13 August 2021 Episode 161 Merck, Sanofi and GSK in COVID vaccine development

Dear colleagues,

Lately, I was wondering why the big multinational vaccine companies, such as Merck, GSK and Sanofi-Pasteur are apparently absent in the COVID vaccine field. And how that reflects on the stock market.

This is what I found:

MERCK: failed on a measles-based vaccine, but develops a potentially successful drug.

Ep 161-1: Merck announced on 15 Jan 2021 to discontinue the development of its COVID vaccine candidate, based on a recombinant measles labeled V590 and V591.  I could not find scientific publications on this work.

In the same text, they announce the development of the polymerase inhibitor Molnupiravir (MK-4482) and a drug called CD24Fc or MK-7110. 

1. More on measles vector vaccines

Ep 161-2: A nice didactic review by Kenneth Lundstrom, published in Feb 2021,  on the different viral vectors that are being used in COVID vaccine development.  The only clinical trial by a measles vector mentioned is indeed the one by Merck.   

However there are other measles-based vaccines still in development

Ep 161-3: Horner et al applied both measles constructs, as proposed by Lundstrom, and one of those (with SARS-COV-2  full native S inserted after the H gene) turned out to be very efficacious in inducing protective immunity in the hamster model (see Fig 7 A-D p. 8).

Ep 161-4: Miija Lu et al produced a recombinant with various S constructs in the other position, i.e. after the P gene (which was suboptimal in the previous paper).  Their prefusion S recombinant was clearly superior in inducing protective immunity.

Would a combination of both approaches: prefusion S after the H gene be even better? 

2. Sialic acid–binding immunoglobulin-like lectin G (Siglec-G) or CD24Fc  is an innate checkpoint against the inflammatory response to tissue injuries or danger-associated molecular patterns (DAMPs).

Ep 161-5: showing that CD24Fc partly protects against viral pneumonia and ARDS in simian

immunodeficiency virus-infected Chinese rhesus monkeys.

After a phase 1 trial in healthy volunteers, showing biological activity (suppression of inflammatory cytokines) and a phase 2 trial in leukemia, showing prevention of graft-versus-host disease (Ep 161-6) a phase 3 trial in  COVID was pursued  https://www.clinicaltrials.gov/ct2/show/NCT04317040

But apparently, it failed….

Ep 161-7:   MSD discontinues development of CD24Fc or MK-1770

• Based on the additional research that would be required – new clinical trials as well as research related to manufacturing at scale – MK-7110 would not be expected to become available until the first half of 2022. 
• MSD has determined to discontinue development of MK-7110 for COVID-19 and to focus its pandemic efforts on advancing molnupiravir and on producing Johnson & Johnson’s COVID-19 vaccine

3. Molnupiravir

Ep 161-8: Painter et al unveil the history of this drug, known as EIDD2801, an orally available prodrug of EIDD-1931.  It was originally developed against the alpha virus VEEV, but turned out to have a very broad antiviral polymerase inhibiting action against Influenza, RSV, Chikungunya, EBOLA and…Coronaviruses. 

Ep 161-9: The group of Johan Neyts shows that the combination of Molnupiravir and Favipiravir (two orally available drugs with a high barrier to resistance for which there is very recent initial evidence that they exert antiviral activity in COVID-19  patients), is particularly effective in the treatment of SARS-CoV2 infections in hamsters.

This efficacy  may be explained by an enhanced accumulation of mutations as compared to monotherapy.

It should be noted that treatment was started very early (1 day after experimental infection), which is not feasible in humans.

Lung viral RNA was reduced by 4 logs and infectious viral titers were undetectable in most cases.  

Ep 161-10: The same research group showed that Molnupiravir monotherapy was similarly active against “wild type” and the alpha and beta variant. (gamma and delta not tested)

Ep 161-11:  Wahl et al show that the dangerous trio (MERS, SARS-CoV, SARS-CoV-2) as well as two bat CoV (WIV1 and SCH-014) are capable to infect human lung in immunodeficient mice, suggesting that the latter bat CoV might directly infect humans

Moreover, Fig 4 also confirms that treatment 24 H after SARS-CoV-2 infection (a) as well as 12 H before infection (c-f) strongly (> 4 logs) reduces viral load in the lung, but the effect is much weaker (1 log) 48 H after infection (b).  

Ep 161-12: At the ECCMID conference positive results of a phase 2 trial were shown.  I could not find the conference data, but a preprint in medRxiv in June shows that the high dose (800 mg) was associated with lower viral isolation from Day 3 on and the time to viral clearance was slightly reduced.  Positive but no spectacular results.

Maybe related to timing of treatment start ?

See eligibility p.5 if they tested positive for SARS-CoV-2 infection within 96 hours and had symptoms of COVID-19 within 7 days of treatment initiation

Ep 161-13 and 14: Apparently based on these results, Merck releases a very positive message and the Biden administration has procured 1.7 million doses.

… ongoing Phase 3 trial for its potential to reduce the risk of hospitalization or death in non-hospitalized patients who have symptoms for five days or less and are at high risk for severe illness. The trial plans to enroll a total of 1,850 patients globally with final data expected in the fall of 2021.

GSK and Sanofi: trial and error

Ep 161-15: Press communication in Dec 2020 about insufficient results in phase ½ of an “adjuvanted recombinant S protein vaccine”, co-developed by Sanofi and GSK.

Ep 161-16: A paper by Goepfert et al in Lancet Infect Dis of April 2021, describing the details:

• The protein is a stabilised SARS-CoV-2 pre-fusion S protein (CoV2 preS-dTM), which is very similar to the successful Novavax vaccine.
• Two adjuvants were compared AF03 from Sanofi and AS03 from GSK.

The results in phase 2 were disappointing: 

the lower than expected immune responses, especially in the older age groups, and the high reactogenicity after dose two were probably due to

- higher than anticipated host-cell protein content

- and lower than planned antigen doses in the formulations tested,

which was discovered during characterisation studies on the final bulk drug substance.  

Ep 161-17 and 18: two press communications in May 2021, where a very successful phase 2 and the start of phase 3 studies with a protein vaccine are announced.  I could not find more information on:

• Is this the same, but optimized vaccine of the Goepfert paper?
• Full results of the Phase 2 study will be published in a peer-reviewed journal. Apparently it did not get through the peer review process yet….?  

Ep 161-19: An earlier communication by Sanofi announced the development of an mRNA vaccine  MRT5500, together with Translate Co.

Ep 161-20: The paper in NPJ Vaccines, published April 2021, provides more preclinical details:

• The mRNA is prefusion stabilized and with a furin cleavage site mutation, formulated in lipid nanoparticles that require storage at -80°C.
• It induces good levels of neutralizing antibodies in mice and macaques
• It provides protection against SARS-COV-2 challenge in Syrian hamsters.   

So, it looks promising, but I’m not sure whether this mRNA will have any competitive benefit as compared to the Pfizer and Moderna vaccines

In summary:

• Merck has been betting on a measles-vector based COVID vaccine, a rather original concept.  It has failed in a clinical trial, but those results have not been published. Merck has stopped the development.  Other measles-based vaccines seem promising in preclinical phase.  
• Merck is now focusing on Molnupiravir, promising in preclinical work, but the question is whether it can be administered early enough in the clinic to have a significant effect.
• Sanofi and GSK are collaborating on an adjuvanted full S protein, which is similar to Novavaxx, but with their own adjuvants.
• Sanofi is also developing an mRNA vaccine, which seems promising, but the question will be if it will be competitive with Pfizer and Moderna
• In the meantime both Merck and Sanofi are producing approved vaccines from J&J and Sanofi also produces  Moderna and Pfizer vaccines (at least such has been announced in press releases).

Epilogue: How does this reflect on the stock market?

Ep 161-21 shows the evolution of share prices  as copied from Yahoo Finance

• No surprise that Moderna and BioNTech are doing very well, but, surprisingly, Pfizer is at a lower level than in 2019 and shows several serious “dips” during 2020-21.
• Astra-Zeneca and J&J are doing well, despite the negative publicity and limitations on the use of their COVID vaccines.
• Merck and Sanofi are fine, but GSK has lost a lot of its value.  

Don’t ask me to analyze these results any further. I’m an MD….

Best wishes,

Guido