Replies to post #245066 on Biotech Values

[willyw]

Thanks for the post with a useful link that provides a good explanation of the issues with resistance.

Below are a few things that caught my eye;
----------
"Phylogenetic analyses indicate that nirmatrelvir-resisting variants have pre-existed the introduction of nirmatrelvir into the human population and are transmissible [56]."

"While the short (5-days) treatment course reduces selective pressure for N/R resistance, widespread deployment as a monotherapy, including to immunosuppressed patients who could fail clearing the virus after the 5-day schedule, makes the probability of resistance emergence in the near future substantial."

2.6. Relapses (rebounds)

"....Explanations proposed so far for the rebound phenomenon include the shortness of the schedule, insufficient dosing in obese patients, pharmacokinetic interactions with concurrent medications lowering plasma levels of nirmatrelvir, and/or failure of the drug to eradicate the virus from yet to be identified drug-inaccessible sanctuary tissues....."

------------------------
(My comment) These are all valid and likely IMHO. (I am simply a layman investor)
The paper makes it clear that we need a superior covid antiviral to Paxlovid.
It's directly analogous to treating with an antibiotic that may be too weak to eliminate the infection completely. There will be remaining infection post TX and that remaining infection might be more resistant.

A better treatment would be able to more fully eliminate all of the virus in the course of the treatment thus decreasing the chances of post treatment transmission to others. A more ideal treatment would be effective for prophylaxis.

Ultimately there is a need for 1) more effective treatments than Paxlovid and 2) treatments that would be more effective for the more immune compromised OR for the emerging protease inhibitor resistant strains, and 3) the idea that a weak/partial treatment could be an engine for creating resistance. It's above my pay grade, but I just hold the idea that we are currently treating with a temporary first generation drug- not the ultimate compound by any metric.

It also occurs to me that there are improved treatments on the way in trials or other treatments which could sidestep the M-pro potential resistance issues. (I'm not actually saying that M-pro isn't effective so much as a weak M-pro treatment is more of a problem)

[vinmantoo]

Discussion starts:
“2.5. Resistance
As with any other antiviral, resistance can be either basal or treatment-emergent.
Mutations in Mpro causing resistance to nirmatrelvir are already found in circulating SARS-CoV-2 viruses (Table 1 and Figure 1)…”

Thanks for the link but resistance to Paxlovid has been slow to develop and has been far less of an issue than with antibody treatment. As far as EDP-235, it is a different chemical entity than Paxlovid so it is highly unlikely any mutants resistant to it will exhibit cross-resistance to EDP-235. The term resistance is also a bit misleading.

Hu et al identified in GISAID sequences 66 prevalent Mpro mutations located at the nirmatrelvir binding site, 11 of them (including S144M/F/A/G/Y, M165T, E166Q, H172Q/F, and Q192T/S/V) showing <10-fold change in enzymatic activity and resistance to nirmatrelvir (Ki > 10-fold increase) [53]. Sasi et al identified 5 mutations (N142L, E166M, Q189E, Q189I, and Q192T) that reduce the potency of nirmatrelvir: in particular, the IC50 of nirmatrelvir was reduced by 24-fold against E166M [54]. Dias Noske et al reported that N/R retained most of its in vitro activity against most of 14 naturally occurring polymorphism close to the binding site, with only G143S and Q189K linked to higher resistance.

So unlike antibody treatments, resistance to Paxlovid isn't an elimination of its efficacy, but a reduction. This means the key is to have your drug be well above the active inhibitory dose to make the barrier to resistance much higher, and the reduction of efficacy much weaker. The data from EDP-235 suggest its potency in the 200mg-400mg dosage being tested in the phase 2 Sprint trial is 6-24x higher than needed to inhibit Covid. The Paxlovid resistance data is from in vitro studies. Resistance to a drug in in vitro studies won't necessarily correspond to greater pathogenicity in humans. The changes that reduced Paxlovid derived protease inhibition could negatively impact viral production by say, reducing the speed of protease cleavage. Alternatively, it could reduced the stability of the protease cells, thereby making the virus less pathogenic.

In addition to in vitro data, nirmatrelvir can restrict viral infection in the respiratory organs of hamsters infected with BA.2 [41]. However, a pharmacokinetically human-equivalent dose of N/R did not significantly reduce shed SARS-CoV-2 titers in ferrets and failed to block virus transmission to untreated direct-contact ferrets, whereas transmission was fully suppressed in a group of animals treated with a human-equivalent dose of molnupiravir. Prophylactic administration of molnupiravir to uninfected ferrets in direct contact with infected animals blocked productive SARS-CoV-2 transmission, whereas all contacts treated with prophylactic N/R became infected[42].

So Paxlovid was unable to block an infected ferret from transmitting Covid to other co-housed ferrets. ENTA just provided data that EDP-235 DID block transmission. That is a big positive for EDP-235 and ENTA. I am holding my breath that the EDP-235 phase 2 Sprint trial shown no safety issues. If so, I think ENTA shareholders will be really smiling.