Are they the magic bullets that saves humanity or just a blah, blah, blah?
Molnupiravir
Reuters
With a sizable number of drugs (Intramuscular vaccines and per oral) available for us to fight the COVID-19 pandemic, some may begin to wonder which options would be appropriate for them. Would the people who have not taken the vaccines so far due to various reasons, some legitimate and others unfounded be willing to take the oral drugs instead? Is it possible to have both the vaccines and then take the oral antivirus drugs when there is a breakthrough infection? Can the oral antivirus drugs be taken prophylactically to fend off potential infections? What are the side effects and contraindications of the oral antiviral drugs? And how do they compare with the vaccines? I will attempt to answer some of these questions by sieving through the available data so far (Paxlovid® is not approved by any country, though the UK government has purchased hundreds of doses already).
Timeline of COViD-19 Drug Discovery
Coronavirus which was named as SARS-CoV-2 and causes COVID19 was first detected in Wuhan, China, in the late 2019 and the World Health Organization (WHO) was notified in December 2019. Since then, it has gone on to kill more than 5 million people worldwide till date. COVID-19 took the world by surprise with no drug ammunitions to fight if off. Various medications were taunted as being able to cure or prevent hospitalization and death, including notably hydroxychloroquine.
Then came Regeneron®, an antibody recipe, which helped to reduce death in serious cases by providing “oven-cooked” antibodies to fight off the unrelentless replication of the COVID-19 before the recipients own immune system could marshal enough antibodies (or none) to fight the virus. The administration of Regeneron® is complex and is only administered in hospital settings.
The first breakthrough of humanity’s fight against the SARS-CoV-2 was the announcement by Pfizer/BioNTech of the impressive clinical trial results of their vaccine, Comirnaty®, with an efficacy of over 95% against hospitalization, serious illness and death. This was followed by the AstraZeneca vaccine, ChAdOx1-S® which also provided good clinical trial results. Moderna announced a similar efficacy percentage comparable to the Pfizer/BioNTech vaccine. Other countries like China and Russian produced their own vaccines. All vaccines required two doses with different weeks apart. Johnson and Johnson came out with a one dosing vaccine, Janssen® with a lower efficacy than its predecessors but with an advantage of the single dosing (to aid compliance).
The first orally administered COVID-19 drug was the successful large-scale trial of the repurpose use of dexamethasone (a steroid) to reduce excessive inflammation which led to organ failures and death. It must be noted that dexamethasone is not an antivirus, it does not kill nor inactivate the virus. Its efficacy is mainly to modulate the immune response to the virus which sometimes can cause more harm than good.
Merck and Ridgeback were the first group to successfully produce an orally administered antiviral drug named as molnupiravir and licensed in the United Kingdom (first country to do so) as LAGEVRIO®. The oral antiviral drug can reduce serious illness and death by about 50% when taken within 5 days of symptoms and a positive confirmation test. Pfizer announced their own oral antiviral drug, Paxlovid® on the 4th of November with an impressive result of more than 84% efficacy in preventing serious illness and death from COVID-19 when taken alongside an already existing antiviral drug ritonavir (a drug for HIV and a booster for other protease inhibitors) for 5 days after the emergence of symptoms. It must be noted that ritonavir’s role in this combination therapy is to prolong the duration of action of Paxlovid®
| Companies | Pfizer/BioNTech | Pfizer | AstraZeneca | Moderna | J&J | Merck |
| Name of Drug | Comirnaty | Paxlovid | ChAdOx1-S | Spikevax | Janssen | Lagevrio |
| Method of administration | Intramuscular | Oral | Intramuscular | Intramuscular | Intramuscular | Oral |
| Indications | Active immunisation to prevent COVID-19 | At risk adults with mild to moderate COVID19 symptom within 3-5 days of symptoms | Active immunisation to prevent COVID-19 | Active immunisation to prevent COVID-19 | Active immunisation to prevent COVID-19 | Mild to moderate with at least one risk factor |
| Doses | 30 mcg/0.3 mL | 4 tablets of Paxlovid and 2 capsules of ritonavir | 5×10(10) viral particles/0.5 mL | Two doses of 0.5mL | One dose | 4 x 200mg |
| Frequency of dosing | Two doses at 3 weeks apart plus booster 5-6 months apart | Daily | Two doses 12 weeks apart | 28 days apart | Single dose | Every 12 hours |
| Duration of treatment | Two plus boosters | 5 days | Two plus boosters | Two plus boosters | Single dose | 5 days |
| Mechanism of action | mRNA vaccine | Reversibly stops the action of an enzyme essential for the replication of coronavirus | Expression of S-glycoprotein locally to simulate antibody and cellular immune response | mRNA vaccine | Expression of S glycoprotein on of SARS-CoV-2 leading to stimulating of neutralising antibodies | Prodrug with active metabolite stopping viral replication by incorporating a “viral error catastrophe” into replication processes |
| Licensed groups | From 5 years old and older depending on country | Adults based on clinical trial (not yet licensed for any group) | 18 years and older | 12 years and older | 18 years and older | Adults with at least one risk factor for severe COVID19 |
| Contraindications | Hypersensitivity to substance and ingredients not yet determined | Hypersensitivity to substance and ingredients, thrombosis, thrombocytopenia syndrome (TTS) and capillary leakage syndrome | Hypersensitivity to substance and ingredients, myocarditis, pericarditis | Hypersensitivity to substance and ingredients, myocarditis, pericarditis, previous capillary leak syndrome | Hypersensitivity to active substance and excipients | |
| Pregnancy | Based on risk-reward ratio | Unknown | Based on risk-reward ratio | Based on risk-reward ratio | Based on risk-reward ratio | Not recommended |
| Breastfeeding | Suitable | Unknown | Unknown | unknown | Unknown | Not recommended |
| Storage | Special storage conditions (freezing conditions) | Possibly no special storage required | 2-8 oC | Special cold storage facilities | 2-8 oC when out of freezer | At room temperature. No special storage requirements |
| Common side effects | Injection site pain, fatigue, headache. Chills, fever, myalgia, nausea, diarrhoea | Mild (data not available) | Headache, Nausea, Myalgia, arthralgia, chills and other flu-like symptoms, injection site conditions | Fatigue, headache, myalgia, arthralgia, chills, nausea and vomiting, fever | Headache, Nausea, cough, Myalgia, Arthralgia, fatigue, injection site pain, redness and swelling, pyrexia, chills | Diarrhea, dizziness, nausea and headache |
| Adverse drug reaction | Myocarditis, Pericarditis, urticaria, rash, angioedema pruritis | Few (not available) | Cerebral blood clot | Lymphadenopathy including cervical and supraclavicular, anaphylaxis, facial swelling | Anaphylaxis reaction | Unknown |
| Renal impairment | Suitable | Unknown | Suitable | Suitable | Suitable | Suitable for eGFR above 30 mL/min |
| Hepatic impairment | Suitable | Not available | Suitable | Suitable | Suitable | No dose adjustment needed |
| Half-life | Days | Unknown | Days | Days | Days | 3.3 hours |
| Risk of cancer | Not expected | Unknown | Not expected | Unknown | Unknown | Not expected |
| Impairment of fertility | No known risk | unknown | No known risk | No known risk | No known risk | No known risk |
Criteria for the orally administered drugs
To be suitable for the Lagevrio® (and probably the PAXLOVID®) oral antiviral drugs, a patient would have to have at least one of the following comorbidities: 60 years of age or older, diabetes, obesity (BMI>30), chronic kidney disease, serious conditions, COPD or active cancer. All other patients 5 years and older (depending on the country’s licensing criteria) would have to be vaccinated to safeguard against the virus unless the new oral antiviral drugs are prescribed unlicensed, or a new clinical trial is done for people outside the initial criteria. The type of vaccine would depend on patient’s age and other risk factors.
Production of antibodies and T-cells
It should be noted that the oral antiviral drugs would not induce an immune response as expected in intramuscular vaccination. Patients may however have a naturally induced antibodies and T-cells as a result of exposure to the virus. This type of immune induction is likely to be subdued due to mechanism of actions of the oral drugs, which is to prevent replication of the virus and thus suppress immune response. Patients suitable for the oral antiviral drugs and who would prefer the oral antiviral drugs to the intramuscular vaccines would have to have several courses of the oral antiviral drugs depending on their exposure to the virus and their symptoms. This possibility does not appear to be addressed in the clinical trial so far. Data from the trials shows only exposures, development of symptoms, testing positive for the virus and administration of the oral antiviral drugs within 3-5 days of testing positive. There are no records of the participants having more than one course of treatment.
Asymptomatic Patients
Throughout the pandemic there have been several cases of asymptomatic people, harboring the virus and yet not developing any significant symptoms. If the 3-5 days of exposure requirement is to be adhered to, then what happens when a patient has been exposed longer than 5 days (initially asymptomatic) but has begun to show symptoms and has subsequently tested positive. Would they be suitable for the oral antiviral drugs, and would the drugs be efficacious based on the length of exposure?
Duration of Protection
While at present we cannot tell how long immunity against the virus after vaccination last, we can predict a fair level of protection at least five to six months after vaccination depending on the type of vaccine. The same cannot be said of the new oral antiviral drugs. How long after finishing a course would one need a further course if they show symptoms after a new exposure? In the absence of either natural or vaccine-induced immunity, it is difficult to ascertain the duration of protection. The peak plasma concentration (Tmax) of Lagevrio® is 1.5 hours and a half-life of approximately 3.3 hours. So far, one course comprise of twice daily dosing for 5 days. What happens after say 10 days when the majority if not all the drug and its metabolites would have been eliminated from systemic circulation? Also, it is worth noting that the new oral antiviral drugs are not protein-binding and therefore unlikely to have residues in systemic circulation to continue its activity for long. The patient is likely to be at risk of infection from the COVID19 virus when exposed again since the drug is meant to reduce replication and could prevent enough exposure for natural immunity to occur.
Conclusion
The two new oral antivirus drugs are an additional armament in our fight against the virus and must be welcomed. However, I do not think they replace the need to have the vaccines. They could be useful for breakthrough infections in the at-risk groups after vaccination. It is worth investigating further whether an at-risk patient having had two or three jabs might be better protected with the oral-antiviral drug than a yearly booster. Another possibility is an at-risk patient taking the oral-antiviral drugs prophylactically, especially just before the autumn and winter seasons to fend off COVID19 during the most dangerous winter season. The new drugs could also be of huge benefit to people in continents like Africa and some parts of Asia where caseloads are low. This would depend on whether the pharmaceutical companies are willing to lower their price to make it affordable to the ordinary person in those countries.