from the Clinical trials .gov website
From Brilacidin Phase 2 clinical trials .gov
Primary Outcome Measures :
Time to sustained recovery through Day 29 [ Time Frame: Day 1 through Day 29 ]
Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale with response sustained through Day 29:
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate);
Not hospitalized, limitation on activities and/or requiring home oxygen;
Not hospitalized, no limitations on activities.
Secondary Outcome Measures :
Proportion of subjects achieving recovery status scores at Day 29 [ Time Frame: Day 29 ]
Recovery status scores are the following three categories from the ordinal scale:
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate);
Not hospitalized, limitation on activities and/or requiring home oxygen;
Not hospitalized, no limitations on activities.
Proportion of subjects that die or develop respiratory failure by Day 29 [ Time Frame: Day 1 through Day 29 ]
Composite endpoint, defined as: Death OR Respiratory failure (requires invasive mechanical ventilation)
Subject Clinical status [ Time Frame: Day 1 through Day 29 ]
Clinical status is measured with an 8-point ordinal scale:
Death
Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
Hospitalized, on non-invasive ventilation or high flow oxygen devices
Hospitalized, requiring low-flow supplemental oxygen
Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise)
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate)
Not hospitalized, limitation on activities and/or requiring home oxygen
Not hospitalized, no limitations on activities
Proportion of subjects achieving at least one category improvement in clinical status [ Time Frame: Day 8, Day 15, Day 29 ]
Proportion of subjects achieving at least two category improvement in clinical status [ Time Frame: Day 8, Day 15, Day 29 ]
Time to at least one category improvement in clinical status [ Time Frame: Day 1 through Day 29 ]
Time to at least two category improvement in clinical status [ Time Frame: Day 1 through Day 29 ]
Time to a National Early Warning Score 2 (NEWS2) of </= 2 and maintained for 24 hours [ Time Frame: Day 1 through Day 29 ]
The NEWS2 score is based on seven clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, systolic blood pressure, pulse, level of consciousness, temperature)
Change from baseline in National Early Warning Score 2 (NEWS2) [ Time Frame: Day 1 through Day 29 ]
Incidence of treatment-emergent adverse events [ Time Frame: Day 1 through Day 60 ]
Treatment-emergent Adverse Events (TEAEs) have onset dates on or after the study treatment start date
Incidence of treatment-emergent graded laboratory abnormalities [ Time Frame: Day 1 through Day 29 ]
Treatment-emergent abnormalities have onset dates on or after the study treatment start date
Other Outcome Measures:
Duration of hospitalization [ Time Frame: Day 1 through Day 29 ]
Measured in days
Time to discharge [ Time Frame: Day 1 through Day 29 ]
Measured in days
Duration of invasive mechanical ventilation [ Time Frame: Day 1 through Day 29 ]
Measured in days (if applicable)
Duration of supplemental oxygen support [ Time Frame: Day 1 through Day 29 ]
Measured in days (if applicable)
Duration of extracorporeal membrane oxygenation (ECMO) [ Time Frame: Day 1 through Day 29 ]
Measured in days (if applicable)
Proportion of subjects with no oxygen therapy (and/or peripheral oxygen saturation SpO2 > 93% on room air) [ Time Frame: Day 8, Day 15, Day 29 ]
Subjects not using supplemental oxygen
Subject 28-day mortality [ Time Frame: Day 1 through Day 29 ]
Incidence of death
Change from baseline in disease biomarkers [ Time Frame: Day 1 through Day 29 ]
Concentrations of C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH), D-dimer, troponin hs, absolute neutrophil count
Change from baseline in inflammatory cytokines [ Time Frame: Day 1 through Day 15 ]
Concentrations of interleukin (IL)-1ß, IL-6, IL-10, total IL-18, tumor necrosis factor (TNF)-a
Change from baseline in Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) viral load [ Time Frame: Day 1 through Day 29 ]
Concentrations of SARS-CoV-2 from nasopharyngeal (or oropharyngeal) samples
Brilacidin measurements [ Time Frame: Day 1 through Day 4 ]
Concentrations of Brilacidin from plasma samples
GLTA,Farrell
"Rumor is everyone changed their minds about the lab leak because a Chinese counterintelligence chief defected to DIA with proof. FDA political and conflicted? Sadly, yes"
Evidently some of the information gleaned may reflect poorly on Dr Fauci.
Recently Rand Paul questioned Dr Fauci about the US government support for the Wuhan lab as well as the controversial gain of function viral research supported by the NIH in the US and China. It will be interesting to see if Fauci's down playing of the US governments role in these matters will be supported or countered by our {rumored} Chinese defector.
"The site had questioned the integrity of Dr. Anthony Fauci and said that the defector’s information has put him under the spotlight."
GLTA,Farrell
https://www.opindia.com/2021/06/chinese-counterintelligence-officer-defected-to-usa-with-wuhan-lab-info/
https://www.upi.com/Top_News/World-News/2021/06/21/china-China-Dong-Jingwei-COVID-US-defect/5391624284922/
https://www.dailymail.co.uk/news/article-9699221/Has-Chinese-official-defected-Rumors-swirl-diplomat-told-DC-Wuhan-lab.html
Thanks for posting .Nice summary of defensin's pharmacologic properties.The good news is the properties attributed to natural defensins have been found in Brilacidin. The graphs in the article demonstrate many of the properties proven to be in Brilacidin:
antibiotic, antiviral, immune modulation, immune stimulation of T cells and B cells to fight infection, intracellular interruption of viral DNA and halt of viral protein synthesis,blocks viral entry.
"Defensin acts on the membrane or envelopes wall by its amphipathic nature"
Interesting to note natural defensins have been shown to block viral binding site for not only Coronavirus,but influenza, Ebola and Lassa viruses.
The George Mason RBL has done a number of studies regarding defensins prior to the Covid 19 epidemic. They are aware of their properties and have already found Brilacidin to have activity against Alpha Viruses {including Encephalitis} bunyaviruses as well as Coronavirus.
I am looking forward to the July American Society of Virology presentation to see what new properties of Brilacidin have been discovered.
GLTA,Farrell
https://www.globenewswire.com/news-release/2021/06/18/2249692/0/en/Innovation-Pharma-Announces-New-Brilacidin-Antiviral-Research-on-Non-SARS-CoV-2-Endemic-Viral-Diseases-to-be-Presented-at-the-2021-Military-Health-System-Research-Symposium.html
https://science.gmu.edu/news/innovation-pharmaceuticals-and-george-mason-university-release-laboratory-testing-results
https://science.gmu.edu/news/innovation-pharmaceuticals-and-george-mason-university-release-laboratory-testing-results
https://www.globenewswire.com/en/news-release/2021/04/14/2210088/0/en/Innovation-Pharma-s-Broad-Spectrum-Antiviral-Drug-Candidate-Brilacidin-Highlighted-in-Biodefense-and-Infectious-Diseases-COVID-19-Presentation.html
Brilacidin was tested against the Washington and Italian virus strains in the RBL in vitro studies.
"This assay was performed using two different strains of SARS-CoV-2 (Washington strain-nCoV/USA-WA1/2020 and Italy strain-Italy-INMI1)"
https://www.mdpi.com/1999-4915/13/2/271/htm
In the Phase 2 study no mention is made of testing for different strains or variants. Basically anyone testing postive for Covid19 that met the study inclusion guidelines is eligible for treatment.
Russia reported last week the Covid 19 delta variant is producing a third wave of infection and accounts for 90% of the new cases.It would seem likely some of the treated cases would be the delta variant.
https://www.dw.com/en/covid-19-russia-battles-delta-variant-in-deadly-3rd-wave/av-58072948
I will send an email to IPIX to see if testing and treatment of variants is a part of the study.
GLTA, Farrell
Lilly's Covid 19 drugs, bamlanivimab and etesevimab, paused due to poor activity against Beta and Gamma Covid19 variants. Its EUA was previously revoked.
Bamlanivimab and etesevimab were approved for use only in high risk patients with mild to moderate Covid19
"Due to the presence of variants, the US said Friday that it’s pausing shipments of Eli Lilly’s monoclonal antibody combo for the treatment of Covid-19 on a national basis until further notice.
The pause, which could amount to the loss of about $375 million in sales according to one biotech analyst, is another blow to Lilly’s efforts to treat Covid-19 outside of the hospital, as the company previously had its EUA for bamlanivimab revoked.
“The CDC identified that the combined frequencies of the SARS-CoV-2 P.1/Gamma variant (first identified in Brazil) and the B.1.351/Beta variant (first identified in South Africa) throughout the United States now exceed 11% and are trending upward,” John Redd, CMO of the Office of the Assistant Secretary for Preparedness and Response, said in a letter obtained by Endpoints News.
“Results from in vitro assays that are used to assess the susceptibility of viral variants to particular monoclonal antibodies suggest that bamlanivimab and etesevimab administered together are not active against either the P.1 or B.1.351 variants,” Redd wrote."
https://endpts.com/us-pauses-use-of-eli-lillys-covid-19-treatment-nationwide-due-to-variants/
GLTA Farrell
CDC states Covid vaccines likely related to myocarditis.
"There have been more than 1,200 cases of a myocarditis or pericarditis mostly in people 30 and under who received Pfizer’s or Moderna’s Covid-19 vaccine, according to CDC data."
JMO this risk balanced against the small benefit from Covid vaccination for young people is unacceptable. The M RNA vaccines should be limited to older individuals.
GLTA Farrell
https://www.cnbc.com/2021/06/23/cdc-reports-more-than-1200-cases-of-rare-heart-inflammation-after-covid-vaccine-shots.html
I do not think it is untenable for countries outside of N America and Europe to pay for Brilacidin for Covid19. Covid has and will ruin economies and overwhelm healthcare systems. The logic for treatment is simple...it will save them money and preserve their economies.
Glta, Farrell
White Square's closing may be due to a more fundamental change...their backers are backing out.
"In the investor letter announcing the fund’s closure, White Square said that last year, despite that year’s strong performance, two large investors had opted to withdraw their cash and put it in cheap passive funds or private equity. “We experienced first-hand the shift in trend away from hedge fund investing to cheaper alternatives,” it added."
https://www.ft.com/content/397bdbe9-f257-4ca6-b600-1756804517b6
GLTA, Farrell
If the Brilacidin phase 2 study confirms efficacy against Covid there will be intensive research to develop alternate delivery systems.
IPIX has already announce its interest in developing an inhaler for Covid. Small peptides are already available for clinical use eg insulin inhaler
Other possible options include depo intramuscular injections
eg DepoMedrol DepoProvera
Trans dermal eg nitrate patches
Developing oral medications from IV pharmaceuticals has become an area of research and development. The article below summarizes some of this research:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471246/
"To meet the increasing demand for biopharmaceutical oral products, research has been focused on developing devices for oral delivery. While still at an early stage, recent devices include intestinal patch systems, microneedle capsules and particulate systems [51]. The intestinal patch systems are based on a unidirectional drug release depot, which is similar to a microdevice adhered to the intestinal wall [52]. The microneedle capsule increases the penetration rate of drug molecules by piercing the mucosa directly with microneedles. A recent study developed a method to inflate a microneedle into the mucosa by responding to the change in pH [53]. Particulate devices are the most common oral vehicles, which have been investigated for the encapsulation and targeting of a vast variety of therapeutics. In general, the current technologies are still at the preclinical stage. Therefore, more research efforts should be directed to solve the existing technical challenges of oral drug delivery systems and prove the feasibility in clinical use."
GLTA Farrell
Good point. The military stock piles pharmaceuticals. A DOD, Department of Defense,contract would be very lucrative.
Why would that be of interest to the military?
Because infectious diseases around the world interfere with military preparedness.
An army can not move if the soldiers are in the infirmary.
GLTA,
Farrell
Wow 10 million for Brilacidin phase 3 and 2.99 million Brilacidin EUA doses @ 1000 a dose.
Good to see Biden planning ahead.
GLTA Farrel
It's just so quiet....but is it?
Good luck to all,
Farrell
There are a number of examples of the FDA issuing EUA's after smaller studies.
The most recent was Sotrovimab
Sotrovimab study was stopped before it was completed due to the interim analysis. We do not know how many were treated , but 583 were approved for treatment before the trial was stopped.
"The data supporting this EUA for sotrovimab are based on an interim analysis from a phase 1/2/3 randomized, double-blind, placebo-controlled clinical trial in 583 non-hospitalized adults with mild-to-moderate COVID-19 symptoms and a positive SARS-CoV-2 test result."
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-monoclonal-antibody-treatment-covid-19
GLTA, Farrell
I have reviewed the viruses article again. I do not understand your concerns.
The in vitro tests are just for a few hours, but Brilacidin will be dosed over 5 days which should result in virtual elimination of Covid 19 very quickly. Its virucidal property will be accentuated by its direct antiviral action in the plasma since Brilacidin is not a prodrug.
Brilacidins half life is long, not short, and has been reported to be up to 23 hours with "consistent and linear pharmacokinetics in plasma"
Remember in ABSSI one IV dose of Brilacidin was equivalent to 1 week of Daptomycin.
https://static1.squarespace.com/static/5715352e20c647639137f992/t/583f8286d2b85731b8713a36/1480557192947/A-Randomized-Double-Blind-Study-Comparing-Single-Dose-and-Short-Course-Brilacidin-to-Daptomycin-in-the-Treatment-of-Acute-Bacterial-Skin-Skin-Structure-Infections-ABSSSI1.pdf
The IC 50 dose is .565 um; IC 90 was 2.63 um while the maximum serum level in ABBSI was 7.67 um at .6mg/kg
Brilacidin's serum level is 13.5 greater than the IC50 and 3 times greater than the IC90 which should give a nice margin of effectiveness against Covid19 with Brilacidin's long half life . In addition the peak and trough levels should increase with each IV dose.
Fortunately safety is not a concern with Brilacidin.The paresthesias were all transient and the BP would be easily treatable if it became elevated to significant levels.Neither should play a significant role when treating a life threatening disease like Covid19.
Of course all of this is a guess at this point since we do not know the dose given in the phase 2 clinical trial.
It is possible the most important attribute of Brilacidin for Covid19 could prove to be its anti-inflammatory properties.
We will find out when the Phase 2 results are available.
GLTA,Farrell
What we know is Remdesivir has been studied in multiple clinical trials leading many experts to conclude it just does not work well on the mild,moderate, or severely ill Covid 19 patients.
The articles I posted demonstrate Remdesivir's in vitro promise could not be fulfilled due to its pharmacologic short comings which limit its effective dose.
Brilacidin's studies to date suggest it will be able to treat Covid19 due to the properties discovered in the RBL and reported in the Viruses article.
Fortunately Brilacidin is demonstrating tremendous promise.
"Its virucidal mechanism of action means it kills Covid19 on contact. It does not have to be converted to an active form so with infusion it kills the virus at first in the serum. With its good pharmcokinetics and high SI number it is well distributed throughout the body and kills the virus in the extracellular spaces as well as inside the cells. It was shown in the Viruses publication to block entry of Covid19 in the cells. And, computer modeling suggests it can disrupts the viral M-protein of Covid19 to prevent viral replication.
These multiple mechanisms of action, high SI number and safety all should make Brilacidin a superior antiviral, but also be active against Covid variants. It should make viral resistance much less likely."
Of course many promising drugs have failed in clinical trials.
Time will tell if Brilacidin will prove effective in its clinical trials against Covid19
GLTA,
Farrell
Fortunately Brilacidin is not limited by these factors.
Its virucidal mechanism of action means it kills Covid19 on contact. It does not have to be converted to an active form so with infusion it kills the virus at first in the serum. With its good pharmcokinetics and high SI number it is well distributed throughout the body and kills the virus in the extracellular spaces as well as inside the cells. It was shown in the Viruses publication to block entry of Covid19 in the cells. And, computer modeling suggests it can disrupts the viral M-protein of Covid19 to prevent viral replication.
These multiple mechanisms of action, high SI number and safety all should make Brilacidin a superior antiviral, but also be active against Covid variants. It should make viral resistance much less likely.
We will know for sure soon.
GLTA, Farrell
Remdesivirs in vitro studies were one of the reasons it was quickly studied for Covid 19. Unfotunately further studies showed it lack efficay against Covid 19. Why?
Redesivir's poor clinical showing in spite of relative good in vitro studies is due to its hepatic toxicity which limits higher dosing and its relatively complicated conversion to its active metabolite requires an intracellular conversion.
https://www.statnews.com/2020/05/14/gilead-should-ditch-remdesivir-and-focus-on-its-simpler-safer-ancestor/
"Remdesivir’s lackluster results in patients with advanced Covid-19 in the NIAID-sponsored trial and the finding that it provided no statistically significant benefit in a clinical trial conducted in China among patients with severe Covid-19 symptoms are likely due to the suboptimal level of active GS-441524 triphosphate in the lungs. Patients with advanced or severe Covid-19 generally have a high viral load in their lungs and would need a high concentration of GS-441524 triphosphate to combat it. The benefit of using GS-441524 over remdesivir is that GS-441524 can almost certainly be given at much higher doses due to its lower toxicity. This would result in more conversion to the active compound, GS-441524 triphosphate, in the lungs."
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 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
Alfasigma planning clinical trial of Brilacidin for Ulcerative Proctitis
from 10Q May2021
...in the pipeline, Alfasigma S.p.A. (“Alfasigma”)—the licensee of worldwide rights to develop, manufacture and commercialize rectally-administered Brilacidin for treatment of Ulcerative Proctitis/Ulcerative Proctosigmoiditis (UP/UPS)—notified the Company, in April, of its intentions to commence, in 2021, a Phase 2 multinational clinical trial of Brilacidin for UP/UPS. Alfasigma has placed an order with the Company for Brilacidin drug substance needed for the trial, which the Company is in the process of supplying. Per the licensing agreement, Innovation Pharma is eligible to receive $24 million in upfront and milestone payments, and a 6 percent royalty (net sales), upon the successful marketing of Brilacidin for UP/UPS."
"Ehrlich continued: “Elsewhere, it was exciting to learn that Alfasigma is planning to commence a Phase 2 trial of Brilacidin for treatment of UP/UPS this year, which complements our goal to develop oral Brilacidin in Inflammatory Bowel Diseases. That Alfasigma is investing substantial resources and monies in the clinical development of Brilacidin is a reassuring sign they continue to see therapeutic promise and commercial merit in Brilacidin in the area of IBD, as do we. Development work related to the formulation and manufacture of Brilacidin in capsule form is underway to support our Phase 2 trial in Ulcerative Colitis planned to commence this year. Additional work tied to starting, in 2022, a planned Phase 3 study of Brilacidin in Oral Mucositis is also in progress. We aim to maintain momentum across our clinical programs.”
Every positive result takes Brilacidin another step forward and lowers the risk of my investment
GLTA,Farrel
Agree very well written.
Glta,Farrell
"In studies with serious outcomes, all parties would wish that any major treatment advance be identified and made available as soon as possible. It is critical, however, that the study yield a valid and definitive result. Thus, tensions between ethical and scientific considerations may arise. Consider, for example, a placebo-controlled trial of a new product for a serious illness or condition for which there is no standard treatment. If the emerging data suggest that those receiving the treatment are doing better, one might expect that a DMC would consider whether the study should be terminated earlier than planned. Estimates of treatment effect, however, will be unstable at early points in a study, and the chance is substantial of observing a nominally statistically significant benefit (e.g., p<0.05) at one of multiple interim analyses during a study of an ineffective product (see Section 4.4.2). A DMC, guided by a pre-specified statistical monitoring plan acceptable to both the DMC and the study leadership, will generally be charged with recommending early termination on the basis of a positive result only when the data are truly compelling and the risk of a false positive conclusion is acceptably low."
https://www.fda.gov/media/75398/download
GLTA, Farrell
.49 cent shares {$4.9 post split} I bought in March are looking better every day.
GLTA Farrell