What I Learned Watching the Molnupiravir Committee Meeting

My Ugly, Chicken Scratch Notes

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.

1. 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.

2. 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).

30:45 Start

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?

1:01:40

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

reversible

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

6 studies

1 phase I

3 phase II

2 phase II/III

2 ongoing outpatient trials (one Phase I/II-outpatient, one Phase II-inpatient)

1:24:40

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

1:52 conclusion

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

EUA Request

Molnupiravir: Nonclinical Toxicology Findings Mark Seaton

2:18:00

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.

2:22:40

2:29

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

Embryofetal toxicity

Potential for mutagenicity

potential for enhanced viral evolutionary

03:04:00

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

PATIENT CRITERIA

18 or older

positive test result

within 5 days of symptom onset

at high risk for worsening outcomes

not hospitalized

*considerations to not provide to pregnant women

Suggest using restrictive criteria

3:10:35 High Risk Sheet****

CLARIFYING QUESTIONS

*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

****03:24:00

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.

***03:25:00

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.

Immunocompromised Q??

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

4:12:50

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

5:12:35 McGillis

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

5:22 Frederick

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

Data Fudging???

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

6:05:15 Coffin

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???

Cragan 06:12:05

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

Eastmond: Yes

• 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

Cragen: Yes

• require pregnancy testing for women before/after treatment.

• If pregnant must seek counseling before receiving prescription

Green: Yes

• Difficult decision,

• 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

Reddy: Yes

• 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

Swaminathan: No

• 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

Dublin: Yes

• difficult decision

• 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??

Burgess: No

• challenging decision

• 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

Le: 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

Weina: No

• 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

Hardy: Yes

• 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

Gillespie: No

• Biggest reason is not enough evidence on embryofetal development

• benefits do not seem good enough to outweigh risks

Baden: Yes

• 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

Walker: Yes

• 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

Poirier: Yes

• 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

Murphy: No

• 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

Sidberry: Yes

• 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

Perez: Yes

• 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

Horton: No

• 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

Hunsberger: No

• 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

Coffin: Yes

• 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

Fuller: No

• 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

Yes side

• 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

No Side

• 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