Nazroel.id – In this article, we will summarize the material presented at the Diazepam event (4/16/2022) under the title Development of the production of COVID-19 drugs and vaccines. Divided into 5 sub-topics namely Overview, COVID-19, COVID-19 Medicines and Vaccines, Conditions in Indonesia, Conclusions and Suggestions
Overview: New Drug Discovery and Development Process
The discovery and development of new drugs, including vaccines, really only consists of 5 stages. However, this stage is time consuming and expensive.
The five stages are the discovery and development stage, preclinical testing, clinical trial development, reviews by authoritative bodies such as the FDA in the US or BPOM in Indonesia, and finally post-marketing.
If we look at the picture of the journey from in vitro testing to post-marketing (see slide below), it still requires secondary steps that are of course time-consuming and expensive, and not necessarily successful.
What’s going to be highlighted a little bit is the post-marketing process, which means it’s still in the final stage of testing, this is where the FDA/BPOM issues the emergency use authorization, or the emergency use permits, especially for COVID-19 medications that are currently needed.
According to a review by Duxin Sun, a professor of pharmacy at the University of Michigan, 90% of drugs have failed clinical trials; out of over 10,000 drug candidates, only 1 drug candidate will go on to become a new drug that is ready for circulation in the community.
Here it is clear, it is very difficult and time consuming to find a new drug for COVID-19, especially during this rapidly passing pandemic.
COVID-19 SARS-CoV-2 Elimination Strategy
Before discussing the development of COVID-19 drug production, let’s take a look back where COVID-19 originally appeared in 2019 in Wuhan.
The Indonesian government has started to get a handle on the COVID-19 pandemic, especially after the wave of the Delta variant hit. Some of the posters that circulate from time to time show a change in management until the Independent Isolation program has been intensified. Including rapid regulatory changes related to flight rules.
If we conclude based on Asselah et al, the SARS-CoV-2 elimination strategy has 3 main things, namely strengthening testing, protection, therapy, and prevention. In this paper, we will discuss drug development and prevention of COVID-19.
COVID-19 medicines: development of the production of medicines/vaccines for prevention and therapy
Divided into Drug Reuse, New Drugs and Vaccines. Before discussing these 3 things, we must first understand the structure of the SARS-CoV-2 virus where the coronavirus has a long, closed, polyadenylated RNA genome, containing between 8 and 10 ORFs, which allows the synthesis of structure, proteins nonstructural, structural, and accessory viruses.87 SARS-CoV-2 has a base length of 29,903 and contains 6 major ORFs, as well as additional accessory genes; reference sequence registered in GenBank with ID: MN908947.3.1 (A, B) Potentially up to 28 different polypeptides could be finely produced from different ORFs and after polyprotein processing by viro-encoded proteases.87 If the RNA genome contained in the virion it is already functional, after entering the cell, as a template for the synthesis of nonstructural proteins, which are involved in the early phase of viral replication (mainly by forming replication complexes), subgenomic messenger RNA is also produced in the late phase of the virus. cycle to allow the synthesis of structural proteins (eg, spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins), as well as other accessory polypeptides. Another important means of replication is the complementary RNA of negative sense, which is used by RdRp, which is encoded by the virus, within the replication complex, to amplify the full-length genome, which is then capped and polyadenylated by viral and host enzymes before being incorporated into viral progeny.
In addition, you must observe the therapeutic and preventive goals of COVID-19 drugs, by entering ACE2-positive (receptor entry) and TMPRSS2-positive (cofactor for entry) cells, and membrane fusion (i.e., process of stripping), the full-length genome is released into the cell cytoplasm. This full-length polycistronic RNA was used directly to efficiently encode polyproteins from the first ORF present in the molecule, starting at the 5′ end, ie, ORF1a and ORF1b; the latter was read after the ORF1a ribosome scan frameshift. (A, B) The polyprotein is then processed by 2 viral-encoded proteases, PLpro/Nsp3 and 3CLpro/Nsp5 (also known as major proteases). [Mpro]), in 16 proteins/polypeptides (Nsp1 to 16). (B) This nonstructural protein/polypeptide is important for the early stages of infection, as it allows the formation of a replicase complex around the enzymatic activity of RdRp, which is also involved in the synthesis of full-length negative RNA. as subgenomic messenger RNA through a discontinuous transcriptional strategy.87 The latter allows efficient and stoichiometric synthesis of all other viral proteins/polypeptides, which are essential for viral assembly and release of progeny virions. (b) Specific goals for drug development and current treatment options are demonstrated. ACE2, angiotensin-converting enzyme 2; 3CLpro/Nsp5, a chymotrypsin-like protease; ORF, open reading frame; PLpro/Nsp3, cysteine proteases such as papain; RdRp, an RNA-dependent RNA polymerase; SARS-CoV-2, severe acute respiratory syndrome-coronavirus 2.
Looking down the pipeline in the world, very few drugs have received emergency approval or full approval.
The use of drugs again for different indications is a shortcut to eliminate the COVID-19 pandemic, because the safety test stage is no longer needed, so you can go to the clinical trial stage, which has clearly passed 2 stages of the process which is quite time consuming.
Existing antiviral drugs target viruses
Existing antiviral drugs target inflammation
Tocilizumab and sarilumab
New drug for COVID-19
New inhibitor of viral replication – Molnupiravir
antiviral drugs that inhibit the replication of certain RNA viruses. Approved by the UK in November 2021. In December 2021, the US Food and Drug Administration (FDA) granted an Emergency Use Authorization (EUA)
New protease inhibitor: nirmatrelvir/ritonavir
sold under the brand no. In December 2021, the US Food and Drug Administration (FDA) granted an emergency use authorization for co-packaged drugs for the treatment of COVID-19 ame Paxlovid.
New antibody drug
As of May 2021, there is strong evidence that convalescent plasma treatment is not associated with clinical improvement for people with moderate or severe disease and does not reduce the risk of death.
Bamlanivimab/etesevimab and Casirivimab/imdevimab
In January 2022, the US Food and Drug Administration (FDA) reviewed the authorization of two monoclonal antibody treatments: bamlanivimab/etesevimab (co-administered) and casirivimab/imdevimab. As the data indicates, it is highly unlikely that this treatment is active against the omicron variant.
Regdanvimab, sold under the trademark Regkirona. The antibodies are directed against the spike protein of SARS-CoV-2. It was developed by Celltrion
Sotrovimab, sold under the brand name Xevudy. It is being developed by GlaxoSmithKline and Vir Biotechnology, Inc.
Sold under the Evusheld brand. It is being developed by the British-Swedish pharmaceutical and biotech multinational AstraZeneca.
Vaccine for COVID-19
Looking at the slide below, in general, vaccines are in the process of clinical trials, only Pfizer vaccines and modern vaccines that have been fully approved by the FDA.
Conditions in Indonesia
Through a consortium organized by BRIN, currently in clinical trials for convalescent plasma, herbal flu booster, quinine pills, anti-COVID-19 serum, mesenchymal stem cells, and red and white vaccine production.
Meanwhile, drugs that received emergency approval from the BPOM included remdesivir powder for injection and remdesivir infusion, fapivirapir film-coated tablets, molnupiravir, and regdanvimab.
For the vaccine itself, there are many options, a total of 11 vaccines can be used in Indonesia according to the slide below.
Producers of medicines and vaccines against COVID-19 in Indonesia
Molnupiravir – PT. Amarox Pharma Global and manufactured by Hetero Labs Ltd., India.
Favipiravir – PT Kimia Farma Tbk,
Remdesivir – PT Indofarma, Tbk is ready to market the anti-Corona drug Remdesivir under the brand name Desrem. This medicine is manufactured by Mylan Laboratories Limited, under license from Gilead Sciences Inc, Foster City and the United States of America.
Regdanvinab-PT. Dexa Medica and Rengkirona TM
Chloroquine, Hydroxychloroquine, Azithromycin, Favipiravir, Dexamethasone and Methylprednisolone – PT Phapros Tbk
Coronavac vaccine – PT. Biopharmacy and Sinovac
Covac Vaccine – PT. Biopharma and AstraZenecca
Red and White Vaccine – PT. Biopharma and PT Biotis Pharmaceutical Indonesia
BUMN vaccine – PT Biofarma and Baylor College of Medicine, USA.
The bottom line image is on the slide illustrating that in terms of COVID-19 transmission, only the variant of the virus changes a lot with changes in the spike protein.
It is necessary to accelerate the discovery of COVID-19 drug development with the most possible scheme, namely drug reuse, covalent plasma, stem cells and immunoglobulins.
Prevention is clearly needed through vaccines, with subunit protein technology, virus inactivation, adenovirus and gene-based (RNA, DNA, plasmids)