Did the Gilead company hide the true toxicity of Veklury © (remdesivir) ?
The media have focused on the scripted binary debate around the use of hydroxychloroquine. In the meantime, Veklury © (remdesivir) has been acclaimed to become the ideal remedy despite almost ineffective therapy. In recent days, we learn that the United States would have taken control of the stocks of Veklury © and that the European Medicines Agency (EMA) gave a marketing authorization for this drug for serious forms of Covid-19, AMM remaining to be validated by member states.
We are very surprised by these decisions, for several reasons.
The efficacy of the Veklury © against the Covid-19 has not been demonstrated and the only study to attribute it a “modest” efficacy concludes, in a haphazard manner, that its use would allow a quicker hospital discharge of a few days, evaluation criterion which did not appear in the initial version of the protocol. We invite you to refer to our analysis of this study to assess for yourself the weakness of the conclusions.
It is customary to use antivirals at an early stage of viral infections, when they are most likely to be effective. Indeed, many doctors believe that at the very advanced stages of the disease, it is no longer the virus that affects the body but the immune reaction, and therefore a pure antiviral like Veklury © is therefore not justified. The positioning of the Veklury © at the advanced stage of the disease raises questions.
The toxicity of the molecule, GS-5734, and of its metabolite GS-441524 has not been seriously studied and the data on its metabolism in the organism are not only incomplete but also based on a poor biological model defined, in any case incomplete. The supposed target is RNA polymerase without its principle of action being established. However, the pharmacodynamics of this molecule identified since 2012 would have had plenty of time to be fully characterized since.
Since its creation, this drug has never proven real effectiveness in humans, regardless of the virus for which it was tested: Ebola, SARS-CoV, MERS-CoV.
Worse, in each of these pandemics, hasty conclusions were systematically published on its effectiveness and presented to the general public while being based on studies more than doubtful, if not hazardous. For Ebola, for example, it was concluded to be effective after having tested it on two patients who have recovered from the infection, without ever having demonstrated that it was due to the administration of remdesivir. Unfortunately for the French, despite its blatant failure during the Ebola epidemic, Gilead’s scientific hoax seems to stand the test of time. Recall that the patent expires in October 2035, and that this molecule is now recommended by the European Medicines Agency (EMA) for therapeutic use against Covid-19.
Scientists at Gilead, and other researchers heavily subsidized to sell this new synthetic molecule, highlight an in vitro mode of action explaining the clinical effectiveness of remdesivir. This is not a reality when we measure the huge difference between the efficacy results presented in studies in humans and those obtained in vitro.
Worse, we have arguments to believe that remdesivir is in fact a very toxic molecule and that the results obtained in vitro are explained above all by the cytotoxicity of the molecules GS5734 and its metabolite GS-441524. We also believe that the late use of this molecule can hide its toxicity since the organs affected by Covid-19 and remdesivir are the same. Our comments are based on tangible data from official bodies and scientific publications validated by reading committees.
Also, if by chance our suspicions about the toxicity of remdesivir were not founded, we would be happy if Gilead and / or the health authorities provide us with complete data demonstrating its safety, since in the requirements of clinical research prior to use of a drug, it is not for patients to demonstrate the toxicity of a molecule but for the laboratory to demonstrate its safety.
The results of a study published on July 6 on 5 patients treated with remdesivir at Bichat hospital report serious side effects. "This case series of five COVID-19 patients requiring intensive care for respiratory distress and treated with remdesivir highlights the complexity of using remdesivir in these critically ill patients. Remdesivir has been discontinued for side effects secondary in four patients, including 2 elevations of ALT (3 to 5 N) and 2 renal insufficiencies requiring renal transplantation ". The results of the study can be found in the article entitled: case study on the first five patients treated with COVID-19 with remdesivir in France. A shocking element is the date of publication of this study on June 30, 2020 (date of online availability) while the patients were treated between January 24 and March 1, 2020. Such information on the toxicity of a drug and consequences should have been taken into account by the EMA.
We present a global analysis of the toxicity data in order not to get lost in the details of the studies in the MA dossier that we invite you to read. These elements are important, but all too often allow drug manufacturers to ditch information, we have highlighted the main information in Annex I, as well as the deficiencies.
We, European citizens and patients, demand that these shortcomings be corrected.
1 / Analysis of factual data on the toxicity of remdesivir
A- “Official” data When a drug begins to be used in humans, doctors have information about pre-clinical toxicity studies (data in vitro and in animals). For more information, you can refer to our article on pre-clinical drug development (our article on pre-clinical developments)
From the first clinical studies, adverse events reported by patients and sought by doctors are recorded. This information is recorded in a document called an "investigator's brochure" which is updated as clinical studies progress before pre-marketing authorization. A drug can benefit from a Temporary Authorization of Use (ATU) before Marketing Authorization, doctors must then have access to the tolerance information known at this stage.
Once the drug is on the market, it is packaged with an information leaflet which, among other things, informs about potential adverse events. To date, this notice is not available for France.
The document which will act as a leaflet for hospital doctors is not yet available and therefore the only document serving as a leaflet for side effects is today the document produced by the EMA that we mentioned and partly analysed in annex I.
However, this drug, which has existed since 2015, has already been used in France, in particular during the Covid-19 pandemic, and would a priori benefit from an ATU. His notice was not found, just like his ATU sheet was not found on the ANSM (National Agency for the Safety of Medicines and Health Products) website. It would seem that in the recent European MA file, not all the adverse events known to health agencies are reported, since in the first half of 2020 alone in France, there were at least 8 serious events reported on 22 / 06/2020, including 3 cases of renal failure requiring dialysis. The sales figures of the product not being available, the risk analysis cannot be deduced, but knowing that the product has been little used in France, this already questions these only elements.
Note that Gilead does not publish on its website any specific information on the side effects of the drug, and even less on its drug interactions. If the company or the doctors under agreements speak well of the benefits of the product, no one talks about the side effects (press releases and other announcements on the financial markets). In addition, in his patent pending, Gilead repeatedly asserts the safety of the drug if it is dosed correctly, from infinitesimal doses up to 100 mg / kg / day (1). It should be noted that the current mode of administration of this molecule is intravenous.
Official data on toxicity, side effects and drug interactions are therefore almost non-existent or very patchy. It is strange to note that the document produced by the EMA which reproduces that addressed to the FDA (Food and Drug Administration, the American health authority) does not raise the question of toxicity in general, and more particularly of the genotoxicity and mutagenicity, studies which should be available today for this molecule whose "first administration to human" is not new. But it is not the only element of toxicity of Veklury (remdesivir) which is obscured by the EMA document.
We are therefore surprised by the respective decisions of the international authorities, WHO, FDA and EMA, to authorize, as a first step, the use of Veklury © on a compassionate basis and recently as a treatment for Covid-19. We have referred to the FDA press release authorizing its use (2). According to data provided by Gilead to the FDA, Veklury (remdesivir) poses no risk of toxicity to the body, except for rats given doses higher than 3 mg / kg / day. It would thus only be a question of contraindication or of an administration adapted for certain patients suffering from renal or hepatic disorders.
Gilead and the EMA jointly claim that the toxicity of Veklury (remdesivir) is "acceptable" in view of the benefits which up to that point, it must be admitted, are more than poor. The only benefit actually measured in phase III is in fact a reduction in the number of hospital days from 15 to 11 for patients who would have recovered anyway, the mortality rate remaining the same with or without Veklury (remdesivir) . It should be recalled in this regard that the initial criterion of the study having arrived at these conclusions was precisely the mortality rate, and that if it had not been modified, the study could never have concluded at the slightest efficiency.
This could be in line with the results of phases III of the Chinese and American trials which failed to demonstrate the efficacy of Veklury (remdesivir) in patients of Asian or African origin.
In terms of effectiveness, despite a very questionable attempt to make believe that the use of Veklury (remdesivir) could shorten the number of days in intensive care, all serious studies do not note the beginning of an effectiveness, whatever its use. And as FranceSoir wrote, the pivotal study of the European MA dossier is also doubtful. It is urgent that European citizens request a re-analysis of the data and additional information. Evoking the benefit / risk dimension in the context is daring.
Gilead however takes care to specify that precautions are to be taken for patients with kidney and liver problems, even recommend the use of Veklury (remdesivir) in some cases, this proves that the tolerance of the molecule is not harmless .
However, the toxicities indicated by Gilead are far from being the reality.
B- Data from research
Researching the National Center for Biotechnology Information's PubChem site (3) found no information on the toxicity of Veklury (remdesivir) but the reader is referred via a link to a Canadian drug database, DrugBank (4). In this database, it is advisable to refer to a drug with structural analogies, aciclovir which it is specified that it has significant side effects which can go as far as acute encephalopathy , or vidarabine (5)
The common element of these two molecules is an analogous group of nucleosides (flat conjugated group, nitrogenous base) which can potentially produce chromosomal damage in human cell cultures or be degraded into potentially toxic substances.
But what does the research say?
More and more serious cases of side effects from Veklury (remdesivir) are being revealed around the world. This is how liver and kidney damage, but also cardiovascular problems have been reported and bizarrely little reported by the media. As FranceSoir points out, the American Society of Health-System Pharmacists, an American foundation that offers pharmacovigilance carried out by pharmacists themselves, is starting to report alerts concerning the side effects observed (6). Indeed, Barbara F. Young, an editor of this foundation, a pharmacist, explains that “the first data on the human safety of remdesivir came from the treatment system for the Ebola virus, where the drug inhibitor of the nucleotide analogue and polymerase had what an examination called "an acceptable safety profile" although it was not more effective than other experimental options tried. The only adverse events reported in this trial were deaths, and the only event deemed to be potentially attributable to remdesivir was a case of hypotension quickly followed by cardiac arrest. "
The pharmacist added about the side effects retained: "It was surprising when these came out; there was a very short list of side effects. It is either the safest drug there is, or ... ". Or everything is done to conceal the toxicity of this drug. To convince ourselves of this, we must therefore review the tests carried out with the Veklury (remdesivir). We are therefore browsing the publications of the dedicated site, PubChem of the National Center for Biotechnology Information (3). Again, despite the very large number of clinical trials carried out since 2015, there are no precise and rigorous elements, whereas normally phase I and II trials are specifically aimed at evaluating the tolerance of a drug. It is noted that either the trials were stopped early for imprecise reasons, or that it was considered that the damage was caused by the disease. In both cases, we would like to have a clear analysis of the conclusions of accountability for the molecule.
This study was removed from the file without anyone knowing why. It is surprising to see a preliminary study withdrawn, especially since the researchers were only putting forward hypotheses. And of course, we will put the results of this study in perspective of what follows in the following paragraphs.(7)
On the description of remdesivir, we note that the toxicity is not evaluated due to the lack of sufficient data. But in the “Safety and hazards” section, i.e. Health and Risks, we are challenged by a pictogram which seems to evoke a fairly significant toxicity.
How is it that a molecule with such a serious warning about its impact on the body has not been the subject of further clinical safety studies? To understand this paradox, we carried out a prospective analysis based on the chemistry of this molecule whose proprietary identifying code is unique GS-5734.
II / Prospective analysis of the toxicity of Veklury (remdesivir).
To be able to consider the toxicity of this drug, we looked at the chemistry of the molecule, a natural avenue of investigation.
A- Veklury biochemistry (remdesivir).
Veklury (remdesivir) is an analogue of adenosine (8), a molecule used in cardiology whose pharmacodynamic effect is at the root of potential cardiac side effects, and which is also responsible for pulmonary adverse events (9). Its short lifespan in the body (which is explained by the carbon-carbon bridge between the ribose part and the adenine part) generally allows this toxicity to be quickly controlled. Gilead claims to have transformed this bridge to make the molecule more stable. You have to realize that Veklury (remdesivir) (GS5734) is a prodrug, which means that once metabolized in the body, it will break down to give the active molecule, identified as GS-441524.
Chemists have voluntarily created a nucleoside analogue close to adenosine since the objective was precisely to be able to interact with viral RNA in order to neutralize it and thus block replication. Gilead exposes simple models through numerous diagrams explaining how this drug works.
This diagram is only a model and only partially takes into account the many possible and even probable molecular interactions within the organism. You should know that this model was developed in vitro with isolated cells. However, the two states in which the Veklury (remdesivir) is going to be in the organism suggests many interactions which question the simplified, if not simplistic, model which underlies the effectiveness of this drug. Indeed, these two molecules have chemical groups with high reactivity.
It is important to begin by clarifying that the prodrug, GS-5734, is accompanied intravenously by an adjuvant that serves as a vehicle, SBECD. It is a long oligosaccharide that can affect kidney and liver functions. Its manufacturer Gilead states that the doses used are tiny and the duration of exposure short (10). However, it is questionable whether part of the renal and hepatic damage observed in certain patients is not due to this SBECD.
The structure of the active molecule, GS-441524, is actually very close to adenosine. There are, however, two basic differences. GS-441524 is much more stable than adenosine and therefore lasts longer in the body. However, the toxicity of adenosine is formidable when the organism is exposed to it durably, it is only the very short life time of the molecule which makes its toxicity temporary and therefore tolerable. Heart, liver, kidney problems would otherwise be more than common in its therapeutic use. In addition, the mutagenic character of adenosine is very powerful, it is also the very essence of the molecule since it is that it is incorporated into viral RNA.
It is important to emphasize the mutagenic and carcinogenic character of adenosine and, by extrapolation, of the mutagenic and carcinogenic potential of GS-441524. Adenosine plays an important role in the development of many cancers, in particular through its immunosuppressive role in the anti-tumour response (11). So much so that it is one of the most promising avenues in cancer research. Unfortunately, these effects have never been evaluated for the Veklury ©, the study on its long-term effects is absent from the pre-clinical file. We can, however, refer to the numerous studies on the toxicity of adenosine analogues and nucleosides which are eloquent on the short and long term effects of this type of molecules (12).
Unless Gilead has found a magic formula, nothing in the current state suggests that these toxic properties are absent for Veklury ©.
The groups added to make the molecule more efficient have a high reactivity. Thus, to minimize this reactivity, the phosphate group was protected with esters and amides which, once in the cell, will be cleaved. What about the fate of these decompositions?
Another, not least, addition was made by the researchers to inhibit the interactions between the mitochondrial RNA enzymes and the active molecule, interactions that kill the cell more than the virus. Gilead chemists then admit to having tested several combinations to reduce this deleterious effect of the initial molecule and according to their tests, which we would like to be able to consult, it was the safest group. According to Katherine Seley-Radtke, Professor of Chemistry and Biochemistry and President-Elect of the International Society for Antiviral Research, "You can't predict activity. You have to do it and test it. " And to add: “But even small changes can have astonishing consequences. "
It should then be noted that this research was carried out in vivo, in the absence of many other elements which can demonstrate precisely the behaviour of the molecule in the organism. Also, one can wonder if this cyanide grouping has much more “astonishing consequences” than lets envisage it the researches in vitro presented by Gilead. And considering the reactivity and the many potential interactions, we can even ask if Veklury (remdesivir) really reaches its pharmaceutical target: SARS-CoV-2. It would seem that for Ebola, SARS-CoV and MERS, its antiviral activity in vivo is speculative.
If Veklury © alias remdesivir does not reach the virus, it only has its very high toxic potential as an impact on the body.
B- Veklury © or remdesivir is an altrononitrile.
Remdesivir is a nitrile. More specifically, an altrononitrile. This is described in its IUPAC name: l-alanine, N - ((S) -hydroxyphenoxyphosphinyl) -, 2-ethylbutyl ester, 6-ester with 2-C- (4-aminopyrrolo (2,1-f) (1, 2,4) triazin-7-yl) -2,5-anhydro-d-altrononitrile.
Nitriles are very well known to chemists. These are very reactive and very often toxic molecules. They are also used in the chemical industry to make insecticides, pesticides, powerful detergents for hard-to-scour materials such as metals.
Nitriles are cyan compounds. This class of compounds is characterized by the presence of a C≡N group (cyanide) and includes cyanides and nitriles (R – C≡N), as well as related chemical compounds such as cyanogen’s, isocyanates and cyanamides . They owe their toxicity mainly to the cyanide ion which, when released in the body, is capable of inhibiting many enzymes, in particular cytochrome oxidase. Death, which occurs more or less quickly depending on the speed of release of the cyanide ion, is the result of chemical asphyxiation at the cellular level.
The question that arises is the stability of this group within the molecule. If we judge by the warning pictogram, nothing is less certain.
Nitriles or organic cyanides are therefore organic compounds characterized by the presence of a cyanide functional group (–C≡N) whose general formula is RCN. They can be considered as hydrocarbon derivatives in which three hydrogen atoms linked to a primary carbon atom are replaced by a Nitrile group or by derivatives of carboxylic acids (R – COOH) in which the oxo and hydroxyl radicals have been replaced by a Nitrile group (– C≡N). By hydrolysis, they give an acid which contains the same number of carbon atoms and it is by this analogy that they are usually called hydrocyanic acid, rather than as derivatives of hydrogen cyanide. Nitriles are very dangerous compounds because they release hydrogen cyanide when they decompose under the effect of heat.
Here is the type of symptoms that a cyanide agent can cause:
The question is therefore whether our altrononitrile should be considered as the many toxic nitriles. Is Veklury (remdesivir) stable enough compared to the nitrile group so that it is not directly released or hydrolysed to a carboxylated acid residue?
What do we know about altrononitriles? Very little. Cyanide agents have a long military history. Since the First World War, they have come in many forms and have proven to be formidable chemical weapons, like the Zyklon B.
C- Veklury © or remdesivir manufacturing precaution
By referring to one of the prevention notices for the manufacture of the molecules GS-5734 and GS-441524, the two forms of remdesivir in the body, we see that we are actually dealing with a hyper toxic and corrosive nitrile, this which brings us back to the pictogram mentioned at the beginning of this article, which is present on the PubChem site of the National Centre for Biotechnology Information (3).
Indeed, we note that the warnings in the manufacturers' instructions (14) alert to the significant toxicity of the product: acute toxicity, corrosion / irritation of the skin, serious eye damage / irritation, respiratory or skin sensitization, germ cell mutagen, reproductive toxicity, specific target organ toxicity (single exposure), specific target organ toxicity (repeated exposure). We find absolutely all the potential damage that we find in the most toxic nitriles which there is no need to recall their sinister use as combat gas.
If you are interested in the precautions to take when handling the products, you learn that you should not use leather because the product pierces the leather and that rubber clothing must be washed immediately after use. We also learn that we must equip ourselves with an oxygen mask because the product attacks the pulmonary epithelium, the same tissue which is preferentially seriously affected by Covid-19.
One element surprises us: there are risks of decomposition into different very toxic substances: carbon monoxide, carbon dioxide, nitrogen oxide (15). With regard to the active metabolite GS-441524, the manufacturer's instructions list the same elements of acute toxicity (16)
Would the toxicity of remdesivir and its metabolite, GS-441524, stop on the surface of the skin?
Skin that it would pierce if unfortunately a single drop was deposited there.
Gilead would oppose the low dosage (<3 mg / kg / day) and the short duration of exposure to minimize the toxicity with regard to the supposed benefit. However, there are no benefits, apart from a reduction of 4 days in the average hospital stay.
No study clearly suggests today that this drug would bring any other benefit.
It therefore seems that, with regard to the elements presented previously, we can strongly think that Veklury (remdesivir) is a harmful drug and that these elements were hidden by Gilead. We believe that the lobbying operation carried out in the media and certain public health authorities in order to discredit hydroxychloroquine, specifically in hospitals, was intended to make Veklury (remdesivir) the only solution in this situation.
We are still waiting for pharmacovigilance data and records from the first quarter of 2020 for these two molecules that the ANSM resists producing.
Given the very great potential toxicity of remdesivir, we hypothesize that, despite its antiviral nature which would in principle make it intended for early use, Gilead has, for the moment, wanted to bring Veklury © onto the market only 'in the Covid-19 late phase. As the side effects and toxicity of the molecule can be "confused" with Covid-19 damage, it is very difficult to attribute to taking Veklury ©, worsening of respiratory distress, kidney damage or hepatic as well as cardiovascular complications. Moreover, the phase III trial published in the NEJM carefully avoids giving the final mortality (at 28 days) in the Veklury arm (remdesivir) compared to placebo, which is more than abnormal. This essay is all the more questionable since it is almost impossible to find the figures corresponding to the data tables in the text. This study gives the impression of a scientific smoke in order seeking to drown the fish and to find at all costs some form of result, while being careful not to speak of the side effects (Annex II).
In conclusion, it seems obvious to us that it is necessary to officially question the toxicity of this molecule with highly harmful properties and which has so far shown no patient benefit.
Annex I: on toxicity
The company should provide, for example, the genotoxicity data which is mentioned in the summary of product characteristics (SPC) for compassionate use, provided to the FDA and in which it is mentioned very briefly that "remdesivir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays ", which translates to" Remdesivir did not demonstrate a genotoxic effect in a series of tests, including a study of bacterial mutagenesis, detection of chromosomal aberrations in human lymphocytes, and in studies performed in vivo in rats. » It is strange to note that by arriving then on the desk of the evaluator of the European health agency (EMA), the remdesivir qualified as non-genotoxic and not mutagenized becomes implicitly to a very vague degree which remains to be defined ." A short discussion regarding assessment of mutagenic and potentially mutagenic impurities is presented and is acceptable considering the acute, potentially life-saving use. It is expected that this section is further extended for any upcoming applications. ", Which translates to:" A brief discussion on the evaluation of the mutagenicity of the product and potentially of its impurities is presented and is acceptable considering the urgency of its potential use to save lives. It is expected that this section will be further developed for future registrations. " This implies that the Veklury (remdesivir) is intended to be used on a larger scale, even on a very large scale, beyond compassionate care, which is obviously the aim of Gilead. The document explains that the missing data on the genotoxic and mutagenic nature of remdesivir will be completed when the time comes. If the subject was not so serious, the semantic contortion of this document would be most delightful. This kind of process is sneaky because it allows to pass to the hatch, under the pretext of the emergency, crucial elements on the appreciation of the real toxicity of the remdesivir. Everyone has been able to measure in the course of existence that postponing an essential task generally results in a disaster. The more time passes, the less these elements will be brought to the attention of health authorities and therefore of treating physicians in hospitals. Faced with such carelessness, we are entitled to wonder if after years of use, harmful effects will end up appearing frequently enough to cause yet another health scandal. Who is laughing at, then, Mrs. Janet Koënig, the rapporteur of the EMA responsible for the edition of this document which will be the basis of the blank check given to the Veklury © (remdesivir), first in compassionate use and then to widespread in the treatment of Covid-19?
We asked for an interview with EMA president Christa Wirthumer-Hoche in order to understand the approval procedure for the Veklury © in detail.
And the answer was that the president was not the right person to answer us because the molecule had been evaluated through a centralized procedure, and it was the CHMP which had given a favourable opinion.
Translation: @Smackenziekerr & @PaulGreeff
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