For obvious reasons, there has been a lot of attention paid to work going into developing vaccines that could prevent Covid-19 infection, and drugs that could treat it. In particular, there has been some excitement about new animal trial data for remdesivir, a drug developed by Gilead Sciences. Gilead's share price rose nearly 10% on the day the trial data were announced.
It will be some time yet before the safety and efficacy of remdesvir is established, if ever (it's worth noting that it was tried, unsuccessfully, as a treatment for Ebola). And since I started work on this post yesterday, the results of the first full trial have leaked out and are frankly discouraging. Remdesvir made no difference to mortality or recovery time and more than 10% of treatments had to be halted because of adverse effects.
But what if we already had an antiviral drug that was effective against Covid infection? (No, not hydroxychloroquine, which for all Donald Trump's marketing efforts is performing badly in trials.) Its an active field of inquiry and the HIV advocacy site i-Base has published a list of potential candidates – which include remdesivir – with a focus on the cost of generic manufacture.
It's another treatment on that list that Australian doctor James Freeman believes may have emerged as an effective treatment in trials in Iran: a daily oral dose combining sofosbuvir (which was developed by Gilead) and daclatasvir (which was developed by Bristol-Myers Squibb). The two have been previously combined as a treatment for hepatitis C – indeed, that's pretty much the only way daclatasvir is used. The combination was easy to use in a trial in Iran because it's manufactured there as a fixed-dose tablet called Sovodak.
There's a description of such a trial here in the Iran Registry of Cinical Trials.
Dr Freeman's analysis was outlined in an email newsletter sent out to his network this week, which I've pubished below with his permission.
I know Dr Freeman through work I've done over five years writing about hepatitis C and the new generation of direct-acting antivirals that have emerged in recent years as functionally a miracle cure for that infection. He has cooperated here with Professor Ed Gane, initially on validating generic DAAs as a treatment, then, as funded treatments became available, promoting a "test and treat" campaign as he did in Australia. He continues to advise Hep C Action here.
It was also through writing about Hep C that I learned about Gilead's market strategy for sofosbuvir. The company beat everyone else to market in 2013 – in part by acquiring other pharmaceutical companies for their IP – and sought to quickly recoup its investment via predatory pricing. Gilead priced by country and in developed nations, it charged as much as $US1000 a tablet for a one-tablet-daily 12 week course. The drug, marketed as Sovaldi, cost $11 billion to get to market, trial costs included. A 12-week course contains about $300 in actual ingredients – and it made $31.5 billion in its first three years on the market.
It was that pricing that drove Dr Freeman to set up the Fix Hep C buyers' club to get generically-manufactured antivirals to patients who needed them. The pricing issue was only fully resolved in New Zealand when Pharmac struck a deal for a new, competing antiviral, Maviret.
Pharma is a brutal business in a number of ways. In particular, it relies on novelty to sustain revenue growth. It's plausible that Gilead might choose to focus on a "new" drug rather than one which has had its market cycle and can be cheaply produced in a number of countries – Iran included. More so if the effective medicine is a combination with another company's drug. It might not make financial sense to conduct trials that benefit another company. Or sofosbivur/daclatasvir might simply have got lost in the rush – everywhere but Iran.
Dr Freeman has a line of communication with Iranian researchers and is sufficiently certain of what he's seeing and hearing that he has offered to put up his own money for a trial. The case for trials outside Iran would seem to be no less then for remdesvir, or for hydroxychloroquine – particularly given that sofosbuvir/daclatasvir poses a notably low risk of adverse effects.
There are currently three hydroxychloroquine trials underway in New Zealand – two examing it as a treatment and one as a prophylactic measure for health workers. In Australia, the ASCOT trial of hydroxychloroquine and kaletra (a combination of the antiviral drugs lopinavir and ritonavir which has previously been used to treat HIV) involves 50 hospitals.
There are complexities in dose and formulation around all these drugs, and a question as to whether sofosbuvir, a prodrug, would be activated in the lungs the same way as it is in the liver (Dr Freeman believes that to be the case). But if Iranian researchers have found that a treatment already in manufacture offers benefit as even a short-term treatment, it would be a tragedy if culture, commerce or geopolitics got in the way.
----
Letter from James Freeman, 21/4/20
For those of you who like executive summaries, here it is. It may surprise you to know that doctors in Iran have commenced 109 clinical trials on treatments for COVID-19 and have recently announced that they have found a cure, where that cure looks like no ICU deaths and rapid recovery for patients.
While Iran has not announced the name of the drug it can be accurately deduced via an analysis of their clinical trials database. The drug is a locally produced fixed-dose combination of Sofosbuvir (Sovaldi) and Daclatasvir (Daklinza) which is normally used to treat Hepatitis C virus. In what I personally consider a staggering oversight doctors in developed countries are not testing this combination. It has been right under our noses the whole time and we have left it to Iran to prove it works.
What follows gets a little technical for a moment then moves on to some Sherlock Holmes style investigation and a call for action to duplicate the trials in Iran as see if their observations hold true.
Keeping in mind that both Hepatitis C (HCV) and SARS-CoV-2 are +ve sense RNA viruses (quite similar in plain English) it would be reasonable to assume that nucleotide analogues (NUCs) proven to work for HCV might work on SARS-CoV-2. In simple terms, NUCs are fake letters in the RNA genetic alphabet CGAU.
Ribavirin, Remdesvir and Sofosbuvir are all NUCs and represent fake letters "G", "A" and "U" respectively. The strategy of using fake genetic letters to impair the activity of critical viral polymerases (the thing that clones the genetic material) is well known and will not be discussed further.
With Hepatitis C we can observe Ribavirin is weak with a log kill of only 0.5 (2/3 viruses killed) and a wide range of well-known side effects because it is not very selective. Conversely, Sofosbuvir is very potent with a log kill of 4.5 (31999/32000 viruses killed). Besides staggering potency, the key feature of Sofosbuvir is its lack of toxicity. Almost every other NUC developed for HCV, HIV and other viruses failed, not due to a lack of potency, but rather
due to toxicity on human cells.
While there are high hopes for a Gilead drug called Remdesvir, the reality is that Remdesvir is intravenous only and currently only exists at experimental scale, so, even if it is proven to work, the likely global utility is small unless you are super-rich.
Conversely, Sofosbuvir is a tablet and widely deployed,making it a superior trials candidate on those grounds alone. We know Sofosbuvir is safe in humans, we know the doses, so why are we not testing it? We did, in fact, consider testing it way back in February but for reasons that elude me that avenue of investigation appears to simply evaporate.
Fortunately, some people are testing it, in humans, and the results appear very encouraging.
In an article titled Abadan Protocol in the Treatment of COVID-19 (in Persian) we see a news report, which translated to English reads as follows:
Abadan Protocol in the Treatment of COVID-19
Today, Iranian news agencies reported the success of a new treatment in Abadan that has been effective in improving patients with COVID-19. But unlike the usual procedure, no explanation has been given about the details of the treatment.
"In this study, the effect of an antiviral drug on critically ill patients with COVID-19 was examined at Ayatollah Taleghani Hospital in Abadan," said Dr. Salmanzadeh, head of the Abadan School of Medical Sciences.
Dr. Sara Mubarak, the faculty's vice chancellor for education and research, said: "Patients were divided into two groups: the first group received the national standard protocol and the second group received the proposed Abadan protocol, and the result was zero. "The group has also declined."
"It was very important that the people who were in the intensive care unit and received artificial respiration return to normal breathing after four days and get the conditions for discharge from the hospital," Mubarak added.
Due to the unknown type of treatment, we asked one of the members of the treatment team for this research. He also insisted on not naming the drug used, citing the possibility of individuals and patients invading pharmacies to supply and use it arbitrarily, adding that "we have left the Ministry of Health to confirm the results of the study and the introduction of the drug."
"According to the national protocol, hydroxychloroquine is in the treatment and only one antivirus has been added to the protocol," he said in a brief description of the treatment.
"The new protocol was prescribed to 30 patients and compared with 30 patients in the control group compared to the national protocol after one month," the researcher said of the study groups.
The doctor of Taleghani Hospital in Abadan also said about the results: "Five
patients who were intubated were all extubated." [ie patients on ventilators were taken off them]
A longer version of this press release was published by the Islamic Republic News Agency here and sheds more light on the clinical impact of the Abadan protocol as well as a relevant fact, namely that ethics approval for a clinical trial was sought. That allows us to find the trial. The report selected for translation above was used to shed some light on the secrecy around this.
- In Iran, Sofosbuvir/Daclatasvir is available as a locally manufactured single-pill fixed-dose combination under the name Sovodak.
- There are a total of 109 clinical trials for COVID-19 registered in Iran with 5 trials of Sofosbuvir/Daclatasvir, one each for Sofosbuvir/Velpatasvir and Sofosbuvir alone, and 102 others researching various therapies.
- A trial of Sofosbuvir/Daclatasvir for COVID-19 in Abadan, for 60 patients (30 controls, 30 treatment) — is listed on the Iranian Clinical Trials Registry and the responsible person listed is Sara Mubarak as mentioned in the news story.
- There are 4 COVID-19 trials registered as being in progress in Abadan, so with N-acetylcysteine, Vitamin D, Vitamin C and Naproxen not being recognised as antiviral medications the only candidate trial that fits the mystery description of “one antiviral” is the Sofosbuvir/Daclatasvir trial noted above.
- An astute observer will note this trial corresponds to the time the death rate in Iran started to fall and further note the Abadan trial has recently been updated with a comment: “Adding other hospitals for recruiting patients”.
- Although relations between many nations and Iran are frosty, their medical system is first class and their clinical trial system stringent, so it seems unwise to simply ignore or discount their observations.
With respect to Daclatasvir, we know it is easy to make, in the Medicines Patent Pool, and currently widely deployed. It is broad-spectrum on Hepatitis C (working for all genotypes) and has very few side effects. It was predicted by South Korean rational drug designers to be active against SARS-CoV-2 back at the end of January but to the best of my knowledge is not being tested outside of Iran, although trials are scheduled to start in Algeria and Uruguay soon.
As a generic, Daclatasvir costs about $0.50 a tablet so could treat patients in bulk at an affordable price. It has a simple 4 step synthesis making it trivial to manufacture at mass scale if existing stocks exhaust as they have done for Kaletra (an HIV drug being repurposed for COVID-19).
As a single agent virological breakthrough is not observed for 6-8 weeks which, if it turns out to be more important than Sofosbuvir in the Abadan protocol, appears adequate for the short term requirements of treating acute COVID-19.
Because the drug used in the Abadan protocol is a fixed-dose combination it is unclear if the efficacy observed relates to only one, or both components.
Urgent further investigation seems warranted so my call to action is for researchers worldwide to add this seemingly proven combination to the array of medications we are looking to re-purpose. It would, I think be sad if cure was indeed right under our noses but we refused to research/use it because Iran found it first.