So I guess I couldn’t post a document onto Substack, so instead I’ll post my notes here. It’s a bit unnecessary but it’s for the sake of transparency. Also, in case there is anything that people would like to view for themselves. Please keep these in mind when viewing the notes.
These notes are a reflection of my note taking, and not what was spoken by the presenters. Any discrepancies are due to me and is my error.
Many names are included in my notes, mainly for the sake of separating the notes. As they are public figures, and since the meeting with their names are public, I do not see this as a form of doxxing. However, please do not use the names here as an indictment against any of the people mentioned.
Also, if you would like the results and reasons for the vote by the members of the committee, they are at the bottom of the notes (it’s in order of the presentation).
47:30 800 mg (4 200 mg pills) every 12 hours for 5 days (40 total pills????)
53:00 concerns brought up in research literature
54:50 merck starts sean curtis md, phd
references need for safe and effective therapeutics 56 min
59:10 reference interim data, why not final data?
MoA Daria Hazuda, PhD
Nonclinical Safety Kerry Blanchard, PhD
Clinical Safety, Benefit/Risk Conclusion Nicholas Kartsonis, MD- main spokesperson for Merck
1:03:10 interchange between oxime and hydroxylamine changes recognition
1:04 antiviral activity similar across all variants, MoA isn’t based on the variants
1:04:50 does not work on viruses that use dNTPs or DNA viruses
1:05:50 relationship between error rate and infectious virus titer
01:07:40 mutations distributed randomly, not focused on certain genes such as spike. Error rate level higher than infectious rate
01:08:20 all spike substitutions observed are present in currently circulating strains. Usually from transversions or other mechanism and not drug
01:09:40 MoA conclusion
1:11:40 bacterial ames assay showed positive mutagenicity, human TK6 cells showed negative mutagenicity, Zhou showed positive study (taken into account mutagenicity)
1:12:35 Rat Micronucleus in vivo study showed negative genotoxicity
Followed by Pig-a and Transgenic (Big Blue) rat studies
1:13:20 Not clearly positive, not clearly negative (did they mention beforehand that the studies were negative??); met 1 of 3 criteria: showed difference compared to control, cannot be called positive or negative,
1:15:10 transgenic mice assay (Big Blue) showed no increase in mutation rate in both slow and rapid growing tissues
lack of in vivo genotoxicity from big blue study
1:16:40 Hematopoetic study in dogs
Mild Hematology findings
Severe pancytopenia (reduction in blood cells and platelets) and bone marrow depletion > 2 weeks of continuous exposure
not seen in other animals
not observed in clinical trials
1:17:45 3-month rat study showed dose-dependent increased thickness of growth plate observed in rapidly growing rats
increased thickness of growth plate/low bone growth
does not occur in adults (growth plates not an issue)
high dosage used
concerns in children
1:19:00 no effects on fertility (eggs and sperm)
effects on embryo-fetal developmental study (toxic to developing fetuses-teratogen)
no effect on pregnant rats
High dose led to lethal malformations
above regular lead to reduced body weights, no teratogenicity
Not recommended for use in pregnancy*****
supports short term use but not in pregnant women and children******
in vivo genotoxicity low
hematology not shown clinically
growth plate not relevant to adults, research in children
1:22:35 Clinical Overview
1 phase I
3 phase II
2 phase II/III
2 ongoing outpatient trials (one Phase I/II-outpatient, one Phase II-inpatient)
Easily absorbed, prodrug cleaved in intestine/liver, taken up by cells. No drug-drug interactions and no enzyme interactions.
1:25:40 3.3 h half-life, no food needed
Phase 2 trial
1:30:45 Substitutions/mutations increased with doses
1:36:10 interim data used to end study abruptly due to superiority of data
Phase III comprised predominately of participants outside of US
Obesity most common risk of severe COVID Illness**** 1:30:20
1:40:50 20% people had antibodies
1:42:00 still referencing interim data??? was considered statistically significant enough to stop trial
1:44:30 used as supportive data??? interim data was sufficient enough; efficacy data considered complete at interim data…. *****
1:47:20 Diabetes played greater risk factor in molnupiravir group as composed to placebo
1:58:50 mentions seasonality of COVID
2:02:10 Does not recommend molnupiravir for pregnant/lactating women. Suggests women use contraception on the drug. Suggests there may be times it may be warranted to outweigh the risk.
Test to look at outcomes for women who were exposed to drug while pregnant.*****
Not intended to be used in children.
Aimee Howdowenac, MD 2:16:15
Molnupiravir: Nonclinical Toxicology Findings Mark Seaton
2:18:50: Mentions severe bone toxicity in dogs*****
lead to thrombocytopenia and hemorrhage
*occurred at exposure lower than the mean clinical exposure at the recommended human dose
2:19:40 mentions same mutagenicity as mentioned previously
2:20:10 bone cartilage abnormalities. Same issues mentioned by Merck previously (occurred in rats after 3 months, not after 1 month)
incomplete ossification in rabbits, delayed ossification in rats.
2:40 Zhou et al study referenced. Says that it fits prior studies of in vitro studies with bacteria.
Considered not an in vivo mutagen
2:48:40 “For reasons unknown hospitalizations/deaths lower in the second half of the study in placebo”
2:54:50 UC/ CU mutations most common
2:56:10 shows areas under selective pressure (E484K mutation)
3:00:00 Indicates many factors that may affect mutations, including vaccines. Also indicated that greater mutations lead to decreased fitness, typical of viral mutations
03:02:20****** Proposed risk mitigation strategies.
Bone and cartilage toxicity
Potential for mutagenicity
potential for enhanced viral evolutionary
MOV not used in under 18. No data and bone & cartilage concerns
Children studies may be coming
2 pathways for pregnant women; do not provide to women out of fear of teratogenicity, or in rare circumstances.
Low mutagenicity, only used for up to 5 days and dispensed in original container *****
Potential for Enhanced Viral Evolution
hypothetical concern, may occur in immunocompromised patients
18 or older
positive test result
within 5 days of symptom onset
at high risk for worsening outcomes
*considerations to not provide to pregnant women
Suggest using restrictive criteria
3:10:35 High Risk Sheet****
*Dr. Kartsonis answers for Merck
3:20:00 Dr. Baden
1. Brings up question about reduced death in part 2 and hospitalizations inversed in second half (my question!!!)
A: Don’t know where it comes from. Did not find a driving factor… The second half enrolled older populations and women, more antibody positive (27 in placebo, 19 in mol), later course of the disease (wouldn’t that mean that either molnupiravir was ineffective or caught too late in the study?)
No clear explanation… second half had population from Europe… all Delta
protocol 1 (MOVe-IN) and greater deaths in molnupiravir group. This one in hospital setting/discontinued study. 14 overall molnupiravir deaths vs placebo. Remdesivir effect (worse outcomes after continued use, late stage disease?)???
fewer adverse events in treatment group or all similar.
All deaths attributed to COVID, many had severe COVID at time of trial, older than 60, several comorbidities.
Comparable to other in hospital studies.
Those hospitalized who continued treatment had better outcomes
Dr. Hardy Q 3:27:50
Dr. Green Q 3:32:10
Did not have effect on diabetes group??
Seemed to be beneficial in Diabetic group, but Diabetes plus 2 other comorbidities led to worse outcomes in treatment group (25 vs 18)
No explanation, Diabetes plus 3 other comorbidities had 0 deaths in both groups
Dr. Dublin 3:35:40 Q
Could concomitant therapies explain reduction? People were not allowed, and they were not included in study, could not be used to explain discrepancies.
Death rate brought up again.
Dr. Le 03:39:45
Absolute risk reduction declined. Any effects due to regionality?
3:42:10 shows country demographic difference. Brazil outlier for biggest decrease with molnupiravir use, Guatemala in favor of placebo.
Hospitalization as measured in study required people be hospitalized for more than 24 hours.
Dr. Coffin 3:43:30
Concern about escape mutations. Consistent efficacy, no egregious changes in RdRp or exonuclease to be concerned about.
Real question: Action as a mutagen leading to possible formation of more dangerous viruses.
Dr. Hazuda responds.
All spike changes seen are changes already seen in circulation. More seem to occur with Molnupiravir. Occurs in very small number of patients. Possible sampling or contamination error accounting for differences in mutations?
Most mutations transitional w/ molnupiravir. Most virus not infectious in time period.
Follow up Q: did they sample during infectious period? Did not see spike mutations except in a placebo one.
4% included, in cancer treatment group half had better outcomes than placebo.
33:56:00 Dr. Hildreth- calls them out about escape mutations
Data for likelihood of mutation? No data!
Decrease in concern? Complete treatment course.
4:00:50 Dr. Swaminathan
Clade dependent efficacy? Delta showed lower efficacy.
Viral RNA load reduction similar among groups.
04:05:40 Dr. Fuller
After 5 days no more infectious viral load from study. If longer, what could happen? Could they spread mutant viruses?
4:10:15 Dr Burgess
Clade-specific reduction. Was there absolute reduction
Dr. Weina- monitoring around family contacts and infections
5:00:45 OPEN PUBLIC HEARING DISCUSSION
5:03:00 Dr. Michael Carom
Do benefits outweigh risks?
Study shows modest reduction of hospitalization/death
Absolute risk reduction of 3%. Relative risk reduction 30%
Proposed benefit may be lower in delta than other variants, marginal for Delta.
Greater concentration needed for Delta than Gamma in in vitro studies
Half life of 3.3 hours, dosing every 12 hours means low serum concentrations.
FDA needs to assess if 12 hours dosage works against Delta
Pregnant women should be excluded
No evidence of presence of drug in lactation; lactating individuals should not breast feeding
Other drugs should be considered and remove EUA
Millions of people are likely to produce dangerous variants
dosage may be too low to lead to viral clearance
5:18 Dr. Meg Seymour
No evidence on Vaccinated, yet wants to be used for all at-risk patients
3% absolute risk reduction marginal, especially for people not at large risk
Disregarded mutagenicity studies, and chose only negative results
control values used in Pig-A assay far too high than what’s in literature
Merck measured upper bound confidence interval at 6 mutations/million when database usually uses 1-3/million
1 pig a assay indicated mutagenicity, yet Merck and FDA arguing it is equivocal
No “gold standard” toxicology study
Big Blue did not indicate detection of DEN in bone marrow, yet Pig a did
Mutagenicity most likely to occur in bone marrow, not liver as is used by Big Blue assay
Researchers at North Carolina indicate shift from ribose to deoxyribose in study
discarded all positive assays, chose single big blue negative assay for determination
Did not to studies to indicate shift from ribose to deoxyribose; have not evaluated that enzymatic process
05:31:30 CLARIFYING QUESTIONS AGAIN
Burgess: When is complete assessment of virologic available? 1st quarter 2022
Questions about mutations and sensitivity of tests.
5:34:15 Siberry to Merck
around 15% did not have detectable viruses
tested positive before, tested negative on day 1, not all had antibodies
Dr. Green 5:37:15 to Merck
Tested positive first, then negative after may not benefit from the treatment
5:39:40 Dr. Eastmond to FDA
historical control and concurrent control; are they commonly seen values?
Potency of drug in vitro assay
Concentration to see in human serum
A: Negative control frequencies higher for populations
Historical control database; highest control seen
FDA even mentions suspicions about the control values
Data not reliable, sponsor’s evaluation of “equivocal” seems fit, and yet they have control over values
5:42:30 Dr. Schoeny to FDA
Comment on in vitro study exposure time; what was gained from study?
A: Confirms mutagenicity in vitro, used a cell line with many deficiencies in DNA processing
Brings up Pig-A assay results
5:46:55 Dr. Weina
5:51:10 Dr. Swaminathan
Brings up Pig-A assay results
did not choose good historical control?
Yet indicates great increase in mutations in blood cells. Poor control should not lead to high negative predictive value
A: 3 factors used to evaluate data
1. Comparison to control which was high
2. Toxicology trend. Did not conduct own test; examined Merck’s data which showed toxicological trend “eyeball test says there is a trend”
3. Comparison to historical database- no mutagenesis indicated, any mutagenesis at that low level not meaningful
Merck could not differentiate with that level.
Follow up: Assay can measure different tissue samples, look at tissue-specific differences
bone marrow and liver are examples chosen
should expand to other rapidly dividing tissues, if they should be studied to look for mutagenicity
A: Evidence evaluated only based on the studies, and the studies indicate “valid results”
6:00:50 Dr. Horton
Pig-A Assay only done in 5-6 animals, not enough to measure statistical dose dependent response?
Test doesn’t measure dose dependence, but genotoxicity. Pig-A checked for toxicology increase which was statistically insignificant. Falls back onto evidence from Merck and have no studies of their own.
Follow up: If low mutagenicity may have effects on larger population.
A: Only given to high-risk groups with low risk of mutations
What is mutational load over genome?
Test only looks at one gene. What’s the possibility of genome mutation and passing on mutation.
Assay assume correlation between gene mutation and genomic mutation?
Dr. Kirkland: Large target, very sensitive
Comments on Dr. Frederick: TGR being flawed cause of negative on bone marrow.
A: However, positive in liver. Mutations easier to detect in liver than in bone marrow.
Credits Merck laboratory, says negative data is very credible???
Teratogenicity in different pregnancy stages?
How to assess in use of pregnant women and unborn infants?
No data to differentiate teratogenic effects in different phases
Establish pregnancy surveillance program
do follow up
Must contact Merck about exposure
6:17:20 Possible sperm mutations? Possible latent effect
Can affect all males who take the drug.
Checked for performance of males; no issues in studies
Looked in studies, no disruption of spermatogenensis
Long term concern about sperm?
Terminal half life is 14-16 hours.
5 treatment days plus 4 additional days due to half life- 9 day overall treatment
6:35:00 CHARGE TO COMMITTEE
6:44:00 DISCUSSING USE OF MOLNUPIRAVIR IN PREGNANT WOMEN
Molnupiravir may be used in pregnant women IF mAB are ineffective against new variants.
**One presenter (OB/GYN) pivots comment about people with prior immunity (natural) to discussing vaccination. The study never contained vaccinated, but did contain people with natural or occurring immunity.
Dr. Swaminathan: Treat 30 women to reduce hospitalization in 1?
1/34 in molnupiravir vs 1/15 for Mab
Dr. Hildreth: Reduction of 30% for risk of harm to fetuses not permissible. Does not recommend for pregnant women
Dr. Porier: 83% reduction in hospitalization/death in people over 60
7:33 DISCUSSING INCREASE IN VIRAL MUTATION RATES
No big concerns about mutations, although concerns in immunocompromised people.
Dr. Green: 7:42:45 Mitigation strategies in home? Isolate those on this therapeutic from family members for several days after?
In case after 5 days they are still infectious, up to day 10??
Is this logistically feasible???
Similar to HIV, if there are concerns about mutations should other drugs be used in conjuction??
Should people who may have extended viral replication not be provided, especially with low adherence to drug? OR not limit and do studies to confirm at the same time.
Unlike Mabs, does not put selective pressure on the virus.
***Was there concern about rebound of viral load???
Big Questions: How much is used, how widely, compliance to medications (parallels to antibiotics/HIV)
Prolonged Infection groups are the biggest concern.
7:59:00 VOTING QUESTION
Big concern raised as to the actual effectiveness of the drug (never fully discussed)
08:01:20 DR DUBLIN BRINGS UP WHETHER THEY KNOW THERE WAS ACTUAL EVIDENCE OF EFFECTIVENESS
“NO, IT’S ABOUT THE GENERAL PROCESS. I FEEL LIKE WE’VE KICKED THE CAN DOWN THE ROAD A LOT OF TIMES ABOUT WHETHER THERE’S TRULY A BENEFIT AND WHETHER WE BELIEVE THERE’S A BENEFIT, AND I WAS JUST ASSUMING THERE WOULD BE SOME TIME FOR DISCUSSION OF THAT AS A GROUP.”
Response: Incorporate it into justification. We should only be voting.
08:20:10 VOTING DONE
benefits outweigh risks, FDA should not approve for use in women except exceptional circumstances
use in high risk individuals
engage in post exposure monitoring for mutations in treatment groups
require pregnancy testing for women before/after treatment.
If pregnant must seek counseling before receiving prescription
stat signal impacted decision making
lack of other alternatives, especially with use of Mab in case of variants
Should be used for unvaxxed and obese
less outcome in those under 60
Possibly for those with multiple risk factors
may use it for transplant recipients
may use it in pregnant women but not in first trimester
multiple mitigation strategies, especially in homes???
If alternative with better safety profile and efficacy profile may remove EUA approval
stick with high-risk criteria
unvaxxed/had adverse reaction to vax
lack of alternatives
if other alternatives appear, prioritize those over molnupiravir
risks outweigh benefit in first trimester, but may provide if only alternative, although data should be collected on US population and stronger surveillance data
overall absolute effect modest at best
risk of mutagenicity not well-established or characterized
concerns about birth defects, especially delayed effects in male spermatazoa not been adequately studied
consider results overall
population important- stick to trial population and not broaden treatment groups
no age limitation, although suggest limiting to those over 60
does not recommend in pregnant women except in dire circumstances (no alternatives, or safety of mother a concern)
recommend for those unvaccinated, poor response to vaccines, or immunocompromised
vaccinated who may have poor immune system such as over 75 or immunocompromised
important to continue efficacy monitoring- understand if there really is reduced efficacy against Delta
suggests comparative study against other alternatives
escape mutations are concern
suggest conducting pregnancy tests
if another therapy receives EUA, reconsider Molnupiravir EUA and possibly revoke
multiple therapy strategy??
Persuaded to vote no due to large discrepancy before/after interim data and large heterogeniety in data (i.e. diabetes)
risk for genotoxicity
additional therapeutics needed, especially against different strains
However, based on available data no
safety tends to be evident post-marketing, but pre-marketing signals are concerning
modest benefit for mild-moderate symptoms, and not severe symptoms in reducing hospitalizations/deaths
No based on current data
prefer more efficacy and safety data, possibly with more subjects and tested against other strategies
not convinced with absolute risk reduction of 3%, does not outweigh risks of the drug
large number of treatment needed causes concern with spike protein mutagenicity
patients may not adhere to the regimen
potential to transmit new mutants to family members
results of diabetic group calls into question effects in other high risk groups not considered in trials
COVID-19 still emergency
Need for outpatient therapy, although questions about it’s longterm efficacy
met its prespecified statistical bound (based on interim data)
does not seem to be a warning for pregnant women, but discussion must be made with doctors, pregnancy testing may need to occur
may be concern in first trimester
preferred use for outpatient, high-risk
Schoeny: Yes (hard to hear this)
the high-risk groups considered is appropriate
mitigation strategies are also important
pregnant women should discuss with physicians
hardly any alternatives available for pregnant women?
Suggests for use in those aged 60 or over?
Hildreth: Firm No
genotoxicity/mutagenicity data leaves more questions than answers
concerns about the chance to drive stronger variants
Biggest reason is not enough evidence on embryofetal development
benefits do not seem good enough to outweigh risks
although agrees with both yes and no votes
based on regulatory evidence, mortality data seems compelling
inpatient study did not work, Phase III showed strong evidence in 1st half and opposite effect in second half- suggests its use is based on “right population, right time”
some populations may benefits, more studies required to see which cohorts most likely to benefits
using the CDC’s criteria for high-risk individuals makes sense
start with assumption drug works similarly across all variants, although studies should be conducted
unvaccinated/those with prior infection are important demographics
studies should be conducted in vaccinated and immunocompromised individuals- need to understand safety and concerns with several replication cycles causing variants of concern to possibly emergence
secondary transmission should be looked into
absence of data is what is making many people uncomfortable
sees scenarios where this drug may be beneficial
using EUA considerations
difficult, hobbled back and forth
efficacy in overall population should be addressed
should be given to high-risk groups who are unvaccinated, be sympomatic
the need to require prescription may mean lack of access for minority populations?
More data in monorities/women of child-bearing age
post-exposure monitoring needs to be done, immunocompromised individuals and transplant individuals
check-ins to check if people are taking the full dosage
proper language needs to be disseminated so people know risks
appropriate authorized population is for those 60 and over
should not be used in pregnancy, but if so lactating women, child-bearing women and men hoping to be fathers should also be given this drug (all or nothing stance?)
individuals who are immunocompromised should follow mitigation strategies and should have routine viral testing
genotoxicity situation still “black box”
Agency should reconsider when more evidence comes out
Came down to under most ideal circumstances had modest efficacy
uncertain efficacy against Delta
logistics of getting drug to people within first 5 days
risk for escape and mutagenicity, not settled in discussion
if given EUA should not be considered preferred, but alternative if Mabs are not available or ineffective against new variant
if another drug gains EUA approval, Molnupiravir EUA should be reconsidered
disappointed in seeing decrease in efficacy between interim and final data
final dataset still represented 30% relative reduction
significant reduction in death
evidence shows low risk of mutagenicity
CDC high-risk criteria should be taken into account
vaccination status and emergence of variants should be taken into account as well
should be used only in adults due to concerns about growth plate closure
reproductive toxicity big risk, but indicates a safety signal that’s a potential risk, not known risk
women who are or want to become pregnant should seek counseling, but they should not be stopped from using the drug if they meet criteria for high-risk of hospitalization or death and no other alternatives available
serves as an alternative to Mabs for those it is not available
eligibility criteria used in study are valid
immunocompromised individuals should be included and studied
women of reproductive age may need pregnancy test
unvaccinated pregnant women without access to Mabs may consider drug
struck by modest benefit
unclear efficacy in second half of trial where Delta variant prevalent
early benefits no longer apparent
concerns over lower effectiveness in real-world setting and low adherence to drug
safety concerns especially possible mutagenic effects, especially when used in large populations
concerns over driving viral mutations, especially if low adherence in real world setting
pretty minimal benefit
change in efficacy in placebo group between two parts concerning
another study needs to be done, and if EUA stops that then vote is no
issue of pregnancy and mutagenesis needs to be evaluated further.
Limiting initial authorization to high-risk groups other than pregnancy, perhaps over the age of 60
not the drug they’ve been waiting for, but one of the only ones they have right now
mutagenesis may not be as severe, although needs further researcher
good idea to broaden high-risk group by broadening criteria to all those positive whether symptomatic or not
efficacy seen and questions left unanswered (rebound effect, men’s reproduction, women who want to become pregnant, etc)
too many questions to release a reagent that may lead to viral mutation
too many risks for level of benefit, especially since there may be other options
would need to be for unvaccinated, not pregnant, complaint patient, and no rebound- too many variables to consider effective
Recap: 13 Yes, 10 No
Some who think absolutely no
some inclined for yes
most in middle
big questions are how to interpret efficacy
efficacy outweighed risks and heterogeneity of data
post-exposure monitoring needed
should be limited to high-risk individuals
many concerns over pregnancy
very few alternatives available
concerns about genotoxicity, mutagenesis weigh less because of lack of alternatives and reduction in mortality
role in high-risk patients such as transplant recipients need to be addressed
have to look into those who are unvaxxed but immunocompromised
too many uncertainties
efficacy data is “wobbly”
inconsistencies with data in 1st half and 2nd half of MOVe-OUT trial
genotoxicity, mutagenicity, impact on viral replication and viral escape all concerns-data lacking to inform those risks
risks in context of marginal benefit did not seem appropriate
Green says "lack of other alternatives". What he or she means is lack of other pharmaceutical companies paying us to look at their drugs, so we might as well approve this one. Thanks for the chicken scratch notes. 🐤🐤🐤🐤🐤🐤