“COVID Therapeutics” – What does that mean?
Biological Drugs, Antibodies, Old Drugs, Vaccines and More…
Dr. Paul S. Anderson
INTRODUCTION:
Why am I hearing “We’ll soon have COVID Therapeutics” on the News? It sounds like this is our road back to something near normal… Is it?
The term “COVID Therapeutics” as used in most media mean drug or like therapies used in the “standard medical system” (i.e. hospitals, clinics etc.). At this point it does NOT include things I have written about in my other newsletters or spoken of in my podcasts such as diet, lifestyle, nutrients, pharmacological use of nutrients (IV Vitamin C) and the like.
Generally, when the media or an official healthcare system refers to a “therapeutic” it is the group I am addressing in this newsletter. My goal is to provide factual information for you the reader to use in whatever way helps you most. I’m NOT writing this to convince you to take or not to take any of these therapies (Yes, I am a doctor, but I’m not your doctor…) this is to help you navigate the emerging world of “COVID Therapeutics” you’ll be hearing about.
We will look at the following categories: Targets of the various categories of therapeutics; Currently approved therapeutics; Therapies in the “pipeline”; and COVID Vaccine information.
***Note-1: This is current as of 12-04-2020; due to the speed of drug approval and development sone items which are not approved as of today may be approved when you are reading this.
***Note-2: This is about “Standard Drug Therapies” and not integrative and nutritional therapies. For those please see my other Newsletters or podcast.
***Note-3: I am asked a lot if the actual virus has been sequenced. In a report made [1] in March 2020 researchers from Sunnybrook, McMaster University and the University of Toronto had isolated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent responsible for COVID-19. So, unless they are not to be believed we have the sequence. Is everyone (such as the people making the PCR test assays) using this? That is a question for another forum, but an important one to ask and investigate.
THE TARGETS OF THE “THERAPEUTICS”:
Before we launch into the list of (some of) the therapeutics being given or proposed for COVID a quick look at why these are used (what they do to the virus or the patient) will help. The main mechanisms of the agents are:
1. Block Viral Activity (Agents such as remdesivir, ivermectin or others).
Antiviral drug therapies usually block replication of the virus via many potential mechanisms. Because of this they often work better when given earlier in an infection but can be helpful at any time in many cases. A consideration in the use of antiviral drugs is since they stop replication there is still virus for the immune system to deal with. Clinically I have found antiviral therapies work better in a setting of immune support (such as some botanical and nutrient therapies provide, see the newsletters referenced below).
2. Modulate Immunity / Immune Reactions (Many drugs such as steroids, biological drugs that block immune chemistry, off label drugs like Pepcid and many others).
3. Treat Disease Induced Dangers such a clotting, excessive inflammation, cytokine release syndrome etc. (Forms of heparin, many biological drugs, and others). This category has a lot of crossover with category 2.
Categories 2 and 3 generally work by slowing or blocking a particular action (such as slowing H2 receptors or clotting) or shifting a process like inflammation to a more balanced state. One example may be the use of a drug early in a case before hospitalization to modulate immunity and promote a healthy inflammatory response. Another example may be the use of heparin in a hospitalized patient to lower abnormal clotting risk.
4. Mimic Natural Immunity (Convalescent plasma, “antibody cocktails” such as bamlanivimab that mimic a natural response (passive immunity) and others).
Antibodies are produced by the “B-cells” of the immune system when we are exposed to an infection. One reason we have immune “memory” is that we usually keep antibodies to past infections around for a long time. These become “neutralizing antibodies” which block the infection if it enters us again. The B-cells are part of “Antibody/Humoral” immunity and do communicate with the “Cell Mediated” (T-cell) side of immunity as well.
Giving a person with an infection either human antibodies purified from the blood of other people who had the infection (“Convalescent Plasma”) or laboratory made antibodies with the same purpose such as bamlanivimab from Eli Lilly or Regeneron’s casirivimab and imdevimab combination.
5. Trigger Artificial Active Immunity (Vaccines).
In the past vaccines have been made by using parts of the infectious agent grown in a lab which, when injected, trigger a memory immune response providing an artificial active immunity against the infection. (It is called “artificial” because to have a natural active immunity you would need to have had the actual infection in the past).
In the age of COVID we now have new vaccine technology that is not really like former vaccines and is discussed at length below.
CURRENTLY APPROVED THERAPEUTICS:
With credit to the Regulatory Affairs Professional Society (RAPS) [2] drugs approved to treat COVID-19:
*Dexamethasone in the United Kingdom and Japan
*Avigan (favilavir) in China, Italy and Russia
*Veklury (remdesivir) in the United States, Japan and Australia.
Recieving emergency use authorizations (EUAs) in the US:
*Convalescent plasma (Blood donated by people recovered from COVID-19 has antibodies to the virus and the blood is processed to remove blood cells, leaving behind liquid (plasma) and antibodies)
*The monclonal antibody bamlanivimab (man-made antibodies that are similar to the antibodies of patients who recovered from COVID-19)
*A drug combination of Veklury (remdesivir, an antiviral drug that stops or heavily delays replication of the virus) and the JAK inhibitor Olumiant (a Janus kinase (JAK) inhibitor. JAK inhibitors help disrupt how cells respond to some cytokines)
Casirivimab and imdevimab as a combination therapy (these are human monoclonal antibodies and bind to the spike protein receptor binding domain of SARS-CoV-2 to block binding to the ACE2 receptor.)
***As mentioned above, these two lists may change daily.
What’s in a name?
Drug names are long and confusing in many cases. If you look at the last letters of the generic name (not it’s trade / brand name) sometimes you can tell it’s category: Ending in “vir” it is probably an antiviral; Ending in “sone, zone or onide” it is probably a steroid; If it ends in “mab, mib, nib, mod” it is likely a targeted biological therapy.
THERAPIES IN THE PIPELINE:
Non-vaccine therapies:
As of today, there are just over 50 therapies in the development pipeline from many drug classes. They range from very old (aspirin, colchicine) to off label over the counter drugs (Pepcid) to repurposed infectious disease agents (Ivermectin, Hydroxychloroquine and Azithromycin with Zinc) to modern ‘biological’ targeted therapies (probably the biggest class here). You can check the RAPS data online for an updated list [2]. All of these candidate drugs are in a variety of stages of study (see notes on Phase 1 through 4 trials below).
A couple of notable updates:
*Zinc plus low-dose Hydroxychloroquine and Azithromycin
I add this as Hydroxychloroquine (HCQ) based therapies have had mixed press and there are subtleties to their ability to work with COVID in most people’s opinions. HCQ works at least via two methods in COVID, one being as a “zinc ionophore” and the other being as an anti-infective / inflammation modulator which may help in other parts of COVID illness. HCQ may have more ways it potentially helps which are beyond the scope of this newsletter. As a zinc ionophore HCQ lets zinc in cells and once inside a cell the zinc can slow viral activity. (Yes, there are natural zinc ionophores such as quercetin which I talk about in other places). The combination of zinc and HCQ makes some sense and the addition of the antibiotic azithromycin likely also adds protection against other infections “piggy backing” on the COVID infection. People who become very ill or die from viral infections often develop potentially deadly bacterial (or other) infections in the lungs and elsewhere. While a lot of media reporting may make one think HCQ based approaches are dangerous the data are not all that way. In one paper [3] looking at COVID patient outcomes the combination of Zinc, low dose HCQ and Azithromycin showed safety and benefit. Highlights from that study (the first COVID-19 outpatient study based on risk stratification and early antiviral treatment at the beginning of the disease) included: Low-dose HCQ combined with zinc and azithromycin was an effective therapeutic approach against COVID-19; Significantly reduced hospitalization rates in the treatment group; Reduced mortality rates in the treatment group. I have referenced the study [3] below.
*Ivermectin
I have used Ivermectin in infectious disease patients as well as in cancer patients over the years. It is a known “anti-worm” medicine in animals and humans but has many effects on the immune system and has antiviral and other properties.
Rather than rely on my experience I will relay information on a large number of patients treated with Ivermectin by Dr. José Natalio Redondo in the Dominican Republic. While this is not a peer reviewed publication but rather an interview, I have included the link below in the references [4]. In the interview they report “At least 6,000 Covid-19 positive patients have been treated with excellent results using the drug ivermectin, by doctors belonging to the Rescue group, with health facilities located in Puerto Plata, La Romana, and Punta Cana.” I will let you look at the link and read the interview if desired but my experience with Ivermectin in some COVID patients and some other severe viral infections acquired in China in the past (a story for another day) would say we should be considering this drug in COVID cases.
Vaccines:
Vaccines of course are in the news. There are, according to the World Health Organization (WHO) 163 vaccines in pre-clinical candidacy and 51 vaccines in clinical evaluation (Phase 1 through Phase 3 trials). [5] Phase-1 through Phase-3 trials are trials of escalating numbers of people being given the trial drug in more and more complex settings. When you hear a drug is in a “Phase-3 Trial” it is generally going to be approved and released to public use as its next step. There is a “Phase-4” trial in the US where the already approved drug is tracked for post approval adverse events.
The three leading vaccines for fast-track approval in the US are two “mRNA” vaccines (Pfizer and Moderna) and one “non-replicating viral vector DNA” vaccine (AstraZeneca/Oxford).
Both the mRNA and DNA platforms mentioned above have the same end point, the production of a “spike protein”. The mechanism used is the genetic information from the vaccine instructs the recipient’s own cells to produce the SARS-CoV-2 spike protein on their surfaces which their immune system then recognizes as foreign and mounts an immune response.
Messenger RNA (mRNA) makes copies of parts of the DNA code in the cell nucleus and then takes that copy out to the cytoplasm of the cell (the larger space outside the nucleus) where it is used to assemble amino acids into proteins. The mRNA vaccines are pre-made mRNA codes in a “lipid micelle” (fat envelope which helps protect the mRNA and deliver it to the cells) that are injected into the recipient. After they travel to the cells, they trigger the formation of the spike protein. Production benefits are that these are relatively easy and fast to manufacture. Downside is that they need to be kept at very cold sub-zero temperatures most hospitals and clinics cannot provide.
The DNA platform is incorporated in a non-replicating viral vector (which is a cold virus called an adenovirus which is not a human “cold” virus but a virus from chimpanzees). The non-replicating part means that the genetics to allow the carrier virus to replicate itself are removed or damaged. Think of “opening up” the adenovirus and harming the replication genes while inserting the code to make a spike protein – that is what this is. So, the recipient has this adenovirus injected, it travels to the cells and delivers the spike protein code and then (after a few more steps) does basically what the mRNA did. Chimpanzee, really? Modern vaccine development has turned to Chimpanzee virus use especially in “emerging” viral threats such as MERS, SARS, Lassa fever, Nipah and others. For those wishing a deep dive into this idea the paper by Ewer, et al (2017) is referenced below [11].
This vaccine has been produced in large quantity for its Phase-3 trials and does not need the extra cold storage that the mRNA versions do. Potential downsides include the fact that we do not fully know what chimpanzee adenovirus (even inactivated ones) do in humans. We know some things about chimpanzee adenovirus [11] but not everything, the real effects of which would only come out after widespread use and adverse event monitoring.
Efficacy?
We hear a lot of information in the media about “XX% this and YY%” that around these vaccines. In an excellent review Professor Roger Seheult, MD shared the following information [6].
First, everything we know now about the statistics around these vaccines comes from (company written) press releases rather than scientific peer reviewed publications. This really must be taken into consideration.
Second, the reports of efficacy from each vaccine manufacturer are based on different measures. One mRNA vaccine company reports “95% efficacy” based on 95 subjects who developed COVID and only 5 of those had received the vaccine (90 got the placebo). AstraZenica reports that they are tracking actual post vaccine COVID infections (by lab testing everyone). AstraZenica report in 9000 people in Brazil receiving the full dose twice a 62% “no COVID infection” rate after the vaccine and in the UK 3000 people got a ½ dose then a full dose and 90% did not develop COVID based on post vaccine testing.
Safety?
Much like efficacy we really do not “know” long term. And we at this point mostly are relying on company generated press releases (and some other data). Adverse events are reported in levels of severity. For example, in Moderna’s Phase 3 trials, the company said the most common side effects were fatigue, muscle soreness and aches, joint pain, headache, and pain, redness or swelling at the injection site. Of interest more than half of Moderna’s study participants had side effects from the vaccine in Phase 1 trials (the early trials with smaller numbers), according to a preliminary report published in July [12] in the New England Journal of Medicine. Like efficacy we really do not have the large population long term data to assess safety. Everything at this moment is preliminary – but in the US and other places we have accelerated (“warp speed” etc.) programs for these vaccines.
As I said above, I am not here to tell you what to do. I am a doctor but not your doctor, so this newsletter is simply to give you information to think about and hopefully talk through with your healthcare team.
In the words of Paul Offit, MD (from an excellent Journal of the American Medical Association (JAMA) lecture about these vaccines[7]) “These new (mRNA and DNA) vaccines are easy to make but keep in mind the best and safest vaccine isn’t always the first vaccine…”
If you have read this far, congratulations! The bulk of the information on COVID therapeutics you may be given in the event you need them is above. But many people have asked me if there is any concern in the medical and scientific community about the vaccines being rushed to the public so the following is an extra section I have added to address that issue.
COVID VACCINE INFORMATION:
A recent publication [8] conveying concerns around the unique situation created by COVID relays the following:
“In general, for a vaccine to be approved or licensed by regulatory authorities, it must demonstrate both safety and high efficacy in the prevention of a specific disease in the relevant populations. However, the COVID-19 pandemic poses specific logistic and scientific challenges with respect to the assessment of SARS-CoV-2 vaccine candidates. Evaluation of the efficacy of SARS-CoV-2 vaccines must consider population risk of exposure, susceptibility to the virus, current social distancing practices and geography. Moreover, SARS-CoV-2 vaccines need to be evaluated in populations at greatest risk for severe COVID-19.”
KEY POINTS [8]
* Challenges to the evaluation of candidate vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) before approval or licensure during the ongoing pandemic include rapidly changing levels of exposure to the virus and population immunity and social distancing practices.
* To measure vaccine efficacy accurately, researchers should account for these factors in sample size calculations and carefully consider selection of trial end points.
* Vaccines for SARS-CoV-2 must also be evaluated in populations known to be at increased risk for severe coronavirus disease 2019, such as older adults, Black people and people with multiple comorbidities.
* Given the speed of vaccine development for SARS-CoV-2, careful attention must be paid to postlicensure assessment of vaccines, including the risk of antibody-dependent enhancement of disease, which must be actively monitored closely over multiple years after vaccination.
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While there are not a great deal of scientific papers specifically on new vaccines like mRNA, an extensive paper written in 2018 summarizes the data known to date. [9] Considerations around development of autoimmunity, triggering inflammation, edema and clot formation should not be taken lightly. I have excerpted one section as well as the authors cited reverences below:
“A possible concern could be that some mRNA-based vaccine platforms 54,166 induce potent type I interferon responses, which have been associated not only with inflammation but also potentially with autoimmunity 167,168. Thus, identification of individuals at an increased risk of autoimmune reactions before mRNA vaccination may allow reasonable precautions to be taken. Another potential safety issue could derive from the presence of extracellular RNA during mRNA vaccination. Extracellular naked RNA has been shown to increase the permeability of tightly packed endothelial cells and may thus contribute to oedema 169. Another study showed that extracellular RNA promoted blood coagulation and pathological thrombus formation 170.”
54. Edwards DK, et al. Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate response. J Transl Med. 2017; 15:1. [PubMed: 28049494]
166. Pepini T, et al. Induction of an IFN-mediated antiviral response by a self-amplifying RNA vaccine: implications for vaccine design. J Immunol. 2017; 198:4012–4024. [PubMed: 28416600]
167. Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (α/β) in immunity and autoimmunity. Annu Rev Immunol. 2005; 23:307–336. [PubMed: 15771573]
168. Nestle FO, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J Exp Med. 2005; 202:135–143. [PubMed: 15998792]
169. Fischer S, et al. Extracellular RNA mediates endothelial-cell permeability via vascular endothelial growth factor. Blood. 2007; 110:2457–2465. [PubMed: 17576819]
170. Kannemeier C, et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA. 2007; 104:6388–6393. [PubMed: 17405864]
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A feature article in the British Medical Journal “Will covid-19 vaccines save lives? Current trials aren’t designed to tell us” [10] brings up other points I believe we should be considering. Again these are unusual times and things are proceeding in unusual ways, but the contributors to this article call out some themes I do not believe we know are happening in the scientific community if all we see is media coverage of vaccine development. Excerpts of this paper [10] are below:
“Only a “safe and effective” vaccine will be approved, they say…”
“But what will it mean exactly when a vaccine is declared “effective”? To the public this seems fairly obvious. “The primary goal of a covid-19 vaccine is to keep people from getting very sick and dying,” a National Public Radio broadcast said bluntly.”
“… “Ideally, you want an antiviral vaccine to do two things . . . first, reduce the likelihood you will get severely ill and go to the hospital, and two, prevent infection and therefore interrupt disease transmission.” Yet the current phase III trials are not actually set up to prove either”
“Medscape’s Eric Topol has been a vocal critic of the trials’ many interim analyses. “These numbers seem totally out of line with what would be considered stopping rules,” he says. “I mean, you’re talking about giving a vaccine with any of these programmes to tens of millions of people. And you’re going to base that on 100 events?””
““If we don’t have adequate data in the greater than 65 year old group, then the greater than 65 year old person shouldn’t get this vaccine, which would be a shame because they’re the ones who are most likely to die from this infection,” said vaccinologist Paul Offit.8 “We have to generate those data,” he said. “I can’t see how anybody—the Data and Safety Monitoring Board or the FDA Vaccine Advisory Committee, or FDA decision-makers—would ever allow a vaccine to be recommended for that group without having adequate data.”
“I feel the same way about minorities,” Offit added. “You can’t convince minority populations to get this vaccine unless they are represented in these trials. Otherwise, they’re going to feel like they’re guinea pigs, and understandably so.””
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What should you do?
Only you can decide that. My goal in preparing this newsletter is to add information I do not believe is easily accessible to the majority of people (without a lot of digging around). And the concern of some quoted above around the vaccine technology should be weighed heavily before deciding if that is the best thing for you or not. Of significant note, those scientists quoted above are not “outside the system” or “AntiVax” but rather are respected members of the scientific community who believe in vaccination done safely. A concern those quoted above (and I) have is that we seem to be getting a more “rosy and happy” picture of the risks and benefits of the therapies from mainstream sources than may be realistic. It is never all bad, but also, it’s never as good as it seems with new medical technology.
The words of Professor Roger Seheult [6] “everything we know now about the statistics around these vaccines comes from (company written) press releases rather than scientific peer reviewed publications.” Are worth consideration.
REFERENCES:
2. Regulatory Affairs Professional Society; COVID-19 therapeutics tracker – Posted 23 November 2020; By Jeff Craven (Accessed 12-02-2020) https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-therapeutics-tracker
3. Roland Derwand, Martin Scholz, Vladimir Zelenko, COVID-19 outpatients: early risk-stratified treatment with zinc plus low-dose hydroxychloroquine and azithromycin: a retrospective case series study, International Journal of Antimicrobial Agents, Volume 56, Issue 6, 2020, https://doi.org/10.1016/j.ijantimicag.2020.106214.
5. WHO COVID-19 Landscape Document Vaccines last updated 12-02-2020 file:///C:/Users/Owner/Downloads/Novel-Coronavirus_Landscape_COVID-19abff2b57-1a18-47d2-933f-ac9745f9954f.pdf
6. Professor Roger Seheult, MD; Coronavirus Update 118: https://www.youtube.com/watch?v=GOq8-FR8s1E&feature=youtu.be medcram.com
7. JAMA Network, Coronavirus Vaccines – An Introduction, October 2, 2020 https://www.youtube.com/watch?v=KMc3vL_MIeo&feature=youtu.be
8. Bahaa Abu-Raya MD, Soren Gantt MD PhD, Manish Sadarangani, Challenges in evaluating SARS-CoV-2 vaccines during the COVID-19 pandemic, CMAJ 2020 August 24;192:E982-5. doi: 10.1503/cmaj.201237; early-released July 9, 2020
9. Pardi N, et.al. mRNA vaccines — a new era in vaccinology. Nat Rev Drug Discov. 2018 April ; 17(4): 261–279. doi:10.1038/nrd.2017.243.
10. Doshi Peter. Will covid-19 vaccines save lives? Current trials aren’t designed to tell us BMJ 2020; 371 :m4037 (downloaded from: https://www.bmj.com/content/371/bmj.m4037?fbclid=IwAR10NZ7T80zy-f6zUZVhNS6MK2gLfOriXXTjrQtbluJKtzix_tOSNO43M9A)
11. Ewer K, Sebastian S, Spencer AJ, Gilbert S, Hill AVS, Lambe T. Chimpanzee adenoviral vectors as vaccines for outbreak pathogens. Hum Vaccin Immunother. 2017;13(12):3020-3032. doi:10.1080/21645515.2017.1383575
12. Jackson LA, et.al, An mRNA Vaccine against SARS-CoV-2 — Preliminary Report, N Engl J Med 2020; 383:1920-1931, DOI: 10.1056/NEJMoa2022483
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