Episode 279: BA.2.75, novel monoclonal Ab, polymerase and anti-inflammatory treatment options
As promised, a long chapter on novel treatments.
Par 1 ABOUT BA.2.75 and monoclonal Ab therapies
First a nice over view of the mutations in the various BA.2 sublineage Omicron variants (from Ep 279-2)
As can be seen BA.2.75 has 7 additional mutations, not seen in other BA.2 sublineages, but it also lacks the 69-70 deletion (which produces the S-failure for BA.4/5), as well as the 452 and 486 mutations, which are believed to be important determinants of immune escape by BA.4/5.
Ep 279-1 Tom Wenseleers: https://twitter.com/TWenseleers/status/1554189994482442249
Updated fit to GISAID+COG-UK lineage frequencies with estimated growth of BA.2.75 (unofficial nickname Centaurus). Here using all data from countries with at least 1 sequenced BA.2.75 cases & showing those with >10 sequenced. Estimates + BA.2.75 growth also for UK, but small
The estimated growth rate advantage of BA.2.75 relative to the Omicron BA.2 variant is quite sizeable at ca. 0.15 per day, but smaller compared to BA.5 (ca 0.05 per day , a bit lower still for the US). Outside India & Nepal, these estimates could still be affected by importation biases.
Ep 279-2: Henning Gruel Neutralization sensitivity of BA.2.75 bioRxiv 4 August 2022 from Germany
- Neutralization activity from mRNA boosted vaccination individuals: BA.2 > BA. 2.75 > BA.2.12 > BA.4/5
- Some therapeutic monoclonal antibodies with low activity against other Omicron sublineages demonstrated high BA.2.75 neutralizing potency e.g. Sotrovimab, Casivirimab and Tixagevimab
- Tixagevimab and Cilgavimab separately = more active against BA.2.75 than against all other BA.2 sublineages. This suggests a higher activity of the combination (Evusheld), but that is NOT
confirmed by Yonlun Cao Ep 279-5).
- Bebtelovimab (LY-CoV1404) is clearly the most active mAb
Conclusion: less pronounced degree of antibody evasion of BA.2.75 compared with BA.4/5 → factors beyond immune evasion may be required for an expansion of BA.2.75 over BA.4/5.
Ep 279-3: Sheward bioRxiv 19 July 2022 Very similar data from Stockholm
Also shown is the effect of “boosting” neutralization activity in the population of blood donors by the BA.1/2 infection wave between Nov 2021 and April 2022.
Ep 279-4: Xun Wang Neutralization of Omicron BA.4/BA.5 and BA.2.75 by Booster Vaccination or BA.2 Breakthrough Infection Sera bioRxiv 6 August 2022 = similar data from China (with use of inactivated and protein based vaccines)
Our results demonstrated that all Omicron sub-lineages showed substantial evasion of neutralizing antibodies induced by vaccination and infection, although BA.2.75 accumulated the largest number of mutations in its
spike, BA.4 and BA.5 showed the strongest serum escape. However, BA.2 breakthrough infection
could remarkably elevated neutralization titers against all different variants, especially titers
against BA.2 and its derivative sub-lineages.
As could be expected: neutralization titers increased most after BA.2 breakthrough infection (after 3 doses of the inactivated BBIPB vaccine) > boosting with the heterologous Zifavax ( = S protein vaccine after 2 doses of BBIPB > boosting with the same inactivated BBIPB vaccine.
Ep 279-5: Yunlong Cao bioRxiv 18 July 2022 Binding and neutralization evasion by BA 2.75
The Omicron subvariants BA.2.75 is rapidly raising in India. BA.2.75 also shows a local growth advantage compared to BA.2.38 and BA.4/BA.5.
- BA.2.75 is more neutralization evasive than BA.2.12.1 against the plasma from post-vaccination BA.2 infection, but less evasive compared to BA.4/BA.5.
- As shown in a small sample of plasma from post-vaccination Delta infection, BA.2.75 seems to be more immune evasive than BA.4/BA.5 in Delta-stimulated immune background, which may explain BA. 2.75's growth advantage over BA.4/BA.5 in India.
With regard to therapeutic monoclonals: Compared to BA.2, REGN10933 and COV2-2196 partially recovered neutralization against BA.2.75 due to R493Q reversion. However, the efficacy of their corresponding cocktail (Rgeneron and Evusheld) was not significantly changed, since REGN10987 and COV2-2130 showed reduced neutralizing activity due to G446S.
In fact BA 2.75 has a very similar profile of sensitivity/resistance as BA.4/5
BA 2.75 just like BA.4/5 completely resistant to
- Lilly’s cocktail = bamlanivimab + etesevimab or LY-CoV016 + LY-CoV555
Strongly reduced activity of:
- Regeneron cocktail = Casirivimab/imdevimab (REGN 10933 + REGN 10987)
- Evusheld = tixagevimab and cilgavimab (COV2-2196 + COV2-2130)
BA 2.75 remains sensitive to:
- Bebtelovimab (LY-CoV 1404)
- BD55-5840 (SA58) and BD55-5514 (SA55) from Singlomics Co. https://www.singlomics.com/
The affinity of the BA.2.75 receptor-binding domain (RBD) is higher than that of BA.2, which may explain why this new variant is spreading, despite not such excellent “immune escape” characteristics.
Ep 279-6: Daichi Yomasoba bioRxiv 15 July Sensitivity of BA.2.75 to various therapeutic mAbs
According to this author: although bebtelovimab exhibited robust antiviral effect against BA.2 and BA.4/5, BA.2.75 was significantly more resistant to this antibody than BA.2 (21.2-fold, FWER=0.01) and BA.4/5 (25.6-fold,
FWER=0.01). These results suggest that bebtelovimab may not be a good choice to treat BA.2.75 infection.
Ep 279-7: Turelli bioRxiv 28 July 2022: P2G3 human monoclonal antibody neutralizes SARS-CoV-2 Omicron subvariants including BA.4 and BA.5 and Bebtelovimab escape mutants
P2G3 is similarly potent against BA.4 and BA.5 as Bebtelovimab
BA.2 or BA.4 viruses, rendered resistant to P2G3 are also not neutralized by bebtemovimab, but those rendered resistant to bebtelovimab are still quite sensitive to P2G3.
Ep 279-8: Saito Virological characteristics of BA.2.75 bioRxiv 8 August 2022
- Confirmation that the sensitivity of BA.2.75 to vaccination- and BA.1/2 breakthrough infection-induced humoral immunity is comparable to that of BA.2.
- Immunogenicity profile: BA.1 infection hamster sera were ineffective against BA.2, BA.5 and BA.2.75 (Figure 2G), both BA.5 (17-fold) and BA.2.75 (23-fold) exhibited significant resistance to BA.2 infection hamster sera than BA.2 (Figure 2H)
- The fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were comparable to those of BA.5 but were greater than those of BA.2.
- Remdesivir, Molnupiravir and Nirmatrelvir werev effective against BA.2.75 in hamsters
BA.2.75 acquired virological properties independently of BA.5, and the potential risk of BA.2.75 to global
health is greater than that of BA.5.
Interesting summary on BA.2.75 by William Haseltine
- BA.2.75 is making substantial progress in India, Nepal, Singapore, Japan, Australia, but less in UK, Canada, Denmark. The dynamics of previous waves may influence its relative growth advantage e.g. may be more immune evasive than BA.4/BA.5 in Delta-stimulated immune background (such as India)
- It has clear immune escape characteristics towards previous vaccination (either mRNA or inactivated) and breakthrough infections, but slightly less than BA.4/5
- There is clear reduction of activity of approved therapeutic moAb, whereas Bebtelovimab (LY-CoV 1404) as well as BD55-5840 (SA58) and BD55-5514 (SA55) remain active. P2G3 may certainly also be active, but needs confirmation.
- The RBD of BA.2.75 has a higher affinity for the ACE-2 receptor than BA.2 (and presumably also BA.4/5, but needs confirmation).
PAR 2 NOVEL SMALL MOLECULES
2.1. China’s COVID antivirals
Ep 279-9: Yvain Ye Nature Briefings 26 July briefly discussed 2 novel polymerase inhibitors antivirals, manufactured and being tested in China:
- Azvudine or FNC is a cytidine analogue 2′-deoxy-2′-β-fluoro-4′-azidolcytidine, acting as a chain terminator
- VV116: an orally available Remdesivir prodrug, also acting as chain terminator.
Both molecules are claimed to be active in COVID patients, but formally published phase 3 trials are lacking. I will present the main information:
On Azvudine/FNC (2’-deoxy-2’-b-fluoro-4’-azidocytidine)
Ep 279-10: Fayzullina in Front Oncology Feb 2022 nicely describes the history of this Azvudine.
- It was discovered in 2009 as active against single stranded positive RNA viruses (first hepatitis C and later also enteroviruses) by chain-termination during RNA replication.
- Activity against HIV-1 and HIV-2 was shown, with remaining activity against nucleotide (e.g. Lamuvidine) resistant viruses, having also the capacity to restore the activity of the cellular HIV restriction factor APOBEC3G in CD4 T cells.
- FNC can suppresses tumor progression by inhibiting adhesion, migration, and invasion of tumor cells in a dose dependent manner. A possible anti-cancer mechanism is inhibition of endogenous retroviruses (HERV)
- Most recently, it showed activity against SARS-CoV-2 ( which is a positive strand RNA virus).
This review mentions “ongoing” phase 3 trials for HIV and SARS-CoV-2, but no published data can be found.
Ep 279-11: Jin-Lan Zhang in Signal Transduction and Targeted Therapy 2022: Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective (?) in treating COVID-19 patients.
This is a complex paper, showing
- In vitro anti-SARS-CoV-2 activity at 1.2 µM (versus 0.59 µM for Remdesivir)
- Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray
- A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range:
1–9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2–25 days
Clearly, there is some promise, but there is no proof of “effectiveness” as suggested in the title.
Ep 279-12: Yu and Chang also in Signal Transduction and Targeted Therapy 2022: Azvudine (FNC) is a promising clinical candidate for COVID-19 treatment.
This is rather a comment, without much data: they refer to an “open label pilot study” in 20 patients where FNC was compared to hydroxychloroquine:
- FNC 100 % negativation of PCR within 4 days vs HCQ 73 % after 28 days
As this is a very small number and we have no data about the randomization and clinical staging, these results are very preliminary indeed!
VV116 = derivative of Gilead’s oral Remdesivir prodrug GS-621763
The orally bioavailable nucleoside prodrug GS-621763, is designed for optimal delivery of the parent nucleoside GS-441524 into systemic circulation, which is then metabolized inside cells into the same active nucleoside triphosphate formed by RDV.
Ep 270-13: Yuanchao Xie Cell Res 2021 Design and development of an oral remdesivir derivative
X6 = derivative further referred to as VV116: was able to suppress viral load in lung tissue of infected mice:
VV116 at 100 mg/kg shows a similar activity as Molnupiravir (EIDD-2801) at 250-500 mg/kg
Ep 279-14: Yinzhong Shen Emerg Micr Infect 2022: open prospective cohort of VV116 in Chinese COVID patients
60 patients who received VV116 (300 mg, BID×5 days) versus and 76 patients in the control group with only standard treatment. While comparable for most parameters, the control group was more symptomatic
Participants who received VV116 within 5 days since the first positive test had a shorter viral shedding time than the control group (8.56 vs 11.13 days), and cox regression analysis showed adjusted HR of 2.37 [95%CI 1.50-3.75], P < 0.001.
NOTE: Despite very encouraging preclinical results (Ep 236-3) Gilead stopped the development of its own oral Remdesivir GS-621763.
Ep 236-4: Press release indicating that Gilead is NOT going to proceed with oral Remdesivir:
“There are currently no immediate plans to study GS-621763 in clinical trials; the compound has been used in the preclinical studies as a tool for the design of oral antivirals for COVID.
“Gilead is working with Georgia State University because of their extensive expertise in animal models for SARS-CoV-2 infection that are suitable for testing the preclinical efficacy of new investigational antiviral agents,”
Not clear to what extent this company is involved in the present Chinese research.
2.2 Oral Sabizabulin (Veru-111) = anti-inflammatory drug
This compound is a “orally available” microtubule depolymerization agent, derived from colchicine and as such has potent anti-mitotic activity, hence, is was first proposed as an anticancer drug (Ep 279-15). There are several in vitro studies, showing activity against various cancer cell lines, including only published melanoma; breast cancer, cervical carcinoma (with resistance to taxane. The only published clinical trial in this regard is a phase ½ trial in men with Metastatic
Castration-resistant Prostate Cancer with Progression on an Androgen Receptor–targeting Agent (Ep 279-16).
The chosen dose was 63 mg daily While side effects were acceptable, there was some favorable effects: 20 % complete or partial remission and 29 % with decline of Prostate-Specific-Antigen decline.
Already in August 2020 there was a press release on potential use in COVID-19 (Ep 279-17 A and B), based on an anti-inflammatory effect at 40 nM concentrations, which is in the clinical range: a very significant suppression of cytokines (TNF-IL-1, IL-6, IL-8) in vitro (mouse spleen cells with LPS stimulation), similar to Dexamethasone at 10 nM.
As far as I can see, these results have not been published, even not as preprint.
Ep 279-18: Barnette NEJM 6 July 2022 Oral Sabizabulin for High-Risk, Hospitalized Adults with Covid-19
Sabizalubin was administer at only 9 mg daily for 21 days in WHO 4 (requiring oxygen); WHO 5 (mechanical ventilation) and WHO 6 (intubated) severe COVID patients, all with co-morbidities and all with additional medication, including dexamethasone (80 %), Remdesivir (30 %) and anti-IL6 or JAK/STAT inhibitors (20 %). See Table 1.
Over 60 days, there was a 29 % decrease in mortality, as well as reduction in secondary outcome measures (days on mechanical ventilation, ICU and hospital).
Clearly, there is evidence here of an additional clinical effect on top of dexamethasone, remdesivir and other agents in very severe COVID patients
- Increases fusogenic capacity and similar pathogenicity in hamsters as BA.5, greater than BA.2
- Sensitivity to vaccination- and BA.1/2 breakthrough infection-induced humoral immunity is comparable to that of BA.2.
- Sensitive to Remdesivir, Molnupiravir and Nirmatrelvir
- The successive omicron variants have undermined the therapeutic potential of approved monoclonal antibodies. There are, however, very valuable new candidates such as Bebtelovimab (Ly CoV 1404) from Eli Lilly, BD55-5840 (SA58) and BD55-5514 (SA55) from Singlomics and P2G3 from the Ecole Polytechnique de Lausanne
- Two new polymerase inhibitors for oral use (Azvudine and FNC) are being developed in China. More clinical data are awaited.
- A remarkable new anti-inflammatory drug, Sabizabulin, shows very promising results in severe COVID patients, on top of Dexamethasone.
28 Jan 2023 Episode 311 Will variant CH.1.1 or CD3.2 beat XBB.1.5? Are Remdesivir and Molnupiravir out?
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25 Jan 2023 Episode 310: Life cycle, BA.1 bivalent vaccine, MISC and myocarditis, cross-reactivity and PASC
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