Pros & Cons of today's best therapeutic option for Covid-19. What to do when we don't have time?


"After reviewing the existing literature on possible therapeutic options; treating patients with severe or critical Covid-19-induced pneumonia with chloroquine or, if failing that, with hydroxychloroquine, provided they tolerate it, is an option that could save many lives while waiting for a more suitable drug to be approved."

There is no need to repeat what we all know: we are facing a serious health emergency like never before in history. The pandemic affects everyone. Although the death rates are relatively low for the normal population, it poses to be extremely dangerous for vulnerable groups; mainly the elderly and people with previous pathologies. The main symptoms that lead to the death of these patients is virus-induced pneumonia. In severe cases, patients must be treated with oxygen and on many occasions, require respiratory assistance by mechanical ventilation. This fact, in addition to the necessity to keep the patient isolated, are the fundamental reasons that are giving rise to the most dramatic part of the pandemic: death of underprivileged people who either cannot be cared for due to lack of resources, or if they are, they cannot survive and they must also spend their last moments in isolation - that is to say, alone.


There are several drugs being studied, as well as vaccines under development. Unfortunately, the outspread of the virus is so fast, that when these products would have passed all stages of investigation, many will have died in the meantime.


I remember the approval of protease inhibitors in 1996-1997 when I was working as product manager at Roche. Given the speed at which AIDS cases were growing and the health problem it posed, with young people dying, health authorities made the approval of the three drugs much faster than it had ever been before. Despite the progression, the process took months and cost many people to lose their lives.


Since then, both the FDA and EMA have established an ‘fast track approval’ system for exceptional cases, but even those deadlines are insufficient to meet the needs of the present situation. Recent data from two days ago (https://www.worldometers.info/coronavirus/), shows the recorded number of new daily deaths reached 1,600, with a daily average increase of over 300 cases in the last five days. Taking into account that the United States and UK are becoming part of the countries with high-growing cases of infection, and that Italy and Spain are far from having the viral spread under control, the death toll can be as much as 3,000 or 4,000 cases daily.


According to a study published by Qu Li et al in the New England Journal of Medicine (NEJM) (https://www.nejm.org/doi/full/10.1056/NEJMoa2001316),  14% of infected hospitalized patients showed severe symptoms, and 5% had critical symptoms, with high mortality, especially in the latter group. Making a linear projection using the same sources mentioned above, in two weeks the number of infected hospitalized patients will be close to 800,000 - of which 112,000 will be severe cases and 40,000 critical. Therefore, it will be necessary to decide what to do with the 150,000 patients who have a high probability of imminent death, as they will surely not be provided with intensive care, at least not everyone.


Available treatments

As mentioned above, there are several drugs under experimental trials to treat patients as well as some vaccines to prevent the spread of the epidemic. We have selected six treatment options that we think have the best chance of short-term success. The following contents are a brief summary and informative details of the advantages and disadvantages of each of these possible options as of today.


Alpha interferon 

Interferon alfa-2b is an antiviral and antineoplastic medicine. It is a recombinant form of the interferon alpha-2 protein that was originally sequenced in e. coli in Charles Weissmann's laboratory at the University of Zurich. It has been used for a wide range of indications, including viral infections and cancers. This medication is approved worldwide for the treatment of chronic hepatitis C, chronic hepatitis B, hairy cell leukemia, Behçet's disease, chronic myelogenous leukemia, multiple myeloma, follicular lymphoma, carcinoid tumor, mastocytosis, and malignant melanoma. A Cuban company developed a version of the product that has been successfully tested (along with other drugs) on Covid-19 victims in China . It is listed in the recommendations of the Chinese International Exchange and Promotive Association for Medical and Health Care (CPAM) along with other therapeutic options. The specific recommendation is 5 million units nebulized twice a day. (https://www.elsevier.com/__data/assets/pdf_file/0007/988648/COVID-19-Drug-Therapy_Mar-2020.pdf)


Advantages:

  • Aerosol inhalation is convenient for patients with difficulties swallowing an oral drug.

  • It is a known drug and there is clinical experience with it in high-risk patients.

Disadvantages:

  • Adverse effects are multiple and severe. It could only be applied in cases where the benefits outweigh the potential risks

  • It is a product for hospital use that can be complex to handle in the outpatient setting.

Lopinavir / Ritonavir:

Best known by its trade name, Kaletra, even if currently existing as generics on the market. There are currently various clinical trials for use this therapeutic option in combination with others, but at the moment there are no conclusive results that support its effectiveness.

Among the various combinations being tested are interferons, guanosine analog RNA synthesis inhibitors, reverse transcriptase inhibitors, or influenza drugs such as baloxavir, marboxil, oseltamivir, and umifenovir. The first results are scheduled for the end of May.


Advantages:

CPAM recommends it as treatment option combined with interferon alpha (5 million units nebulized twice a day). It was recommended based on data from a retrospective cohort and various individual case studies. Despite not being solid scientific evidence, it is however properly documented.

  • Generic cost is relatively low

  • His safety profile is proven by years of treatment of HIV patients

  • There are many companies that can manufacture it

Disadvantages:

  • As a single treatment, it has been shown not to provide therapeutic benefit over standard treatment (https://www.nejm.org/doi/full/10.1056/NEJMoa2001282) 

Remdesivir (GS-5734):

A drug currently in clinical development. A nucleoside analog that was originally studied to stop Ebola. In the treatment of SARS-Cov-2 or Covid-19, it has shown very promising preliminary results. In preclinical testing, the Remdesivir has shown significant activity against coronavirus and a high genetic barrier to resistance. It is considered the specific drug most likely to become the therapeutic option of choice, but there is still a long way to go. Currently, and based on preliminary data, Remdesivir has been administered to several hundred patients with severe SARS-CoV-2 infections in the United States, Europe, and Japan through compassionate use. There is also a clinical trial evaluating the efficacy of Remdesivir in infected patients with SARS-Cov 2 in China. The first results are expected in April 2020. There is also a clinical trial in Europe with the participation of several Spanish hospitals (https://www.diariofarma.com/2020/03/15/coronavirus-varios-hospitales-espanoles-involucrados-en-ensayos-clinicos-con-remdesivir-de-gilead).

Using current data, this drug has the following profile:


Advantages:

  • Promising results

  • The genetic barrier that shows the appearance of resistance would make it an ideal alternative in the future if the first results are confirmed

Disadvantages:

  • Experimental drug, no management experience

  • Only one company manufactures it (except in China, where a biosimilar has been performed). It is unclear whether the necessary universal access would be possible under current conditions

  • Potentially expensive, as it depends on the negotiations that are established with the manufacturer (Gilead Sciences). We have already some experience in the past with the hepatitis C.



Favipiravir

 Also known as T-705, it is a chemical entity that is experimentally used as an antiviral drug against different kinds of virus RNA. It is a pyrazinamide derivative that has been shown to be active against influenza virus, yellow fever virus, West Nile virus, and other flaviviruses, arenaviruses, bunyaviruses, and alphaviruses. China has concluded the clinical investigation of the drug, showing its efficacy against the Covid-19 coronavirus, as confirmed by the country's government and reported by the Xinhua News Agency 8. This drug was approved for clinical use in Japan in 2014. (https://www.biospace.com/article/fujifilm-influenza-drug-shows-efficacy-in-treating-coronavirus-chinese-researchers-say/).

According to the results of clinical trials conducted with affected patients in Wuhan and Shenzhen by Chinese medical authorities, favipiravir (also known as Avigan) has been shown to be effective in both reducing the duration of the COVID-19 virus in patients and improving the lung conditions of those who received treatment with the drug.


The trials were carried out on 340 patients, and since the drug has already been developed and approved for the treatment of influenza, it has a "high degree of safety," according to the Chinese Ministry of Science and Technology official Zhang Xinmin. The tests showed a reduction in the period during which the patients tested positive for the new coronavirus from 11 days to only four, and showed improvements in the lung condition of about 91 percent of the patients treated with favipiravir, compared to only 62 percent for those without among trial participants.


Advantages:

  • Product already approved, with an acceptable safety profile

Disadvantages:

  • Efficacy not yet tested on this virus according to standards. More clinical trials are required to prove its effectiveness in patients with Cov-19 and to know what type of patients it should be administered to.

  • Only available (as an approved drug) in Japan

  • Only one company manufactures it, complicating its worldwide availability in the short term

Umifenovir

In February 2020, Li Lanjuan, an expert from the China National Health Commission, proposed using Arbidol (umifenovir) together with darunavir to treat the Wuhan coronavirus outbreak. He claimed that preliminary tests had shown that Arbidol and Darunavir could inhibit the replication of the virus. We have found no published scientific evidence on this product, except a generic mention to a clinical trial (https://www.nature.com/articles/d41587-020-00003-1)

Advantages:

  • Another therapeutic option to try

Disadvantages:

  • Not approved in the EU or in any country with high regulatory requirements

  • Efficacy not proven according to usual standards

  • Only manufactured by a company and in a very specific geographical area, which complicates its availability worldwide in the short term.

Chloroquine and Hydroxychloroquine

Chloroquine phosphate is a long-standing product on the market that has been used to treat malaria. Hydroxychloroquine for its part is used to reduce inflammation in the treatment of rheumatoid arthritis and lupus.


On March 12th, a document appeared from a consensus group in Guangdong province (https://www.ncbi.nlm.nih.gov/pubmed/32164085), that referred to chloroquine treatment as follows: "We found that treating patients diagnosed with pneumonia from the new coronavirus with chloroquine could improve the rate of treatment success, shorten hospital stay and improve patient outcome. To guide and regulate the use of chloroquine in patients with novel coronavirus pneumonia, the multi-center collaborative group of the Guangdong Province Department of Science and Technology and the Guangdong Province Health Commission for chloroquine in the treatment of Novel coronavirus pneumonia developed this expert consensus after extensive discussion. The chloroquine phosphate tablet, 500 mg twice daily for 10 days, is recommended for new patients diagnosed as mild, moderate and severe cases of coronavirus pneumonia who have no contraindications to chloroquine.”


A study published in the last days, Gautret et al, ( https://www.mediterranee-infection.com/wp-content/uploads/2020/03/Hydroxychloroquine_final_DOI_IJAA.pdf ), showed that hydroxychloroquine treatment was significantly associated with reduction/disappearance of viral load in patients with COVID- 19 and its effect was reinforced by the co-administration of azithromycin, another well-known drug.


Advantages:

  • Drug available in significant quantities

  • Manufacturing companies in many countries

  • Controllable security profile (has been in use for many years)

  • Recommended by Chinese consensus groups that have treated patients with the disease

  • Successfully used in both China and Korea

Disadvantages:

  • Possible serious ocular adverse effects in prolonged treatments



Discussion / Conclusions / Suggestions

There are undoubtedly many more drugs under investigation than we know little about. However, with the existing data, the six mentioned are the ones that we can consider today to be the closest alternatives. The best strategy should be to continue studying the effectiveness of all the options in parallel. The more alternatives we try, the more likely we are to find one that works.


However, if we wait to validate the drugs with the usual criteria, many people will die in the meantime. A pandemic that is carrying around 2,000 people a day and that will soon be 3,000 or 4,000 cannot last up to three or four months. The priority must be to reduce contagions to prevent systems from collapsing, but realistically this goal is in many places beyond our means.


Without being a doctor, but with more than 20 years of experience in the pharmaceutical world, I suggest the most logical solution as of today would be to assume certain risks and introduce treatment with chloroquine or alternatively hydroxychloroquine. It would be open to discussion whether the administration in all cases would be justified since on many occasions the adverse effects could be important in patients with long life expectancy.


However, in the case of patients with severe and critical pneumonia symptoms (14% and 5% of the total), it should be done immediately. My arguments are the following:

  • The situation in these patients justifies the assumption of risks of the aforementioned adverse effects. Without treatment, the possibility of death is quite high and the administration of these products seems to have shown some efficacy.

  • It is a well-known drug and there is clinical experience.

  • There are many companies that manufacture it globally, which would facilitate access to it in a period of time and in much greater quantities than in other products reviewed here.

  • It is an oral administration product, which would allow outpatient treatment (under supervision)

The possible scenarios that could be given are:

  • Significant improvement of patients. In such a case, expanding coverage to moderate patients could be studied.

  • Reduced improvement of patients. At least we would save time

  • It does not improve at all. In such a case, treatment would be discontinued, but the loss would be minimal.

  • General worsening. Quite unlikely from clinical experience in China and Korea. In desperate situations, any specialist knows that they must take certain risks. Without a doubt this is one of them.


Last, but not least…

Emergpharma has a network of contacts of more than 28,000 professionals in the pharmaceutical industry worldwide. Among these contacts are companies that manufacture or market chloroquine phosphate and hydroxychloroquine in the main countries. We would like to make this information available to people who may need it. Likewise, we offer ourselves as service to establish contacts and facilitate, as far as possible, into discussions to find a solution for this global issue. We do this because it is a global emergency and our role is to collaborate so that it happens as soon as possible. Of course, we make this offer as non-profit.


It is possible that our analysis is not complete, or that we are wrong. We encourage readers to provide their opinion and correct us if any of the aspects presented is incorrect. There is too much in the game and time is playing against us.

PS: We have a list of companies that manufacture or market chloroquine and hydroxychloroquine in different countries. This information is available to anyone who may need it for justified reasons. ignacio.diaz@emergpharmalinks.com

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