What changed in this filing

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Item 1. Business

2022-02-24 compared with 2021-02-25 · 263 added, 170 removed, 425 unchanged (50% of the section changed)

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We are a clinical-stage biopharmaceutical company focused on the development and commercialization of innovative therapeutic candidates for the treatment of cardiovascular, metabolic, and liver diseases.

Our lead product candidate, MGL-3196

(resmetirom), is a proprietary, liver-directed, selective thyroid hormone receptor-ß, or THR-ß,

Our lead product candidate, resmetirom, is a proprietary, liver-directed, selective thyroid hormone receptor-ß, or THR-ß,

agonist being developed as a once-daily oral pill that can potentially be used to treat a number of disease states with high unmet medical need, including non-alcoholic

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NASH and NAFLD have grown as a consequence of rising worldwide obesity-related disorders.

In 2016, in the United States alone, NAFLD was estimated to affect approximately 26% of the population, or an estimated 85M people, and approximately 20% of this population was projected to progress from NAFLD to NASH.

Current estimates place NASH prevalence at approximately 17M people in the United States, or five percent of the population.

Slightly lower prevalence is seen in EU and Asia with approximately 2.5-4.5%

of the population having NASH.

In the United States, NAFLD is estimated to affect approximately 25% of the population, and approximately 25% of those will progress from NAFLD to NASH.

Current estimates place NASH prevalence at approximately 20 million people in the United States, or five to six percent of the adult population, with similar prevalence in Europe and Asia.

The prevalence of NASH is also increasing in developing regions due to the adoption of a more sedentary lifestyle and a diet consisting of processed foods with high fat and fructose content.

Our Completed Studies.

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results at the conclusion of the Phase 2 clinical trial in May 2018.

We have completed treatment in a 36-week,

open-label extension study in 31 participating NASH patients from our Phase 2 clinical trial, which includes 14 patients who received placebo in the main study.

We also completed a 36-week,

open-label extension study in 31 participating NASH patients from our Phase 2 clinical trial, which included 14 patients who received placebo in the main study.

On December 18, 2019 the Company announced it had opened for enrollment MAESTRO-NAFLD-1,

non-invasive,

multi-center, double-blind, placebo-controlled Phase 3 clinical study of patients with biopsy-confirmed or presumed NASH recruited from sites in the U.S.

Key endpoints are safety, including safety biomarkers.

Secondary endpoints include LDL cholesterol, lipid biomarkers, MRI-PDFF,

NASH and fibrosis biomarkers.

Except for serial liver biopsies, the study protocol is similar to the MAESTRO-NASH study (discussed below

under “—Our Ongoing and Planned Studies”), with resmetirom doses of 80 mg or 100 mg or placebo.

Enrollment objectives for this study were exceeded, with approximately 1,300 patients enrolled overall.

The MAESTRO-NAFLD-1

study will help support the adequacy of the safety database at the time of NDA submission for Subpart H approval for treatment of NASH in patients with F2 or F3 fibrosis.

In November of 2021, we reported data from the open label non-cirrhotic

arm of MAESTRO-NAFLD-1,

and in January 2022 we announced that we achieved primary and secondary endpoints for the double-blind portion of MAESTRO-NAFLD-1,

as summarized in

“- Key Developments” below.

We also completed a 116 patient Phase 2 clinical trial and announced results in February 2018 for the use of resmetirom in patients with heterozygous familial hypercholesterolemia, or HeFH.

In addition to the NASH and HeFH Phase 2 clinical trials, resmetirom has also been studied in eight completed Phase 1 trials in a total of 219 subjects.

Resmetirom appeared to be safe and was well-tolerated in these trials, which included a single ascending dose trial, a multiple ascending dose trial, two drug interaction trials with statins, a multiple dose mass balance study, a single dose relative bioavailability study of tablet formulation versus capsule formulation, a multiple dose drug interaction study, and a multiple dose drug interaction with food effect study.

In addition to the NASH and HeFH Phase 2 clinical trials, resmetirom has also been studied in multiple completed Phase 1 trials in a total of

more than 300 subjects.

Resmetirom was well-tolerated in these trials, which included a single ascending dose trial, a multiple ascending dose trial, several drug interaction studies, a multiple dose mass balance study, a single dose relative bioavailability study of tablet formulation versus capsule formulation, a multiple dose drug interaction study, a multiple dose drug interaction with food effect study, and a hepatic impairment study.

Our Ongoing and Planned Studies.

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Patients with liver biopsy confirmed NASH with stage 2 or 3 fibrosis are being randomized 1:1:1 to receive a single oral daily dose of placebo, resmetirom 80 mg or resmetirom 100 mg.

A second liver biopsy at week 52 in the first 900 patients will be the basis of filing for subpart H-accelerated

the primary endpoint will be the percent of patients treated with either dose of resmetirom as compared with placebo who achieve NASH resolution on the week 52 liver biopsy, defined as the absence of hepatocyte ballooning (score=0), and minimal lobular inflammation (score 0-1),

A second liver biopsy at week 52 in the first 900 patients will be the basis of filing for accelerated approval under subpart H of applicable FDA regulations, which we refer to as subpart H-accelerated

The primary endpoint pertains to the percent of patients treated with either dose of resmetirom as compared with placebo who achieve NASH resolution on the week 52 liver biopsy, defined as the absence of hepatocyte ballooning (score=0), and minimal lobular inflammation (score 0-1),

associated with at least a 2-point

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Patients will continue in the study for a total of approximately 54 months, and will be evaluated for a composite clinical outcome including cirrhosis on liver biopsy, or a liver related event such as hepatic decompensation.

The total anticipated enrollment is approximately 2,000 patients, and will include up to 15% high risk F1 fibrosis stage NASH patients whose efficacy responses will be evaluated as exploratory endpoints.

On December 18, 2019 the Company announced it had opened for enrollment MAESTRO-NAFLD-1,

double-blind, placebo controlled Phase 3 clinical study originally targeting enrollment of 700 patients with biopsy-confirmed or presumed NASH recruited from sites in the U.S.

Key endpoints are safety, including safety biomarkers, LDL cholesterol, lipid biomarkers, and fibrosis biomarkers.

Except for serial liver biopsies, the study protocol is similar to the MAESTRO-NASH study with resmetirom doses of 80 mg or 100 mg or placebo and includes key secondary lipid, MRI-PDFF

and NASH biomarker endpoints.

Enrollment objectives for this study have been exceeded, with approximately 1,200 patients enrolled overall.

In October 2020 we completed enrollment of the double-blind, placebo controlled arms of the study.

The MAESTRO-NAFLD-1

study will help support the adequacy of the safety database at the time of NDA submission for subpart H approval for treatment of NASH in patients with F2 or F3 fibrosis (MAESTRO-NASH, NASH resolution surrogate endpoint).

The following chart summarizes the status of our product candidate development programs for resmetirom and MGL-3745,

a preclinical compound which has similar thyroid receptor selectivity to resmetirom and is thus a potential backup compound for resmetirom:

The total anticipated enrollment currently is approximately 2,000 patients, and will include up to 15% high risk F1 fibrosis stage NASH patients whose efficacy responses will be evaluated as exploratory endpoints.

On June 30, 2021 we announced our achievement of the requisite enrollment of patients to support the planned Subpart H (Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses) submission to the US Food and Drug Administration (FDA).

On July 13, 2021 we announced first patient dosed in a planned 52-week

open label active treatment extension study of MAESTRO-NAFLD-1,

named MAESTRO-NAFLD-Open Label Extension (OLE).

The OLE study allows patients who complete MAESTRO-NAFLD-1

to consent to 52 weeks of active treatment with resmetirom, making this treatment available to both patients who were assigned to placebo in MAESTRO-NAFLD-1

and patients who were on resmetirom in MAESTRO-NAFLD-1.

The following chart summarizes the status of our product candidate development programs for resmetirom:

Key Developments

Ongoing MAESTRO-NASH Phase 3 clinical trial

In March 2019 we initiated a Phase 3 trial in NASH, described in detail above under “—Our Ongoing and Planned Studies.”

Ongoing MAESTRO-NAFLD-1

Phase 3 clinical trial

In December 2019 we initiated a Phase 3 trial in presumed NASH, described in detail above under “—Our Ongoing and Planned Studies.” In October 2020 we completed enrollment of the double-blind, placebo controlled arms of the study.

FDA grants Fast Track designation for resmetirom in NASH

In October 2019, FDA granted Fast Track designation to resmetirom for NASH.

Pandemic Effects on Madrigal

In January 2022, Madrigal announced topline results from the Phase 3 MAESTRO-NAFLD-1

safety study of resmetirom.

Madrigal reported that resmetirom demonstrated statistical significance for primary and key secondary endpoints summarized below, from the double-blind placebo-controlled 969-patient

portion of the study.

These endpoints indicated that resmetirom (1) was well-tolerated at 80 and 100 mg in patients treated for 52 weeks, (2) provided significant and clinically relevant reductions in liver fat as measured by MRI-PDFF

and (3) significantly reduced atherogenic lipids, including LDLc, apolipoprotein B and triglycerides.

A total of 972 patients were randomized in the double-blind arms of the MAESTRO-NAFLD-1

969 patients were included in the safety population and 943 patients in a modified intent-to-treat

population for evaluation of key secondary and other endpoints.

Important inclusion criteria included the presence of three risk factors of metabolic syndrome, a level of liver fibrosis (measured by FibroScan) consistent with a range of stages of liver fibrosis, and >=8% liver fat (measured by MRI-PDFF).

Adverse events observed in the MAESTRO-NAFLD-1

trial were generally mild to moderate in severity.

The frequency of serious adverse events was similar across treatment arms and discontinuation for adverse events was low.

Consistent with published data, the most common adverse event reported with greater frequency in the resmetirom groups vs placebo was generally mild diarrhea or increased stool frequency at the beginning of therapy, which occurred in 9% and ~17% over the placebo rate in the 80 and 100 mg dose groups, respectively.

Safety population

At least one TEAE

At least one Serious TEAE

TEAE ≥ Grade 3 Severity

AE discontinuations from study

All treatments combined, n=21;

Maximum NCI CTCAE Severity Grade

AE (adverse event);

TEAE (treatment emergent adverse event);

NCI (National Cancer Institute);

CTCAE (Common Terminology Criteria for Adverse Events)

The following hierarchically-controlled key secondary endpoints were reported for both the 80 and 100 mg resmetirom dose groups.

Resmetirom provided significant reductions in liver fat as measured by MRI-PDFF

and reduced atherogenic lipids, including LDLc, apolipoprotein B and triglycerides.

Open-label arm data is reported in the far left column below and double-blind arm data are reported in the remaining columns below.

Although both arms were randomized in MAESTRO-NAFLD-1,

lipid reductions were numerically greater in the 100 mg open label treatment arm compared to the 100 mg double-blind arm, and we believe this is due to greater visit and dose interruptions experienced by open-label arm patients during the height of the COVID-19

patients in the open-label active 100 mg treatment arm were less impacted by COVID-related dose interruptions than double-blind patients.

Resmetirom 100

LDLc %CFB (SE) (Week 24)

ApoB %CFB (SE) (Week 24)

%CFB (Week 16)

Liver volume PDFF correction %CFB

%CFB (Week 52)

Liver volume PDFF correction %CFB

Triglycerides baseline >150 mg/dL, CFB (SE)

Triglycerides baseline >150 mg/dL (geomean) %CFB (95% CI)

-21.5 (-28.0 to

-2.1 (-10.6 to

CFB (change from baseline);

SE (standard error);

APOB (Apolipoprotein B);

(magnetic resonance imaging proton density fat-fraction);

CI (confidence interval);

OL, open label non-cirrhotic

arm randomized concurrently with double-blind arms

Pandemic Effects on Madrigal Phase 3 Trials

In April 2020 we announced that in response to guidance from regulatory agencies, measures for COVID-19

at impacted sites have been put in place for our Phase 3 MAESTRO-NASH and MAESTRO-NAFLD-1

at impacted sites were put in place for our Phase 3 MAESTRO-NASH and MAESTRO-NAFLD-1

studies, allowing both studies to continue without changes to the protocol.

At a recently conducted Data Monitoring Committee (DMC) meeting it was recommended that Phase 3 studies proceed without significant modification.

pandemic had no material adverse impact on our operating results, MAESTRO-NAFLD-1

study or liquidity for the period ended December 31, 2020, but it did introduce clinical trial and operational risks and uncertainties that are both general in nature and relate specifically to our MAESTRO-NASH study.

These risks and uncertainties, which are beyond our control, are summarized in the section entitled “Risk Factors” in Part I, Item 1A of this Annual Report.

Following a Data Monitoring Committee (DMC) meeting it was recommended that Phase 3 studies proceed without modification.

pandemic had no material adverse impact on our operating results, our conduct of the MAESTRO-NAFLD-1

study or our liquidity for previous periods.

However, COVID-19

did introduce clinical trial and operational risks and uncertainties that are both general in nature and relate specifically to our MAESTRO-NASH study.

In addition, at the height of COVID-19,

MAESTRO-NAFLD-1

double blind patients had an average of two missed visits and two dose interruptions, with the dose interruptions primarily related to third-parties.

These risks and uncertainties, which are beyond our control, are summarized in the section entitled “Risk Factors” in Part I, Item 1A of this Annual Report on Form 10-K.

Resmetirom Phase 2 Clinical Trial in NASH

The Company successfully completed a Phase 2 clinical trial in NASH in 2018.

As summarized above, the Company successfully completed its Phase 2 clinical trial in NASH in 2018.

In this clinical trial, resmetirom demonstrated statistical significance in the primary endpoint (p<0.0001), the relative reduction of liver fat compared with baseline on magnetic resonance imaging-estimated proton density fat fraction, or MRI-PDFF,

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This clinical trial was published in the Lancet in November, 2019.

Specific data from this study is as follows.

Responders(1)

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Statistically significant reductions in liver enzymes (ALT, AST and GGT) relative to placebo (all p=0.002) and a 40% reduction in ALT in patients with elevated baseline levels (p=0.01);

Statistically significant reductions in fibrosis biomarkers in MGL-3196

treated patients as compared with placebo patients;

Statistically significant reductions in fibrosis biomarkers in resmetirom treated patients as compared with placebo patients;

On liver biopsy, fibrosis was reduced by at least one point in 23% of placebo patients and 29% of resmetirom treated patients;

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There were two serious AEs in the study, both considered unrelated to treatment, one in a placebo and one in a drug-treated patient.

Lead Product Candidate—MGL-3196

Lead Product Candidate—Resmetirom

We believe that resmetirom may be the first THR-agonist

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In addition, a study using radiolabeled resmetirom, a study of a tablet versus capsule formulation of resmetirom, and a multiple dose drug interaction and food effect study have also been completed.

In Phase 1 studies, resmetirom appeared safe and was well-tolerated up to 200 mg once daily.

In Phase 1 studies, resmetirom was well-tolerated up to 200 mg once daily.

The results of these studies suggest that resmetirom is suitable for once-daily oral dosing.

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(range, p =0.027-p<0.0001)

and 24% for ApoB (range, p =0.008-0.0004),

and 24% for ApoB (range,

p =0.008-0.0004),

and statistical trends of up to 60% reduction in TG (range, p =0.13-0.016).

The near maximal lipid effects were observed at a resmetirom dose of 80 mg once-daily.

Resmetirom was well-tolerated at all doses, with no dose-related

adverse events or liver enzyme, electrocardiography, or vital-sign changes.

Resmetirom was well-tolerated at all doses, with no dose-related adverse events or liver enzyme, electrocardiography, or vital-sign changes.

At the highest dose of resmetirom (200 mg), there was a reversible reduction of 20% in the level of a precursor hormone to T3, free T4, which was significantly different from placebo (p < 0.0001) that may be explained by increased liver metabolism of free T4.

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The study employed an adaptive dosing design whereby, in a blinded fashion, the dose could be adjusted by small amounts (i.e.

20 mg up or down) or remain at 80 mg in each resmetirom-treated patient based on a pharmacokinetic analysis of drug level performed in each patient at 2 weeks.

The primary endpoint of the study was the reduction of liver fat at 12 weeks compared with baseline (relative change), assessed by MRI-PDFF,

with efficacy confirmed at the end of the trial (36 weeks) by repeat MRI-PDFF

and conventional liver biopsy to examine histological evidence for the resolution of NASH.

20 mg up or down) or remain at

80 mg in each resmetirom-treated patient based on a pharmacokinetic analysis of drug level performed in each patient at 2 weeks.

The primary endpoint of the study was the reduction of liver fat at 12 weeks compared with baseline (relative change), assessed by MRI-PDFF, with efficacy confirmed at the end of the trial (36 weeks) by repeat MRI-PDFF and conventional liver biopsy to examine histological evidence for the resolution of NASH.

Other secondary endpoints included changes in clinically relevant biomarkers at 12 and 36 weeks, improvement in fibrosis by at least one stage with no worsening of steatohepatitis, and safety and tolerability.

Resmetirom demonstrated statistical significance (p<0.0001) in the primary endpoint, the relative reduction of liver fat on MRI-PDFF

Resmetirom demonstrated statistical significance (p<0.0001) in the primary endpoint, the relative reduction of liver fat on MRI-PDFF at 12 weeks.

At 36 weeks, statistically significant results were demonstrated in multiple histology endpoints including key secondary endpoints related to the reduction and resolution of NASH.

At 36 weeks, resmetirom treated patients demonstrated sustained, statistically significant (p<0.0001) reductions compared to placebo treated patients in LDL-C

and ApoB of more than 20%, TGs of 36% and Lp(a) of 37%.

At 36 weeks, resmetirom treated patients demonstrated sustained, statistically significant (p<0.0001) reductions compared to placebo treated patients in LDL-C and ApoB of more than 20%, TGs of 36% and Lp(a) of 37%.

In addition, resmetirom demonstrated statistically significant reductions in liver enzymes (ALT, AST and GGT) relative to placebo (all p=0.002).

Published data [Lancet] showed that patients with >=30% PDFF reduction at Week 12 had a higher rate of NASH resolution and accompanying fibrosis reduction.

Published data showed that patients with >=30% PDFF reduction at Week 12 had a higher rate of NASH resolution and accompanying fibrosis reduction.

A secondary analysis of the Phase 2 NASH clinical trial further supported the potential of PDFF to predict NASH response.

Percentages of patients with NASH resolution at Week 36 increased with greater PDFF reduction (agreement between two independent pathologist central biopsy readers)

In resmetirom-treated patients with ³

50% fat reduction at Week 12, 64% had NASH resolution with a component response driven primarily by ballooning and inflammation

PDFF reduction ³

50% at Week 12 was associated with improvement in all NAS components including fibrosis reduction on subsequent liver biopsy and achievement of both endpoints:

NASH resolution and ³

1 point fibrosis reduction PDFF reduction ³

50% at Week 12 was also associated with fibrosis reduction on subsequent liver biopsy

In resmetirom-treated patients with ≥ 50% fat reduction at Week 12, 64% had NASH resolution with a component response driven primarily by ballooning and inflammation

PDFF reduction ≥ 30 and ≥ 50% at Week 12 was associated with improvement in all NAS components including fibrosis reduction on subsequent liver biopsy and achievement of both endpoints:

NASH resolution and ≥ 1 point fibrosis reduction PDFF reduction ≥ 30 and ≥ 50% at Week 12 was also associated with fibrosis reduction on subsequent liver biopsy

These findings support the pathogenicity of liver steatosis in NASH and fibrosis progression.

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To achieve our goal, we plan to:

Complete clinical development and seek regulatory approval of MGL-3196

(resmetirom) in NASH.

Complete clinical development and seek regulatory approval of resmetirom in NASH.

We successfully completed a Phase 2 clinical trial in NASH in 2018.

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We believe resmetirom is an excellent candidate for the chronic treatment of NASH due to its safety profile and first-in-class

pleiotrophic actions in liver cells and potential to reduce cardiovascular risk in NASH patients.

Establish commercial capabilities to market MGL-3196

(resmetirom) as a leading treatment for NASH.

pleiotropic actions in liver cells and potential to reduce cardiovascular risk in NASH patients.

Establish commercial capabilities to market resmetirom as a leading treatment for NASH.

If approved, we may choose either to establish a sales and marketing organization with technical expertise and supporting distribution capabilities to commercialize resmetirom, or to collaborate with one or more third parties to accomplish these tasks.

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We believe this will enable us to launch resmetirom in NASH in a cost-effective, targeted manner.

Grow our pipeline through additional indications for MGL-3196

(resmetirom) potentially including orphan indications.

Grow our pipeline through additional indications for resmetirom potentially including orphan indications.

We believe that resmetirom has the potential to be an effective treatment for other disease indications that are rare diseases or may be designated rare diseases and we may pursue orphan drug designation where possible.

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NAFLD has become the most common liver disease in the United States and other developed countries and is characterized by an accumulation of fat in the liver with no other apparent causes.

The rising worldwide prevalence of obesity-related disorders has contributed to a rapid increase in the global prevalence of NASH and NAFLD.

In the United States, NAFLD is estimated to affect approximately 27% to 34% of the population, or an estimated 86 million to 108 million people, and approximately 10% to 20% of those will progress from NAFLD to NASH.

Current estimates place NASH prevalence at approximately 9 million to 15 million people in the United States, or three percent to five percent of the population, with similar prevalence in Europe and Asia.

NASH and NAFLD have grown as a consequence of rising worldwide obesity-related disorders.

In the United States, NAFLD is estimated to affect approximately 25% of the population, and approximately 25% of those will progress from NAFLD to NASH.

Current estimates place NASH prevalence at approximately 20 million people in the United States, or five to six percent of the adult population, with similar prevalence in Europe and Asia.

The prevalence of NASH is also increasing in developing regions due to the adoption of a more sedentary lifestyle and a diet consisting of processed foods with high fat and fructose content.

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The Centers for Disease Control and Prevention projects the prevalence of obesity to increase from 34% of the United States population to 42% of the United States population by 2030.

Driven by this epidemic of obesity, NASH is projected to become the leading cause of liver transplants by 2020.

Driven by this epidemic of obesity, NASH is projected to become the leading cause of liver transplants in the near future.

Given the extremely limited availability of organ donors and high transplant costs, NASH patients who require transplantation will place a significant economic burden on the healthcare system.

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study which was completed in 2019.

In September 2013, the American Association for the Study of Liver Disease and the FDA conducted a joint workshop focused on trial designs and endpoints in drug and diagnostic development for liver disease secondary to NAFLD, including NASH.

In December 2014, the journal Hepatology accepted for publication a manuscript summarizing the workshop output, including potentially acceptable surrogate endpoints for clinical studies supporting the approval of agents for NASH and liver fibrosis.

We believe that our Phase 2 NASH study design incorporated surrogate secondary endpoints consistent with the current FDA requirements for demonstration of efficacy in registrational trials.

Following completion of our Phase 2 clinical trial of resmetirom in NASH patients, we held an end of Phase 2 meeting with the FDA, received positive feedback.

In March 2019 the Company announced that it had initiated a Phase 3 trial in NASH with its once daily, oral thyroid hormone receptor beta selective agonist, MGL-3196

(resmetirom).

This double-blind, placebo-controlled study will be conducted at more than 150 sites in the United States and the rest of the world.

Madrigal has ongoing Phase 3 resmetirom studies for patients with NASH or presumed NASH as discussed in detail in this report.

We believe that the designs of our Phase 2 and Phase 3 NASH studies are consistent with principles for NASH drug development outlined by the FDA in its public communications and draft guidance for industry and based on our past interactions with FDA, including our end of Phase 2 meeting with the FDA in 2019.

Because of the slow progression of NASH and the time required to conduct an outcomes trial that would evaluate clinical endpoints such as progression to cirrhosis or survival, the FDA recommends sponsors consider the following liver histological improvements as Phase 3 trial endpoints reasonably likely to predict clinical benefit to support accelerated approval under subpart H regulations:

Resolution of steatohepatitis on overall histopathological reading and no worsening of liver fibrosis;

Improvement in liver fibrosis greater than or equal to one stage and no worsening of steatohepatitis;

Both resolution of steatohepatitis and improvement in fibrosis.

In March 2019, the Company announced that it had initiated a Phase 3 trial of resmetirom in patients with NASH.

This double-blind, placebo-controlled study has been and will be conducted at more than 150 sites in the United States and the rest of the world.

Patients with liver biopsy confirmed NASH with stage 2 or 3 fibrosis will be randomized 1:1:1 to receive a single oral daily dose of placebo, resmetirom 80 mg or resmetirom 100 mg.

A second liver biopsy at week 52 in the first 900 patients will be the basis of filing for subpart H-accelerated

the primary endpoint pertains to the percent of patients treated with either dose of resmetirom as compared with placebo who achieve NASH resolution on the week 52 liver biopsy, defined as the absence of hepatocyte ballooning (score=0), and minimal lobular inflammation (score 0-1),

associated with at least a 2 point reduction in NAS, and no worsening of fibrosis stage.

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Patients will continue in the study for a total of approximately 54 months and will be evaluated for a composite clinical outcome including cirrhosis on liver biopsy, or a liver related event such as hepatic decompensation.

The total anticipated enrollment is approximately 2,000 patients and will include up to 15% high risk F1 fibrosis stage NASH patients whose efficacy responses will be evaluated as exploratory endpoints.

The total anticipated enrollment is approximately 2,000 patients and is expected to include up to 15% high risk F1 fibrosis stage NASH patients whose efficacy responses will be evaluated as exploratory endpoints.

In December 2019 the Company announced it had opened for enrollment MAESTRO-NAFLD-1,

double-blind, placebo controlled Phase 3 clinical study in 700 patients with biopsy-confirmed or presumed NASH recruited from sites in the U.S.

double-blind, placebo controlled Phase 3 clinical study in 700 patients with biopsy-confirmed or

presumed NASH recruited from sites in the U.S.

Key endpoints are safety, including safety biomarkers, LDL cholesterol, lipid biomarkers, and fibrosis biomarkers.

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The MAESTRO-NAFLD-1

study will help support the adequacy of the safety database at the time of NDA submission for subpart H approval or treatment of NASH in patients with F2 or F3 fibrosis (MAESTRO-NASH, NASH resolution surrogate endpoint).

Madrigal has agreement on liver biopsy endpoints with the FDA, and long term liver related benefit endpoints for the treatment of NASH.

Given that NASH is an evolving field, and FDA evaluates risk versus benefit prior to approval, Phase 3 data will be carefully reviewed by FDA.

However, currently there are ongoing Phase 3 clinical trials of compounds to treat NASH by other companies in which it is contemplated that accelerated approval of the compounds under FDA subpart H, which provides for accelerated approval of certain new drug products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments, would be based on the surrogate endpoint of histological evidence of NASH resolution without the worsening of fibrosis.

It is expected that these trials would continue after approval to confirm the long term clinical benefit of NASH resolution based on a reduction in patients progressing to cirrhosis and other liver related events.

study will help support the adequacy of the safety database at the time of NDA submission for subpart H approval or treatment of NASH in patients with F2 or F3 fibrosis.

MAESTRO-NAFLD-1

also includes an open label arm with approximately 170 non-cirrhotic

patients with NASH treated with 100 mg resmetirom.

Data from this open label portion of the MAESTRO-NAFLD-1

study have been reported at various professional society conferences, demonstrating statistically significant reductions from baseline in liver fat as assessed by MRI-PDFF

and Fibroscan CAP, as well as reductions in liver stiffness as determined by MRE and Fibroscan TE (a surrogate for liver fibrosis).

Markers of liver fibrosis and inflammation were also reduced by resmetirom relative to baseline.

Additionally, atherogenic lipids, including LDL-cholesterol,

apolipoprotein B, triglycerides, and lipoprotein (a) were reduced relative to baseline.

The adverse event profile in this open label cohort has been similar to that observed in Phase 2.

The MAESTRO-NAFLD-1

open label arm over-enrolled and includes more than 150 patients with NASH and compensated cirrhosis to obtain a preliminary assessment of the use of resmetirom in patients with more advanced disease.

In January 2022, Madrigal announced topline results from the Phase 3 MAESTRO-NAFLD-1

safety study of resmetirom.

Primary and key secondary endpoints from the double-blind placebo-controlled 969-patient

portion of the study were achieved, as described herein.

See “ – Key Developments” above.

Collaborations

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Pursuant to the terms of the Roche Agreement, we, as successor-in-interest

to VIA, assumed control of all development and commercialization of MGL-3196

(resmetirom) and will hold exclusive worldwide rights for all potential indications.

to VIA, assumed control of all development and commercialization of resmetirom and will hold exclusive worldwide rights for all potential indications.

Under the Roche Agreement, Roche exclusively licensed certain patent rights and know-how

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attract and retain high-quality research, development and commercial personnel.

There are currently no therapeutic products approved and marketed for the treatment of NASH.

There are currently no therapeutic products approved and marketed for the treatment of NASH in North America and Europe.

There are several commercially available products that are currently used off-label

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In addition, there are numerous drugs in development for the treatment of NASH.

We are aware of several companies that have product candidates in clinical development for the treatment of NASH, including Intercept Pharmaceuticals, Inc., Gilead Sciences, Inc., Galectin Therapeutics, Inc., Galmed Medical Research Ltd., Genfit Corp., Cirius Therapeutics, Novartis AG, Novo Nordisk A/S, Takeda, Inventiva, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Pfizer, Inc., Merck & Co., Lilly, Genentech, Sanofi S.A., NGM Biopharmaceutical, Viking Therapeutics, Akero Therapeutics, Enanta Pharmaceuticals, 89Bio Inc., and MedImmune LLC, and there are other companies with candidates in earlier stages of development.

We are aware of several companies that have product candidates in clinical development for the treatment of NASH, including Intercept Pharmaceuticals, Inc., Gilead Sciences, Inc., Galectin Therapeutics, Inc., Galmed Medical Research Ltd., Cirius Therapeutics, Novartis AG, Novo Nordisk A/S, Takeda, Inventiva, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Pfizer, Inc., Merck & Co., Lilly, Genentech, Sanofi S.A., NGM Biopharmaceutical, Viking Therapeutics, Akero Therapeutics, Enanta Pharmaceuticals, 89Bio Inc., Axcella, Can-Fite,

Hepion, NorthSea, Terns, Zydus Cadila and MedImmune LLC, and there are other companies with candidates in earlier stages of development.

Given resmetirom’s actions on the underlying biological pathways across the spectrum of early to late stages of NASH, its CV beneficial effects, and its complementary mechanism to other therapies, we believe that resmetirom has the potential to be used alone or in combination with some of these potential NASH products.

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We do not own or operate, and currently have no plans to establish, any manufacturing facilities.

We currently rely, and expect to rely, on third-party contract manufacturers, or CMOs, for the manufacture of any product candidates that we may develop for larger-scale preclinical and clinical testing, as well as for commercial quantities of any drug candidates that are approved.

We currently rely, and expect to rely, on third-party contract manufacturers, or CMOs, for all required starting materials, API and finished product for the manufacture of any product candidates that we may develop for larger-scale preclinical and clinical testing, as well as for commercial quantities of any drug candidates that are approved.

We do not have long-term supply agreements for any of our product candidates and regularly obtain supplies and services related to our product candidates from CMO’s on a purchase order basis.

We currently have

a single source for API and finished product for resmetirom and are developing a second source for API.

We plan to continue to rely on CMOs for API, finished product, packaging, storage, and distribution for both clinical supplies and any of our product candidates that receive health authority approval.

Research and Development

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We own or co-own:

four United States and 23 foreign issued patents and allowed patent applications;

and six United States and 43 foreign pending patent applications, each of which relates to composition-of-matter

of resmetirom, including certain dosage forms, methods of making resmetirom, and its use in the treatment of key disease indications.

five United States and 32 foreign issued patents and allowed patent applications;

six United States and 45 foreign pending patent applications;

and two international patent applications filed under the Patent Cooperation Treaty.

Each of these patents and applications relates to resmetirom, including composition-of-matter, certain dosage forms, methods of making resmetirom, its use in the treatment of key disease indications, or other THR beta analogs and uses thereof.

Our current patent portfolio covers the United States and certain other jurisdictions worldwide.

The two international patent applications can be used as the basis for multiple additional patent applications worldwide.

In addition, pursuant to the Roche Agreement, Roche granted us an exclusive license to certain United States and foreign patents and patent applications owned by Roche and Roche know-how

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We have pending patent applications for resmetirom that, if issued, would be expected to expire in the United States and in countries outside of the United States between 2033 and 2042, excluding any patent term adjustment that might be available following the grant of the patent and any patent term extensions that might be available following the grant of marketing authorizations.

We have a pending patent application for other THR beta analogs that, if issued, would be expected to expire in the United States and in countries outside of the United States in 2043, excluding any patent term adjustment that might be available following the grant of the patent and any patent term extensions that might be available following the grant of marketing authorizations.

Our trademarks are protected under the common law and/or by registration in the United States and other countries.

We seek to protect our proprietary processes, in part, by confidentiality agreements and invention assignment agreements with our personnel, including consultants and commercial partners.

We seek to protect our proprietary processes, in part, by confidentiality agreements and invention

assignment agreements with our personnel, including consultants and commercial partners.

These agreements are designed to protect our proprietary information.

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Government Regulation and Product Approval

Government authorities in the United States, at the federal, state and local level, and other countries extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, marketing and export and import of products such as those we are developing.

A new drug must be approved by the FDA through the new drug application, or NDA, process before it may be legally marketed in the United States, and must be approved by foreign regulatory authorities via various procedures before it can be marketed in the applicable country.

Government authorities in the United States, at the federal, state and local level, and other countries extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, monitoring and reporting, promotion, advertising, distribution, marketing and export and import of drug products such as those we are developing.

A new drug must be approved by the FDA through the new drug application, or NDA, process before it may be legally marketed in the United States, and must be approved by foreign regulatory authorities via various analogous procedures before it can be marketed in the applicable country.

The animal and other non-clinical

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In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and implementing regulations.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local, and foreign statutes and regulations require the expenditure of substantial time and financial resources.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state and local statutes and regulations require the expenditure of substantial time and financial resources.

Failure to comply with the applicable United States requirements at any time during the product development process, approval process or after approval, may subject an applicant to administrative or judicial sanctions.

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The process required by the FDA before a drug or biologic may be marketed in the United States generally involves the following:

completion of preclinical laboratory tests, animal studies and formulation studies according to GLP or other applicable regulations;

completion of preclinical laboratory tests, animal studies and formulation studies, some in accordance with the FDA’s current Good Laboratory Practices, or GLP, the Animal Welfare Act administered and enforced by the United States Department of Agriculture, and other applicable regulations;

submission to the FDA of an IND which must become effective before human clinical trials may begin;

performance of adequate and well-controlled human clinical trials according to Good Clinical Practices, or GCP, to establish the safety and efficacy of the proposed drug for its intended use;

approval by an institutional review board, or IRB, before each trial may be initiated at each clinical site;

performance of adequate and well-controlled human clinical trials under protocols submitted to the FDA and reviewed and approved by each IRB, conducted in accordance with federal regulations and according to Good Clinical Practices, or GCP, to establish the safety and efficacy of the proposed drug for its intended use;

submission to the FDA of an NDA;

completion of registration batches and validation of the manufacturing process to show ability to consistently produce quality batches of product;

satisfactory completion of a FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with current good manufacturing practice, or cGMP, to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

satisfactory completion of an FDA Advisory Committee review, if applicable;

satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with current good manufacturing practice, or cGMP, to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

FDA review and approval of the NDA.

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Preclinical tests include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies, to assess the safety and quality of the product.

Animal studies must be performed in compliance with FDA’s GLP regulations and the U.S.

Department of Agriculture’s Animal Welfare Act.

Animal studies must be performed in compliance with federal regulations and requirements, including, as applicable, GLP and the Animal Welfare Act.

An IND sponsor must submit the results of the preclinical tests, together with manufacturing information and analytical data, to the FDA as part of the IND.

The sponsor will also include a protocol detailing, among other things, the objectives of the first phase of the clinical trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated, if the first phase lends itself to an efficacy evaluation.

The sponsor will also include a protocol detailing, among other things, the objectives of the clinical trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated, if the trial lends itself to an efficacy evaluation.

Some preclinical testing may continue even after the IND is submitted.

The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day

time period, places the clinical trial on a clinical hold or a partial clinical hold.

In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.

waiting period after the submission of each IND is required prior to the commencement of clinical testing in humans.

If during this 30-day

period the FDA does not raise any concerns or issues that must be addressed prior to the commencement of clinical trials or does not impose a clinical hold, the IND becomes effective 30 days following the FDA’s receipt of the IND and the clinical trial proposed in the IND may begin.

Clinical holds also may be imposed by the FDA at any time before or during studies due to safety concerns or non-compliance,

or other reasons.

All clinical trials must be conducted under the supervision of one or more qualified investigators in accordance with good clinical practice regulations.

All clinical trials must be conducted under the supervision of one or more qualified investigators in accordance with GCP.

They must be conducted under protocols detailing the objectives of the trial, dosing procedures, subject selection and exclusion criteria and the safety and effectiveness criteria to be evaluated.

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In addition, timely safety reports must be submitted to the FDA and the investigators for serious and unexpected adverse events or animal test results that suggest a significant risk to human subjects.

An institutional review board, or IRB, at each institution participating in the clinical trial must review and approve each protocol before a clinical trial commences at that institution and must also approve the information regarding the trial and the consent form that must be provided to each trial subject or his or her legal representative, monitor the study until completed and otherwise comply with IRB regulations.

An IRB at each institution participating in the clinical trial must review and approve each protocol before a clinical trial commences at that institution and must also approve the information regarding the trial and the consent form that must be provided to each trial subject or his or her legal representative, monitor the study until completed and otherwise comply with IRB regulations.

Foreign studies conducted under an IND must meet the same requirements that apply to studies being conducted in the U.S.

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Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

The product candidate is initially introduced into healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution and excretion.

In the case of some products for severe or life-threatening diseases, such as cancer, especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients with the target diseases.

This phase involves studies in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage.

The product candidate is initially introduced into humans.

Phase 1 clinical trials are typically conducted in healthy human subjects, but in some situations are conducted in patients with the target disease or condition.

Phase 1 clinical trials are generally designed to evaluate the safety, dosage tolerance, absorption, metabolism, distribution and excretion of the product candidate in humans, and, if possible, to gain early evidence of effectiveness.

This phase involves studies in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product candidate for specific targeted diseases and to determine dosage tolerance and optimal dosage.

This phase involves trials undertaken to further evaluate dosage, clinical efficacy and safety in an expanded patient population at geographically dispersed clinical study sites.

These studies are intended to establish the overall risk-benefit ratio of the product candidate and provide, if appropriate, an adequate basis for product approval and product labeling.

These studies are

intended to establish the overall risk-benefit ratio of the product candidate and provide, if appropriate, an adequate basis for product approval and product labeling.

In most cases, the FDA requires two adequate and well controlled Phase 3 clinical trials to demonstrate the efficacy of the product candidate, although a single Phase 3 clinical trial with other confirmatory evidence may be sufficient in certain instances.

The FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.

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United States Review and Approval Processes

The results of product development, preclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling, and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product.

The submission of an NDA is subject to the payment of user fees;

The submission of an NDA is subject to the payment of user fees under the Prescription Drug User Fee Act, or PDUFA, as amended;

a waiver of such fees may be obtained under certain limited circumstances.

The FDA conducts a preliminary review of all NDAs submitted to ensure that they are sufficiently complete for substantive review before it accepts them for filing.

The FDA conducts a preliminary review of a submitted NDA within 60 days from receipt to ensure that the application is sufficiently complete for substantive review before it accepts the application for filing.

The FDA may request additional information rather than accept an NDA for filing.

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substantive review.

The FDA’s PDUFA performance goals generally provide for action on an NDA within 10 months of the 60-day

That deadline can be extended under certain circumstances, including by the FDA’s requests for additional information.

The targeted action date can also be shortened to within 6 months of the 60-day

filing date for products that are granted priority review designation because they are intended to treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs.

The FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the product’s identity, strength, quality and purity.

Before approving an NDA, the FDA will inspect the facility or facilities where the product is manufactured.

addition, the FDA often will conduct a bioresearch monitoring inspection of the clinical trial sites involved in conducting pivotal studies to ensure data integrity and compliance with applicable GCP requirements.

The FDA may refer the NDA to an advisory committee for review, evaluation and recommendation as to whether the application should be approved and under what conditions.

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Data obtained from clinical trials are not always conclusive, and the FDA may interpret data differently than we interpret the same data.

The FDA may issue a complete response letter, which generally outlines the deficiencies in the submission and may require additional clinical or other data or impose other conditions that must be met in order to secure final approval of the NDA, or an approval letter following satisfactory completion of all aspects of the review process.

Before approving an NDA, the FDA will inspect the facility or facilities where the product is manufactured.

In addition, the FDA often will conduct a bioresearch monitoring inspection of the clinical trial sites involved in conducting pivotal studies to ensure data integrity and compliance with applicable GCP requirements.

At the end of the review period, the FDA may issue an approval letter following satisfactory completion of all aspects of the review process, or the FDA may issue a complete response letter, or CRL, which generally outlines the deficiencies in the submission and may require additional clinical or other data or impose other conditions that must be met in order to secure final approval of the NDA.

If and when deficiencies outlined in a CRL have been addressed to the FDA’s satisfaction in a resubmission of the NDA, the FDA may issue an approval letter.

The FDA’s PDUFA review goal is to review such resubmissions within two or six months of receipt, depending on the type of information included.

Notwithstanding the submission of any requested additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval and deny approval of a resubmitted NDA.

NDAs receive either standard or priority review.

A drug representing a significant improvement in treatment, prevention or diagnosis of disease may receive priority review.

An application for a drug that treats a serious condition and, if approved, would provide a significant improvement in treatment, prevention or diagnosis of disease may qualify for priority review.

Priority review for an NDA for a new molecular entity will be six months from the date that the NDA is filed.

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The FDA does not always meet its goal dates and in certain circumstances the goal date may be extended.

In addition, products studied for their safety and effectiveness in treating serious or life-threatening illnesses and which provide meaningful therapeutic benefit over existing treatments, may receive accelerated approval.

In that situation, the product may be approved on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on the basis of an effect on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, or IMM, that is reasonably likely to predict an effect on IMM or other clinical benefit.

As a condition of approval, the FDA may require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.

Priority review and accelerated approval do not change the standards for approval, but may expedite the approval process.

If a product receives regulatory approval, the approval may be significantly limited to specific diseases, dosages or patient populations, or the indications for use may otherwise be limited, which could restrict the commercial value of the product.

Priority review does not change the standard for approval, but may expedite the approval process.

Product candidates may qualify for review and approval under the subpart H-accelerated

approval pathway if the candidates are intended to treat a serious condition, provide meaningful therapeutic benefit over existing treatments, and demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on an intermediate clinical endpoint.

In clinical trials, a surrogate endpoint is a measurement of laboratory or clinical signs of a disease or condition that substitutes for a direct measurement of how a patient feels, functions, or survives.

Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints.

As a condition of accelerated approval, the FDA requires that a sponsor of a drug receiving accelerated approval perform confirmatory adequate and well-controlled post-marketing clinical trials.

Accelerated approval does not change the standards for approval.

All promotional materials for drug candidates approved under the accelerated approval pathway are subject to prior review by the FDA.

An approval letter authorizes commercial marketing of the product candidate with specific prescribing information for specific indications.

If a product receives regulatory approval, the approval may be further limited to specific diseases, dosages or patient populations, or the indications for use may otherwise be limited, which could restrict the commercial value of the product.

In addition, the FDA may require a sponsor to conduct Phase 4 testing which involves clinical trials designed to further assess a drug’s safety and effectiveness after NDA approval, and may require testing and surveillance programs to monitor the safety of approved products which have been commercialized.

The Food and Drug Administration Safety and Innovation Act, or FDASIA, which was enacted in 2012, made permanent the Pediatric Research Equity Act, or PREA, which requires a sponsor to conduct pediatric studies for most drugs and biologics, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration.

Under PREA, original NDAs and supplements thereto must contain a pediatric assessment unless the sponsor has received a deferral or waiver.

Under PREA, original NDAs and supplements thereto must contain a

pediatric assessment unless the sponsor has received a deferral or waiver.

The required assessment must assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

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A deferral may be granted for several reasons, including a finding that the drug or biologic is ready for approval for use in adults before pediatric studies are complete or that additional safety or effectiveness data needs to be collected before the pediatric studies begin.

After April 2013, the FDA must send a non-compliance

The FDA must send a non-compliance

letter to any sponsor that fails to submit the required assessment, keep a deferral current or fails to submit a request for approval of a pediatric formulation.

Patent Term Restoration and Marketing Exclusivity

Depending upon the timing, duration and specifics of FDA approval of our product candidates, some of our United States patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, referred to as the Hatch-Waxman Amendments.

The Hatch-Waxman Amendments permit a patent restoration term of up to five years as compensation for patent term lost during product development and the FDA regulatory review process.

However, patent term

restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date.

Patent Term Restoration and Regulatory Exclusivities

The Hatch-Waxman Act permits a patent restoration term of up to five years as compensation for patent term lost during product development and the FDA regulatory review process.

However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date.

The patent term restoration period is generally one-half

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The United States Patent and Trademark Office, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

The Hatch-Waxman Act also provides periods of regulatory exclusivity for products that would serve as a reference listed drug, or RLD, for an abbreviated new drug application, or ANDA, or application submitted under section 505(b)(2) of the FDCA, or 505(b)(2) application.

If a product is a new chemical entity, or NCE—generally meaning that the active moiety has never before been approved in any drug—there is a period of five years from the product’s approval during which the FDA may not accept for filing any ANDA or 505(b)(2) application for a drug with the same active moiety.

An ANDA or 505(b)(2) application may be submitted after four years, however, if the sponsor of the application makes a “Paragraph IV” certification.

A product that is not an NCE may qualify for a three-year period of exclusivity if the NDA contains new clinical data (other than bioavailability studies), derived from studies conducted by or for the sponsor, that were necessary for approval.

In that instance, the exclusivity period does not preclude filing or review of an ANDA or 505(b)(2) application;

rather, the FDA is precluded from granting final approval to the ANDA or 505(b)(2) application until three years after approval of the RLD.

Additionally, the exclusivity applies only to the conditions of approval that required submission of the clinical data.

Once the FDA accepts for filing an ANDA or 505(b)(2) application containing a Paragraph IV certification, the applicant must within 20 days provide notice to the RLD NDA holder and patent owner that the application has been submitted and provide the factual and legal basis for the applicant’s assertion that the patent is invalid or not infringed.

If the NDA holder or patent owner files suit against the ANDA or 505(b)(2) applicant for patent infringement within 45 days of receiving the Paragraph IV notice, the FDA is prohibited from approving the ANDA or 505(b)(2) application for a period of 30 months or the resolution of the underlying suit, whichever is earlier.

If the RLD has NCE exclusivity and the notice is given and suit filed during the fifth year of exclusivity, the regulatory stay extends until seven and a half years after the RLD approval.

The FDA may approve the proposed product before the expiration of the regulatory stay if a court finds the patent invalid or not infringed or if the court shortens the period because the parties have failed to cooperate in expediting the litigation.

Pediatric exclusivity is another type of marketing exclusivity available in the United States.

The FDASIA made permanent the Best Pharmaceuticals for Children Act, or BPCA, which provides for an additional six months of marketing exclusivity if a sponsor conducts clinical trials in children in response to a written request from the FDA, or a Written Request.

The FDASIA made permanent the Best Pharmaceuticals for Children Act, or BPCA, which provides for an additional six

months of marketing exclusivity if a sponsor conducts clinical trials in children in response to a written request from the FDA, or a Written Request.

If the Written Request does not include studies in neonates, the FDA is required to include its rationale for not requesting those studies.

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Orphan drug exclusivity, however, also could block the approval of one of our product candidates for seven years if a competitor obtains approval of the same drug as defined by the FDA or if our product candidate is determined to be contained within the competitor’s product for the same indication or disease.

The FDA also administers a clinical research grants program, whereby researchers may compete for funding to conduct clinical trials to support the approval of drugs, biologics, medical devices, and medical foods for rare diseases and conditions.

The FDA also administers an orphan drug clinical research grants program, whereby researchers may apply for funding to conduct clinical trials to support the approval of drugs, biologics, medical devices, and medical foods for rare diseases and conditions.

A product does not have to be designated as an orphan drug to be eligible for the grant program.

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The study may address an unapproved new product or an unapproved new use for a product already on the market.

Fast Track Designation and Accelerated Approval

The FDA is required to facilitate the development, and expedite the review, of drugs that are intended for the treatment of a serious or life-threatening disease or condition for which there is no effective treatment and which demonstrate the potential to address unmet medical needs for such a disease or condition.

Under the fast track program, the sponsor of a new drug candidate may request that the FDA designate the drug candidate for a specific indication as a fast track drug concurrent with, or after, the filing of the IND for the drug candidate.

Expedited Programs

The FDA maintains several programs to facilitate and expedite the development and review of drug applications that are intended for the treatment of a serious or life-threatening disease or condition for which there is no effective treatment and that demonstrate the potential to address unmet medical needs for such a disease or condition, including Fast Track Designation, Breakthrough Designation, Priority Review (discussed above in United States Review and Approval Processes), and the Accelerated Approval pathway (discussed above in United States Review and Approval Processes).

Under the Fast Track Designation program, the sponsor of a new drug candidate may request that the FDA designate the drug candidate for a specific indication as a fast track drug concurrent with, or after, the filing of the IND for the drug candidate.

The FDA must determine if the drug candidate qualifies for fast track designation within 60 days of receipt of the sponsor’s request.

Under the fast track program, the FDA may designate a drug for fast-track status if it is intended to treat a serious or life-threatening illness and nonclinical or clinical data demonstrate the potential to address an unmet medical need.

Similarly, the agency may designate a drug for accelerated approval if it treats a serious condition and generally provides meaningful therapeutic benefit to patients over existing treatments based upon a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than IMM, that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints.

A drug candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint.

Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies, will allow the FDA to withdraw the drug from the market on an expedited basis.

All promotional materials for drug candidates approved under accelerated regulations are subject to prior review by the FDA.

In FDASIA, Congress encouraged the FDA to utilize innovative and flexible approaches to the assessment of products under accelerated approval.

The law required the FDA to issue related draft guidance within a year after the law’s enactment and also promulgate confirming regulatory changes.

In May 2014, the FDA published a Guidance for Industry entitled, “Expedited Programs for Serious Conditions-Drugs and Biologics” which provides guidance on FDA programs that are intended to facilitate and expedite development and review of new drugs as well as threshold criteria generally applicable to concluding that a drug is a candidate for these expedited development and review programs.

In addition to the Fast Track, accelerated approval and priority review programs discussed above, the FDA also provided guidance on a new program for Breakthrough Therapy designation.

A request for Breakthrough Therapy designation should be submitted concurrently with, or as an amendment to an IND.

The FDA has already granted this designation to over 30 new drugs and has approved several.

Under the Fast Track Designation program, the FDA may grant fast track designation for a product candidate if it is intended to treat a serious or life-threatening condition and nonclinical or clinical data demonstrate the potential to address an unmet medical need.

Features of Fast Track Designation include more frequent interactions with the review team, and the possibility of rolling review.

Under the Breakthrough Designation Program, FDA may grant a drug Breakthrough Therapy Designation if it is intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint over available therapies.

Features of Breakthrough Therapy Designation include intensive guidance on an efficient drug development program, an organizational commitment by the agency involving senior managers in a proactive, cross-disciplinary review of the drug application, and the possibility of rolling review.

Post-Approval Requirements

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The FDA may withdraw the approval if, among other things, compliance with regulatory standards is not maintained or if safety or efficacy problems occur after the product reaches the market.

Later discovery of previously unknown problems with a product may result in restrictions on the product or even complete withdrawal of the product from the market.

If new safety issues are identified following approval, the FDA may require the NDA sponsor to take certain measures, such as revising the approved labeling to reflect the new safety information, conducting post-market studies or clinical trials to assess the new safety information, and/or implementing or changing a REMS Program to mitigate newly-identified risks.

Later discovery of previously unknown problems with a product may result in restrictions on product marketing or even withdrawal of approval for the product application.

After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further FDA review and approval.

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In addition to regulations in the United States, we will be subject to a variety of foreign regulations governing clinical trials and commercial sales and distribution of its products.

Whether or not we obtain FDA approval for a product, we must obtain approval by the comparable regulatory authorities of foreign countries or economic areas, such as the 28-member

European Union, before we may commence clinical trials or market products in those countries or areas.

Whether or not we obtain FDA approval for a product, we must obtain approval by the comparable regulatory authorities of foreign countries or economic areas, such as the European Union, before we may commence clinical trials or market products in those countries or areas.

The approval process and requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary greatly from place to place, and the time may be longer or shorter than that required for FDA approval.

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The centralized procedure, which is compulsory for medicinal products produced by biotechnology or those medicinal products containing new active substances for specific indications such as the treatment of AIDS, cancer, neurodegenerative disorders, diabetes, viral diseases and designated orphan medicines, and optional for other medicines which are highly innovative.

Under the centralized procedure, a marketing application is submitted to the EMA where it will be evaluated by the Committee for Medicinal Products for Human Use and a favorable opinion typically results in the grant by the European Commission of a single marketing authorization that is valid for all EU member states within 67 days of receipt of the opinion.

Commission of a single marketing authorization that is valid for all EU member states within 67 days of receipt of the opinion.

The initial marketing authorization is valid for five years, but once renewed is usually valid for an unlimited period.

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Under the decentralized approval procedure, an applicant submits an application, or dossier, and related materials to the reference member state and concerned member states.

The reference member state prepares a draft

assessment and drafts of the related materials within 120 days after receipt of a valid application.

The reference member state prepares a draft assessment and drafts of the related materials within 120 days after receipt of a valid application.

Within 90 days of receiving the reference member state’s assessment report, each concerned member state must decide whether to approve the assessment report and related materials.

If a member state does not recognize the marketing authorization, the disputed points are eventually referred to the European Commission, whose decision is binding on all member states.

In addition to the centralized procedure and the decentralized procedure, it may also be possible to obtain a marketing authorization for one single EU Member State through a national procedure.

Under a mutual recognition procedure, a national marketing authorization granted by one EU Member State may be recognized by one or more other EU Member States resulting in harmonized marketing authorizations in those EU Member States.

When conducting clinical trials in the EU, we must adhere to the provisions of the EU Clinical Trials Directive and the laws and regulations of the EU Member States implementing them.

These provisions require, among other things, that the prior authorization of an Ethics Committee and the submission and approval of a clinical trial authorization application be obtained in each Member State before commencing a clinical trial in that Member State.

As of January 31, 2022, the new EU Clinical Trials Regulation will apply.

The EU Clinical Trials Regulation will repeal and replace the EU Clinical Trials Directive, introduces a complete overhaul of the existing regulation of clinical trials for medicinal products in the EU, including a new coordinated procedure for authorization of clinical trials that is similar to the mutual recognition procedure for marketing authorization of medicinal products, and increased obligations on sponsors to publish clinical trial results.

As in the United States, it may be possible in foreign countries to obtain a period of market and/or data exclusivity that would have the effect of postponing the entry into the marketplace of a competitor’s generic product.

For example, in the EU, if any of our products receive marketing approval in the European Economic Area, or EEA, which is comprised of the 27 member states of the EU plus Norway, Iceland and Liechtenstein, we expect that we will benefit from eight years of data exclusivity and an additional two years of marketing exclusivity.

An additional one-year

extension of marketing exclusivity is possible if during the data exclusivity period we obtain an authorization for one or more new therapeutic indications that is deemed to bring a significant clinical benefit compared to existing therapies.

An additional one-year extension of marketing exclusivity is possible if during the data exclusivity period we obtain an authorization for one or more new therapeutic indications that is deemed to bring a significant clinical benefit compared to existing therapies.

The data exclusivity period begins on the date of the product’s first marketing authorization in the EU and prevents biosimilars from relying on the holder of the marketing authorization for the reference biological medicine’s pharmacological, toxicological and clinical data for a period of eight years.

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Significant uncertainty exists regarding the coverage and reimbursement status of products approved by the FDA and other government authorities.

In the United States, sales of any products for which we may receive regulatory approval for commercial sale will depend in significant part on the availability and adequacy of coverage and reimbursement from third-party payors.

In the United States, sales of any products for which we may receive

regulatory approval for commercial sale will depend in significant part on the availability and adequacy of coverage and reimbursement from third-party payors.

Third-party payors include government authorities, managed care providers, private health insurers and other organizations.

The process for determining whether a payor will provide coverage for a product may be separate from the process for setting the reimbursement rate that the payor will pay for the product.

Third-party payors may limit coverage to specific products on an approved list which might not include all of the FDA-approved

products for a particular indication.

Third-party payors may limit coverage to specific products on an approved list which might not include all of the FDA-approved products for a particular indication.

Moreover, a payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved.

5 unchanged sentences

government and state legislatures have shown significant interest in implementing cost containment programs to limit the growth of government-paid health care costs, including price controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs.

For example, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Affordability Reconciliation Act, or collectively, ACA, contains provisions that may reduce the profitability of drug products, including, for example, increased rebates for drugs reimbursed by Medicaid programs, extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts for certain Medicare Part D beneficiaries and annual fees based on pharmaceutical companies’ share of sales to federal health care programs.

For example, the Patient Protection and Affordable Care Act, as amended the ACA, contains provisions that may reduce the profitability of drug products, including, for example, increased rebates for drugs reimbursed by Medicaid programs, extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts for certain Medicare Part D beneficiaries and annual fees based on pharmaceutical companies’ share of sales for branded prescription drugs to federal health care programs.

Adoption of government controls and measures, and tightening of restrictive policies in jurisdictions with existing controls and measures, could limit payments for pharmaceuticals.

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Human Capital

As of February 19, 2021, we had forty two full-time employees, including thirty two engaged in research, development, and regulatory activities, and ten in executive, commercial, general and administrative functions, and multiple part-time consultants.

As of February 21, 2022, we had seventy one full-time employees, including fifty two engaged in research, development, and regulatory activities, and nineteen in executive, commercial, general and administrative

functions, and multiple part-time consultants.

We believe that our future success will be shaped by our continued ability to attract and retain highly skilled employees.

5 unchanged sentences

No portion of our website is incorporated by reference into this Annual Report on Form 10-K.

We advise you to read this Annual Report on Form 10-K

in conjunction with other reports and documents that we file from time to time with the SEC.

In particular, please read our definitive proxy statement, which will be filed with the SEC in connection with our 2021 annual meeting of stockholders, our quarterly reports on Form 10-Q

and any current reports on Form 8-K

that we may file from time to time.

We advise you to read this Annual Report on Form 10-K in conjunction with other reports and documents that we file from time to time with the SEC.

In particular, please read our definitive proxy statement, which will be filed with the SEC in connection with our 2022 annual meeting of stockholders, our quarterly reports on Form 10-Q and any current reports on Form 8-K that we may file from time to time.

You may obtain copies of these reports after the date of this annual report directly from us or from the SEC at its website at www.sec.gov.

1 unchanged sentence

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business