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== Research ==
== Research ==
In February 2021, Pfizer began their first [[Phases of clinical research#Phase I|phase I trial]] of PF-07321332 (nirmatrelvir).<ref>{{cite web |title=Study Of PF-07321332 In Healthy Participants |url=https://clinicaltrials.gov/ct2/show/NCT04756531 |publisher=clinicaltrials.gov |date=18 October 2021}}</ref>
In February 2021, Pfizer began their first [[Phases of clinical research#Phase I|phase I trial]] of PF-07321332 (nirmatrelvir).<ref>{{cite document |title=Study Of PF-07321332 In Healthy Participants |url=https://clinicaltrials.gov/ct2/show/NCT04756531 |publisher=clinicaltrials.gov |date=18 October 2021}}</ref>


In September 2021, Pfizer began a [[Phases of clinical research#Phase III|phase II/III trial]] of nirmatrelvir combined with ritonavir.<ref name="trials">{{Cite web |date=2 September 2021 |title=Pfizer begins dosing in Phase II/III trial of antiviral drug for Covid-19. |url=https://www.clinicaltrialsarena.com/news/pfizer-antiviral-covid-trial/ |website=Clinical Trials Arena}}</ref>
In September 2021, Pfizer began a [[Phases of clinical research#Phase III|phase II/III trial]] of nirmatrelvir combined with ritonavir.<ref name="trials">{{Cite web |date=2 September 2021 |title=Pfizer begins dosing in Phase II/III trial of antiviral drug for Covid-19. |url=https://www.clinicaltrialsarena.com/news/pfizer-antiviral-covid-trial/ |website=Clinical Trials Arena}}</ref>


In December 2021, Pfizer completed a Phase III study of nirmatrelvir combined with ritonavir.<ref>{{cite web |title=EPIC-HR: Study of Oral PF-07321332/Ritonavir Compared With Placebo in Nonhospitalized High Risk Adults With COVID-19 |url=https://clinicaltrials.gov/ct2/show/NCT04960202 |publisher=clinicaltrials.gov |date=19 November 2021}}</ref>
In December 2021, Pfizer completed a Phase III study of nirmatrelvir combined with ritonavir.<ref>{{cite document |title=EPIC-HR: Study of Oral PF-07321332/Ritonavir Compared With Placebo in Nonhospitalized High Risk Adults With COVID-19 |url=https://clinicaltrials.gov/ct2/show/NCT04960202 |publisher=clinicaltrials.gov |date=19 November 2021}}</ref>


On 14 December 2021, Pfizer announced that the result of the Phase II/III study of nirmatrelvir combined with ritonavir results showed a reduced risk of hospitalization or death.<ref name="pfizer2">{{Cite press release |date=14 December 2021 |title=Pfizer Announces Additional Phase 2/3 Study Results Confirming Robust Efficacy of Novel COVID-19 Oral Antiviral Treatment Candidate in Reducing Risk of Hospitalization or Death | url = https://www.businesswire.com/news/home/20211214005548/en/Pfizer-Announces-Additional-Phase-23-Study-Results-Confirming-Robust-Efficacy-of-Novel-COVID-19-Oral-Antiviral-Treatment-Candidate-in-Reducing-Risk-of-Hospitalization-or-Death | publisher=[[Pfizer]] | via=Business Wire | access-date=25 December 2021}}</ref>
On 14 December 2021, Pfizer announced that the result of the Phase II/III study of nirmatrelvir combined with ritonavir results showed a reduced risk of hospitalization or death.<ref name="pfizer2">{{Cite press release |date=14 December 2021 |title=Pfizer Announces Additional Phase 2/3 Study Results Confirming Robust Efficacy of Novel COVID-19 Oral Antiviral Treatment Candidate in Reducing Risk of Hospitalization or Death | url = https://www.businesswire.com/news/home/20211214005548/en/Pfizer-Announces-Additional-Phase-23-Study-Results-Confirming-Robust-Efficacy-of-Novel-COVID-19-Oral-Antiviral-Treatment-Candidate-in-Reducing-Risk-of-Hospitalization-or-Death | publisher=[[Pfizer]] | via=Business Wire | access-date=25 December 2021}}</ref>

Revision as of 15:39, 1 January 2022

Nirmatrelvir
Clinical data
Other namesPF-07321332
License data
Routes of
administration		By mouth
ATC code
  • None
Legal status
Legal status
Identifiers
  • (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H32F3N5O4
Molar mass499.535 g·mol−1
3D model (JSmol)
Melting point192.9 °C (379.2 °F) [6]
  • CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C
  • InChI=1S/C23H32F3N5O4/c1-21(2,3)16(30-20(35)23(24,25)26)19(34)31-10-13-14(22(13,4)5)15(31)18(33)29-12(9-27)8-11-6-7-28-17(11)32/h11-16H,6-8,10H2,1-5H3,(H,28,32)(H,29,33)(H,30,35)/t11-,12-,13-,14-,15-,16+/m0/s1
  • Key:LIENCHBZNNMNKG-OJFNHCPVSA-N
Xray crystal structure PDB:7si9
Xray crystal structure (PDB:7SI9 and 7VH8) of the SARS-CoV-2 protease inhibitor nirmatrelvir bound to the viral 3CLpro (Mpro) protease enzyme. Ribbon diagram of the protein with the drug shown as sticks. The catalytic residues (His41, Cys145) are shown as yellow sticks.

Nirmatrelvir is an antiviral medication developed by Pfizer which acts as an orally active 3CL protease inhibitor.[7][8][9][10]

In December 2021, the combination of nirmatrelvir co-packaged with ritonavir was granted emergency use authorization by the US Food and Drug Administration (FDA) for the treatment of coronavirus disease COVID-19.[3][4][11] The co-packaged medications are sold under the brand name Paxlovid.[4][11][12] Paxlovid is not authorized for the pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in those requiring hospitalization due to severe or critical COVID-19.[4]

On 31 December 2021, the UK Medicines and Healthcare products Regulatory Agency (MHRA) approved the combination of nirmatrelvir co-packaged with ritonavir "for people with mild to moderate COVID-19 who are at high risk of developing severe COVID-19".[13][14]

Medical uses

Nirmatrelvir, co-packaged with ritonavir, is indicated for the treatment of mild-to-moderate coronavirus disease (COVID-19) in people aged twelve years of age and older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.[3][4] The co-packaged medication is not authorized for the pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in those requiring hospitalization due to severe or critical COVID-19.[4]

Adverse effects

There are no human data on the use of nirmatrelvir during pregnancy related to the risk of birth defects, miscarriage or adverse outcomes. There are also no human data on the presence of nirmatrelvir in human milk, its effects on milk production or the infant. In pregnant rabbits, a reduction in fetal body weight was observed with systemic exposure 10 times higher than the authorized human dose of Paxlovid. A temporary reduction in body weight was observed in the offspring of nursing rats.[5]

Development

Pharmaceutical

Coronaviral proteases cleave multiple sites in the viral polyprotein, usually after glutamine residues. Early work on related human rhinoviruses showed that the flexible glutamine side chain could be replaced by a rigid pyrrolidone.[15][16] These drugs had been further developed prior to the SARS CoV2 pandemic for other diseases including SARS.[17] The utility of targeting the 3CL protease in a real world setting was first demonstrated in 2018 when GC376 (a prodrug of GC373) was used to treat the previously 100% lethal cat coronavirus disease, feline infectious peritonitis, caused by Feline coronavirus.[18]

Nirmatrelvir is an analog of GC373, where the aldehyde covalent cysteine acceptor has been replaced by a nitrile.[19][20]

Nirmatrelvir was developed by modification of the earlier clinical candidate lufotrelvir,[21][22] which is also a covalent 3CL protease inhibitor but its warhead is a phosphate prodrug of a hydroxyketone. Lufotrelvir needs to be administered intravenously limiting its use to a hospital setting. Stepwise modification of the tripeptide protein mimetic led to nirmatrelvir, which is suitable for oral administration.[6] Key changes include a reduction in the number of hydrogen bond donors, and the number of rotatable bonds by introducing a rigid bicyclic non-canonical amino acid, which mimics the leucine residue found in earlier inhibitors. This residue had previously been used in the synthesis of boceprevir.[23] Tert-leucine (abbreviation: Tle) used in the P3 position of nirmatrelvir was identified first as optimal non-canonical amino acid in potential drug targeting SARS-CoV-2-Mpro using combinatorial chemistry (Hybrid Combinatorial Substrate Library technology).[24][25]

Chemistry and pharmacology

Full details of the synthesis of nirmatrelvir were first published by scientists from Pfizer.

In the penultimate step, a synthetic homochiral amino acid is coupled with a homochiral amino amide using the water-soluble carbodiimide EDCI as coupling agent. The resulting intermediate is then treated with Burgess reagent, which dehydrates the amide group to the nitrile of the product.[6]

Nirmatrelvir is a covalent inhibitor, binding directly to the catalytic cysteine (Cys145) residue of the cysteine protease enzyme.[26]

In the co-packaged medication, ritonavir serves to slow down metabolism of nirmatrelvir by cytochrome enzymes to maintain higher circulating concentrations of the main drug.[27]

Society and culture

Economics

The UK placed an order for 250,000 courses in October 2021,[28][29] Australia pre-ordered 500,000 courses of the drug,[30] and the US secured 10 million courses for $5.295 billion.[31]

Licensing

In November 2021, Pfizer signed a license agreement with the United Nations–backed Medicines Patent Pool to allow nirmatrelvir to be manufactured and sold in 95 countries.[32] Pfizer stated that the agreement will allow local medicine manufacturers to produce the pill "with the goal of facilitating greater access to the global population". However, the deal excludes several countries with major COVID-19 outbreaks including Brazil, China, Russia, Argentina, and Thailand.[33][34]

On 16 November 2021, Pfizer submitted an application to the U.S. Food and Drug Administration (FDA) for emergency use authorization for nirmatrelvir in combination with ritonavir.[35][36][37] The authorization was granted on 22 December 2021.[4][12] The European Medicines Agency (EMA) issued guidance about the use of Paxlovid for the treatment of COVID-19 in the EU on 16 December 2021.[38] The Israeli Ministry of Health approved the use of Paxlovid on 26 December 2021.[39] South Korea approved the use of Paxlovid on 27 December 2021.[40] The UK Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional approval of Paxlovid on 31 December 2021.[41][13]

Misleading comparison with ivermectin

Further information: Ivermectin during the COVID-19 pandemic

The combination of nirmatrelvir with ritonavir is sometimes falsely claimed to be a "repackaged" version of the antiparasitic drug ivermectin, which has been promoted as a COVID-19 therapeutic. Such claims, sometimes using the nickname "Pfizermectin",[42] rely on superficial similarities between the pharmacokinetics of both drugs and the claim that Pfizer is suppressing the benefits of ivermectin.[43] If one assumes ivermectin is not administered near the site of infection or locally to vulnerable tissue, or rapid diffusion to a uniform concentration within the body, then, to be effective against COVID-19, the concentration of ivermectin in the blood would require a dose that is 10-20 times higher than is safe.[42][43]

Research

In February 2021, Pfizer began their first phase I trial of PF-07321332 (nirmatrelvir).[44]

In September 2021, Pfizer began a phase II/III trial of nirmatrelvir combined with ritonavir.[45]

In December 2021, Pfizer completed a Phase III study of nirmatrelvir combined with ritonavir.[46]

On 14 December 2021, Pfizer announced that the result of the Phase II/III study of nirmatrelvir combined with ritonavir results showed a reduced risk of hospitalization or death.[9]

On 31 December 2021, the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) approved the use of nirmatrelvir combined with ritonavir for adults who have mild to moderate infection and are at high risk of their illness worsening.[41][13]

The efficacy of the combination against hospitalization or death in adult outpatients when administered within five days of symptom onset is about 88% (95% CI, 75–94%).[5]

References

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  2. ^ "Regulatory approval of Paxlovid". Medicines and Healthcare products Regulatory Agency (MHRA). 31 December 2021. Retrieved 31 December 2021.
  3. ^ a b c "Paxlovid- nirmatrelvir and ritonavir kit". DailyMed. Retrieved 30 December 2021.
  4. ^ a b c d e f g "FDA Authorizes First Oral Antiviral for Treatment of COVID-19". U.S. Food and Drug Administration (FDA) (Press release). 22 December 2021. Retrieved 22 December 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  5. ^ a b c Fact sheet for healthcare providers: Emergency Use Authorization for Paxlovid (PDF) (Technical report). Pfizer. 22 December 2021. LAB-1492-0.8. Archived from the original on 23 December 2021.
  6. ^ a b c Owen DR, Allerton CM, Anderson AS, Aschenbrenner L, Avery M, Berritt S, et al. (November 2021). "An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19". Science. 374 (6575): 1586–1593. doi:10.1126/science.abl4784. PMID 34726479. S2CID 240422219.
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  40. ^ Reuters (27 December 2021). "S.Korea authorises emergency use of Pfizer's oral coronavirus treatment". Reuters. Retrieved 28 December 2021. {{cite news}}: |last= has generic name (help)
  41. ^ a b Aripaka P (31 December 2021). "Britain approves Pfizer's antiviral COVID-19 pill". Reuters. Retrieved 31 December 2021.
  42. ^ a b Bloom J (2 December 2021). "How Does Pfizer's Pavloxid Compare With Ivermectin?". American Council on Science and Health. Retrieved 12 December 2021.
  43. ^ a b Gorski D (15 November 2021). "Pfizer's new COVID-19 protease inhibitor drug is not just 'repackaged ivermectin'". Science-Based Medicine.
  44. ^ "Study Of PF-07321332 In Healthy Participants" (Document). clinicaltrials.gov. 18 October 2021. {{cite document}}: Unknown parameter |url= ignored (help)
  45. ^ "Pfizer begins dosing in Phase II/III trial of antiviral drug for Covid-19". Clinical Trials Arena. 2 September 2021.
  46. ^ "EPIC-HR: Study of Oral PF-07321332/Ritonavir Compared With Placebo in Nonhospitalized High Risk Adults With COVID-19" (Document). clinicaltrials.gov. 19 November 2021. {{cite document}}: Unknown parameter |url= ignored (help)
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