Is there anything to Madagascar’s herbal remedy COVID-Organics?

Over here in eastern Africa, a lot of news has been made of Madagascar’s COVID-Organics extract made from a local plant, introduced by that country’s Institut Malgache de Recherches Appliquées (Malagasy Institute of Applied Research) IMRA, and promulgated not least by the president of Madagascar himself, Andry Rajoelina.

(Prev article #2 of 5) Note: this is the 3rd of 5 articles in our series on flavonoids. Here is the more technical version of it. (Next article #4 of 5)

COVID-Organics as extracted from Artemisia Annua

My experience is that articles on the topic particularly written for audiences outside Africa, like this one from the WSJ tend to have a condescending tone. Contrast coming from within Africa, representatives of many African countries have made a pilgrimage to ecologically-rich Madagascar to pick up a shipment of COVID-Organics, citing their own nations’ histories of relying on traditional medicine.

Meanwhile, on the heels of my last two Medium articles and an MIT Africa takes on COVID venture competition, I’m part of a team investigating plant medicinals of many sources on the protease of the virus that causes COVID-19, SARS-CoV-2.

So while we’ve been proving out our toolchain and getting a UK patent filed on these screening endeavours and the candidate compounds they are yielding, we would be remiss not to look at a purported plant-derived medicinal like COVID-Organics in the same level of detail as we look at our own drug candidates.

Then first, some epidemiology — the proof needs to be in the pudding, no matter what. So we collected the data from Worldometer on sub-Saharan Africa countries’ case statistics. We isolated number of fatalities and number of cases for each country, took the ratio, and arrived at this chart:

Recorded fatalities per recorded case, sub-Saharan African countries as of 25 May

Why did we select this particular statistical ratio? First because it features a degree of tolerance to each countries’ unique patient data collection and recording regime — A country might overcount or undercount cases based on its health system’s unique challenges and incentives. But they are less likely to misclassify or hide a death from among those already registered into ‘the system’. So we see it as a fairer comparison metric of how each country’s health system treats cases that are accepted into it.

More than that however is that in the context of a treatment like COVID-Organics that has been incorporated as the go-to therapeutic for Madagascar’s caseload, we would expect to see signal in this particular statistical ratio uniquely vis a vis other countries that don’t incorporate this therapeutic, assuming all other factors were held equal.

Therefore, note that Madagascar sits in the top-10 of the 47 countries in the data collection. Not a bad showing to be sure, but not strong enough to be compelling. So let’s take a deeper look into those countries that seem to be doing better than Madagascar:

This is a measure we call ‘Out-Performance’. It is simply the number of recorded cases in a country, times the WHO’s recorded average Case Fatality Rate (CFR) for that country’s region of Africa, minus the actual number of fatalities of that country. In short, it tells us how many fatalities that country had vs how many they should have had if they had their region’s average CFR.

(RegionalCFR) x (# of cases) — (# of fatalities) = Outperformance

Now a different story starts to emerge. A lot of the countries that show no deaths also have very few cases (less than 50 from Eritrea on down). Based on a typical CFR, we hardly expect any deaths at such low numbers, with departures from the regional CFR being overcome by random noise. Madagascar now sits in 4th place, neck and neck with Rwanda in 3rd, after France’s territorial island of Reunion in 2nd, and Central African Republic in 1st place with its 600 cases and just 1 fatality.

We have now zoomed in to a level that it’s worth looking at special cases of each country. Rwanda is famous for the strength of its public-sector. Its highways are the best kept in East Africa and its capital city is a showpiece capital of government project spending. To its credit it should come as no surprise they have a strong public health sector. Reunion is a French territory, and has the benefit of France’s similarly famous public health system’s resources. So while Reunion’s performance deserves kudos in its own right, it’s not surprising given the France resource influence.

Central African Republic (CAR) however is known for none of these public sector tailwinds. It’s a poor landlocked country with a GDP per capita of $400 per year — one of the lowest in the world. And it’s been wracked with civil war since 2012. Not the kind of place you’d expect to be doing well in a global pandemic of a highly infectious, life-threatening illness as COVID-19. And indeed, CAR has over 600 cases to its name.

But there is one thing notable about Central African Republic. They are the only one of the countries on the shortlist whose health ministers took volume delivery of COVID-Organics from Madagascar by May 8th. (note: see Dec 26 2020 update below). It’s not unreasonable to assume that those volumes reach the hands (and mouths) of that country’s caseload of COVID patients. Then they’ve had 17 days for artemisia administrations take place and start showing up in the epidemiological record as a lack of the fatalities that everyone would otherwise expect to be there.

So we realize now we’re not just looking at a chart of Madagascar vs. all the other countries here, we are looking at a chart of Madagascar & Central African Republic vs all the other countries. Now the chart is delivering an unanticipated message indeed. CAR is top of the list, bar none.

So what does this all mean? We say it’s time to pay extremely close epidemiological and clinical attention to COVID-Organics’ efficacy on COVID-19.

What could be going on in this novel potion? Let’s peer into the cauldron and find out:

COVID-Organics is quite literally an herbal ‘tea’ — a hot water extract of the plant Artemisia Annua. A. annua is a famous plant in phytochemical circles because it contains the famous artemisinin, the compound renowned in pharma circles by its inhibitory efficacy on Plasmodium falciparum, better known as the parasite that causes malaria. Discovered by Chinese western-cum-traditional pharmacologist Tu Youyou, artemisinin earned its uniquely nature-derived place in the mainstream pharmacopoeia as the first-line, WHO-anointed, medication for malaria infection.

But it has a lot of other compounds too. Let’s take a look:

“Flavonoids from Artemsia Annua . . . “ (Ferreira et al)

In all 53 identified compounds, plus the famous artemisinin. So we looked at which of these could feature the same kind of inhibitory efficacy on SARS-CoV-2’s protease as we ordinarily screen for in the in silico assay we use in our main-line drug screening. Our screening process, while complicated, is immutably documented in a UK government filing and available for scrutiny by the world’s researchers.

Our screening sits atop an industry-standard drug docking tool called Autodock Vina. (The Autodock family of docking software has been used for screening by life sciences researchers across the body of published biochemistry literature over a decade now). Vina generates results to a -4 to -12 scale, where the more negative number is more inhibitory (i.e. ‘better’) for defeating the virus’ ability to replicate itself. How does inhibition work? Well like most viruses, SARS-CoV-2 has an enzyme called its ‘main protease’. After hijacking its way into the human cell, the protease acts like a seamstress’ scissors: It cuts (‘cleaves’) peptide chains to shape in order to make new copies of the virus, which will go on to infect more cells.

By the way, we calibrated our tool by comparing its results of 27 compounds with actual, in vitro lab inhibitory testing results performed by laboratory researchers on the same 27 compounds during the intervening 17 years since 2003's SARS epidemic. Based on an independent, randomly-selected test set of 8 compounds, our classifier has a demonstrated software-to-laboratory accuracy of 87.5%.

Then on the -4 to -12 scale and with the -7.7 threshold, here are the compounds of A. Annua yielded from our assay as strong performers:

Hits of -7.7 kcal/mol and above Source: EMSKE Phytochem

First, it’s worth noting that artemisinin doesn’t even rate for purposes of COVID-19 virus’ protease. Instead, the majority of these “placers” are common flavonoids and their glycosides. What’s more, while all of these 10 show baseline levels of potency, quercetin-7-glucoside (aka “quercimeritrin”) actually presents rather strongly - In our screening, we consider -9 and above a ‘strong hit’ thanks to those models based on SARS in vitro data to show how being a strong hit translates to greater potency.

Here is the top “pose” determined by Autodock Vina of what quercetin-7-glucoside looks like in it’s lowest energy (read: highest potency) binding state to the protease:

This is in the ‘tunnel’ structure of the SARS-CoV-2 protease, called Mpro.

Pictured is the ‘tunnel’ structure of the protease, which the quercimeritrin slides right into.

In short, we in EMSKE Phytochem come out very much in support of COVID-Organics, and we’re happy to help put a loudspeaker on that. But you don’t have to go all the way to Madagascar to get access to the benefits of this extract. Most of what we see as reasonably efficacious in the extract is in a lot of common everyday fruits & vegetables foods. Most prevalently among them, red onions. (Of course, it would take consuming an entire onion or two per day to achieve the expected inhibitory dose required, so a more isolated / extracted approach might preferred).

We also feel it’s important to recognize the role that traditional medicine has played here. Madagascar’s IMRA health research institute was the originator of trying Artemisia Annua extract on COVID patients. It was a much more efficient route to identifying drug ‘hit’ candidates than the formal Phase I-III clinical trials route espoused by the FDA in the US. While it’s not without side effects, such as headaches, this plant has been known to (Chinese) traditional medicine to be safe for administering by way of ingestion. When the dust settles, the world may end up owing a great debt to Madagascar, IMRA, and the paradigm of traditional medicine development models as conducted through an investigatory (but systematic and safe ) scientific lens for its treatments.

There’s more in the research pipeline in terms of compounds we are identifying efficacy for which we’ll be unveiling in the weeks ahead. Stay tuned on Twitter @EMSKEPhyto or follow us on LinkedIn and you’ll be among the first to hear about new covid-targeting pharmacological content, clinical trial readiness, and medicinals marketing initiatives as we release them.

Update 3 July: The Max Planck Institute in Germany has been carrying out in vitro tests of different formulations of the artemisia extract as well as refined artemisinin. Their results are that the artemisia extract is indeed showing efficacy on SARS-CoV-2 inhibition, and the refined artemisinin has no effect. In other words, very much in agreement so far with the above.

Update 26 Dec 2020: Improving the analysis and availing of Chad media reports and supported by Covid-Organics Africa-wide shipment data (obtained offline), the following findings present themselves:

  • Covid-Organics turns out to contain extracts primarily of two plants artemisia annua and Ravintsara (as cinnamomum camphora).
  • From the audience gained through the above post, I was able to obtain confidential shipment data of CVO to African countries during the pandemic period. (Unfortunately I can’t share that data for confidentiality reasons). Suffice to say that the above list of countries who received CVO wasn’t comprehensive and of course lacked the important nuance of how many doses were shipped to each country.
  • It was found through the shipment data that the nation of Chad was the only country to maintain sustained and significant shipment volumes of Covid-Organics relative to caseload, and was known through local media reports to have administered it with intention to its covid patients.
  • That assertion turned out to be backed up by relevant media reports from Chad (in French). In chronological order they are 12-May: A, 4-June: B, 11-June: C, and 16-June D. (I’ve made inquiries through a WHO program manager contact to Chad’s Ministry of Health; as anywhere, covid-related data is heavily politicized, so I have only learned that they haven’t produced any formal data for public consumption other than the media reports).
  • From article C, we know that 34 ‘high-risk’ covid patients were treated exclusively with Covid-Organics by 4-June. All were brought back to health again. Given Chad’s high initial fatality rate at the start of their outbreak, this is notable.
  • Article C implies that additional patients were treated with covid-organics alongside other medications. However Article D goes on to mention that covid-organics should not be used with hydroxychloroquine. (This isn’t surprising as similar flavonoid glycosides are known to competitively inhibit two liver enzymes known for processing many common chronic medications — and so the possibility of hydroxychloroquine overdoses in patients so treated exists — such unfortunate events would explain their media’s non-reporting of that patient segment)
  • One of their government ministers is quoted saying (Google translated), “We are pleased today to reiterate what our Minister of Health has already said. Covid-Organics has been a positive experience in Chad”

But is that conclusion supported by data?

  • Given that there is typically a lagtime between a reported case and any fatality associated with it, the Outperformance metric described earlier is brought out in terms of zero lag, 1-week lag, 10-day lag, 2-wk lag, and 3-wk lag.
  • The outperformance data for Chad accounting for case-fatality lag, (set relative to an arbitrary 10% baseline) is:
  • What we see is the case fatality rate initially doing poorly; Then from May 12th we start to see an improvement in Chad’s case fatality ratio performance (across all lag metrics).
  • This can be compared to the raw Case vs. Fatality charts for Chad from Worldometer — note the gap of the case trace (blue) over the fatality trace (red) in days 20–40. So the above chart is essentially highlighting the gap seen in yellow below.:
Day 0 = May 3rd. Blue: Chad covid cases (left side scale), Red: Chad covid fatalities (right side scale). Yellow highlighted is anticipateded fatalities that (thankfully) never materialized.
  • Indeed, 12-May (as per Article A) is when the first Covid-Organics (aka Tambavy CVO) shipment is confirmed to have arrived in Chad. We don’t know precisely how soon after 12-May they start administering to patients, but we presume soon afterward as by 4-June they report having already administered to patients and seeing encouraging results.
  • As the right-side and left-side scales have been proportionally well-aligned to each other, then reviewing the yellow highlight, we offer that it’s possible that Chad saved up to 20–25 lives with their CVO intervention.
  • Might any lives have been lost due to the intervention? It’s actually not outside the realm of possibility. Article D seems to acknowledge the possibility when they warn about co-administration of CVO with chloroquine. This drug interaction makes sense, as flavonoids competitively inhibit liver enzymes that are relied upon to process xenobiotics such as chloroquine. (The resulting overdose causes heart arrhythmia which could prove difficult to manage in a low capability health care setting).
  • Net-net of any such complications, it looks like Chad and its patient caseload came out the better for the intervention. In the face of a pandemic outbreak with essentially nil treatment options at the time (remember this is all before dexamethasone’s efficacy was identified), it’s hard not to appreciate the unique actions that their health ministry took during their May outbreak.

Formally what we’re showing here is just a correlation. There can be other causes for Chad’s improvement in performance from the primary outbreak — perhaps improved patient detection and handling protocols as healthcare workers became experienced with the novel pandemic, or additional ventilators made available, etc. But coupled with the reports from their government we believe we are seeing a little more causality than just strict correlation.

Update 10 Mar 2021: The Max Planck lab published in vitro replication inhibition results on artemisia extracts , and more recently, CVO. I’ll link here for now — lots of nuance in these. A WPI / Columbia group also did same with artemisia extracts and came to some interesting findings too. Will discuss the Max Planck artemesia extract results first as the CVO & WPI/Columbia results are still very recent.

The November Max Planck paper saw artemisia extract IC50’s ranging from 128–260 μg/mL, and a selectivity index (multiple of the IC50 before cytotoxicity occurs) of about 7. The question is, is that good or not good for artemisia extracts? It’s really difficult to determine in terms of the usual micromolar IC50 metric, because extracts have many molecular species in them — that doesn’t lend itself to trivial molarity calculation. Also, when there are extracts involved, there’s the question of solvent — was the recorded mass in including solvent or just Dry Weight (DW) recorded at a particular stage of preparation? The sine qua non of course is, how much of a potable extract must be consumed to have a desired effect in animal models and ultimately humans, but that’s going to have to wait for a future publication from some of these great teams.

To stay apprised of our latest in silico studies results and clinical trials readiness, stay tuned on Twitter @EMSKEPhyto

Coming from a multidisciplinary MIT technical background and startups in San Francisco & SE Asia, Rick leads @EMSKEPhyto .