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Item 1. Business

2023-03-27 compared with 2022-03-23 · 389 added, 375 removed, 485 unchanged (61% of the section changed)

Reneo is a clinical-stage pharmaceutical company focused on the development and commercialization of therapies for patients with rare genetic mitochondrial diseases, which are often associated with the inability of mitochondria to produce adenosine triphosphate (ATP).

Our lead product candidate, REN001, is a potent and selective agonist of the peroxisome proliferator-activated receptor delta (PPARδ).

REN001 has been shown to increase transcription of genes involved in mitochondrial function and increase fatty acid oxidation, and may increase production of new mitochondria.

The PPAR family of nuclear hormone receptors, PPAR a , PPAR g , and PPARδ, control the transcription of genes critical for regulating energy metabolism and homeostasis.

PPARδ is highly expressed in muscle, kidney, brain, and liver tissue.

Activation of PPARδ results in changes in the expression of genes involved with multiple aspects of energy metabolism including uptake of fatty acids, utilization of fatty acids as an energy source, and mitochondrial biogenesis.

Increases in PPARδ activity also correlate with a shift in muscle tissue towards oxidative, fat-consuming type I fibers that are associated with endurance as opposed to glycolytic, type II fibers.

In preclinical and clinical studies, increased PPARδ activity through transgenic overexpression or pharmacological activation increases muscular strength and endurance across a variety of functional measures.

REN001 was studied in healthy volunteers with one leg immobilized to produce muscle atrophy.

Compared to placebo, administration of REN001 resulted in statistically significant increases in expression of genes involved in mitochondrial oxidative phosphorylation, and statistically significant improvements in muscle strength.

REN001 was also studied in an open-label trial in patients with primary mitochondrial myopathies (PMM).

In this trial, administration of REN001 improved function, reduced symptoms, and increased expression of genes involved in mitochondrial activity.

As a PPARδ agonist, REN001 may benefit patients with genetic mitochondrial myopathies who experience weakness, fatigue, or deterioration in muscle due to impaired mitochondrial energy production.

We are currently developing REN001 in rare genetic diseases that typically present with myopathy and have high unmet medical needs, including PMM and long-chain fatty acid oxidation disorders (LC-FAOD).

Our lead product candidate, mavodelpar, is a potent and selective agonist of the peroxisome proliferator-activated receptor delta (PPARδ).

Mavodelpar has been shown to increase transcription of genes involved in mitochondrial function and increase fatty acid oxidation (FAO), and may increase production of new mitochondria.

The PPAR family of nuclear hormone receptors, PPARα, PPARγ, and PPARδ, control the transcription of genes critical for regulating energy metabolism and homeostasis.

is highly expressed in muscle, kidney, brain, and liver tissue.

Activation of PPARδ

results in changes in the expression of genes involved with multiple aspects of energy metabolism including uptake of fatty acids, utilization of fatty acids as an energy source, and mitochondrial biogenesis.

Increases in PPARδ

activity also correlate with a shift in muscle tissue towards oxidative, fat-consuming type I fibers that are associated with endurance as opposed to glycolytic, type II fibers.

In preclinical and clinical studies, increased PPARδ

activity through transgenic overexpression or pharmacological activation increases muscular strength and endurance across a variety of functional measures.

Mavodelpar was studied in healthy male volunteers with one leg immobilized to produce muscle atrophy.

Compared to placebo, administration of mavodelpar resulted in statistically significant increases in expression of genes involved in mitochondrial oxidative phosphorylation (OxPhos), and statistically significant improvements in muscle strength.

Mavodelpar was studied in an open-label trial in patients with primary mitochondrial myopathies (PMM).

Patients with PMM in this trial exhibited improved function, reduced symptoms, and increased expression of genes involved in mitochondrial function.

Mavodelpar was also studied in an open-label trial in patients with long-chain fatty acid oxidation disorder (LC-FAOD).

In this trial, patients with LC-FAOD due to certain gene defects exhibited improved function and reduced symptoms.

As a PPARδ

agonist, mavodelpar may benefit patients with genetic mitochondrial myopathies who experience weakness, fatigue, or deterioration in muscle due to impaired mitochondrial energy production.

Patients with these diseases are unable to perform many everyday activities, can experience cardiomyopathy and other organ dysfunction, and typically have a reduced life expectancy.

We are currently developing mavodelpar in rare genetic diseases that typically present with myopathy, including PMM and LC-FAOD.

There are currently no approved therapies for the treatment of PMM, representing a high unmet medical need.

Our Product Pipeline

The following table summarizes our pipeline for REN001.

We are currently developing REN001 in the following rare genetic diseases that are associated with a deficit of energy production in mitochondria and typically present with myopathy:

This rare genetic mitochondrial disease has an estimated prevalence of 20:100,000, representing at least 66,000 patients in the United States and 82,000 in Europe.

Patients with PMM are unable to move their muscles

efficiently because their ability to generate energy through oxidative phosphorylation (OxPhos) is compromised.

We are initially targeting adult patients with PMM.

The following table summarizes our mavodelpar development programs.

We are currently developing mavodelpar in the following rare genetic diseases that are associated with a deficit of energy production by the mitochondria and typically present with myopathy:

This rare genetic mitochondrial disease has an estimated prevalence in adults of 23:100,000, representing at least 66,000 patients in the United States and 82,000 in Europe.

Patients with PMM are unable to move their muscles efficiently because their ability to generate energy through OxPhos is compromised.

We are initially targeting adult patients with PMM due to mitochondrial DNA (mtDNA) defects.

This rare genetic mitochondrial disease has an estimated prevalence of 1.5:100,000, representing at least 5,000 patients in the United States and 6,000 in Europe.

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Muscle exertion in the absence of an adequate source of energy can result in the breakdown of muscle tissue that can subsequently cause kidney and cardiac damage.

We are initially targeting adult patients with LC-FAOD.

We are initially targeting adult patients with LC-FAOD with defects in long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD), carnitine palmitoyltransferase 2 (CPT2), and trifunctional protein (TFP).

Our mission is to bring to market therapies that address high unmet medical needs of patients with genetic mitochondrial diseases.

We plan to achieve this goal by developing mavodelpar initially for adult patients with PMM and LC-FAOD and will continue to explore other patient populations where mavodelpar may provide benefit.

We intend to establish mavodelpar as the standard of care for multiple rare genetic mitochondrial diseases.

The components of our strategy are as follows:

Complete clinical development and seek regulatory approval of mavodelpar in PMM.

Following our interactions with the U.S.

Food and Drug Administration (FDA), European Medicines Agency (EMA), and several other national regulatory agencies in Europe, we believe that positive results from our ongoing global, randomized, double-blind, placebo-controlled pivotal Phase 2b trial of mavodelpar in adult patients with PMM due to mtDNA (STRIDE) along with the open-label, long-term safety trial outside of the United States in adult patients with PMM due to mtDNA (STRIDE AHEAD) could potentially support the registration of mavodelpar for adult patients with PMM due to mtDNA defects in the United States and Europe.

We intend to submit the data from STRIDE, together with the long-term safety data from STRIDE AHEAD, to the FDA and the EMA in planned marketing applications in 2024.

In addition, we are planning to study mavodelpar in patients with PMM due to nuclear DNA (nDNA) defects.

Commercialize mavodelpar in the United States and key European markets, and establish mavodelpar as the standard of care for rare genetic mitochondrial diseases around the world.

We plan to build a fully integrated rare disease pharmaceutical company with a commercial infrastructure in the United States and key European markets.

For regions outside of the United States and key European markets, we plan to explore strategic partnerships to bring mavodelpar to patients.

Maximize the commercial potential of mavodelpar in additional rare genetic mitochondrial disease indications.

We have completed a Phase 1b study of mavodelpar in patients with LC-FAOD and are working with the FDA to map out the development pathway for our LC-FAOD program.

Additionally, we aim to identify and pursue development of mavodelpar in other diseases that are defined by the inability of mitochondria to produce cellular energy.

Expand our rare disease pipeline through acquisitions and/or licensing of complementary programs.

We plan to license and/or acquire additional programs targeting rare genetic diseases with high unmet medical need.

We will leverage our experience in preclinical and clinical development,

commercialization, and strong relationships with clinical investigators and patient advocacy organizations to bring therapeutic options to patients.

How muscle cells generate energy and how that process is deficient in patients with genetic myopathies

Cells generate energy in the form of ATP within intracellular structures called mitochondria.

Mitochondria use proteins, carbohydrates, and fatty acids to make ATP, which is then used by the cell to support all cellular processes.

Muscle tissue requires a high number of mitochondria to support energy needs.

Muscle cells mainly rely on three sources to generate energy:

phosphocreatine, carbohydrates (glycogen), and fatty acids.

Muscle cells initially use readily available phosphocreatine and glycogen to generate this energy.

phosphocreatine (P-Cr), carbohydrates, and fatty acids.

Muscle cells initially use readily available P-Cr and glycogen to generate this energy.

As these sources become depleted, muscle cells turn to fatty acids to generate cellular energy.

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Increasing the capacity of these patients to metabolize fatty acids could potentially reduce their energy deficit and improve their ability to function.

REN001 is designed to selectively activate PPARδ receptors found in the nuclear membrane of muscle and other cells.

PPARδ is a member of a family of nuclear receptors that regulate cellular energy generation by modulating the expression of genes that control proteins involved in mitochondrial enzyme activity and the formation of new mitochondria (mitochondrial biogenesis).

PPARδ is highly expressed in muscle cells and activation of PPARδ either through genetic manipulation or through small molecule agonists has been shown to increase the ability of muscle cells to use fatty acids as well as improve muscle strength and exercise tolerance.

We believe these are the mechanisms by which REN001 will act to help patients with mitochondrial diseases.

We completed an open-label Phase 1b study in patients with PMM to assess the safety and tolerability of REN001, and measure changes in functional tests such as walk distance, exercise capacity and patient-reported symptoms that could serve as potential endpoints in future clinical studies.

REN001 was well-tolerated and had an adequate safety profile in this trial.

Compared to baseline, patients receiving REN001 once-daily for 12 weeks experienced an average increase in distance of 104.4 meters in the 12-minute walk test (12MWT), an average increase in weight-adjusted peak oxygen consumption (VO2) of 1.7 mL/kg/min, a reduction in fatigue and pain, and increased expression of genes involved with transport and metabolism of nutrients in the mitochondria including Pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK4), Angiopoietin-like 4 (ANGPTL4), and Solute carrier family 25 member 34 (SLC25A34).

Based on these results, we initiated a global, randomized, double-blind, placebo-controlled Phase 2b study of REN001 in patients with PMM (STRIDE study).

The first patient was dosed in July 2021 and we expect to complete enrollment by year-end 2022 and announce results in 2023.

We are also conducting an open-label, long-term safety trial outside the United States in a subset of patients from the STRIDE study (STRIDE AHEAD study).

The first patient was dosed in January 2022 and we anticipate preliminary data from this study in 2023.

Following our interactions with United States and several European regulatory agencies, we believe that positive results from these trials could support registration of REN001 for PMM in both the United States and in Europe.

We completed enrollment of an open-label Phase 1b study in patients with four different LC-FAOD enzyme defects to assess the safety and tolerability of REN001, and measure changes in functional tests such as walk distance, exercise capacity and patient-reported symptoms that could serve as potential endpoints in future clinical studies.

We also completed enrollment of a natural history study in patients with LC-FAOD (FORWARD study).

The FORWARD study

is an observational, non-interventional study to better understand the changes in patient function and symptoms over time.

We anticipate results from both studies in the second calendar quarter of 2022.

We completed an open-label Phase 1b study in patients with glycogen storage disease type V (McArdle Disease) to assess the safety and tolerability of REN001, and measure changes in functional tests such as walk distance, exercise capacity and patient-reported symptoms that could serve as potential endpoints in future clinical studies.

Patients with McArdle disease are unable to break down glycogen in the muscle, and during the first several minutes of muscle activity experience acute fatigue and pain, and a significant increase in heart rate.

REN001 was well-tolerated and had an adequate safety profile in this study.

Compared to baseline, patients receiving REN001 once-daily for 12 weeks experienced an average increase in distance of 25.0 meters in the 12MSWT and an increase in fat oxidation of 38.5% as measured by indirect calorimetry.

No corresponding changes in heart rate, fatigue, pain, or other symptoms were observed.

Based on these results, we will not pursue a subsequent Phase 2 study in McArdle Disease at this time.

As of March 4, 2022, REN001 has been dosed in 225 individuals across multiple clinical trials.

In these trials, REN001 was well tolerated, with no drug-related serious adverse events (SAE) reported.

Our mission is to bring to market therapies that address high unmet medical needs of patients with genetic mitochondrial diseases.

We plan to achieve this goal by developing REN001 initially for patients with PMM and LC-FAOD and will continue to explore other patient populations where REN001 may provide benefit.

We intend to establish REN001 as the standard of care for multiple rare genetic mitochondrial diseases.

The components of our strategy are as follows:

● Complete clinical development and seek regulatory approval of REN001 in PMM.

REN001 is an oral small molecule PPARδ agonist that is designed to modulate multiple genes critical for cellular metabolism and the generation of energy in the cell.

Our lead clinical program targets PMM, a rare genetic mitochondrial disease with an estimated prevalence of 20:100,000, and a high unmet medical need due to the lack of any approved pharmaceutical treatment option.

We established proof-of-concept in a Phase 1b study in patients with PMM in which REN001 was shown to be well-tolerated and improvements in exercise performance and patient-reported symptoms were observed.

We also observed increases in the expression of genes responsible for the transport and metabolism of nutrients within the mitochondria.

The first patient in the STRIDE study was dosed in July 2021, and we expect to complete enrollment by year-end 2022 and announce results in 2023.

We are also conducting the STRIDE AHEAD study, an open-label, long-term, safety trial outside the United States in a subset of patients from the STRIDE study, with the first patient dosed in January 2022 and preliminary data anticipated to be available in 2023.

Based on interactions with U.S.

and several European regulatory agencies, we believe that positive results from these trials could support registration of REN001 for PMM in both the United States and in Europe.

● Maximize the commercial potential of REN001 in additional rare genetic mitochondri al disease indications.

We are also studying REN001 in a Phase 1b study in patients with LC-FAOD, a rare genetic disease with high unmet medical need, plus the FORWARD study.

Preliminary data from the Phase 1b study have demonstrated an improvement in a subset of patients in both exercise tests and symptoms, with tolerability of REN001 that is consistent with that observed in other REN001 studies.

We anticipate that data for the full cohort of patients from our Phase 1b study and the FORWARD study will be available in the second calendar quarter of 2022.

We will assess the potential for continued development of REN001 in LC-FAOD following receipt of full data from both studies, and discussion with key opinion leaders.

We also plan to explore further development of REN001 in other diseases that are defined by the inability of mitochondria to produce cellular energy.

● Commercialize REN001 in the United States and key European markets, and establish REN001 as standard of care.

We plan to build a fully integrated rare disease pharmaceutical company with a commercial infrastructure in the United States and key European markets.

For regions outside of the United States and key European markets, we plan to explore strategic partnerships to bring REN001 to patients.

Our goal is to establish REN001 as the standard of care for rare genetic mitochondrial diseases around the world.

● Expand our rare genetic mitochondrial disease pipeline through acquisitions and/or licensing of complementary programs.

We plan to license and/or acquire additional programs targeting rare genetic diseases

with high unmet medical need.

We will leverage our experience in preclinical and clinical development, commercialization, and strong relationships with clinical investigators and patient advocacy organizations to bring therapeutic options to patients.

How muscle cells generate energy and how that process is deficient in patients with genetic myopathies

Cells generate energy in the form of ATP within intracellular structures called mitochondria.

Mitochondria use proteins, carbohydrates, and fatty acids to make ATP, which is then used by the cell to support all cellular processes.

Muscle tissue requires a high number of mitochondria to support energy needs.

Mitochondrial energy production involves a series of highly regulated metabolic processes that are sequenced based on the availability of nutrients and the length of time cells require energy.

In the first minute of exertion, mitochondria utilize readily available phosphocreatine (P-Cr) as a source of fuel to create ATP (Figure 1, step 1).

When phosphocreatine is consumed, muscles turn to carbohydrate metabolism (glucose utilization) as the next source of fuel to create ATP (Figure 1, step 2).

Finally, after several minutes of exercise when phosphocreatine and carbohydrates are depleted, mitochondria turn to fatty acids as the source of fuel to create ATP (Figure 1, step 3).

Fatty acid oxidation (FAO) becomes the primary pathway to generate energy for muscle and other cells during long periods of exercise.

In the first minute of exertion, mitochondria utilize readily available P-Cr as a source of fuel to create ATP (Figure 1, step 1).

When P-Cr is consumed, muscles turn to carbohydrate metabolism, as the next source of fuel to create ATP (Figure 1, step 2).

Finally, after several minutes of exercise when P-Cr and carbohydrates are depleted, mitochondria turn to fatty acids as the source of fuel to create ATP (Figure 1, step 3).

FAO becomes the primary pathway to generate energy for muscle and other cells during long periods of exercise.

The energy source used by muscles shifts from P-Cr and carbohydrates to fatty acids as supplies of P-Cr and carbohydrates are depleted

Oxidative phosphorylation

The energy source used by muscles shifts from phosphocreatine (P-Cr) and carbohydrates to fatty acids as short-term supplies of phosphocreatine and carbohydrates are depleted

Nutrient utilization by mitochondria

Genetic mitochondrial myopathies are caused by deficiencies in specific steps of mitochondrial energy generation.

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We believe that enhancing FAO has the potential to provide therapeutic benefit to patients with genetic myopathies.

PPARδ, a regulator of FAO

PPARs are members of a family of nuclear receptors that, through their distinct functions and tissue distribution, regulate gene transcription involved in many biological processes, including metabolism and energy production.

There are three PPAR isotypes:

alpha (α), gamma (γ) and delta (δ).

agonists drugs have been approved in cardiovascular and endocrine disorders, respectively.

is highly expressed in muscle cells and activation of PPARδ

either through genetic manipulation or through small molecule agonists has been shown to increase the ability of muscle cells to use fatty acids and generate energy.

Transgenic mice with overexpressed PPARδ

were shown to be able to run on a treadmill twice the distance compared to normal mice.

Conversely, PPARδ

knockout mice were shown to run approximately 30% less distance compared to normal mice.

We believe that a selective agonist of PPARδ

such as mavodelpar, has potential therapeutic benefits while avoiding some of the adverse events associated with approved PPAR agonists of the PPARα

and PPARγ

Members of the PPAR family of nuclear receptors have distinct roles in regulating fatty acid metabolism

Disease overview

PMM background

PMM are a group of disorders caused by genetic mutations within the mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that affect the activity of enzymes or other proteins in the mitochondria.

PMM are a group of disorders caused by genetic mutations within the mtDNA or nDNA that affect the activity of enzymes or other proteins in the mitochondria.

In PMM these genetic alterations hamper the ability of mitochondria to generate energy from nutrient sources, resulting in energy deficits that are most pronounced in tissues with high energy demand such as muscle, brain, and heart.

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This is due to several factors including the variability in prevalence of the mutated versus non-mutated genes within each cell across various tissues in the body.

Myopathy is one of the most common clinical manifestations of disease in patients with PMM and can be a debilitating feature because muscle impairment, lack of endurance and exercise intolerance affect mobility and limit the capability of PMM patients to perform day-to-day activities.

There are currently no approved therapies for the treatment of PMM, representing a high unmet medical need.

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Mutations in the genes encoding the enzymes that break down long-chain fatty acids may lead to severe energy deficits.

Specific deficiencies include defects in very long-chain acyl-CoA dehydrogenase, long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency (LCHAD), mitochondrial trifunctional protein deficiency, and carnitine palmitoyltransferase (CPT) deficiency.

Specific deficiencies include defects in very long-chain acyl-CoA dehydrogenase (VLCAD), LCHAD, mitochondrial TFP, and carnitine palmitoyltransferase (CPT).

Patients need at least partial enzyme activity to survive into adulthood.

Patients with the most severe defects in these enzymes

have a high mortality rate.

Patients with the most severe defects in these enzymes have a high mortality rate.

The most severe cases of LC-FAOD are diagnosed within the first few days or weeks of life.

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Patients with LC-FAOD are instructed to avoid fasting, eat frequent meals and, in some cases, supplement with creatinine and medium chain triglycerides (MCT), in order to maintain sources of energy for oxidative metabolism.

In June 2020, a new form of MCT called DOJOLVI® (triheptanoin) was approved in the United States as a source of calories for LC-FAOD patients.

In June 2020, a new form of MCT called DOJOLVI® (triheptanoin) was approved in the United States as a source of calories for patients with LC-FAOD.

However, DOJOLVI® has not demonstrated clear functional benefits on endurance in randomized, controlled clinical trials.

PPAR δ , a regulator of FAO

There are three PPAR isotypes:

alpha (α), gamma (γ) and delta (δ).

PPAR α and γ agonists drugs have been approved in cardiovascular and endocrine disorders, respectively.

Transgenic mice with overexpressed PPARδ were shown to be able to run on a treadmill twice the distance compared to normal mice.

Conversely, PPARδ knockout mice were shown to run approximately 30% less distance compared to normal mice.

We believe that a selective agonist of PPARδ such as REN001, has potential therapeutic benefits while avoiding some of the adverse events associated with approved PPAR agonists of the PPARα and PPARγ class.

Members of the PPAR family of nuclear receptors have distinct roles in regulating fatty acid metabolism

Our Solution, REN001

REN001 is an oral, small molecule selective PPARδ agonist designed to modulate genes critical to metabolism and generation of energy.

By selectively targeting PPARδ, REN001 may address the cellular energy deficit in patients with genetic mitochondrial myopathies such as PMM and LC-FAOD by:

We are not aware of any drug interventional studies underway or currently announced for LC-FAOD.

Our Solution, Mavodelpar

Mavodelpar is an oral, small molecule selective PPARδ

agonist designed to modulate genes critical to metabolism and generation of energy.

Mavodelpar is designed to selectively activate PPARδ

receptors found in the nuclear membrane of muscle and other cells.

is a member of a family of nuclear receptors that regulate cellular energy generation by modulating the expression of genes that control proteins involved in mitochondrial enzyme activity and the formation of new mitochondria (mitochondrial biogenesis).

is highly expressed in muscle cells and activation of PPARδ

either through genetic manipulation or through small molecule agonists has been shown to increase the ability of muscle cells to use fatty acids as well as improve muscle strength and exercise tolerance.

We believe these are the mechanisms by which mavodelpar will act to help patients with mitochondrial diseases.

By selectively targeting PPARδ, mavodelpar may address the cellular energy deficit in patients with genetic mitochondrial myopathies such as PMM and LC-FAOD by:

Increasing OxPhos activity of mitochondria resulting in enhanced production of ATP;

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Increasing the proportion and/or absolute number of functioning mitochondria which may compensate for poorly functioning or non-functional mitochondria.

To date, mavodelpar has been administered to more than 380 subjects across 10 clinical trials.

Experiments in cell lines derived from patients with genetic mitochondrial myopathies have shown that increasing respiratory chain enzyme (complex I, III or IV) levels and activity can compensate the underlying energy deficit.

Agonism of PPARδ can increase the activity of these respiratory chain enzymes.

In addition, pharmacological upregulation of mitochondrial biogenesis in PMM patients may result in improved energy generation.

Agonism of PPARδ

can increase the activity of these respiratory chain enzymes.

In addition, pharmacological upregulation of mitochondrial biogenesis in patients with PMM may result in improved energy generation.

PPAR agonists have been shown to activate genes that play a central role in regulating mitochondrial biogenesis.

We believe that activation of these genes may alleviate the ATP deficient state in patients with genetic mitochondrial myopathies by increasing mitochondrial mass through enhanced mitochondrial biogenesis.

In preclinical models, administration of REN001 led to a concentration-dependent increase of FAO and an increase in expression of genes involved in mitochondrial biogenesis.

Similarly, data from a prior Phase 1 clinical trial of REN001 in healthy volunteers who were randomized to receive 4 weeks of treatment with 100 mg REN001 orally twice-daily (n=12) or placebo (n=12) showed increased expression of PPARδ regulated genes.

Compared to placebo, analysis of muscle biopsies from REN001 treated volunteers showed substantial changes in known PPAR regulated target genes involved in fatty acid metabolism and new mitochondria formation.

We have received orphan drug designations for REN001 in the United States for PMM and LC-FAOD.

Additionally, we have received orphan drug designations for REN001 for mitochondrial encephalomyopathy, lactic acidosis, and neurological stroke-like episodes (MELAS), a form of PMM, and LCHAD, a form of LC-FAOD in Europe.

In preclinical models, administration of mavodelpar led to a concentration-dependent increase of FAO and an increase in expression of genes involved in mitochondrial biogenesis.

Similarly, data from a prior Phase 1 clinical trial of mavodelpar in healthy volunteers who were randomized to receive 4 weeks of treatment with 100 mg mavodelpar orally twice-daily (n=12) or placebo (n=12) showed increased expression of PPARδ

regulated genes.

Compared to placebo, analysis of muscle biopsies from mavodelpar treated volunteers showed substantial changes in known PPAR regulated target genes involved in fatty acid metabolism and new mitochondria formation.

We have received orphan drug designations for mavodelpar in the United States for PMM and LC-FAOD.

Additionally, we have received orphan drug designations for mavodelpar for mitochondrial encephalomyopathy, lactic acidosis, and neurological stroke-like episodes (MELAS), a form of PMM, and LCHAD, a form of LC-FAOD in Europe.

As further clinical data becomes available, we plan to apply for additional orphan designations in the United States and Europe.

We licensed exclusive, worldwide rights to develop and commercialize REN001 and other related compounds from vTv Therapeutics in 2017.

REN001 for the Treatment of PMM

Phase 1b clinical results in PMM

We completed an open-label Phase1b clinical trial of REN001 in patients with PMM and myopathy due to mtDNA mutations, which was conducted under a Clinical Trial Authorisation submitted to the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom (UK) and accepted in November 2018.

The primary objective of the trial was to evaluate the safety and tolerability of REN001, and REN001 was generally well-tolerated.

We selected PMM patients with mtDNA mutations and excluded PMM patients with nDNA mutations to reduce heterogeneity in the study.

Also, in contrast to PMM patients with nDNA mutations who have all their mitochondria affected, patients with mtDNA mutations harbor both normal and mutated mitochondria within their cells (heteroplasmy).

In PMM patients with mtDNA mutations, REN001 has the potential to improve the function of affected mitochondria and to increase the overall function of otherwise normal mitochondria.

This could potentially happen by impacting mitochondrial biogenesis or by improving mitochondrial function, resulting in improved cellular energy levels for PMM patients.

We have received Fast Track designation for mavodelpar for the treatment of patients with PMM and LC-FAOD due to LCHAD deficiency, one of the predominant LC-FAOD genotypes.

Mavodelpar for the Treatment of PMM

Phase 1b clinical trial in PMM

We completed an open-label Phase 1b trial of mavodelpar in patients with PMM due to mtDNA defects.

The primary objective of the trial was to evaluate the safety and tolerability of mavodelpar, and mavodelpar was generally well-tolerated.

We selected patients with PMM due to mtDNA defects and excluded patients with PMM due to nDNA defects to reduce heterogeneity in the study.

Also, in contrast to patients with PMM due to nDNA defects who have all their mitochondria affected, patients with PMM due to mtDNA defects harbor both normal and mutated mitochondria within their cells (heteroplasmy).

In patients with PMM due to mtDNA defects, mavodelpar has the potential to improve the function of affected mitochondria and to increase the overall function of otherwise normal mitochondria.

This could potentially happen by impacting mitochondrial biogenesis or by improving mitochondrial function, resulting in improved cellular energy levels for patients with PMM.

The Phase 1b trial was conducted in two parts:

Part A (12 weeks dosing) and Part B (optional 36-week treatment extension).

All patients were dosed orally with 100 mg REN001 once daily.

A total of 24 patients were enrolled and 23 patients received REN001 in Part A.

The planned maximum treatment duration for each patient in both Part A and Part

B was 48 weeks.

The Phase 1b study was closed early as a result of the COVID-19 pandemic.

All patients were dosed orally with 100 mg mavodelpar once daily.

A total of 24 patients were enrolled and 23 patients received mavodelpar in Part A.

The planned maximum treatment duration for each patient in both Part A and Part B was 48 weeks.

The Phase 1b trial was closed early as a result of the COVID-19 pandemic.

At the point of trial closure, a total of 17 patients had completed Part A, 13 patients had entered Part B, and the maximum duration of treatment was approximately 40 weeks.

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therefore, was not designed to show statistical significance as compared to a placebo control arm.

REN001 PMM Phase 1b study enrollment

To evaluate changes in patient function, we used a 12MWT.

We believe that the 12MWT is an ideal assessment of functionality in patients with genetic mitochondrial diseases who commonly lack endurance as the latter half of the exercise period permits the evaluation of patients as they move from phosphocreatine and carbohydrate metabolism into FAO in the mitochondria.

REN001 was generally well tolerated with no drug related SAEs observed.

Mavodelpar PMM Phase 1b trial enrollment

To evaluate changes in patient function, we used a 12-minute walk test (12MWT).

We believe that the 12MWT is an ideal assessment of functionality in patients with genetic mitochondrial diseases who commonly lack endurance as the latter half of the exercise period permits the evaluation of patients as they move from P-Cr and carbohydrate metabolism into FAO in the mitochondria.

There were 114 treatment emergent adverse events (TEAE) experienced by 21 out of 23 subjects, with 66 of the 114 TEAEs (57.9%) experienced by 15 subjects which are considered related to study drug.

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Physical performance measures

Baseline 12MWT in the Phase 1b study was 603.2 meters.

Following 12 weeks of 100 mg once-daily dosing with REN001, patients achieved an average increase of 104.4 meters (95% CI:

53.1, 155.6) in distance walked during the

12MWT compared to baseline.

An increase in distance walked was observed in 15 of 17 patients (88%), with 13 of 17 (76%) increasing by 60 meters or greater as illustrated in Figure 5a.

REN001-treated PMM patients had improved 12MWT distances after 12 weeks of treatment

The largest improvement in distance walked in the 12MWT at week 12 occurred in the second half of the 12-minute period (Figure 5b), which we believe is consistent with REN001’s mechanism of action.

We expect REN001 to improve muscle cell energy by increasing mitochondrial oxidative phosphorylation, and this process occurs several minutes into exercise (See Figure 1 above).

REN001-treated PMM patients had greatest improvement in walking distances in the latter half of the 12MWT, consistent with the proposed mechanism of REN001 to stimulate fatty acid metabolism

An additional outcome measure in our Phase 1b study was measurement of peak oxygen consumption during maximal exercise.

Baseline 12MWT in the Phase 1b trial was 603.2 meters.

Following 12 weeks of 100 mg once-daily dosing with mavodelpar, patients achieved an average increase of 104.4 meters (95% CI:

53.1, 155.6) in distance walked during the 12MWT compared to baseline.

An increase in distance walked was observed in 15 of 17 patients (88%), with 13 of 17 patients (76%) increasing by 50 meters or greater as illustrated in Figure 5a.

Mavodelpar-treated patients with PMM had improved 12MWT distances after 12 weeks of treatment

The largest improvement in walk velocity during the 12MWT at week 12 occurred in the second half of the 12-minute period (Figure 5b), which we believe is consistent with mavodelpar’s mechanism of action.

We expect mavodelpar to improve muscle cell energy by increasing mitochondrial OxPhos, and this process occurs several minutes into exercise (See Figure 1 above).

Mavodelpar-treated patients with PMM had the greatest improvement in walking velocity in the latter half of the 12MWT, consistent with the proposed mechanism of mavodelpar to stimulate fatty acid metabolism

An additional outcome measure in our Phase 1b trial was measurement of peak oxygen consumption (peak VO 2 ) during maximal exercise.

The amount of oxygen used during maximal exercise is a marker of aerobic capacity and is directly correlated with the ability to metabolize fatty acids which require higher amounts of oxygen than other energy sources such as carbohydrates.

An average healthy person has a weight-adjusted peak oxygen consumption of 35 to 40 ml/kg/min for males and 27 to 30 ml/kg/min for females.

A weight-adjusted peak oxygen consumption of 14 mL/kg/min or lower has been determined to predict increased mortality in other patient populations (congestive heart failure).

Baseline weight-adjusted peak oxygen consumption in the Phase 1b study was 14.6 mL/kg/min.

Following 12 weeks of 100 mg once-daily dosing with REN001, patients achieved an average increase in weighted average peak oxygen consumption of 1.7 mL/kg/min (95% CI:

An average healthy person has a weight-adjusted peak VO 2 of 35 to 40 mL/min/kg for males and 27 to 30 mL/min/kg for females.

A weight-adjusted peak VO 2 of 14 mL/min/kg or lower has been determined to predict increased mortality in other patient populations (congestive heart failure).

Baseline weight-adjusted peak VO 2 in the Phase 1b trial was 14.6 mL/min/kg.

Following 12 weeks of 100 mg once-daily dosing with mavodelpar, patients achieved an average increase in weighted average peak VO 2 of 1.7 mL/min/kg (95% CI:

-0.329, 3.665) compared to baseline (Figure 5c).

Peak exercise oxygen consumption increased in PMM patients after 12 weeks of REN001 treatment

Peak exercise peak VO 2 increased in patients with PMM after 12 weeks of mavodelpar treatment

Another outcome measure was the sub-maximal exercise test.

This test is conducted using a stationary bike for 30 minutes of cycling at 60% of the patient’s maximal capacity.

At baseline, 7 of the 17 patients (41%) were able to complete the 30-minute test compared to 11 of 17 patients (65%) after 12 weeks of REN001 treatment.

This test is conducted using a stationary bike for 30 minutes of cycling at 60% of the patient’s maximal capacity.

At baseline, 7 of the 17 patients (41%) were able to complete the 30-minute test compared to 11 of 17 patients (65%) after 12 weeks of mavodelpar treatment.

Overall, a mean improvement of approximately 3 minutes was observed at week 12 compared to baseline, with no increase in heart rate or perceived exertion.

A 30-second sit-to-stand test was also performed.

The 30-second sit-to-stand test measures lower extremity strength and endurance which are needed for daily activities such as climbing stairs, getting out of a chair or bathtub, or rising from a horizontal position.

A 30-second sit-to-stand (30STS) test was also performed.

The 30STS test measures lower extremity strength and endurance which are needed for daily activities such as climbing stairs, getting out of a chair or bathtub, or rising from a horizontal position.

Patients are asked to stand from a sitting position in a chair as many times as possible in 30 seconds and to do so without the use of their arms.

At baseline, the PMM patients in our Phase 1b study were able to perform this task 6.9 times, which is worse than the typical performance of an elderly person in his or her late 80s.

After 12 weeks of treatment with REN001, patients were able to complete the task 8.5 times.

At baseline, the patients with PMM in our Phase 1b trial were able to perform this task 6.9 times, which is worse than the typical performance of an elderly person in his or her late 80s.

After 12 weeks of treatment with mavodelpar, patients were able to complete the task 8.5 times.

Because this test is completed in only 30 seconds, the improvement in performance is more likely due to increased muscle strength rather than improvements in FAO.

As shown in Figure 5d below, approximately 40% of PMM patients showed improvements in lower extremity muscle strength and stamina after 12 weeks of REN001 treatment as evaluated with the 30-second sit-to-stand test.

PMM patients showed improvements in lower extremity muscle strength and stamina after 12 weeks of REN001 treatment as evaluated with the 30-second sit to stand test

As shown in Figure 5d below, approximately 40% of patients with PMM showed improvements in lower extremity muscle strength and stamina after 12 weeks of mavodelpar treatment as evaluated with the 30STS test.

Patients with PMM showed improvements in lower extremity muscle strength and stamina after 12 weeks of mavodelpar treatment as evaluated with the 30STS test

Patient reported outcomes (evaluation of symptoms)

The Short Form Health Survey (SF-36) is a 36-item questionnaire that assesses general health including physical activities, mental health, pain, and properties such as energy and fatigue over four weeks.

The 36-Item Short Form Health Survey (SF-36) is a 36-item questionnaire that assesses general health including physical activities, mental health, pain, and properties such as energy and fatigue over four weeks.

Each domain of the SF-36 can range from 0 to 100, with a higher score representing improvement.

As illustrated in in the right chart in Figure 5e, after 12 weeks of 100 mg once-daily dosing with REN001, patients (n=17) had a mean improvement in the SF-36 energy/fatigue subscale from 28 at baseline to 39 at 12 weeks.

As illustrated in the right chart in Figure 5e, after 12 weeks of 100 mg once-daily dosing with mavodelpar, patients (n=17) had a mean improvement in the SF-36 energy/fatigue subscale from 28 at baseline to 39 at 12 weeks.

The Modified Fatigue Impact Scale (MFIS) is a questionnaire that measures both the frequency and impact of fatigue on patients physical, cognitive, and psychosocial functioning over a 4-week period.

The total MFIS score scales range from 0 to 84, with a lower score representing less fatigue.

As illustrated in in the middle chart in Figure 5e, after 12 weeks of 100 mg once-daily dosing with REN001, patients (n=17) had a mean improvement in the MFIS score from 50 at baseline to 40 at 12 weeks.

The Brief Pain Inventory (BPI) measures the patient’s perception of pain and the degree that pain interferes with function over the past 24 hours.

As illustrated in the middle chart in Figure 5e, after 12 weeks of 100 mg once-daily dosing with mavodelpar, patients (n=17) had a mean improvement in the MFIS score from 50 at baseline to 40 at 12 weeks.

The Brief Pain Inventory (BPI) measures the patient’s perception of pain and the degree that pain interferes with function over the past 24 hours.

The BPI scales range from 0 to 10, with a lower score representing less pain.

As illustrated in the left chart in Figure 5e, after 12 weeks of 100 mg once-daily dosing with REN001, the patients that reported pain at baseline (n=14), had a mean improvement in the BPI severity scale from 4.5 at baseline to 3.5 at 12 weeks.

Mean change from baseline to week 12 in patient reported outcome questionnaires in patients with PMM participating in the Phase 1b study

As illustrated in the left chart in Figure 5e, after 12 weeks of 100 mg once-daily dosing with mavodelpar, the patients that reported pain at baseline (n=14), had a mean improvement in the BPI severity scale from 4.5 at baseline to 3.5 at 12 weeks.

Mean change from baseline to week 12 in patient reported outcome questionnaires in patients with PMM participating in the Phase 1b trial

Muscle biopsies (evaluation of gene expression)

Muscle biopsies were performed at baseline and after 12 weeks of treatment with REN001 to evaluate changes in gene expression (mRNA).

Muscle biopsies were performed at baseline and after 12 weeks of treatment with mavodelpar to evaluate changes in gene expression (mRNA).

Differential gene expression was performed on biopsies from seven subjects that had sufficient sample quantity and quality for analysis at baseline and week 12.

As shown in Figure 5f, a statistically significant increase over baseline was observed in the expression of PDK4, ANGPTL4, and SLC25A34.

Change in PPARδ-regulated gene expression from human muscle following REN001 treatment from a Phase 1b clinical trial in PMM patients

As shown in Figure 5f, a statistically significant increase over baseline was observed in the expression of Pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK4), Angiopoietin-like 4 (ANGPTL4), and Solute carrier family 25 member 34 (SLC25A34).

Change in PPARδ-regulated gene expression from human muscle following mavodelpar treatment from a Phase 1b clinical trial in patients with PMM

Clinical development plans in PMM

We have initiated the STRIDE study, a global Phase 2b study of REN001 in patients with PMM and dosed the first patient in July 2021.

STRIDE is a randomized, double-blind, placebo-controlled, multi-center clinical trial designed to investigate the efficacy and safety of 100 mg REN001 administered once-daily over a 24-week period to PMM patients with mtDNA mutations.

We anticipate enrolling approximately 200 adult patients with a history of myopathy.

The primary endpoint of the trial is the change from baseline in the distance walked during the 12MWT at 24 weeks.

Secondary endpoints include changes from baseline in the MFIS and the patient global impression of change scale.

Other exploratory endpoints include the 30-second sit-to-stand test, step counts, patient global impression of severity scale, BPI, and additional patient-reported outcome measures.

Results from the STRIDE study is expected to be available in 2023.

We have also initiated the STRIDE AHEAD study, an open-label extension trial, which will enroll a subset of the patients from the STRIDE study.

Based on interactions with the U.S.

Food and Drug Administration (FDA) and several European regulatory agencies, we believe that positive results from the STRIDE study and the STRIDE AHEAD study could support registration of REN001 for PMM in both the United States and in Europe.

REN001 for the Treatment of LC-FAOD

Phase1b Study in LC-FAOD

In December 2021, we completed enrollment in an open-label Phase 1b study in adult patients with LC-FAOD.

The primary objective of the trial is to evaluate the safety and tolerability of REN001 in the LC-FAOD patient population, and we will also explore multiple clinical outcomes.

We initiated the trial with a dose of 50 mg once-daily in the first three patients followed by 100 mg once-daily in all subsequent patients.

We completed enrollment of this study in late 2021, and we expect results to be available in the second calendar quarter of 2022.

We obtained data from the first six patients who completed 12 weeks of dosing, and both doses have been well tolerated.

As shown in Figure 6, after 12 weeks of treatment with REN001, 5 of the 6 patients showed an improvement in the 12MWT, with 4 of the 6 showing an

improvement over 50 meters.

Improvements in symptoms, including a decrease in MFIS and BPI and an increase in SF-36, were also observed in several patients.

Results from the first six LC-FAOD patients dosed with REN001 in a Phase 1b Study

Based on these results, we initiated the STRIDE study, a global, randomized, double-blind, placebo-controlled pivotal Phase 2b trial of mavodelpar in adult patients with PMM due to mtDNA defects.

We achieved the target enrollment of 200 patients in the pivotal STRIDE study in March 2023 and anticipate announcement of topline results in the fourth quarter of 2023.

STRIDE study is designed to investigate the efficacy and safety of 100 mg mavodelpar administered once-daily over a 24-week period.

The primary efficacy endpoint of the trial is the change from baseline in the distance walked during the 12MWT at week 24.

Key secondary endpoints include changes from baseline in the MFIS measures and the patient global impression of change scale.

Additional secondary endpoints include the 30STS test, step counts, patient global impression of severity scale, BPI, and additional patient-reported outcome measures.

We are also conducting the STRIDE AHEAD study, a 24-month-year, open-label, long-term safety trial outside of the United States in patients with PMM due to mtDNA.

STRIDE AHEAD study was recently amended to also allow enrollment of adult patients with PMM due to nDNA defects.

Based on interactions with the FDA, EMA, and several other national regulatory agencies in Europe, we believe that positive results from the ongoing pivotal STRIDE and STRIDE AHEAD studies could potentially support registration of mavodelpar for adult patients with PMM due to mtDNA defects in the United States and Europe.

We intend to submit the data from STRIDE, together with the long-term safety data from STRIDE AHEAD, to the FDA and the EMA in planned marketing applications in 2024.

Mavodelpar for the Treatment of LC-FAOD

Phase1b clinical trial in LC-FAOD

We completed an open-label Phase 1b study in LC-FAOD adult patients with nDNA defects to assess the safety and tolerability of mavodelpar, and measure changes in functional test such as walk distance, exercise capacity and patient-reported symptoms that could serve as potential endpoints in future clinical studies.

The study included patients with defective LCHAD, CPT2, VLCAD, or TFP.

A total of 24 patients were enrolled, including patients with defective LCHAD (n=5), CPT2 (n=8), VLCAD (n=9), or TFP (n=2).

We initiated the trial with a dose of 50 mg once-daily in the first three patients followed by 100 mg

once-daily in all subsequent patients.

The LCHAD and CPT2 groups had the greatest improvement over baseline in 12MWT (73.7 and 51.9 meters, respectively).

In the LC-FAOD Phase 1b study, mavodelpar was well tolerated.

The most common adverse events experienced by patients were rhabdomyolysis (4 patients) and myalgia (4 patients), the majority reported to be mild or moderate in severity.

Results of the 12MWT, SF-36 energy/fatigue domain score, and MFIS total score for patients who completed both baseline and week 12 are summarized in Figure 6.

Symptom improvement is represented by an increase in SF-36 energy/domain score or a decrease in MFIS total score.

Mean standard error (SE) baseline and week 12 change by genotype 1

1 TFP not summarized as only 1 subject completed the study

LC-FAOD Natural History Study

We completed enrollment in the FORWARD study, an observational, non-interventional study of REN001 in patients with LC-FAOD, to better understand these patients’ natural history and disease characteristics through exercise tests and symptom questionnaires.

The FORWARD study will also include work for validation of a new Reneo-developed patient questionnaire focused on muscle symptoms in LC-FAOD, which we plan to use in future trials.

We expect to announce results of both the LC-FAOD Phase 1b study and the FORWARD study in the second calendar quarter of 2022.

Additional Clinical Trials for REN001

We also completed a 16-week, observational, non-interventional study in patients with LC-FAOD with different nDNA mutations to better understand the natural history of LC-FAOD and changes in patient function and symptoms over time (FORWARD).

A total of 58 patients participated in the FORWARD study, including patients with defective LCHAD (n=16), CPT2 (n=30), or VLCAD (n=12).

In the FORWARD study, the most common adverse events experienced by patients were rhabdomyolysis (7 patients) and COVID-19 infection (5 patients), the majority reported to be mild or moderate in severity.

Results of the 12MWT, 12-Item Short Form Health Survey (SF-12) vitality domain score, and MFIS total score for patients who completed both baseline and week 16 are summarized in Figure 7.

Symptom improvement is represented by an increase in SF-12 vitality score or a decrease in MFIS total score.

Mean (SE) baseline and week 16 change by genotype

Based on the results of the LC-FAOD Phase 1b study, in conjunction with the results of the FORWARD study, we intend to continue the development of mavodelpar for certain genotypes of patients with LC-FAOD.

Results of the studies were presented at the International Network of Fatty Acid Oxidation Research and Management Conference in August 2022.

We have received Fast Track designation for mavodelpar for the treatment of patients with LC-FAOD due to LCHAD deficiency, one of the predominant genotypes.

We are continuing to collaborate with the FDA and European regulatory agencies to advance the LC-FAOD program which will include patients with LCHAD as well as other genotypes.

These discussions include obtaining alignment on the study design, patient population, and endpoints for the LC-FAOD program’s next clinical trial.

Additional Clinical Trials for mavodelpar

randomized double-blind placebo-controlled clinical trial

Limb impairment Phase 1 clinical trial in healthy volunteers

In a prior placebo-controlled Phase 1 clinical trial completed by vTv Therapeutics, 24 healthy volunteers were randomized 1:1 to receive 4 weeks of treatment with either 100 mg REN001 orally twice daily (n=12) or placebo (n=12).

In a prior placebo-controlled Phase 1 clinical trial completed by vTv Therapeutics, 24 healthy volunteers were randomized 1:1 to receive 4 weeks of treatment with either 100 mg mavodelpar orally twice daily (n=12) or placebo (n=12).

In the trial, all volunteers had one leg immobilized with a brace for the first 14 days to cause muscle atrophy and weakness.

Changes from baseline in muscle strength and gene expression from muscle biopsies were evaluated at various timepoints throughout the clinical trial.

REN001 treated volunteers had substantially more leg strength than

placebo treated volunteers immediately and one week after the removal of the leg brace.

No SAEs related to REN001 were reported, and TEAEs were similar among subjects who received REN001 or placebo.

Mavodelpar treated volunteers had substantially more leg strength than placebo treated volunteers immediately and one week after the removal of the leg brace.

No serious adverse events (SAEs) related to mavodelpar were reported, and TEAEs were similar among subjects who received mavodelpar or placebo.

Results from the muscle strength test from a Phase 1 clinical trial in healthy volunteers

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A p-value of less than or equal to 0.05 is a commonly used threshold for identifying statistically significant outcomes.

The FDA’s evidentiary standard of efficacy when evaluating the results of a clinical trial generally relies on a p-value of less than or equal to 0.05.

Muscle biopsies were collected and analyzed for mRNA of PPARδ-regulated genes involved in mitochondrial biogenesis and function (Figure 8).

Muscle biopsies obtained from REN001 treated individuals showed substantial increases in the mRNA of the following PPAR-regulated genes compared to placebo-treated controls:

● Pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK4) , encodes a mitochondrial protein.

The FDA’s evidentiary standard of efficacy when evaluating the results of a clinical trial generally relies on a p-value of less than or equal to 0.05.

Muscle biopsies were collected and analyzed for mRNA of PPARδ-regulated genes involved in mitochondrial biogenesis and function (Figure 9).

Muscle biopsies obtained from mavodelpar treated individuals showed substantial increases in the mRNA of the following PPAR-regulated genes compared to placebo-treated controls:

PDK4 encodes a mitochondrial protein.

This kinase plays a key role in regulation of glucose and fatty acid metabolism.

● Angiopoietin-like 4 (ANGPTL4) is a target of PPARs.

ANGPTL4 is a target of PPARs.

The encoded protein is a serum hormone directly involved in regulating lipid metabolism.

● Solute carrier family 25 member 34 (SLC25A34) belongs to the SLC25 family of mitochondrial carrier proteins.

SLC25A34 belongs to the SLC25 family of mitochondrial carrier proteins.

Members of the solute carrier family 25 are known to transport molecules over the mitochondrial membrane.

Change in PPAR δ -regulated Gene Expression from Human Muscle Following REN001 Treatment from a Phase 1 clinical trial in healthy volunteers.

Overall, REN001 has been well tolerated in all clinical trials conducted and there have been no drug related deaths or SAEs reported to date.

Change in PPARδ-regulated gene expression from human muscle following mavodelpar treatment from a Phase 1 clinical trial in healthy volunteers

Overall, mavodelpar has been well tolerated in all clinical trials conducted and there have been no drug related deaths or SAEs reported to date.

Most observed TEAEs were mild or moderate in severity.

In clinical trials where patients were randomized to REN001 or placebo, the incidence and severity of adverse events were similar among individuals who received REN001 or placebo.

In clinical trials where patients were randomized to mavodelpar or placebo, the incidence and severity of adverse events were similar among individuals who received mavodelpar or placebo.

To date, mavodelpar has been administered to more than 380 subjects across 10 clinical trials.

Preclinical Results and Plans

A substantial package of preclinical data along with Phase 1 placebo-controlled clinical data was in-licensed from vTv Therapeutics.

This package has been expanded through additional in vitro and in vivo studies to support the future registration of REN001.

In these studies, it has been observed that REN001 is a potent and selective agonist of PPARδ with an EC50 value of 31 nM for PPARδ and over 300-fold increased selectivity over PPARα and PPARγ.

REN001 has shown minimal or no activity against other ligand-activated nuclear receptors.

These other receptors, including the liver X and farnesoid X receptors, were evaluated because they have a role in regulating lipid homeostasis and energy

REN001 has also been evaluated for these receptors in transcriptional assays with similar findings (Figure 9).

REN001 is a selective agonist of PPAR δ

To access effects of REN001 on fatty acid oxidation, incubation of REN001 on XM5 human muscle cell line with REN001 demonstrated a concentration-dependent increase in FAO as shown in Figure 10 below.

REN001 led to a concentration-dependent increase in FAO in XM5 human muscle cell line

In an in vivo experiment, administration of REN001 to mice led to increased expression of a number of FAO genes and genes involved in mitochondrial biogenesis including PGC1α, a fatty acid transcriptional co-factor;

This package has been expanded through additional in vitro and in vivo studies to support the future registration of mavodelpar.

In these studies, it has been observed that mavodelpar is a potent and selective agonist of PPARδ

with an EC50 value of 31 nM for PPARδ

and over 300-fold increased selectivity over PPARα

and PPARγ.

Mavodelpar has shown minimal or no activity against other ligand-activated nuclear receptors.

These other receptors, including the liver X and farnesoid X receptors, were evaluated because they have a role in

regulating lipid homeostasis and energy metabolism.

Mavodelpar has also been evaluated for these receptors in transcriptional assays with similar findings (Figure 10).

Mavodelpar is a selective agonist of PPARδ

To access effects of mavodelpar on FAO, incubation of mavodelpar on XM5 human muscle cell line with mavodelpar demonstrated a concentration-dependent increase in FAO as shown in Figure 11 below.

Mavodelpar led to a concentration-dependent increase in FAO in XM5 human muscle cell line

In an in vivo experiment, administration of mavodelpar to mice led to increased expression of a number of FAO genes and genes involved in mitochondrial biogenesis including PGC1α, a fatty acid transcriptional co-factor;

CPT1B, the rate-limiting enzyme in the transport of fatty acids into the mitochondria;

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The transcription of fatty acid metabolism genes was increased after seven days of dosing with

REN001 in mice

PPAR ϒ co-activating factor 1 α

mavodelpar in mice

co-activating factor 1α

Mitochondrial Biogenesis

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Fatty acid metabolism

PPARα and PPARγ agonists have been approved for dyslipidemia and glycemic control in diabetes mellitus, respectively.

and PPARγ

agonists have been approved for dyslipidemia and glycemic control in diabetes mellitus, respectively.

Liver and cardiac toxicity associated with PPAR drugs have been observed.

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The purpose of carcinogenicity studies is to identify tumorigenic potential of a new drug candidate in rodents and to assess the relevant risk to humans.

Reneo is conducting a 104-week carcinogenicity study in rats and mice using low, medium and high doses of REN001 as well and control groups.

Reneo is conducting a 104-week carcinogenicity study in rats and mice using low, medium and high doses of mavodelpar as well and control groups.

These studies are being conducted according to FDA good laboratory practice (GLP) regulations.

We expect results from both studies in 2023.

We are unaware of any data suggesting that there is a clinical cancer risk with selective PPARδ agonists.

CymaBay Therapeutics’ clinical development programs includes dosing the selective PPARδ agonist seladelpar for up to 52 weeks and is currently conducting a 60-month open-label, long-term safety and tolerability study.

Astellas Pharma has announced it intends to conduct a Phase 2/3 clinical trial of up to 52-weeks with ASP0367, a selective PPARδ agonist.

Collectively, this suggests that both seladelpar and ASP0367 have been cleared in two-year carcinogenicity studies and that there is no evidence of a carcinogenicity signal for the selective PPARδ agonist class.

We are currently conducting the required two-year carcinogenicity studies with REN001.

We expect results from both studies in the fourth quarter of 2023.

We are unaware of any data suggesting that there is a clinical cancer risk with selective PPARδ

CymaBay Therapeutics, Inc.

is conducting a Phase 3 clinical trial of up to 52 weeks with seladelpar, a selective PPARδ

agonist in patients with primary biliary cholangitis.

Astellas Pharma Inc.

is conducting a Phase 2/3 clinical trial of up to 52-weeks plus 24-weeks extension with bocidelpar, a selective PPARδ

Collectively, this suggests that both seladelpar and bocidelpar have likely been cleared in two-year carcinogenicity studies and that there is no evidence of a carcinogenicity signal for the selective PPARδ

agonist class.

We are currently conducting the required two-year carcinogenicity studies with mavodelpar.

We have completed a 6-month toxicology study in rats and a 12-month toxicology study in primates.

No adverse effects associated PPARα or PPARγ agonists were observed with administration of REN001 at any dose level.

The COVID-19 pandemic continues to evolve, and we will continue to monitor the COVID-19 situation closely.

The extent of the impact of COVID-19 on our business, operations and clinical development timelines and plans remains uncertain, and will depend on certain developments, including the duration and spread of the pandemic, including new variants of the virus, and its impact on our clinical trial enrollment, trial sites, contract research organizations, third-party manufacturers, and other third parties with whom we do business, as well as its impact on regulatory authorities and our key scientific and management personnel.

For example, our Phase 1b study of REN001 in PMM patients was closed early as a result of COVID-19, and we may face future clinical trial disruptions.

The ultimate impact of the COVID-19 pandemic or a similar health epidemic is highly uncertain and subject to change.

As a result of COVID-19, we have taken precautionary measures in order to minimize the risk of the virus to our employees and the communities in which we operate.

While we have experienced impacts to our clinical development activities as a result of COVID-19 as set forth in this Annual Report, there has been a minimal disruption to date in our ability to ensure the effective operation of our business.

We will continue to actively monitor the rapidly evolving situation related to COVID-19 and may take further actions that alter our operations, including those that may be required by federal, state or local authorities, or that we determine are in the best interests of our employees and other third parties with whom we do business.

At this point, the extent to which the COVID-19 pandemic may affect our business, operations and clinical development timelines and plans, including the resulting impact on our expenditures and capital needs, remains uncertain.

No adverse effects associated with PPARα

or PPARγ

agonists were observed with administration of mavodelpar at any dose level.

Sales and Marketing

We currently do not have a commercial organization for the marketing, sales, and distribution of pharmaceutical products.

We plan to build a fully integrated rare genetic mitochondrial disease pharmaceutical company and will retain commercial rights to REN001 in the United States and key European markets.

For other territories, we will seek strategic partnerships to bring REN001 to market with the goal of establishing REN001 as the standard of care around the world.

We plan to build a fully integrated rare genetic mitochondrial disease pharmaceutical company and will retain commercial rights to mavodelpar in the United States and key European markets.

For other territories, we will seek strategic partnerships to bring mavodelpar to market with the goal of establishing mavodelpar as the standard of care around the world.

We may also opportunistically seek strategic collaborations to benefit from the resources of biopharmaceutical companies specialized in either relevant disease areas or geographies.

License Agreement with vTv Therapeutics

In December 2017, we entered into a License Agreement with vTv Therapeutics (vTv License Agreement), under which we obtained an exclusive, worldwide, sublicensable license under vTv Therapeutics intellectual property relating to vTv Therapeutics’ PPARδ agonist program, to develop, manufacture and commercialize PPARδ agonists and products containing such PPARδ agonists, including REN001, or licensed products, for any therapeutic, prophylactic or diagnostic application in humans.

agonist program, to develop, manufacture and commercialize PPARδ

agonists and products containing such PPARδ

agonists, including mavodelpar, or licensed products, for any therapeutic, prophylactic or diagnostic application in humans.

Under the terms of the vTv License Agreement, we made an upfront payment of $3.0 million to vTv Therapeutics and issued to vTv Therapeutics shares of our common stock representing a minority interest in our outstanding equity.

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In addition, we are obligated to make royalty payments to vTv Therapeutics at mid-single digit to low teen percentage royalty rates, based on tiers of annual net sales of licensed products, subject to certain customary reductions.

Such royalties will be payable on a licensed product-by-licensed product and country-by-country basis until the latest of (i) expiration of the last-to-expire licensed patents covering a licensed product in a country, which are expected to expire in 2034, absent any patent term adjustments or extension, (ii) expiration of regulatory exclusivity rights for a licensed product in a country, which is expected to be five years of new chemical entity exclusivity upon approval of a licensed product, such as REN001, in the United States, where such exclusivity would run concurrently with seven years of orphan drug exclusivity, if we are the first to receive marketing approval of a licensed product for an orphan disease or condition for which we have received orphan designation, such as approved orphan uses of REN001 for treatment of PMM and LC-FAOD, in the United States, and (iii) the tenth anniversary after the first commercial sale of a licensed product in a country.

Such royalties will be payable on a licensed product-by-licensed product and country-by-country basis until the latest of (i) expiration of the last-to-expire licensed patents covering a licensed product in a country, which are expected to expire in 2034, absent any patent term adjustments or extension, (ii) expiration of regulatory exclusivity rights for a licensed product in a country, which is expected to be five years of new chemical entity exclusivity upon approval of a licensed product, such as mavodelpar, in the United States, where such exclusivity would run concurrently with seven years of orphan drug exclusivity, if we are the first to receive marketing approval of a licensed product for an orphan disease or condition for which we have received orphan designation, such as approved orphan uses of mavodelpar for the treatment of patients with PMM and LC-FAOD, in the United States, and (iii) the tenth anniversary after the first commercial sale of a licensed product in a country.

In July 2021, a milestone under the vTv License Agreement was achieved, and we made a payment of $2.0 million to vTv Therapeutics.

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The vTv License Agreement, unless terminated earlier, will continue until expiration of the last to expire royalty term.

Either party may terminate the vTv License Agreement for the other party’s uncured material breach or insolvency.

We may terminate the vTv License Agreement at will upon prior written notice.

Upon expiration (but not earlier termination) of the vTv License Agreement, the licenses granted to us will survive on a royalty-free basis in perpetuity.

Upon termination of the vTv License Agreement, we are required to, upon vTv Therapeutics’ request, (i) grant to vTv Therapeutics a non-exclusive, worldwide, royalty-free, fully paid, perpetual, irrevocable, sublicensable license under our intellectual property solely for vTv Therapeutics and its sublicensees to develop, manufacture, and commercialize the licensed products for any therapeutic, prophylactic or diagnostic application in humans or (ii) if vTv Therapeutics agrees to pay us a low single digit percentage royalty on net sales of licensed products by vTv Therapeutics, then such license grant to vTv Therapeutics will be exclusive, and we will assign and transfer to vTv Therapeutics all regulatory materials and approvals related to the licensed product.

Upon termination of the vTv License Agreement, we are required to, upon vTv Therapeutics’

request, (i) grant to vTv Therapeutics a non-exclusive, worldwide, royalty-free, fully paid, perpetual, irrevocable, sublicensable license under our intellectual property solely for vTv Therapeutics and its sublicensees to develop, manufacture, and commercialize the licensed products for any therapeutic, prophylactic or diagnostic application in humans or (ii) if vTv Therapeutics agrees to pay us a low single digit percentage royalty on net sales of licensed products by vTv Therapeutics, then such license grant to vTv Therapeutics will be exclusive, and we will assign and transfer to vTv Therapeutics all regulatory materials and approvals related to the licensed product.

Intellectual Property

The proprietary nature of, and protection for, REN001, any future product candidates, and other proprietary technologies are important to our business.

We strive to protect our product candidates and other proprietary technologies, processes

and know-how through a variety of methods.

The proprietary nature of, and protection for, mavodelpar, any future product candidates, and other proprietary technologies are important to our business.

We strive to protect our product candidates and other proprietary technologies, processes and know-how through a variety of methods.

In regard to our product candidates, we seek and maintain patents intended to cover our products and compositions, their methods of use for treating diseases, the processes for their manufacture, and, as our product candidates proceed through clinical studies, the innovations that arise from these efforts.

As a result, we seek to obtain domestic and international ( i.e.

, PCT) patent protection and endeavor to promptly file patent applications for new commercially valuable inventions to expand our intellectual property portfolio.

As a result, we seek to obtain domestic and foreign patent protection and endeavor to promptly file patent applications for new commercially valuable inventions to expand our intellectual property portfolio.

Our policy is to pursue, maintain and defend patent rights in strategic areas, whether developed internally or licensed from third parties, and to protect the technology, inventions and improvements that are commercially important to the development of our business.

We also rely on trade secrets and other proprietary know-how that may be important to the development of our business.

We have developed and continue to expand our patent portfolio for REN001.

We have licensed from vTv Therapeutics seven issued patents in the United States and 19 issued patents in foreign countries, including Australia, Canada, Great Britain, Germany, France, Austria, Belgium, Switzerland, Spain, Ireland, Italy, the Eurasian Patent Organization, Israel, Japan, South Korea, Mexico, New Zealand, South Africa, and Taiwan covering composition of matter of REN001, among other things, which are expected to expire in 2026, absent any patent term adjustments or extensions.

Additionally, we have licensed four issued patents in the United States, six issued patents in foreign countries, including Canada, Germany, Spain, France, Great Britain, and Italy, one pending application in the United States, and one pending application in Europe, from vTv Therapeutics covering methods of using REN001, which are expected to expire in 2034, absent any patent term adjustments or extensions.

In addition to the licensed vTv Therapeutics patents and applications relating to REN001, we have filed our own patent applications.

We co-own one international application, and own three pending applications in the United States, one pending international patent application, an issued patent in Lebanon, and over 25 pending applications in foreign countries, directed to various methods of use of REN001.

These patent applications, if issued, would be expected to expire between 2040 and 2043, absent any patent term adjustments or extensions.

We also own one issued patent in the United States, one pending application in the United States, two pending international patent applications, and two pending applications in foreign countries directed to methods of manufacturing, and crystalline forms (polymorphs) of REN001.

The issued patent, and patent applications if issued, are expected to expire in 2041, absent any patent term adjustments or extensions.

Patents related to REN001 may be eligible for patent term extensions in certain jurisdictions, including up to five years in both the United States and the EU, upon approval of a commercial use of the corresponding product by a regulatory agency in the jurisdiction where the patent was granted.

In addition, we currently have Orphan Drug Designation for REN001 for the treatment of LC-FAOD and PMM in the United States and LCHAD deficiency and mitochondrial encephalomyopathy, lactic acidosis, and neurological stroke-like episodes in the EU, providing the opportunity to receive seven years of orphan exclusivity in the United States (upon approval of NDA), and ten years of market exclusivity in the EU and Japan (upon receipt of marketing authorization).

As REN001 has not previously been approved in the United States for any indication, REN001 may be eligible for five years of new chemical entity exclusivity upon approval in the United States, where such exclusivity would run concurrently with its seven years of orphan drug exclusivity, if we obtain orphan drug exclusivity for its approved uses.

Further, as REN001 has not previously been approved in the EU for any indication, REN001 may be eligible for eight years of data exclusivity upon approval in the EU, as well as two years of market exclusivity.

In the EU, an additional one year of exclusivity may be obtained if REN001 is approved for a new indication that provides a significant clinical benefit.

In addition to patent protection around REN001, we have also licensed from vTv Therapeutics three issued patents in the United States and 20 issued patents in foreign countries, including Germany, France, Great Britain, Switzerland, Spain, Ireland, Italy, Canada, India, Japan, South Korea, Mexico, and Taiwan directed to composition of matter around other PPARδ agonists, which are expected to expire in 2026, absent any patent term adjustments or extensions.

We have developed and continue to expand our patent portfolio for mavodelpar.

We have licensed from vTv Therapeutics eight issued patents in the United States and 19 issued patents in foreign countries covering composition of matter of mavodelpar, among other things, which are expected to expire in 2026, absent any

patent term adjustments or extensions.

Additionally, we have licensed four issued patents in the United States, six issued patents in foreign countries, one pending application in the United States, and one pending application in Europe, from vTv Therapeutics covering methods of using mavodelpar, which are expected to expire in 2034, absent any patent term adjustments or extensions.

In addition to the licensed vTv Therapeutics patents and applications relating to mavodelpar, we have filed our own patent applications.

We co-own one pending application in the United States and five pending applications in foreign countries, and own three pending applications in the United States, one pending international patent application, an issued patent in foreign country, and over 25 pending applications in foreign countries, directed to various methods of use of mavodelpar.

These pending patent applications, if issued, would be expected to expire between 2040 and 2043, absent any patent term adjustments or extensions.

We also own one issued patent in the United States, one pending application in the United States, one pending international patent applications, and over 15 pending applications in foreign countries directed to methods of manufacturing, and crystalline forms (polymorphs) of mavodelpar.

The issued patent, and pending patent applications if issued, are expected to expire in 2041, absent any patent term adjustments or extensions.

Patents related to mavodelpar may be eligible for patent term extensions in certain jurisdictions, including up to five years in both the United States and the EU, upon approval of a commercial use of the corresponding product by a regulatory agency in the jurisdiction where the patent was granted.

In addition, we currently have Orphan Drug Designation for mavodelpar for the treatment of LC-FAOD and PMM in the United States and LCHAD deficiency and MELAS in the EU, providing the opportunity to receive seven years of orphan exclusivity in the United States (upon approval of NDA), and ten years of market exclusivity in the EU and Japan (upon receipt of marketing authorization).

As mavodelpar has not previously been approved in the United States for any indication, mavodelpar may be eligible for five years of new chemical entity exclusivity upon approval in the United States, where such exclusivity would run concurrently with its seven years of orphan drug exclusivity, if we obtain orphan drug exclusivity for its approved uses.

Further, as mavodelpar has not previously been approved in the EU for any indication, mavodelpar may be eligible for eight years of data exclusivity upon approval in the EU, as well as two years of market exclusivity.

In the EU, an additional one year of exclusivity may be obtained if mavodelpar is approved for a new indication that provides a significant clinical benefit.

In addition to patent protection around mavodelpar, we have also licensed from vTv Therapeutics an issued patent in the United States directed to composition of matter around other PPARδ

agonists, which is expected to expire in October 2023, absent any patent term adjustments or extensions.

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained.

In most countries in which we file, the patent term is 20 years from the earliest date of filing a non-provisional patent application.

In the United States, the patent term of a patent that covers an FDA-approved drug may also be eligible for patent term extension, which permits patent term restoration as compensation for the patent term lost during the FDA

regulatory review process.

The Hatch-Waxman Act permits a patent term extension of up to five years beyond the expiration of the patent.

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In the future, if and when our products receive FDA approval, we expect to apply for patent term extensions on patents covering those products.

We plan to seek patent term extensions from applicable authorities, including the United States Patent and Trademark Office (USPTO) in the United States, to any of our issued patents covering REN001, and any future product candidates, in any jurisdiction where these patent term extensions are available.

We plan to seek patent term extensions from applicable authorities, including the United States Patent and Trademark Office (USPTO) in the United States, to any of our issued patents covering mavodelpar, and any future product candidates, in any jurisdiction where these patent term extensions are available.

There is no guarantee that the applicable authorities, including the USPTO in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions.

For more information regarding the risks related to our intellectual property, see “Risk Factors—Risks Related to Our Intellectual Property.” We also seek to protect our intellectual property in part by entering into confidentiality agreements with companies with whom we share proprietary and confidential information in the course of business discussions, and by having confidentiality terms in our agreements with our employees, consultants, scientific advisors, clinical investigators, and other contractors and also by requiring our employees, commercial contractors, and certain consultants and investigators, to enter into invention assignment agreements that grant us ownership of any discoveries or inventions made by them while in our employ.

For more information regarding the risks related to our intellectual property, see “Risk Factors—Risks Related to Our Intellectual

Property.”

We also seek to protect our intellectual property in part by entering into confidentiality agreements with companies with whom we share proprietary and confidential information in the course of business discussions, and by having confidentiality terms in our agreements with our employees, consultants, scientific advisors, clinical investigators, and other contractors and also by requiring our employees, commercial contractors, and certain consultants and investigators, to enter into invention assignment agreements that grant us ownership of any discoveries or inventions made by them while in our employ.

In addition to patent protection, we also rely on trademark registration, trade secrets, know how, other proprietary information and continuing technological innovation to develop and maintain our competitive position.

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In addition, some courts inside and outside the United States are less willing or unwilling to protect trade secrets.

For more information regarding the risks related to our intellectual property, see “Risk Factors—Risks Related to Our Intellectual Property.”

Manufacturing

We do not own or operate manufacturing facilities.

We rely on contract manufacturing organizations (CMOs) to produce REN001 in accordance with the FDA’s current Good Manufacturing Practices (cGMP) regulations for use in our clinical trials.

We rely on contract manufacturing organizations (CMOs) to produce mavodelpar in accordance with the FDA’s current Good Manufacturing Practices (cGMP) regulations for use in our clinical trials.

The manufacture of pharmaceuticals for human use is subject to extensive cGMP regulations, which impose various procedural and documentation requirements and govern all areas of record keeping, production processes and controls, personnel training, and quality control.

We obtain our supplies from these CMOs on a contract work order basis and do not have long-term supply arrangements in place.

We believe there are multiple sources for all the materials required for the manufacture of REN001.

As REN001 advances through development, we expect to enter into longer-term commercial supply agreements with key suppliers and manufacturers to fulfill and secure our production needs.

We believe there are multiple sources for all the materials required for the manufacture of mavodelpar.

As mavodelpar advances through development, we expect to enter into longer-term commercial supply agreements with key suppliers and manufacturers to fulfill and secure our production needs.

Our relationships with CMOs are managed by internal personnel with extensive experience in pharmaceutical development and manufacturing.

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For example, anti-convulsant drugs are used to prevent or control seizures.

Astellas Pharma is also developing a PPARδ agonist for PMM and has announced that it has initiated a Phase 2/3 trial in April 2021.

Other companies are developing therapies for mitochondrial diseases, including, Stealth BioTherapeutics Corp., Abliva AB, Cyclerion Therapeutics, Inc.

and Khondrion B.V.

CymaBay Therapeutics, Inc.

is conducting a Phase 3 clinical trial of up to 52 weeks with seladelpar, a selective PPARδ

agonist in patients with primary biliary cholangitis.

Astellas Pharma Inc.

is conducting a Phase 2/3 clinical trial of up to 52-weeks plus 24-weeks extension with bocidelpar, a selective PPARδ

Other companies are developing therapies for mitochondrial diseases, including, Stealth BioTherapeutics Corp., Abliva AB, Cyclerion Therapeutics, Inc., Khondrion B.V.

and Minovia Therapeutics.

There is one product approved in the United States for LC-FAOD.

In June 2020, a new form of MCT called DOJOLVI (triheptanoin) was approved and indicated in the United States as a source of calories for LC-FAOD patients.

In June 2020, a new form of MCT called DOJOLVI® (triheptanoin) was approved and indicated in the United States as a source of calories for patients with LC-FAOD.

However, DOJOLVI® has not demonstrated clear functional benefits on endurance in clinical trials.

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Government Regulation and Product Approval

As a pharmaceutical company that operates in the United States, we are subject to extensive regulation.

As a pharmaceutical company we are subject to extensive regulation.

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

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requirements at any time during the product development process, approval process or after approval, may subject an applicant to administrative or judicial sanctions.

FDA sanctions could include, among other actions, refusal to approve pending applications, withdrawal of an approval, a clinical hold, warning letters, product recalls or withdrawals from the market, product seizures, total or partial suspension of production or distribution injunctions, fines, refusals of

government contracts, restitution, disgorgement, or civil or criminal penalties.

criminal penalties.

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

● completion of extensive preclinical laboratory tests, preclinical animal studies and formulation studies in accordance with applicable regulations, including the FDA’s GLP) regulations, and other applicable regulations;

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

completion of extensive preclinical laboratory tests, preclinical animal studies and formulation studies in accordance with applicable regulations, including the FDA’s GLP regulations, and other applicable regulations;

submission to the FDA of an Investigational New Drug (IND) application, which must become effective before human clinical trials may begin;

approval by an IRB at each clinical site before each clinical trial may be initiated;

● performance of adequate and well-controlled human clinical trials in accordance with applicable regulations, including the FDA’s current good clinical practices (GCP) regulations to establish the safety and efficacy of the proposed drug for its proposed indication;

performance of adequate and well-controlled human clinical trials in accordance with applicable regulations, including the FDA’s current good clinical practices (GCP) regulations to establish the safety and efficacy of the proposed drug for its proposed indication;

submission to the FDA of a new drug application (NDA) for a new drug;

a determination by the FDA within 60 days of its receipt of an NDA to file the NDA for review;

● satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities where the drug is produced to assess compliance with the FDA’s current cGMP requirements 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 pre-approval inspection of the manufacturing facility or facilities where the drug is produced to assess compliance with the FDA’s current cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality, and purity;

potential FDA audit of the preclinical and/or clinical trial sites that generated the data in support of the NDA;

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The FDA may also impose clinical holds on a drug candidate at any time before or during clinical trials due to safety concerns or non-compliance.

Clinical trials involve the administration of the drug candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial.

Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and assess efficacy.

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Further, each clinical trial must be reviewed and approved by an IRB or ethics committee, at or servicing each institution at which the clinical trial will be conducted.

An IRB is charged with protecting the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.

relation to anticipated benefits.

The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.

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The FDA, the IRB, 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.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee.

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Review and Approval Processes

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, 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 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.

Data may come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a number of alternative sources, including studies initiated by investigators.

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Once the submission is accepted for filing, the FDA begins an in-depth review of the NDA.

Under the Prescription Drug User Fee Act (PDUFA) guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission.

This review typically takes 12 months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after it the application is submitted The FDA does not always meet its PDUFA goal dates for standard and priority NDAs, and the review process is often significantly extended by FDA requests for additional information or clarification.

After the NDA submission is accepted for filing, the FDA reviews the NDA to determine, among other things, whether the proposed product is safe and effective for its intended use and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, strength, quality, and purity.

Under the Prescription Drug User Fee Act (PDUFA) guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing”

of a standard NDA for a new molecular entity to review and act on the submission.

This review typically takes 12 months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing”

decision after it the application is submitted The FDA does not always meet its PDUFA goal dates for standard and priority NDAs, and the review process is often significantly extended by FDA requests for additional information or clarification.

The FDA may refer applications for novel drug products or drug products which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation, and a recommendation as to whether the application should be approved and under what conditions.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions and typically follows the advisory committee’s recommendations.

Before approving an NDA, the FDA will inspect the facilities at which the product is manufactured.

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The FDA may also determine that a risk evaluation and mitigation strategy (REMS) is necessary to assure the safe use of the drug.

If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS;

If the FDA concludes a REMS is

needed, the sponsor of the NDA must submit a proposed REMS;

the FDA will not approve the NDA without an approved REMS, if required.

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Orphan designation must be requested before submitting an NDA.

After the FDA grants orphan designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the

After the FDA grants orphan designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

Orphan designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

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Competitors, however, may receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity.

Orphan exclusivity also could block the approval of one of our products 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.

If an orphan designated product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity.

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The FDA will attempt to direct additional resources to the evaluation of an application for a new drug designated for priority review in an effort to facilitate the review.

The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to ten months for review of new molecular entity NDAs under its current PDUFA review goals.

The FDA endeavors to review applications with priority review designations within six months of the

filing date as compared to ten months for review of new molecular entity NDAs under its current PDUFA review goals.

In addition, a product may be eligible for accelerated approval.

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In addition, the FDA currently requires pre-approval of promotional materials as a condition for accelerated approval, which could adversely impact the timing of the commercial launch of the product.

The Food and Drug Administration Safety and Innovation Act established a category of drugs referred to as “breakthrough therapies” that may be eligible to receive breakthrough therapy designation.

A sponsor may seek FDA designation of a product candidate as a “breakthrough therapy” if the product is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically

significant endpoints, such as substantial treatment effects observed early in clinical development.

The Food and Drug Administration Safety and Innovation Act established a category of drugs referred to as “breakthrough therapies”

that may be eligible to receive breakthrough therapy designation.

A sponsor may seek FDA designation of a product candidate as a “breakthrough therapy”

if the product is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

The designation includes all of the Fast Track program features, as well as more intensive FDA interaction and guidance.

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Post-Approval Requirements

Any drug products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, manufacturing, record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, and complying with FDA promotion and advertising requirements, which include, among others, standards for direct-to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved labeling (known as “off-label use”), limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet.

Although physicians may prescribe legally available drugs for off-label uses, manufacturers may not market or promote such off-label uses.

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Discovery of previously unknown problems with a product or the failure to comply with applicable FDA requirements can have negative consequences, including adverse publicity, judicial or administrative enforcement, warning letters from the FDA, mandated corrective advertising or communications with doctors, and civil or criminal penalties, among others.

Newly discovered or developed safety or effectiveness data may require changes to a product’s approved labeling, including the addition of new warnings and contraindications, and also may require the implementation of other risk management measures.

The FDA closely regulates the marketing, labeling, advertising, and promotion of drug products.

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Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising, and potential civil and criminal penalties.

Physicians may prescribe, in their independent professional medical judgment, legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA.

Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances.

The FDA does not regulate the behavior of physicians in their choice of treatments.

The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.

The federal government has levied large civil and criminal fines against companies for alleged improper promotion of off-label use and has enjoined companies from engaging in off-label promotion.

The FDA and other regulatory agencies have also required that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.

However, companies may share truthful and not misleading information that is otherwise consistent with a product’s FDA-approved labelling.

Marketing Exclusivity

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Pediatric exclusivity is another type of non-patent market exclusivity in the United States.

exclusivity, if granted, adds six months to existing exclusivity periods and patent terms.

This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued “Written Request” for such a trial.

Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms.

for such a trial.

Healthcare Laws and Compliance Requirements

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Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all of its facts and circumstances.

Our practices may not in all cases meet all of the criteria for protection under a statutory exception or regulatory safe harbor.

Our practices may not in all cases meet all of the criteria for protection under a statutory exception or regulatory safe

Additionally, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

The federal False Claims Act prohibits, among other things, any person or entity from knowingly presenting, or causing to be presented, a false claim for payment to, or approval by, the federal government or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.

As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand” for money or property presented to the U.S.

As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand”

for money or property presented to the U.S.

Several pharmaceutical and other healthcare companies have been prosecuted under these laws for allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product.

Other companies have been prosecuted for causing false claims to be submitted because of the companies’ marketing of the product for unapproved, and thus non-covered, uses.

Other companies have been prosecuted for causing false claims to be submitted because of the companies’

marketing of the product for unapproved, and thus non-covered, uses.

In addition, the Affordable Care Act codified case law that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal False Claims Act.

The Health Insurance Portability and Accountability Act (HIPAA) also created new federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items, or services.

The Health Insurance Portability and Accountability Act of 1966 (HIPAA) also created new federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items, or services.

Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

Additionally, the federal Physician Payments Sunshine Act and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program (with certain exceptions) annually report information related to certain payments or other transfers of value made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse

practitioners), and teaching hospitals, certain ownership and investment interests held by physicians and their immediate family members.

In order to distribute products commercially, we must also comply with state laws that require the registration of manufacturers and wholesale distributors of pharmaceutical products in a state, including, in certain states, manufacturers, and distributors who ship products into the state even if such manufacturers or distributors have no place of business within the state.

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All of our activities are potentially subject to federal and state consumer protection and unfair competition laws.

If our operations are found to be in violation of any of the federal and state healthcare laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including without limitation, civil, criminal and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in government programs, such as Medicare and Medicaid, injunctions, private “qui tam” actions brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

Pharmaceutical Coverage, Pricing and Reimbursement

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Moreover, the process for determining whether a third-party payor will provide coverage for a drug product may be separate from the process for setting the price of a drug product or for establishing the reimbursement rate that such a payor will pay for the drug product.

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

Further, one payor’s determination to provide coverage for a drug product does not assure that other payors will also provide coverage for the drug product.

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

Further, one payor’s determination to provide coverage for a drug product does not assure that other payors will also provide coverage for the drug product.

Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development.

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Department of Veterans Affairs and Department of Defense, the Public Health Service and certain private Public Health Service designated entities in order to participate in other federal funding programs, including Medicare and Medicaid.

legislative changes require that discounted prices be offered for certain U.S.

Recent legislative changes require that discounted prices be offered for certain U.S.

Department of Defense purchases for its TRICARE program via a rebate system.

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To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost-effectiveness of a particular drug candidate to currently available therapies.

Other member states allow companies to fix their own prices for medicines, but monitor and control company profits.

Other member states allow companies to fix their own prices for medicines, but

monitor and control company profits.

The downward pressure on health care costs in general, particularly prescription drugs, has become very intense.

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For example, in March 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (collectively, the Affordable Care Act) was enacted, which affected existing government healthcare programs and resulted in the development of new programs.

Among the Affordable Care Act’s provisions of importance to the pharmaceutical industry, in addition to those otherwise described above, are the following:

● an annual, nondeductible fee on any entity that manufactures or imports certain specified branded prescription drugs and biologic agents apportioned among these entities according to their market share in some government healthcare programs;

● an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program to 23.1% and 13% of the average manufacturer price for most branded and generic drugs, respectively, and a cap on the total rebate amount for innovator drugs at 100% of the Average Manufacturer Price;

● a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D;

● extension of manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;

● expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals, including individuals with income at or below 133% of the federal poverty level, thereby potentially increasing manufacturers’ Medicaid rebate liability;

● expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program;

● a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.

Since its enactment, there have been judicial and Congressional challenges to certain aspects of the Affordable Care Act.

For example, the Tax Cuts and Jobs Act of 2017 (the Tax Act) was enacted, which includes a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the Affordable Care Act on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” On June 17, 2021 the U.S.

Supreme Court dismissed a challenge on procedural grounds that argued the Affordable Care Act is unconstitutional in its entirety because the “individual mandate” was repealed by Congress.

Thus, the Affordable Care Act will remain in effect in its current form.

Prior to the U.S.

Supreme Court ruling, on January 28, 2021, President Biden issued an executive order that initiated a special enrollment period for purposes of obtaining health insurance coverage through the Affordable Care Act marketplace.

The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the Affordable Care Act.

For example, on June 17, 2021 the U.S.

Supreme Court dismissed a challenge on procedural grounds that argued the Affordable Care Act is unconstitutional in its entirety because the “individual mandate”

was repealed by Congress.

Further, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022 (IRA) into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in Affordable Care Act marketplaces through plan year 2025.

The IRA also eliminates the "donut hole" under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and creating a new manufacturer discount program.

It is possible that the Affordable Care Act will be subject to judicial or Congressional challenges in the future.

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Other legislative changes have also been proposed and adopted in the United States since the Affordable Care Act was enacted.

On August 2, 2011, the Budget Control Act of 2011, among other things, included aggregate reductions to Medicare payments to providers of 2% per fiscal year, which went into effect on April 1, 2013 and due to subsequent legislative amendments to the statute, including the Infrastructure Investment and Jobs Act, will remain in effect through 2031, except for a temporary suspension from May 1, 2020 through March 31, 2022, unless additional congressional action is taken.

On August 2, 2011, the Budget Control Act of 2011, among other things, included aggregate reductions to Medicare payments to providers of 2% per fiscal year, which went into effect on April 1, 2013 and due to subsequent legislative amendments to the statute will remain in effect until 2031, unless additional Congressional action is taken.

Under current legislation the actual reduction in Medicare payments will vary from 1% in 2022 to up to 4% in the final fiscal year of this sequester.

In addition, in January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Additionally, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

There has also been heightened governmental scrutiny recently over the manner in which pharmaceutical companies set prices for their marketed products, which has resulted in several Congressional inquiries, Presidential executive orders, and proposed federal legislation, as well as state efforts, designed to, among other things, bring more transparency to product pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.

At the federal level, the Trump administration used several means to propose or implement drug pricing reform, including through federal budget proposals, executive orders and policy initiatives.

For example, on July 24, 2020 and September 13, 2020, the Trump administration announced several executive orders related to drug pricing in an effort to implement several of the administration’s proposals.

As a result, the FDA concurrently released a final rule and guidance in September 2020 providing pathways for states to build and submit importation plans for drugs from Canada.

Further, on November 20, 2020, the U.S.

Department of Health and Human Services (HHS) finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The implementation of the rule has been delayed by the Biden Administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which

have also been delayed until January 1, 2023.

On November 20, 2020, the Centers for Medicare & Medicaid Services (CMS) issued an interim final rule implementing President Trump’s Most Favored Nation executive order, which would tie Medicare Part B payments for certain physician-administered drugs to the lowest price paid in other economically advanced countries, effective January 1, 2021.

As a result of litigation challenging the Most Favored Nation model, on December 27, 2021, CMS published a final rule that rescinded the Most Favored Nation model interim final rule.

In July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at prescription drugs.

In response to Biden’s executive order, on September 9, 2021, HHS released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles.

No legislation or administrative actions have been finalized to implement these principles.

In addition, Congress is considering drug pricing as part of other health reform initiatives.

It is unclear whether these or similar policy initiatives will be implemented in the future.

For example, in July 2021, the Biden administration released an

executive order, “Promoting Competition in the American Economy,”

with multiple provisions aimed at prescription drugs.

In response to Biden’s executive order, on September 9, 2021, the U.S.

Department of Health and Human Services (HHS) released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles.

Further, the IRA, among other things (i) directs HHS to negotiate the price of certain high-expenditure, single-source drugs and biologics covered under Medicare and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions will take effect progressively starting in fiscal year 2023, although they may be subject to legal challenges.

Additionally, the Biden administration released an additional executive order on October 14, 2022, directing HHS to report on how the Center for Medicare and Medicaid Innovation can be further leveraged to test new models for lowering drug costs for Medicare and Medicaid beneficiaries.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

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In addition, it is possible that there will be further legislation or regulation that could harm our business, financial condition, and results of operations.

Further, it is also possible that additional governmental action is taken in response to the COVID-19 pandemic.

Data Privacy and Security

In the ordinary course of our business, we may process personal or sensitive data.

Accordingly, we are, or may become, subject to numerous data privacy and security obligations, including federal, state, local, and foreign laws, regulations, guidance, and industry standards related to data privacy, security, and protection.

Such obligations may include, without limitation, the Federal Trade Commission Act, the California Consumer Privacy Act of 2018 (CCPA), the European Union’s General Data Protection Regulation 2016/679 (EU GDPR), and the EU GDPR as it forms part of United Kingdom (UK) law by virtue of section 3 of the European Union (EU) (Withdrawal) Act 2018 (UK GDPR).

In addition, several states within the United States have enacted or proposed data privacy laws.

For example, Virginia passed the Consumer Data Protection Act, and Colorado passed the Colorado Privacy Act.

The CCPA and EU GDPR are examples of the increasingly stringent and evolving regulatory frameworks related to personal data processing that may increase our compliance obligations and exposure for any noncompliance.

For example, the CCPA imposes obligations on covered businesses to provide specific disclosures related to a business’s collection, use, and disclosure of personal data and to respond to certain requests from California residents related to their personal data (for example, requests to know of the business’s personal data processing activities, to delete the individual’s personal data, and to opt out of certain personal data disclosures).

Also, the CCPA provides for civil penalties and a private right of action for certain data breaches.

In addition, the California Privacy Rights Act of 2020 (CPRA), effective January 1, 2023, will expand the CCPA.

The CPRA will, among other things, give California residents the ability to limit use of certain sensitive personal data, establish restrictions on personal data retention, expand the types of data breaches that are subject to the CCPA’s private right of action, and establish a new California Privacy Protection Agency to implement and enforce the new law.

federal and state consumer protection laws require us to publish statements that accurately and fairly describe how we handle personal data and choices individuals may have about the way we handle their personal data.

Accordingly, we are, or may become, subject to numerous data privacy and security obligations, including federal, state, local, and foreign laws, regulations, and guidance governing data privacy and security.

Such obligations may include, without limitation, the Federal Trade Commission Act, the California Consumer Privacy Act of 2018, as amended by the California Privacy Rights Act of 2020 (CPRA) (collectively, the CCPA), the European Union’s General Data Protection Regulation 2016/679 (EU GDPR), and the EU GDPR as it forms part of United Kingdom (UK) law (UK GDPR).

In addition to the CCPA, several other states within the United States, such as Virginia, Colorado, Utah, and Connecticut have enacted or proposed comprehensive privacy laws and similar laws are being considered in several other states, as well as at the federal and local levels.

For example, the CCPA imposes obligations on covered businesses to provide specific disclosures related to a business’s collection, use, and disclosure of personal data and to respond to certain requests from California residents related to their personal data (for example, requests to know of the business’s personal data processing activities, to correct or delete the individual’s personal data, and to opt out of certain personal data disclosures).

Also, the CCPA provides for administrative fines and a private right of action for certain data breaches which may include an award of statutory damages.

In addition, the CPRA’s recent amendments to the CCPA established a new regulatory agency to implement and enforce the law.

Foreign data privacy and security laws (including, but not limited to, the EU GDPR and UK GDPR) impose significant and complex compliance obligations on entities that are subject to those laws.

As one example, the EU GDPR applies to any company established in the European Economic Area (EEA) and to companies established outside the EEA that process personal data in connection with the offering of goods or services to data subjects in the EEA or the monitoring of the behavior of data subjects in the EEA.

For example, the EU GDPR applies to any company established in the European Economic Area (EEA) and to companies established outside the EEA that process personal data in connection with the offering of goods or services to data subjects in the EEA or the monitoring of the behavior of data subjects in the EEA.

These obligations may include limiting personal data processing to only what is necessary for specified, explicit, and legitimate purposes;

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and mandating the appointment of representatives in the UK and/or the EU in certain circumstances.

See the section titled “Risk Factors” for additional information about the laws and regulations to which we are become subject and about the risks to our business associated with such laws and regulations.

Further, it is unclear how UK data protection laws and regulations will develop in the medium to long term.

The UK’s Data Protection and Digital Information Bill was laid before the UK Parliament on July 18, 2022, introducing reforms intended to update and simplify the UK’s data protection framework, deviating from the EU GDPR.

This may impose additional compliance costs on companies that operate in both the UK and the EU.

See the section titled “Risk Factors”

for additional information about the laws and regulations to which we are or may become subject and about the risks to our business associated with such laws and regulations.

Foreign Corrupt Practices Act

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Certain countries outside of the United States have a similar process that requires the submission of a clinical trial application much like the IND prior to the commencement of human clinical trials.

Previously, in the EU, pursuant to the EU Clinical Trials Directive 2001/20/EC, a Clinical Trial Application (CTA) had to be submitted to each country’s national regulatory authority in which the clinical trial was to take place, together with an independent ethics committee, much like the FDA and IRB, respectively.

Although the Directive had sought to harmonize the EU clinical trials regulatory framework, EU Member States transposed and applied the provisions of the Directive differently, leading to significant variation in the regulatory regimes of the member states.

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The new Regulation seeks to simplify and streamline the approval of clinical trials in the EU.

Pursuant to the Regulation, the sponsor shall submit a single CTA via the EMA’s Clinical Trials Information System (CTIS), which will cover all regulatory and ethics assessments from the member states concerned

Any submissions made from January 31, 2023 onwards must be made through CTIS and all trials authorized pursuant to the Directive that are still ongoing on January 31, 2025 have their details registered on CTIS, in both cases trials registered on CTIS will have to comply with the Regulation.

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The requirements and process governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.

Clinical trials of medicinal products in the European Union must be conducted in accordance with EU and national regulations and the International Conference on Harmonization (ICH) guidelines on Good Clinical Practices (GCP) as well as the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

Clinical trials of medicinal products in the European Union (EU) must be conducted in accordance with EU and national regulations and the International Conference on Harmonization guidelines on GCP as well as the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

If the sponsor of the clinical trial is not established within the EU, it must appoint an EU entity to act as its legal representative.

The sponsor must take out a clinical trial insurance policy, and in most EU countries, the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the clinical trial.

The sponsor must take out a clinical trial insurance policy, and in most EU countries, the sponsor is liable to provide ‘no fault’

compensation to any study subject injured in the clinical trial.

Prior to commencing a clinical trial, the sponsor must obtain a CTA from the competent authority, and a positive opinion from an independent ethics committee.

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During the development of a medicinal product, the EMA and national regulators provide the opportunity for dialogue and guidance on the development program.

At the EMA level, this is usually done in the form of scientific advice, which is given by the Scientific Advice Working Party of the Committee for Medicinal Products for Human Use, or CHMP.

At the EMA level, this is usually done in the form of scientific advice, which is given by the Scientific Advice Working Party of the Committee for Medicinal Products for Human Use (CHMP).

A fee is incurred with each scientific advice procedure.

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Innovative products that target an unmet medical need and are expected to be of major public health interest may be eligible for a number of expedited development and review programs, such as the PRIME scheme, which provides incentives similar to the breakthrough therapy designation in the U.S.

PRIME is a voluntary scheme aimed at enhancing the EMA’s support for the development of medicines that target unmet medical needs.

It is based on increased interaction and early dialogue with companies developing promising medicines, to optimize their product development plans and speed up their evaluation to help them reach patients earlier.

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Once renewed, the MA is valid for an unlimited period unless the European Commission or the national competent authority decides on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal.

If granted, data exclusivity prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic/biosimilar application.

During the additional two-year period of market exclusivity, a generic/biosimilar MA can be submitted, and the innovator’s data may be referenced, but no generic/biosimilar product can be marketed until the expiration of the market exclusivity.

However, there is no guarantee that a product will be considered by the EU’s regulatory authorities to be a new chemical entity and qualify for data exclusivity.

The criteria for designating an “orphan medicinal product” in the EU are similar in principle to those in the United States.

If granted, data exclusivity prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic/biosimilar application.

However, there is no guarantee that a product will be considered by the EU’s regulatory authorities to be a new chemical entity and qualify for data exclusivity.

The criteria for designating an “orphan medicinal product”

in the EU are similar in principle to those in the United States.

A medicinal product may be designated as orphan if (1) it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition;

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The regulatory authorities may also impose specific obligations as a condition of the MA.

Such risk-minimization measures or post-authorization obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies.

risk-minimization measures or post-authorization obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies.

The advertising and promotion of medicinal products is also subject to laws concerning promotion of medicinal products, interactions with physicians, misleading and comparative advertising and unfair commercial practices.

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The aforementioned EU rules are generally applicable in the EEA which consists of the 27 EU member states plus Norway, Liechtenstein and Iceland.

pharmaceutical products, statutory health insurance, bribery and anti-corruption or with other applicable regulatory requirements may result in administrative, civil or criminal penalties.

Failure to comply with EU and member state laws that apply to the conduct of clinical trials, manufacturing approval, MA of medicinal products and marketing of such products, both before and after grant of the MA, manufacturing of pharmaceutical products, statutory health insurance, bribery and anti-corruption or with other applicable regulatory requirements may result in administrative, civil or criminal penalties.

These penalties could include delays or refusal to authorize the conduct of clinical trials, or to grant MA, product withdrawals and recalls, product seizures, suspension, withdrawal or variation of the MA, total or partial suspension of production, distribution, manufacturing or clinical trials, operating restrictions, injunctions, suspension of licenses, fines and criminal penalties.

GB is no longer covered by the EEA’s procedures outlined above following the expiry of the Brexit transition period on January 1, 2021 (Northern Ireland will be covered by the centralized authorization procedure and can be covered under the decentralized or mutual recognition procedures).

Great Britain (GB) is no longer covered by the EEA’s procedures outlined above following the expiry of the Brexit transition period on January 1, 2021 (Northern Ireland will be covered by the centralized authorization procedure and can be covered under the decentralized or mutual recognition procedures).

A GB or UK MA will be required to market drugs in GB.

However, for two years from January 1, 2021, the MHRA may adopt decisions taken by the European Commission on the approval of new marketing authorizations through the centralized procedure, and the MHRA will have regard to marketing authorizations approved in a country in the EEA (although in both cases a MA will only be granted if any GB-specific requirements are met).

However, for three years from January 1, 2021, the Medicines and Healthcare Products Regulatory Agency (MHRA) may adopt decisions taken by the European Commission on the approval of new marketing authorizations through the centralized procedure, and the MHRA will have regard to marketing authorizations approved in a country in the EEA (although in both cases a MA will only be granted if any GB-specific requirements are met).

Various national procedures are now available to place a drug on the market in the UK, GB, or Northern Ireland, with the main national procedure having a maximum timeframe of 150 days (excluding time taken to provide any further information or data required).

The UK regulatory framework in relation to clinical trials is derived from existing EU legislation (as implemented into UK law, through secondary legislation), and after Brexit, new EU laws on clinical trials (including the EU Clinical Trials Regulation, EU CTR) will not be applicable in GB.

The United Kingdom may diverge from the EU to maintain regulatory flexibility and changes impacting the ability to conduct trials spanning several EU countries will need to be closely monitored going forward.

Already, as a result of Brexit various benefits of membership no longer apply to the United Kingdom, for example, UK sponsored trials that span several EU countries now need to have an individual or organization in the EU to act as a legal representative, or sponsor and the United Kingdom does not have access to new EU clinical trial databases such as CTIS pursuant to the Trade and Cooperation Agreement.

The UK may further diverge from the EU in relation to the regulation of medicinal products which could disrupt cross-border operations between the UK and EU.

The Retained EU Law (Revocation and Reform) Bill 2022, which is currently progressing through the United Kingdom Parliament and seeks to allow the UK Government to repeal or replace certain EU Law that was incorporated into UK law effective as of the end of the Brexit transition period, increases the likelihood of such divergence and will need to be closely monitored going forward.

Already, as a result of Brexit various benefits of membership no longer apply to the UK, for example, UK sponsored trials that span several EU countries now need to have an individual or organization in the EU to act as a legal representative, or sponsor and the UK does not have access to new EU clinical trial databases such as CTIS pursuant to the Trade and Cooperation Agreement.

Additionally, new rules apply to the import of investigational medicinal products from the EU and EEA to GB.

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The European Commission is currently evaluating new legislation in relation to orphan medicines and these laws will no longer be applicable in GB.

Since January 1, 2021, there has been no route to obtain pre-MA orphan designation in GB, however, as a result of the implementation of the Northern Ireland Protocol, EU orphan drug designation and time periods of market exclusivity still remain valid for marketing products in Northern Ireland.

exclusivity still remain valid for marketing products in Northern Ireland.

Instead, the MHRA now reviews applications for GB orphan designation in parallel with the corresponding MA application.

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If we or our potential collaborators fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

As of December 31, 2021, we employed 32 employees, 20 of whom are full-time.

Further, 15 of our employees are located in the United States and 17 are located in the United Kingdom.

None of our employees is subject to a collective bargaining agreement.

As of March 21, 2023, we employed 48 employees, 36 of whom are full-time.

At the same date, 29 of our employees were located in the United States and 19 were located in the UK.

None of our employees are subject to a collective bargaining agreement.

We consider our relationship with our employees to be good.

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We were incorporated in Delaware in 2014.

Our principal executive offices are located at 18575 Jamboree Road, Suite 275-S Irvine, CA 92612, and our telephone number is (858) 283-0280.

Our principal executive offices are located at 18575 Jamboree Road, Suite 275-S, Irvine, California 92612, and our telephone number is (858) 283-0280.

Our corporate website address is www.reneopharma.com.

Information contained on or accessible through our website is not a part of this Annual Report, and the inclusion of our website address in this Annual Report is an inactive textual reference only.

Our design logo, “Reneo,” and our other registered and common law trade names, trademarks and service marks are the property of Reneo Pharmaceuticals, Inc.

Our design logo, “Reneo,”

and our other registered and common law trade names, trademarks and service marks are the property of Reneo Pharmaceuticals, Inc.

Emerging Growth Company

We are an “emerging growth company” as defined in the Jumpstart Our Business Startups Act of 2012 (the JOBS Act).

We may take advantage of certain exemptions from various public company reporting requirements, including being permitted to provide only two years of audited financial statements, in addition to any required unaudited interim financial statements with correspondingly reduced “Management’s Discussion and Analysis of Financial Condition and Results of Operations” disclosure, not being required to have our internal control over financial reporting audited by our independent registered public accounting firm under Section 404 of the Sarbanes-Oxley Act of 2002 (the Sarbanes-Oxley Act), reduced disclosure obligations regarding executive compensation in our periodic reports and proxy statements, and exemptions from the requirements of holding a nonbinding advisory vote on executive compensation and stockholder approval of any golden parachute payments not previously approved.

We may take advantage of these exemptions until December 31, 2026 or until we are no longer an “emerging growth company,” whichever is earlier.

We will cease to be an emerging growth company prior to the end of such period if certain earlier events occur, including if we become a “large accelerated filer” as defined in Rule 12b-2 under the Securities Exchange Act of 1934, as amended (the Exchange Act), our annual gross revenues exceed $1.07 billion or we issue more than $1.0 billion of non-convertible debt in any three-year period.

We are an “emerging growth company”

as defined in the Jumpstart Our Business Startups Act of 2012 (the JOBS Act).

disclosure, not being required to have our internal control over financial reporting audited by our independent registered public accounting firm under Section 404 of the Sarbanes-Oxley Act of 2002 (the Sarbanes-Oxley Act), reduced disclosure obligations regarding executive compensation in our periodic reports and proxy statements, and exemptions from the requirements of holding a nonbinding advisory vote on executive compensation and stockholder approval of any golden parachute payments not previously approved.

We may take advantage of these exemptions until December 31, 2026 or until we are no longer an “emerging growth company,”

whichever is earlier.

We will cease to be an emerging growth company

prior to the end of such period if certain earlier events occur, including if we become a “large accelerated filer”

as defined in Rule 12b-2 under the Securities Exchange Act of 1934, as amended (the Exchange Act), our annual gross revenues exceed $1.235 billion or we issue more than $1.0 billion of non-convertible debt in any three-year period.

In addition, the JOBS Act provides that an emerging growth company can take advantage of an extended transition period for complying with new or revised accounting standards.

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As a result, our consolidated financial statements may not be comparable to companies that comply with new or revised accounting pronouncements as of public company effective dates.

We are also a “smaller reporting company” as defined in the Exchange Act.

We are also a “smaller reporting company”

as defined in the Exchange Act.

We may continue to be a smaller reporting company even after we are no longer an emerging growth company.

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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