A Spotlight on the Development, Pharmaceutical Trends, Innovations and...

[Full title: A Spotlight on the Development, Pharmaceutical Trends, Innovations and Patents of Nirmatrelvir (PaxlovidTM)]

OPEN ACCESS International Journal of Pharmacology ISSN 1811-7775 DOI: 10.3923/ijp.2022.1340.1352 Review Article A Spotlight on the Development, Pharmaceutical Trends, Innovations and Patents of Nirmatrelvir (Paxlovid TM ) 1 Namy George, 2 Mohd. Imran, 1 Shah Alam Khan, 1 Khalid Al Balushi, 3 Syed Mohammed Basheeruddin Asdaq and 4 Shahamah Jomah 1 College of Pharmacy, National University of Science and Technology, P.O. Box 620, PC 130, Muscat, Sultanate of Oman 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia 3 Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Dariyah, Riyadh 13713, Saudi Arabia 4 Department of Pharmacy, Dr. Sulaiman Al-Habib Medical Group, Riyadh, Saudi Arabia Abstract Paxlovid TM is a combination of Nirmatrelvir and Ritonavir antiviral pills with good oral bioavailability. In clinical studies, treatment of the patients infected with SARS-CoV-2 with Paxlovid TM within three to five days of the appearance of symptoms significantly reduced the hospitalization rate as well as mortality. It is the first oral antiviral treatment for the COVID-19 which received USFDA approval for EUA on 22 nd December, 2021. Nirmatrelvir inhibits the replication of SARS-CoV-2 while another antiviral drug, Ritonavir, is given in combination to enhance the bioavailability of Nirmatrelvir. Molecular interaction studies have shown that Nirmatrelvir binds covalently with the catalytic triad of the active site of the viral protease enzyme (3 CL PRO ). It, therefore, acts by stopping the SARS-CoV-2 replication by its ability to block the translation of the viral genetic materials. Research studies conducted have proven the efficacy of this oral anti-viral drug in mild to moderate COVID-19 patients beside its ease of oral administration and good oral bioavailability. Alternative synthetic methods to scale up the synthesis of this potent molecule are needed to reduce the treatment cost of the COVID-19. Extensive clinical research on a larger group population is also underway for ensuring the safety and efficacy of this medication in the battle against the COVID-19 pandemic Key words: SARS-CoV-2, COVID-19, Nirmatrelvir, Ritonavir, Paxlovid TM , pandemic, antiviral Citation: George, N., M. Imran, S.A. Khan, K. Al Balushi, S.M.B. Asdaq and S. Jomah, 2022. A spotlight on the development, pharmaceutical trends, innovations and patents of Nirmatrelvir (Paxlovid TM ). Int. J. Pharmacol., 18: 1340-1352 Corresponding Author: Shah Alam Khan, College of Pharmacy, National University of Science and Technology, P.O. Box 620, PC 130, Muscat, Sultanate of Oman Copyright: © 2022 Namy George et al. This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Competing Interest: The authors have declared that no competing interest exists Data Availability: All relevant data are within the paper and its supporting information files.

Int. J. Pharmacol., 18 (7): 1340-1352, 2022 INTRODUCTION Coronavirus disease-2019 (COVID-19) is a highly infectious disease that has infected more than 499 million people globally in just over two years. Till 11 th April, 2022, it has caused more than 6.18 million mortalities across all age groups 1 . It is transmitted through the respiratory route and affects the pulmonary system therefore based on clinical symptoms it is named a severe acute respiratory syndromecorona virus-2 (SARS-CoV-2). Available data indicates that the elderly population, smokers and persons with pre-existing chronic diseases such as diabetes, cardiovascular, cancer and respiratory disease are at a higher risk 2,3 . Concerted efforts have been put in by the scientific fraternity to treat COVID-19 which has threatened global health. Remdesivir, monoclonal antibodies, convalescent plasma therapy etc., were authorized by USFDA for emergency use in the past two years to treat the COVID-19 (Table 1) 4,5 . These are administered parenterally and are somewhat successful in preventing the progression of mild COVID-19 disease to severe disease in hospitalized patients. However, an effective and safe oral therapy was needed that could be used conveniently in all settings to reduce the burden of this infectious disease In the ongoing pandemic, several viral mutated variants of SARS-CoV-2 (alpha, beta, gamma, delta and omicron) are being identified which further complicates the existing complex discovery process to identify and develop prophylactic and therapeutic modalities for COVID-19. It has been reported that most of the mutations are occurring in the spike (S) protein of the viral structure and these mutations have been originated and identified in different countries such as England, Brazil, South Africa and India 6 . Vaccines have been proved to be the main weapon in reducing the transmission of COVID-19 7 . So far, USFDA has granted Emergency Use Authorization (EUA) to three successful vaccines developed by Pfizer-BioNTech, Moderna and Janssen. But the approved vaccines are neither 100% effective against all the variants nor do prevent transmission completely 8 . Therefore, the best way to put an end to the pandemic is through mass vaccination drive and the development of cost-effective and convenient pharmacological treatment. Recently on December 22, 2021, the USFDA granted EUA to Paxlovid TM , the first oral antiviral therapy to fight against the COVID-19 pandemic 9,10 Molnupiravir, another oral antiviral drug to combat COVID-19 also received approval on December 23, 2021. But, studies have shown that molnupiravir, an RNA-dependent RNA polymerase (RdRp) inhibitor which is three times more effective than placebo in reducing either mortality or hospitalization in non-hospitalized patients, could induce mutations in human DNA and may lead to the development of new viral variants 11,12 Nirmatrelvir (PF-07321332), an active pharmaceutical ingredient of Paxlovid TM , was developed by Pfizer, Inc., the USA for the treatment of SARS-CoV-2 infection. In clinical studies, it significantly reduced the hospitalization or mortality rate by 89% 13 . Its emergency use has been approved in nearly Table 1: USFDA approved therapeutics for emergency use in the treatment of COVID-19 14 Drug name(s) (Dosage form) Manufacturer Date of EUA granted Indication Bebtelovimab-(IV injections) Lilly, USA February 11, 2022 “Mild to moderate COVID-19 adults and children above 12 years of age” Molnupiravir-oral Merck and Co December 23, 2021 Mild to moderate COVID-19 Paxlovid ™ (Nirmatrelvir tablets and Pfizer December 22, 2021 “Mild to moderate COVID-19 adults and children above 12 years of age” Ritonavir tablets, co-packaged)-(tablets) Evusheld™ (Tixagevimab co-packaged AstraZeneca First issuance: December 8, 2021 Pre-exposure prophylaxis for prevention of COVID-19 in adults and with Cilgavimab)-(IM injections) Reissuance: February 24, 2022 children above 12 years of age who are not currently infected, moderate to severe immune-compromised and who cannot be vaccinated due to a history of severe allergic reactions Actemra ® (Tocilizumab)-(IV infusion) Genentech June 24, 2021 Hospitalized COVID-19 adults and children above 12 years of age who are on systemic corticosteroids and require supplemental oxygen Sotrovimab-(IV injections) GlaxoSmith First issuance: May 26, 2021 Mild to moderate COVID-19 adults and children above 12 years of age Kline (GSK) (reissued October 8, 2021, December 16, 2021 and February 23, 2022) Baricitinib (Olumiant)-(oral as tablets) Eli Lilly November 19, 2020, revised on “Hospitalized adults and pediatric patients 2 years of age or older requiring and Incyte December 20, 2021 supplemental oxygen” COVID-19 convalescent plasma (IV) August 23, 2020 COVID-19 patients with the immunosuppressive disease or on Reissued: February 23, 2021, immunosuppressive therapy March 9, 2021 and December 28, 2021 Remdesivir-(IV injections) Gilead May 1, 2020 (Reissued August Mild-to-moderate COVID-19 pediatric patients weighing 3.5 to 40 kg 28, 2020, October 1, 2020, or less than 12 years of age and weighing at least 3.5 kg who are October 22, 2020 and hospitalized or not hospitalized January 21, 2022) 1341

Int. J. Pharmacol., 18 (7): 1340-1352, 2022 Fig. 1: Structures of PF-07304814 (Lufotrelvir), PF-00835231 and PF-07321332 (Nirmatrelvir) 17 40 countries. European Medicines Agency (EMA) authorized its use across the EU in January, 2022 while China issued conditional approval in February, 2022 to fight against omicron strain. It stops the SARS-CoV-2 replication by inhibiting the 3 CL PRO protein. While the other drug in combination, Ritonavir, an HIV-1 protease inhibitor, enhances the bioavailability of Nirmatrelvir by preventing its breakdown and thus allowed a higher concentration of Nirmatrelvir to stay in the body for a longer period. Paxlovid TM has been authorized to treat adults and children above the age of 12 years with mild to moderate COVID-19 symptoms for a maximum of five consecutive days. This review article highlights the development, pharmacology (indication, pharmacokinetic profile, mechanism of action, drug interaction and contraindications), clinical studies and patents granted to Paxlovid TM along with future perspectives. Development of Paxlovid TM : Nirmatrelvir [CAS registry no, 2628280-40-8, PF-07321332, Molecular formula: C 23 H 32 F 3 N 5 O 4 , Molecular weight: 499.54, IUPAC name: (1 R,2 S,5 S)-N-[(1 S)-1- cyano-2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2 S)-3,3-dimethyl- 2-(2,2,2-trifluoroacetamide) butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide] is an orally bioavailable antiviral drug that can inhibit 3 CL PRO . It is packed with another antiretroviral drug known as Ritonavir and has shown promising results in patients with mild-to-moderate COVID-19 infection 15 . Initially in March 2021, Pfizer, Inc., researched and developed another plausible antiviral therapeutic for SARS-CoV-2 known as PF-07304814. This drug is administered intravenously to the patients and requires hospitalization for administration. The drug PF-07304814 is the phosphate form of PF-00835231 and in the body, it gets converted into the active form PF-00835231 in the presence of phosphatase enzyme. The PF-00835231 was converted into its phosphate form (PF-07304814) so that the solubility of the compound could be enhanced and can be continuously infused during administration to the infected patient (Fig. 1). It was developed during the outbreak of SARS in 2002-2003 and the drug was abandoned as the outbreak was self-restrained. This drug is known to show a synergistic effect with remdesivir in hospitalized COVID-19 infected patients 16 PF-00835231 is a peptide-like structure with a sufficient number of Hydrogen Bond Donors (HBDs) 17 . The HBD provides the compound with a polar surface area and thus it gets trapped in the gut. The apt route of administration of the drug is through the intravenous route and requires hospitalization of the patient. Medicinal chemists removed the HBDs that are not required by the molecule to bind to the viral protein and 1342 H C 3 O N H O H N O N H H HO O O O OH O CH 3 CH 3 PF-07304814 Enhances aqueous solubility Phosphatase H C 3 O N H H N CH 3 OH O O O O CH 3 N H NH H PF-00835231 NH CH 3 H C 3 H C 3 CH 3 CH 3 N N N NH O O O O H HN F F F PF-07321332 Second generation orall bioavailable antiviral drug P

Int. J. Pharmacol., 18 (7): 1340-1352, 2022 Fig. 2: Chemical structure of Ritonavir Source: PubChem compound CID: 392622 thus tried to design a second generation of orally bioavailable anti-viral (PF-00835232). The " -hydroxymethyl ketone is one of the HBD's removed by the medicinal chemist to make the drug cross gut to develop an oral antiviral agent. The " -hydroxymethyl ketone group interacted with the cysteine group of the viral protease and thus it was replaced with another group that is not capable of acting as HBD. From the leucine structure, the HBD of PF-00835231 was also removed and replaced by a cyclic amino group that knocks the -NH bond but the structure looks like leucine. Another structural fragment that obtains a leucine-like motif is the fused cyclopropyl ring with two methyl groups. Knocking out the HBDs from the initial molecule also resulted in losing the interaction of the molecule with the glycine moiety present in the active site of the target protease. To replace this interaction, different moieties were tried the including methanesulfonamide acetamide and a trifluoroacetamide and among these moietiesʼ trifluoroacetamide in in vitro assays was found to be successful in penetrating the gut barriers Molecular docking studies revealed the ability of the designed molecules to bind at the binding site of the target protease Pfizer Inc., developed two compounds with two different reactive groups, benzothiazolyl ketone and one with a nitrile reactive group. From this point onwards, the group chose to proceed with nitrile as the reactive group because of three reasons, (i) Nitrile was more soluble than the counterpart and hence easier to make the higher concentration of the drug solution for toxicology studies, (ii) It was easier to scale up the compound and (iii) Benzothiazole-2-yl ketone is more prone to epimerize by the chiral hydrogen. On July 22, 2020, Pfizer Inc., chemists synthesized Nirmatrelvir (PF-07321332). The oral formulation containing Nirmatrelvir has received USFDA Emergency Use Authorization (EUA) on December 22, 2021, which is the provided in combination with Ritonavir, a well-known HIV 1-protease inhibitor Role of Ritonavir combination in bioavailability of Nirmatrelvir: Ritonavir (Fig. 2) is known as a suicide inhibitor of the CYP 3 A 4 cytochrome enzyme and it is used in combination with other HIV protease inhibitors as a bio enhancer. Nirmatrelvir is primarily metabolized by CYP 3 A 4 Hence, co-administration of a CYP 3 A 4 inhibitor such as Ritonavir can enhance its therapeutic serum concentration. It is, therefore, administered with Nirmatrelvir to achieve its higher serum concentration for a better therapeutic outcome Ritonavir forms an isocyanate intermediate, which interacts with the nucleophilic site on the CYP 3 A 4, leading to the carbamylation of the residue at the enzyme site and thus inactivating the metabolizing enzyme 18 . The mechanism of action of Ritonavir in inhibiting the CYP 3 A 4 is illustrated in Fig. 3 Structure of SARS-COV-2 and the target of Nirmatrelvir: Coronavirus (CoV) falls under the family of Coronaviridae, subgenus sarbecovirus and belongs to the genus Betacoronavirus 19 . The CoV can be found in birds and mammals 20 . Both, SARS-CoV and MERS-CoV have the same genome. It is a positive-strand RNA virus. The viral genome contains 30,000 nucleotides and four genes that code for the surface proteins on the virusʼs outer surface. The spike protein found on the virus is made up of Glycoprotein S and this exists as a homotrimer and has an S 1 subunit, S 2 subunit and ACE 2 recognition site. With the help of the ACE 2 recognition site on the spike protein, it can penetrate the human cells. The virus is provided with an outer shield, the envelope protein (E). This shield is connected to the inner matrix with the help of a membrane protein (M). The viral genome is incorporated in the nucleocapsid (N) 21 There is an extended range of inhibitors designed by the medicinal chemists for the main target of 3 CL PRO protease, which is used by the CoV for replication and transcription This enzyme consists of two domains and the active site 1343 H C 3 N H C 3 H C 3 CH 3 CH 3 N N N NH HN H OH S S O O O O

Int. J. Pharmacol., 18 (7): 1340-1352, 2022 Fig. 3: Inactivation of CYP 3 A 4 enzyme by Ritonavir Source: It is slightly modified as given in reference 21 lies between these two domains. The 3 CL PRO consists of 306 amino acid residues. They can cleave 11 sites on the polyproteins. This protein forms a homodimer and each unit consists of three subunits. They have two polypeptide chains namely pp 1 a and pp 1 ab. These polypeptides can transform themselves into non-structural proteins with the help of two main viral cysteine proteases called 3-chymotrypsin-like protease (3 CL PRO ) and papain-like protease. The polyprotein is then cleaved by the main protease into non-structural proteins (nsps). These nsps are responsible for the formation of the subgenomic RNAs, which are useful for the formation of the main structural proteins of the corona virus like the spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins. They also contribute to the conversion of accessory proteins 22,23 . The spike glycoproteins (S) of SARS-CoV-2 have been targeted most by the scientific community to develop COVID-19 vaccines 24 . Chemical synthesis of Nirmatrelvir: Owen et al 13 reported the synthetic route for the preparation of Nirmatrelvir. Among the series of steps in the synthesis of Nirmatrelvir, the important step in the formation is the coupling reaction that takes place between homochiral amino acid and homochiral amino amide by using EDCl as a coupling reagent Covalent interaction of Nirmatrelvir with protease enzyme: The formation of three hydrogen bond interactions between 3 CL PRO and Nirmatrelvir were observed 25-27 . Covalent interactions of the drug molecules, O 2 and H 9 with Cys 145 were observed although these atoms were intact during the simulation. The Cys 145 is a part of the catalytic dyad of the active site in the viral protease. All the interaction distances remained within 4 A E units. The nitrile group of the drug molecule formed a covalent bond with Cys 145-S ( . The pyrrolidinyl group occupies itself in between the space of Glu 166 and Gln 189 and also shows an important inhibitory interaction with the drug molecules. It also forms a hydrogen bond with Gln 189. The Trifluoroacetamide group is observed to exhibit Gln 189-H 2 O interaction and this interaction allows the cyclo-propyl-proline moiety to preoccupy the centre position of the binding site. Research conducted on the SARS-CoV-2 main protease has shown a new conformational space in the important regions of the enzyme. The oxyanion group is involved in substrate identification and enzymatic action. It can acquire a new conformation. As mentioned in the structure of SARS-CoV-2 main protease has two regions in the substrate-binding sites known as S 1 and S 2 . The new confirmation of the S 1 unit will reshape itself because of which a small new subunit is formed. Leu 141 and Gln 142 interact with PF-07321332 and these amino acids are part of the oxyanion group and it is involved in the stabilization of the tetrahedral acyl transition state 26 . Pharmacology of Paxlovid TM Mechanism of action of PF-07321332: The SARS-CoV-2 enters the human cells, reproduces itself and spreads the virus in the host body. The oral antiviral drug inhibits the main protease enzyme that produces viral proteins. There are several steps involved in the host cell for the reproduction of SARS-CoV-2 (Fig. 4): 1344 H C 3 H C 3 S N N N H O O CH 3 CH 3 CH 3 CYP 3 A 4 H C 3 H C 3 CH 3 CH 3 CH 3 O O N N N H S OH H C 3 H C 3 CH 3 O H H N N S + CYP O X N H O CH 3 CH 3 N CYP H O C H C 2 H C 3

Int. J. Pharmacol., 18 (7): 1340-1352, 2022 Fig. 4: Schematic representation of the mechanism of action of the oral anti-viral pill for SARS-CoV-2 Table 2: Pharmacokinetic properties of Nirmatrelvir in healthy humans Pharmacokinetic parameter Values Median T max 3 hrs C max 2.21 µg mL G 1 AUC inf 23.01 µg/hr/mL Mean volume of distribution (V d ) 104.7 L Bound to plasma protein (%) 69% Metabolizing enzyme Substrate of CYP 3 A 4 but minimal in the presence of Ritonavir Half-life (t 1/2 ) 6.05 hrs Major route of elimination Renal Excretion 35.3% in the urine and 49.6% of drug-related material in the faeces C Attachment of the virus to the host cell C After attachment of the virus to the plasma membrane, the virus will release the viral RNA from the nucleus which will then be translated into viral proteins C Viral proteins are synthesized with the action of the main protease enzyme that causes proteolysis of polyproteins C Replication of transcription complex which results in the formation of circulating RNA C Structural and accessory proteins are then subjected to transcription and translation C These synthesized proteins are then assembled into the virus structure and then released The PF-07321332 is involved in the inhibition of step 2 that involves the translational of viral proteins by inhibiting main protease 3 CL PRO Pharmacokinetic profile: Administration of a single oral dose of Nirmatrelvir (300 mg) and Ritonavir (100 mg) in healthy subjects shows the following pharmacokinetic parameters for Nirmatrelvir (Table 2) which is present in the Paxlovid TM (Nirmatrelvir, Ritonavir) product monograph (https://www paxlovid-hcp.ca/files/PAXLOVID̲PM̲EN̲17 Jan 2022.pdf) Indication for Paxlovid TM therapy: Nirmatrelvir is to be co-administered with Ritonavir, to maintain the therapeutic level of the drug in the blood. This combination therapy is indicated for patients with mild to moderate infection and is to be provided orally. One of the advantages of this drug includes the safety of this drug being administered to the pediatric patients under the age category of 12 years and above and weighing at least 40 kg. This can be prescribed to patients with mild to moderate COVID-19 infection and to patients having the chance to develop into a severe infection in the future Dosage and administration of Paxlovid TM : Commencement of the treatment with Paxlovid TM should be initiated within 5 days of onset of symptoms. As mentioned in the limitations the drug treatment is to be prescribed for only 5 consecutive days. The drug Nirmatrelvir is co-packed with Ritonavir Each Nirmatrelvir tablet contain 150 mg of Nirmatrelvir and Ritonavir tablet contain 100 mg API. The daily dosing regimen includes 300 mg Nirmatrelvir (2 tablets) and 100 mg Ritonavir (1 tablet each), twice daily for 5 consecutive days. These three tablets should be taken together with or without food twice a day (3×2×5 = 30 tablets) Dosage adjustment is required for patients suffering from renal impairment as the drug mostly gets eliminated through the renal pathway. The dose is reduced to half for patients with moderate renal impairment (eGFR >30-<60 mL min G 1 ) but should not be used in patients with eGFR <30 mL min G 1 It is also contraindicated in patients suffering from a severe hepatic impairment which falls under the category of Child-Pugh Class C classification The patient should not double the intake of a dose if missed any dose before and should continue with the next dose as the prescribed dosage regimen 1345

Int. J. Pharmacol., 18 (7): 1340-1352, 2022 Fig. 5: Patent searching methodology for Nirmatrelvir Limitations for prescribing Paxlovid TM : The USFDA has stated some limitations regarding prescribing this medication to the public. It is not authorized to be prescribed as a pre-exposure and post-exposure regimen for COVID-19. The drug should not be prescribed for more than 5 consecutive days. It is not authorized for administration for initiating treatment for patients suffering from severe COVID-19 infection and hospitalized patients Contraindications: Co-administration of Paxlovid TM with any medication, whose elimination depends on the interaction with the CYP 3 A enzyme should be avoided. The CYP 3 A inducers can bring down the concentration of Nirmatrelvir and Ritonavir to sub-therapeutic levels and can procreate the virus to become resistant to the treatment. Therefore, CYP 3 A inducers are the contraindicated with this formulation Alteration is not required for co-administering Ritonavir and Cobicistat with Paxlovid TM . The medication is also known to be contraindicated in patients with a relevant history of clinical hypersensitivity reaction to any of the content in the formulation. Close monitoring or withdrawal of the treatment is required if the co-administered drug is having a narrow therapeutic index and the clearance of the drug is dependent on CYP 3 A. Immediate administration of this formulation after the sudden withdrawal of CYP 3 A inducer drugs like apalutamide (anti-cancer agent), carbamazepine (anti-convulsant agent), phenobarbital (anti-convulsant agent), phenytoin (anti-convulsant agent), rifampin (Antimycobacterial) and St. Johnʼs Wort (Herbal product) should be avoided Adverse drug reaction (ADR): Dysgeusia, diarrhoea, hypertension and myalgia are some of the ADRs reported in patients with an incidence rate of less than 1% for Paxlovid TM Clinical studies on Nirmatrelvir: The clinical trials database of NIH, US National Library of Medicine was used to search the clinical studies based on Nirmatrelvir utilizing keywords (Paxlovid, Nirmatrelvir and PF-07321332). The literature also provided information about some clinical studies in Nirmatrelvir (NCT 04960202, NCT 05011513 and NCT 05047601) 10,28 . The summary of the identified clinical studies is provided in Table 3 The results of phase 2-3 clinical trial (NCT 04960202, sponsored by Pfizer) of the combination of Nirmatrelvir (300 mg) and Ritonavir (100 mg) on unvaccinated, symptomatic and non-hospitalized COVID-19 patients have been published. This study is related to the USFDA-regulated product (Paxlovid TM ). The results revealed that the incidence of hospitalization in the combination-treated group was only 0.77% with 0% death in comparison to the placebo (7.01% hospitalization and 7 deaths) by 28 days. The combination therapy also demonstrated a decrease in the viral load after day 5 of the treatment. The progression of the diseases with the combination therapy was lower by 89% in comparison to the placebo group with a promising safety profile. Patent searching and analysis: Ritonavir was approved by the USFDA in 1996 to treat HIV infection 29 . The structure of Ritonavir was disclosed in US 5541206 A as a retroviral protease inhibitor 30 . The US 5541206 A has expired in 2013 in the United States. The term of a patent is generally 20 years 31 Accordingly, all the compound patents of Ritonavir around the world should have expired by now. This opens free use of Ritonavir by pharmaceutical industries The patent literature of Nirmatrelvir was searched on different patent databases (Scifinder, Espacenet, Patentscope and the United States Patent and Trademark Office (USPTO) 32-35 on March 12, 2022. The methodology is depicted in Fig. 5 and the summary of the selected patent application was provided in Table 4 1346

Int. J. Pharmacol., 18 (7): 1340-1352, 2022 Table 3: Summary of the clinical studies on Nirmatrelvir against COVID-19 NCT number (intervention, other) Phase (status, number enrolled, results) Primary purpose (sponsor, location, start date, actual completion date) NCT 04960202 (safety and efficacy of 3 (active, not recruiting, 246, Treatment (Pfizer, United States, July 16, 2021, December 9, 2021) oral nirmatrelvir+ritonavir combination not posted) two times a day for 5 days among non-hospitalized COVID-19 patients) NCT 05011513 (safety and efficacy of 2/3 (active, not recruiting, 1150, Treatment (Pfizer, United States, August 25, 2021, December 13, 2021) oral nirmatrelvir+ritonavir combination not posted) two times a day for 5 days among non-hospitalized COVID-19 high-risk patients) NCT 05047601(prevention of COVID-19 in 3 (recruiting, 2880, not posted) Prevention (Pfizer, United States, September 9, 2021, April 18, 2022) adults exposed to COVID-19 patients using oral nirmatrelvir+ritonavir combination two times a day for 5 days) NCT 05261139 (safety, efficacy and 3 (not yet recruiting, 140, Treatment (Pfizer, United States, March 2, 2022, March 4, 2023) pharmacokinetics of oral not posted) nirmatrelvir+ritonavir combination among pediatric patients) NCT 05263908 (observational study to Not mentioned (not yet Post-marketing study (Pfizer, Japan, March 1, 2022, July 10, 2023) examine the safety and efficacy of recruiting, 3300, not posted) Paxlovid in real medical practice) NCT 05263921 (estimation of the relative 1 (not yet recruiting, 12, Basic Science (Pfizer, Not mentioned, March 11, 2022, May 18, 2022) bioavailability of commercial tablet not posted) (nirmatrelvir+ritonavir combination) and oral powder (nirmatrelvir+ritonavir combination) in healthy participants) NCT 04909853 (effect of the renal 1 (completed, 35, not posted) Basic Science (Pfizer, United States, June 15, 2021, October 7, 2021) impairment on the safety, tolerability and pharmacokinetics of nirmatrelvir+ ritonavir combination) NCT 05178654 (to understand the ADME 1 (withdrawn, 0, not posted) Basic Science (Pfizer, Not mentioned, February 22, 2022, April 1, 2022) of radiolabelled nirmatrelvir in healthy participants in combination with ritonavir) NCT 05129475 (effect of a high-fat meal on 1 (completed, 12, not posted) Basic Science (Pfizer, United States, November 12, 2021, January 12, 2022) the bioavailability of nirmatrelvir (150 mg tablet two times a day) in combination with ritonavir (100 mg once a day) in healthy participants) NCT 04962230 (pharmacokinetic interaction 1 (completed, 12, not posted) Basic Science (Pfizer, United States, July 15, 2021, October 9, 2021) between carbamazepine (CYP 3 A 4 inducer) and oral nirmatrelvir+ritonavir combination) NCT 05064800 (pharmacokinetic interaction 1 (completed, 24, not posted) Basic Science (Pfizer, United States, September 21, 2021, December 6, 2021) between dabigatran (P-gp substrate) and oral nirmatrelvir+ritonavir combination) NCT 04962022 (interaction of itraconazole 1 (completed, 12, not posted) Basic Science (Pfizer, Belgium, July 20, 2021, September 30, 2021) (CYP 3 A 4 inhibitor) on the pharmacokinetics of nirmatrelvir+ritonavir combination) NCT 05005312 (effect of hepatic impairment 1 (completed, 17, not posted) Basic Science (Pfizer, United States, August 31, 2021, December 7, 2021) on the pharmacokinetics of oral nirmatrelvir +ritonavir combination to develop dosing regimen) NCT 05032950 (pharmacokinetic interaction 1 (completed, 12, not posted) Basic Science (Pfizer, Belgium, September 17, 2021, December 9, 2021) of midazolam (CYP 3 A 4 substrate) and oral nirmatrelvir+ritonavir combination in healthy participants) NCT 05263895 (study the bioavailability 1 (not yet recruiting, 12, Basic Science (Pfizer, Not mentioned, March 3, 2022, May 14, 2022) of different formulations of nirmatrelvir) not posted) NCT 04756531 (safety, efficacy and tolerability 1 (completed, 70, not posted) Other (Pfizer, United States, February 11, 2021, September 1, 2021) of nirmatrelvir in healthy participants) Source: Data is retrieved from a clinical database https://clinicaltrials.gov 1347

Int. J. Pharmacol., 18 (7): 1340-1352, 2022 Table 4: Patent data of the selected patent applications Patent applications number (Applicant, Family members (International Priority country, Status on March 12, 2022) patent classification) Summary of the claims US 2022062232 A 1 (Pfizer, United States, WO 2021250648 A 1, EP 3953330 A 1, It claims nirmatrelvir and its solvates/hydrates. It also claims solid Under examination) CL 2021002965 A 1, AU 2021266232 B 1 amorphous form, crystalline form and a pharmaceutical composition (A 61 K 31/403, A 61 K 31/427, A 61 P 31/14, comprising nirmatrelvir for treating COVID-19 37 C 07 D 403/12) US 2021361688 A 1 (Riveros Carlos Alberto, WO 2021234668 A 1, UY 39226 A An inhalation or nebulizer system for administering medication United States, Under examination) (A 61 K 31/573, A 61 K 31/7048, A 61 K 9/00, (nirmatrelvir, remdesivir, molnupiravir, ivermectin, etc.) alone or in A 61 P 31/14) combination with anti-inflammatory drugs (baricitinib, prednisone, dexamethasone and methylprednisolone) for reducing viral (SARS-CoV-2) replication in the upper and lower airways mucosae 38 . No experimental details are available for the claims related to nirmatrelvir WO 2021231872 A 1 (Healion Bio Inc., None (A 61 K 41/00) A synergistic composition of an anti-COVID-19 drug (nirmatrelvir, favipiravir, United States, No national phase entry) remdesivir, molnupiravir, etc.) with a mammalian protease inhibitor (cathepsin inhibitor like balicatib). The composition is claimed to have improved efficacy and lower toxicity/dose of the anti-COVID-19. However, no experimental support is mentioned for the composition of nirmatrelvir 39 WO 2021221043 A 1 (Fujifilm Toyama None (A 61 K 31/07, A 61 K 31/11, It claims novel pyrazine derivatives that can be used to treat COVID-19 Chemical Co. Ltd., Japan, No national A 61 K 31/121, A 61 K 31/122, in combination with anti-COVID-19 drugs (nirmatrelvir, remdesivir, phase entry) A 61 K 31/137, A 61 K 31/138, molnupiravir, etc.). No experimental support is mentioned for the A 61 K 31/216, A 61 K 31/343, composition of nirmatrelvir with the claimed pyrazine derivatives 40 A 61 K 31/351, A 61 K 31/352, A 61 K 31/357, A 61 K 31/366, A 61 K 31/395, 61 K 31/403) WO 2021207632 A 1 (The Regents of the None (A 61 K 31/436, A 61 K 31/497, A composition of anti-COVID-19 drugs (nirmatrelvir, remdesivir, University of California, United States, A 61 K 31/506, A 61 K 31/5377, molnupiravir, etc.) with many drugs, including anticancerous kinase No national phase entry) A 61 K 45/06, A 61 K 9/00, inhibitors to treat COVID-19. However, no experimental support is A 61 P 11/00, A 61 P 31/12, A 61 P 31/14) mentioned for the composition of nirmatrelvir 41 WO 2022035911 A 2 (Tutela Pharmaceuticals, None (A 61 K 41/00) A synergistic composition encompassing an FKBP ligand or derivative United States, No national phase entry) (tacrolimus, everolimus, sirolimus, etc.) and a sub-therapeutic dose of an antiviral drug (nirmatrelvir, remdesivir, molnupiravir, etc.) to prevent/treat SARS-CoV-2 infection. This composition is claimed to have no suppressive effect on the patient's immune system. However, no experimental support is mentioned for the composition of nirmatrelvir 42 CN 114057627 A (Nanjing Huaguan None (C 07 D 209/52) It claims the process for the preparation of intermediates used in the Biotechnology & Jindawei Biotechnology, synthesis of nirmatrelvir 43 China, Publication of the application) WO 2021211609 A 1 (Buck Institute for None (G 01 N 33/50, G 01 N 33/58, A prophylactic/therapeutic composition for COVID-19 comprising an Research on Aging, United States, No G 01 N 33/60) antiviral exogenous ketone-like (R)-3-hydroxybutyrate and an antiviral national phase entry) agent (nirmatrelvir, remdesivir, molnupiravir, etc.). However, no experimental support is mentioned for the composition of nirmatrelvir 44 US 2021322351 A 1 (Immune AG, Europe, WO 2021214033 A 1, EP 3900717 A 4, It claims a composition of DHODH inhibitor (vidofludimus) and an antiviral Notice of Allowance mailed) EP 3900717 A 1 (A 61 K 31/196, (nirmatrelvir, remdesivir and molnupiravir) to treat COVID-19. However, A 61 K 31/706, A 61 K 45/06, A 61 K 9/00, no experimental support is mentioned for the composition of nirmatrelvir 45 A 61 K 9/20, A 61 P 31/14) WO 2021212183 A 1 (Centre for Digestive None (A 61 K 31/165, A 61 K 31/215, It is related to devices (inhaler, nebulizer, nasal spray, respirator, etc.) for Diseases Pty Ltd., United States, No A 61 K 31/351, A 61 K 31/375, delivering anti-COVID-19 drugs like nirmatrelvir. However, no device has national phase entry) A 61 K 31/426, A 61 K 31/4409, been exemplified with nirmatrelvir 46 A 61 K 31/4706, A 61 K 31/495, A 61 K 31/4965) WO 2021250038 A 1 (Apteeus, Europe, None (A 61 K 31/05, A 61 K 47/20, A composition of clofoctol that optionally may contain nirmatrelvir, for No national phase entry) A 61 K 9/08, A 61 P 31/14) use in the prevention or treatment of COVID-19 47 WO 2021262825 A 2 (Genetic Networks, None (A 61 K 31/122, A 61 K 31/216, A method of treating COVID-19 using a fatty acid synthesis inhibitor, United States, No national phase entry) A 61 K 31/343, A 61 K 31/4422, optionally in the combination of nirmatrelvir 48 A 61 K 31/519, A 61 K 31/7048) CN 113999160 A (Jiangsu Institute of None (C 07 D 209/52) It claims the process for preparing an intermediate of nirmatrelvir 49 Materia Medica Co., Ltd., China, Under examination) US 2022040227 A 1 (Reverspah, WO 2022035813 A 1 (A 61 K 31/381, A composition comprising a copper chelator (tetrathiomolybdate salt), United States, No national phase entry) A 61 K 31/495, A 61 K 33/24, A 61 K 45/06) optionally in combination with nirmatrelvir for treating COVID-19 1348

Int. J. Pharmacol., 18 (7): 1340-1352, 2022 DISCUSSION Paxlovid TM containing a combination of Nirmatrelvir- Ritonavir chemicals is the first oral nitrile peptidomimetic drug granted a EUA by USFDA for the treatment of SARS-CoV-2. Paxlovid TM and molnupiravir, another orally administered antiviral drug, are indicated in the treatment of mild to moderate COVID-19. Especially, the development of Paxlovid TM has been seen as a milestone in the fight against the SARS-CoV-2 pandemic as it has demonstrated better efficacy than molnupiravir in reducing hospitalization and death rate in clinical studies. Pfizer, the innovator of Paxlovid TM , has conducted many clinical trials on Paxlovid TM and Nirmatrelvir. These trials relate to prevention, treatment and pharmacokinetic interactions (Table 3). However, the results of many clinical studies have not yet been published. The USFDA has already authorized Paxlovid TM to treat COVID-19 based on the safety and efficacy data of Paxlovid TM . However, very few interaction studies, including drug-drug interaction, drug-food interaction, drug-vaccine interaction, drug-disease interaction and physicochemical interaction studies have been reported for Paxlovid TM or Nirmatrelvir (Table 3). This keeps many unresolved concerns alive (Fig. 6). The drug interaction studies are directly related to the patient safety and efficacy of a drug Therefore, the authors anticipate further drug interactionbased clinical studies on Paxlovid TM and Nirmatrelvir. Further, new variants of SARS-CoV-2 possessing different pathogenicity and transmission rates have appeared recently 28 . This makes it imperative to assess the safety, efficacy and tolerability of Paxlovid TM and Nirmatrelvir among patients infected with new strains of SARS-CoV-2 The patent search revealed a total of 14 patent applications related to Nirmatrelvir. Among the 14 patent applications, 8 have been filed in the United States, three in China, two in Europe and one in Japan. The equivalents of the compound patent of Nirmatrelvir 36 have been filed in Europe, Chile and Australia. The equivalent filing of the compound patent is expectable in most countries around the globe. If the compound patent application of Nirmatrelvir is granted in the United States, its estimated expiry will be August 5, 2041. This expiry date may also be extended based on the patent term extension law of the United States 31 . The patent applications have claimed different aspects of Nirmatrelvir (Fig. 7). However, many patent application filings are foreseeable also (Fig. 6). It is interesting to note that most of the patent applications did not exemplify the outcomes of their claimed compositions/combinations. This opens a research portal to study these combinations. It is believed that Nirmatrelvir encompasses a lot of scope for further research in pharmaceutical/biomedical sciences Fig. 6: Unresolved concern about Paxlovid TM and Nirmatrelvir Fig. 7: Current and foreseeable patent application filing on Nirmatrelvir 1349 Drug-disease interaction Drug-drug interaction Drug-vaccine interaction Physicochemical interaction Drug-food interaction Efficacy against new strains of SARS-CoV-2 Alive unresolved concerns of Paxlovid or Nirmatrelvir Compound patent Crystalline nirmatrelvir Amorphous nirmatrelvir Method of treating COVID-19 Composition patent Inhalation or nebulizer system Synergistic combination Medical devices Identified patent application filings on nirmatrelvir Foreseeable patent application filings on nirmatrelvir Cosmetics Specific impurity Repurposing Mask containing nirmatrelvir Herbal/antibodies combinations New dosage forms Sprays Particle size New process Conjugates and mixture Nanomedicine Process

Int. J. Pharmacol., 18 (7): 1340-1352, 2022 CONCLUSION Paxlovid TM is observed to be more effective than the rest of the anti-viral drugs approved for the treatment of SARS-CoV-2 infected individuals to date. It is also observed to be more effective than the antiviral drugs available on the market. This oral antiviral drug is responsible for slashing the hospitalization of COVID-19 patients and helps to clear the virus more quickly from the infected body. The treatment can be challenging since this oral antiviral drug should be administered to the patients within three days of onset of symptoms. Being a combination and one of the drugs Ritonavir inhibits CYP 3 A 4, it may show drug interactions which are a major concern with Paxlovid TM . Furthermore, the current synthetic route to prepare Nirmatrelvir involves many steps, hence, it is foreseeable that efficient and shorter synthetic methods will be developed that may cut down the treatment cost of the COVID-19 and increase the yield (%) Also, attempts will likely be made to improve its potency by structural modification and to formulate this in other oral dosage forms. Therefore, extensive research on a larger group of populations is essential for ensuring the safety and efficacy of this medication SIGNIFICANCE STATEMENT This review article provides an insight into the pharmaceutical development of Nirmatrelvir (Paxlovid TM ), the first oral nitrile peptidomimetic drug, effective in the treatment of SARS-CoV-2. It succinctly covers the drug design strategies, pharmacology, clinical studies and patents granted to this antiviral drug. Therefore, researchers looking for specific information about either pharmacology or pharmaceutical aspects of Nirmatrelvir will find it a useful source. This is the first study in which all the patents granted to Nirmatrelvir are compiled in one place with an expert opinion. It also opens up a window to study various combinations of Nirmatrelvir to develop products of pharmaceutical interest. ACKNOWLEDGMENTS The authors are thankful to Dr. Sulaiman Al-Habib Medical Groupʼs research centre for their tremendous support. All the authors of this manuscript are thankful to their respective Institutes/Universities for the successful completion of this study REFERENCES 1 Imran, M., S.A. Khan, Abida, M.K. Alshammari and S.M. Alkhaldi et al ., 2022. Nigella sativa L. and COVID-19: A glance at the anti-COVID-19 chemical constituents, clinical trials, inventions, and patent literature. Molecules, Vol. 27 10.3390/molecules 27092750 2 Kim, L., S. Garg, A. OʼHalloran, M. Whitaker and H. Pham et al ., 2021. Risk factors for intensive care unit admission and in-hospital mortality among hospitalized adults identified through the US coronavirus disease 2019 (COVID-19)- associated hospitalization surveillance network (COVID-NET) Clin. Infect. Dis., 72: e 206-e 214 3 Thakur, B., P. Dubey, J. Benitez, J.P. Torres and S. Reddy et al ., 2021. A systematic review and meta-analysis of geographic differences in comorbidities and associated severity and mortality among individuals with COVID-19. Sci. Rep., Vol. 11 10.1038/s 41598-021-88130-w 4 Hsu, J.Y., Y.C. Mao, P.Y. Liu and K.L. Lai, 2021. Pharmacology and adverse events of emergency-use authorized medication in moderate to severe COVID-19. Pharmaceuticals, Vol. 14 10.3390/ph 14100955 5 Moshkovits, I. and D. Shepshelovich, 2022. Emergency use authorizations of COVID-19-related medical products. JAMA Internal Med., 182: 228-229 6 Mallapaty, S., 2021. Indiaʼs massive COVID surge puzzles scientists. Nature, 592: 667-668 7 Kashte, S., A. Gulbake, S.F. El-Amin III and A. Gupta, 2021 COVID-19 vaccines: Rapid development, implications, challenges and future prospects. Hum. Cell, 34: 711-733 8 Pascolo, S., 2021. Vaccines against COVID-19: Priority to mRNA-based formulations. Cells, Vol. 10 10.3390/cells 10102716 9 Saravolatz, L.D., S. Depcinski and M. Sharma, 2022 Molnupiravir and nirmatrelvir-ritonavir: Oral COVID antiviral drugs. Clin. Infect. Dis., 10.1093/cid/ciac 180 10. Hung, Y.P., J.C. Lee, C.W. Chiu, C.C. Lee, P.J. Tsai, I.L. Hsu and W.C. Ko, 2022. Oral nirmatrelvir/ritonavir therapy for COVID-19: The dawn in the dark? Antibiotics, Vol. 11 10.3390/antibiotics 11020220 11. Gandhi, R.T., P.N. Malani and C. del Rio, 2022. COVID-19 therapeutics for nonhospitalized patients JAMA, 327: 617-618 12. Lee, C.C., C.C. Hsieh and W.C. Ko, 2021. Molnupiravir-a novel oral anti-SARS-CoV-2 agent. Antibiotics, Vol. 10 10.3390/antibiotics 10111294 13. Owen, D.R., C.M.N. Allerton, A.S. Anderson, L. Aschenbrenner and M. Avery et al ., 2021. An oral SARS-CoV-2 M pro inhibitor clinical candidate for the treatment of COVID-19. Science, 374: 1586-1593 1350

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