塩野義製薬開発中の新型コロナウイルス感染症（COVID-19）経口治療薬 (S-217622) について

3C-like protease inhibitor clinical candidate, S-217622, as a treatment for SARS-CoV-2

By Susha Cheriyedath, M.Sc. / Jan 31 2022 / Reviewed by Aimee Molineux / NEWS MEDICAL LIFE SCIENCES

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【S-217622について】

新型コロナウイルス感染症（COVID-19）治療薬であるS-217622は、塩野義製薬と北海道大学の共同研究から創製された3CLプロテアーゼ阻害薬です。新型コロナウイルス（SARS-CoV-2）は3CLプロテアーゼというウイルスの増殖に必須の酵素を有しており、S-217622は3CLプロテアーゼを選択的に阻害することで、SARS-CoV-2の増殖を抑制します。SARS-CoV-2感染動物を用いた非臨床試験において、ウイルス量を速やかかつ有意に低下させることが確認されております。日本において、2021年7月から第1相臨床試験を開始しており、現在、軽症のCOVID-19患者または無症候のSARS-CoV-2感染者を対象とした第2/3相臨床試験を実施中です。

＜第2/3相臨床試験のプロトコール概要＞

Study name
A Phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection
Target sample size
n=1929
Study Design
placebo control double blind randomized controlled trial
Countries of Recruitment（Except Japan）
Republic of Korea/Republic of Singapore/Socialist Republic of Vietnam
Inclusion Criteria
● For mild/moderate SARS-CoV-2-infected participants: - Participants who were diagnosed as SARS-CoV-2 positive within 120 hours before randomization. - Participants with time from COVID-19 onset to randomization of =< 120 hours. - Participants who have at least one moderate or severe symptom among the following 12 symptoms of COVID-19 at the time of randomization. (low energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or feverish, stuffy or runny nose, sore throat, cough, shortness of breath, nausea, vomiting, diarrhea)
● For asymptomatic SARS-CoV-2-infected participants (Phase 2a Part): - Participants who were diagnosed as SARS-CoV-2 positive within 120 hours before randomizationt. - Participants who have none of the following 14 symptoms of COVID-19 within 2 weeks before randomization. (low energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or feverish, taste disorder, smell disorder, stuffy or runny nose, sore throat, cough, shortness of breath, nausea, vomiting, diarrhea)
● For asymptomatic/only mild symptoms SARS-CoV-2-infected participants (Phase 2b/3 Part): - Participants who were diagnosed as SARS-CoV-2 positive within 120 hours before randomizationt. - Participants who do not have any symtoms of moderate or severe symptom among the 12 symptoms of COVID-19 at the time of randomization.
Age Minimum
12age old over
Age Maximum
70age old not
Gender
Both
Health Condition(s) or Problem(s) Studied
COVID-19
Intervention(s)
S-217622 Oral administration of S-217622 tablet once daily for 5 days (5 times in total)
Placebo Oral administration of placebo tablet once daily for 5 days (5 times in total)
Primary Outcome(s)
Phase 2a Part
Common for mild/moderate and asymptomatic SARS-CoV-2-infected participants: Change from baseline in SARS-CoV-2 viral titer at each time point
Phase 2b/3 Part
● For mild/moderate SARS-CoV-2-infected participants: Time to improvement of COVID-19 symptoms
● For asymptomatic/only mild symptom SARS-CoV-2-infected participants: Proportion of participants with occurrence/worsening of COVID-19 symptoms ● Common for mild/moderate and asymptomatic/only mild symptom SARS-CoV-2-infected participants: Time to first confirmation of negative SARS CoV-2 viral titer

TEXT

In a recent study posted to the bioRxiv* pre-print server, a team of researchers discovered S-217622, a non-covalent (A non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule.) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease (3CLpro) inhibitor clinical candidate, for the treatment of coronavirus disease 2019 (COVID-19).

To date, over 364 million confirmed COVID-19 cases have been reported globally including 5.6 million deaths. Lack of therapy options for treating COVID-19 infections and related hospitalizations necessitates the development of oral COVID-19 treatment options, especially for non-hospitalized patients to minimize the severity of the disease.

Potential drug candidates for COVID-19 treatment include non-covalent, non-peptidic, small molecule inhibitors which need further optimization to achieve appropriate pharmacokinetic (PK) profile and potency against SARS-CoV-2.

About the study (Preclinical)

The present study described the discovery of the first non-peptidic, non-covalent SARS-CoV-2 3Clpro inhibitor, S-217622, as a clinical candidate for COVID-19 treatment, along with its preclinical characterization.

The study utilized a structure-based drug design (SBDD) strategy that included a virtual screening based on molecular docking (結合解析) and a biological screening conducted with an in-house compound library. Interactions between known inhibitors were used as a basis to investigate pharmacophores (活性基、薬理作用団) in the binding site of 3Clpro. The in-house library compounds were docked followed by the application of the pharmacophore filter on each docking pose.

The assessment of 300 top-scoring compounds was conducted by mass spectrometry using enzymatic assays. One of these compounds, compound 1, was of notable significance due to its favorable PK profile. Multiple parameters in compound 1 were optimized to develop the clinical candidate, S-217622. Cytopathic (細胞変性の/sàitoupǽθik) effects of S-217622 on VeroE6/transmembrane serine protease 2 (TMPRSS2) cells evaluated the antiviral ability of the clinical candidate.

The antiviral efficacy of S-217622 was measured in vivo in SARS-CoV-2 Gamma strain-infected mice. The interactions between the receptor-binding domain (RBD) of the spike protein in the Gamma strain and the angiotensin-converting enzyme 2 (ACE2) were promoted by the mutations in the RBD.

Results

The study results showed that compound 1 had in vitro metabolic stabilities of 97% and 71%, respectively, when measured after 30 minutes of incubation in human and rat microsomes. A clearance of 7.3 mL/min/mg and 111% oral bioavailability (F) was observed in the in vivo PK study conducted in rats. On resolving the X-ray complex structure of compound 1 with 3CLpro, the binding mode of compound 1 was found to be similar to that of the protease.

As compared to compound 1, S-217622 exhibited a 90-fold increase in enzymatic inhibitory activity while conserving its drug metabolism and pharmacokinetics (DMPK) profile. S-217622 also displayed biochemical activity with an IC50 value of 0.013 μM and antiviral activity with an EC50 value of 0.37 μM. Furthermore, oral dose-related DMPK profiles like high metabolic stability of 96% and 88% in human and rat microsomes, respectively, high oral absorption of 97%, and a low clearance rate of 1.70 mL/min/mg in rats were observed.

医薬品の効力をin vitroにおいて評価する上で、
IC50 value of 0.013 μM
EC50 value of 0.37 μM
これらの値が最も重要になります。この値から、経口有効投与量の当りをつける上での基本となります。例えば、10mgを経口投与して、全てが血中に吸収されるとすると (ここでは、全てが血中に吸収されると仮定していますが、本来は薬物の分布容積を用いるべき) 、60kgの人の血液量は体重の約8%なので、4800mlとなり、うち、半量は赤血球が占めるので、薬物が存在する分布容積は2400mlとなり、薬物の血中濃度は、10000μg÷531.88 (S-217622の分子量)÷2400=0.007833μmol/ml=7.833μMの血中濃度が得られると考えられ、IC50値およびEC50値を上回っているので、この場合には薬効が十分期待できると考えられます。

S-217622 also had notable DMPK values in dogs and monkeys as compared to rats, with long half-lives (t1/2) of around 30 hours and 10 hours in dogs and monkeys, respectively, along with low clearance. The drug candidate also exhibited high oral bioavailability in all animals that were tested, indicating significant potential as a once-daily treatment option for COVID-19, without requiring a PK booster like ritonavir. It also exhibited a wide range of usability against all tested SARS-CoV-2 variants.

The antiviral activity of S-217622 against SARS-CoV and SARS-CoV-2 was similar especially at the site where homology of 3CLpro was well conserved. S-217622 also exhibited potent antiviral ability against the Middle East respiratory syndrome (MERS), human coronavirus OC43 (HCoV-OC43), and human coronavirus 229E (HCoV-229E). S-217622 exhibited no inhibitory effect against host-cell proteases, such as cathepsin B/D/G/L, caspase-2, chymotrypsin, and thrombin at up to 100 μM, indicating its high specificity for coronavirus proteases.

Conclusion

The current study findings showed how the SBDD strategy for a de novo (初めから、新たに) search of non-peptidic 3CLpro inhibitors to find an oral therapy for COVID-19 led to the clinical candidate S-217622. The optimization of the structure based on the SBDD strategy enabled 600 times better clinical activity with a good DMPK profile yielded in S-217622. This drug candidate had a favorable preclinical profile as an oral therapeutic drug for the treatment of COVID-19.

The significant antiviral activities of S-217622, in vivo long t1/2 in dogs and monkeys, excellent oral bioavailability, and remarkable efficacy in an in vivo SARS-CoV-2-infected mouse model, have prompted clinical trials on S-217622. This therapeutic candidate also exhibited significant antiviral activity against a wide range of coronavirus variants, indicating its potential as a therapeutic agent in future coronavirus-induced pandemics.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.