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Item 1. Business

2024-03-08 compared with 2023-03-30 · 310 added, 302 removed, 879 unchanged (41% of the section changed)

We are a clinical stage global biopharmaceutical company aiming to develop and deliver novel oral therapeutics to treat a wide range of chronic diseases with unmet medical needs.

We are a clinical stage global biopharmaceutical company aiming to develop and deliver novel oral therapeutics to treat a wide range of chronic diseases with unmet medical need.

Our differentiated technology platform leverages structure-based drug discovery and computational chemistry expertise and enables us to develop oral small molecule therapeutics for the treatment of various diseases including those impacting the metabolic, cardiovascular, and pulmonary systems.

In February 2023, we completed our Initial Public Offering (“IPO”) for net proceeds of $166.7 million, after deducting the underwriting discounts and commissions and estimated offering expenses payable by us.

In February 2023, we completed our Initial Public Offering (“IPO”) for net proceeds of approximately $166.7 million, after deducting the underwriting discounts and commissions and estimated offering expenses payable by us.

In September 2023, we entered into a share purchase agreement with certain institutional investors (the “Purchase Agreement”), pursuant to which we issued and sold an aggregate of 21,617,295 ordinary shares and 2,401,920 non-voting ordinary shares for net proceeds of approximately $281.5 million (the “Private Placement”).

Our initial focus is on G-protein coupled receptors (“GPCRs”) as a therapeutic target class.

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We completed our Phase 1 single ascending dose (“SAD”) study of GSBR-1290 in September 2022.

GSBR-1290 was generally well tolerated and demonstrated dose-dependent pharmacokinetics (“PK”) and pharmacological (“PD”) activity.

We submitted an Investigational New Drug application (“IND”) to the United States Food and Drug Administration (“FDA”) to support initiation of a Phase 1b study in T2DM and obesity and received FDA allowance in September 2022.

We initiated the Phase 1b multiple ascending dose (“MAD”) study in January 2023 and completed dosing in healthy overweight subjects

in March 2023.

We plan to submit a protocol amendment to the FDA to transition to a Phase 2a proof-of-concept study in T2DM and obesity with the expected initiation in the second half of 2023.

We expect to report topline data for the Phase 1b study and Phase 2a study in the second half of 2023.

Beyond GSBR-1290, we are developing next generation GLP-1R candidates, including dual GLP-1R/GIPR agonists, each designed with customized properties to achieve additional benefit.

In September 2022, we completed a Phase 1 SAD and MAD study evaluating ANPA-0073, our small molecule product candidate targeting the apelin receptor (“APJR”) in which it was generally well tolerated in healthy human volunteers.

ANPA-0073 is in development for the treatment of patients with idiopathic pulmonary fibrosis (“IPF”) and pulmonary arterial hypertension (“PAH”).

We expect to conduct additional preclinical studies to be followed by a Phase 1 formulation bridging PK study in Australia.

Moreover, we are advancing a differentiated lysophosphatidic acid 1 receptor (“LPA1R”) antagonist for the treatment of IPF.

We selected a development candidate in January 2023 and expect to initiate a first-in-human study in 2024.

GSBR-1290 was generally well tolerated and demonstrated dose- dependent pharmacokinetic (“PK”) and pharmacodynamic (“PD”) activity.

We submitted an investigational new drug (“IND”) application to the FDA to support initiation of a Phase 1b study in T2DM and obesity and received FDA allowance in September 2022.

We initiated the Phase 1b multiple ascending dose (“MAD”) study of

GSBR-1290 in January 2023 and completed dosing in otherwise healthy overweight subjects in March 2023.

In May 2023, we submitted a protocol amendment to the FDA and initiated dosing of the Phase 2a proof-of-concept study in T2DM and obesity.

We reported topline data for the 28-day Phase 1b MAD study in September 2023, in which GSBR-1290 was generally well-tolerated with no adverse event (“AE”)-related discontinuations and demonstrated an encouraging safety profile and significant weight loss of up to 4.9% placebo-adjusted, supporting once-daily dosing.

In December 2023, we reported clinically meaningful topline data from our Phase 2a T2DM cohort, interim results from our Phase 2a obesity cohort and topline data from a Japanese ethno-bridging study of GSBR-1290.

These data demonstrated that GSBR-1290 was generally well-tolerated, with no treatment-related SAEs over 12 weeks, with only one participant discontinuing the study due to adverse events in the T2DM cohort and none in the obesity cohort.

GSBR-1290 also showed significant reductions in weight in the obesity cohort at 8 weeks, and significant reductions in hemoglobin A1c (“HbA1c”) and weight in the T2DM cohort.

We expect to report the full 12-week Phase 2a obesity data in the latter half of the second quarter of 2024 with additional 24 participant data.

We also fully enrolled a formulation bridging and titration optimization study to evaluate capsule versus tablet PK and explore different titration regimens of GSBR-1290.

We expect to report topline results from this study in the latter half of the second quarter of 2024, in preparation for the global Phase 2b study for obesity which we expect to initiate in the second half of 2024.

A Phase 2 study in T2DM is also planned for the fourth quarter of 2024.

A number of GPCR properties contribute to its importance as a drug target class, including interaction with a diverse set of signaling molecules, involvement in a vast array of physiological and pathological processes, and cell surface expression that enables extracellular drug binding.

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Customizable pharmaceutic properties

Generally not orally available

Scalability and costs

Orally available, better patient compliance

Limited stability, cold supply chain requirements

Limited stability

No cold-chain requirements

Cold supply chain requirements

Large scale manufacturing capability

We believe the strengths of our platform position us to develop oral small molecule drugs that can deliver biologic-like activity and specificity.

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We believe this is particularly important for the most prevalent chronic diseases including those involving the metabolic, cardiovascular, and pulmonary systems.

Our lead product candidate, GSBR-1290, is an oral and biased small molecule agonist of GLP-1R, a validated GPCR drug target for T2DM and obesity.

There are currently five marketed peptide molecules that target GLP-1R;

Our lead product candidate, GSBR-1290, is an oral and biased small molecule agonist of GLP-1R, a validated GPCR drug target for T2DM and obesity, currently in Phase 2 development.

There are currently ten marketed peptide molecules that target GLP-1R;

collectively, these peptide therapies generated worldwide sales of $65 billion in 2023.

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In non-human primate (“NHP”), studies, GSBR-1290 demonstrated glucose-dependent insulin secretion and suppressed food intake, resulting in weight reduction.

Given these findings and other compelling preclinical data, we completed a Phase 1 study in healthy volunteers for GSBR-1290 in September 2022.

GSBR-1290 was generally well tolerated and demonstrated dose-dependent PK and PD related activity.

We submitted an IND to the FDA to support initiation of a Phase 1b study in T2DM and obesity and received FDA allowance in September 2022.

We initiated the Phase 1b MAD study in January 2023 and completed dosing in healthy overweight subjects in March 2023.

We plan to submit a protocol amendment to the FDA to transition to a Phase 2a proof-of-concept study in T2DM and obesity with the expected initiation in the second half of 2023.

We expect to report topline data for the Phase 1b study and Phase 2a study in the second half of 2023.

Beyond GSBR-1290, we are developing next generation GLP-1R candidates, including dual GLP-1R/GIPR agonists, each designed with customized properties to achieve additional benefit.

Given these findings and other compelling preclinical data, we completed a Phase 1 study in healthy volunteers for GSBR-1290 in September 2022, a Phase 2a study development in diabetes in December 2023 and expect to complete a Phase 2a study in obesity in the latter half of the second quarter of 2024.

To date GSBR-1290 has demonstrated generally favorable safety, tolerability and efficacy results in clinical trials.

Beyond GSBR-1290, we are developing next generation GLP-1R candidates, including dual GLP-1R/glucose-dependent insulinotropic polypeptide receptor (“GIPR”) agonists and amylin agonists, each designed with customized properties to achieve additional benefit.

We are also developing oral small molecule therapeutics targeting other GPCRs for the treatment of pulmonary and cardiovascular diseases.

Specifically, we are advancing ANPA-0073, our biased agonist, targeting APJR, a GPCR that has been implicated in IPF and PAH.

Specifically, we are advancing ANPA-0073, our biased agonist, targeting the apelin receptor (“APJR,”) a GPCR that has been implicated in idiopathic pulmonary fibrosis (“ IPF”).

In September 2022, we completed a Phase 1 SAD and MAD study evaluating ANPA-0073 in healthy human volunteers, in which it was generally well tolerated.

Additionally, we are developing an antagonist that targets LPA1R, a GPCR implicated in responses to tissue injury and pro-fibrotic processes.

We have demonstrated substantial anti-fibrotic activity of our LPA1R antagonists in mouse models of fibrotic lung disease and we selected a development candidate (LTSE-2578) in January 2023 and expect to initiate a first-in-human study in 2024.

At Basecamp Bio Inc.

(“Basecamp Bio”), our wholly owned subsidiary dedicated to fueling our pipeline and pursuing drug discovery partnerships, we leverage the power of cryo-electron microscopy (“cryo-EM”) machine learning and X-ray crystallography, as the basis for our molecular designs.

We employ state-of-the-

art small molecule hit identification, including DNA encoded library technology and affinity mass spectrometry selections for membrane proteins.

Additionally, we are developing an antagonist that targets lysophosphatidic acid 1 receptor (“ LPA1R”), a GPCR implicated in responses to tissue injury and pro-fibrotic processes.

We have demonstrated substantial anti-fibrotic activity of our LPA1R antagonists in mouse models of fibrotic lung disease and we selected a development candidate, LTSE-2578, in January 2023 and expect to initiate a first-in-human study in the second quarter of 2024.

We are also dedicated to fueling our pipeline and pursuing drug discovery partnerships.

Through our discovery engine, we leverage the power of cryo-electron microscopy (“cryo-EM”) machine learning and X-ray crystallography, as the basis for our molecular designs.

We employ state-of-the-art small molecule hit identification, including DNA encoded library technology and affinity mass spectrometry selections for membrane proteins.

Our mission is to discover and develop broadly accessible oral therapeutics to treat a wide range of chronic diseases with unmet medical need through advancements in structure-based drug discovery and computational chemistry.

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Our franchise approach involves developing next generation GLP-1R agonists, including dual GLP-1R/GIPR agonists, each designed with customized properties to achieve maximum benefit.

Based on compelling data generated from our preclinical studies, we believe that our lead GLP-1R candidate, GSBR-1290, has the potential to be a differentiated treatment for T2DM and obesity, and we completed a Phase 1 SAD study in September 2022.

We initiated the Phase 1b MAD study in January 2023 and completed dosing in healthy overweight subjects in March 2023.

We plan to submit a protocol amendment to the FDA to transition to a Phase 2a proof-of-concept study in T2DM and obesity with the expected initiation in the second half of 2023.

In addition, our next generation GLP-1R program is focused on the development of orally-available small molecules with GLP-1R and glucose-dependent insulinotropic polypeptide receptor (“GIPR”) activity.

Based on compelling data generated from our preclinical studies, we believe that our lead GLP-1R candidate, GSBR-1290, has the potential to be a differentiated treatment for T2DM and obesity.

In obesity, we expect to complete the Phase 2a study in the latter half of the second quarter of 2024 and initiate a Phase 2b study in the fourth quarter of 2024.

In T2DM, we have completed the Phase 2a study and expect to initiate a Phase 2 study in the second half of 2024.

In addition, our next generation GLP-1R program is focused on the development of orally-available small molecules in combination with GLP-1R, including GIPR, amylin, as well as the APJR for selective or muscle-sparing weight loss.

● Pursue additional opportunities in chronic diseases.

Chronic diseases pose a major burden to patients and healthcare systems worldwide and there is an urgent need for effective and more accessible treatment options.

For our APJR agonist product candidate, ANPA-0073, we completed a Phase 1 SAD and MAD study in healthy human volunteers in September 2022.

ANPA-0073 is in development for the treatment of patients with IPF and PAH.

We expect to conduct additional preclinical studies to be followed by a Phase 1 formulation bridging PK study in Australia.

In addition, we are evaluating LPA1R antagonism in IPF, and selected a development candidate (LTSE-2578) in January 2023 and expect to initiate a first-in-human study in 2024.

We plan to continue to harness insights on GPCR targets, particularly among metabolic, endocrine, pulmonary, and cardiovascular indications, and leverage our platform to fuel our pipeline through our discovery engine at Basecamp Bio.

Our APJR agonist product candidate, ANPA-0073 is in development for the treatment of cardiopulmonary and cardiometabolic conditions.

In addition, we are evaluating LPA1R antagonism in IPF, and selected a development candidate (LTSE-2578) in January 2023 and expect to initiate a first-in-human study in the second quarter of 2024.

(“Basecamp Bio”).

● Maximize the potential of our platform and portfolio through strategic partnerships.

We have an established value- and capability-enhancing collaboration with Schrödinger, our co-founder and strategic partner.

We have established value- and capability-enhancing collaborations with Schrödinger, our co-founder and strategic partner.

We intend to continue to explore additional collaborations with third parties to further strengthen our platform capabilities and enable expansion of our portfolio.

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We pursue opportunities to target GPCRs in human diseases on the basis of validated biology, safety, development feasibility and market potential.

We are building a pipeline of wholly-owned oral small molecule

drugs targeting chronic diseases with unmet medical need and commercial potential.

We are building a pipeline of wholly-owned oral small molecule drugs targeting chronic diseases with unmet medical need and commercial potential.

Our initial focus is in areas of metabolic, cardiovascular and pulmonary diseases.

The following table summarizes key information on our current product candidates:

We are initially advancing our GLP-1R franchise as a treatment for T2DM and obesity, conditions affecting approximately 537 million and 764 million people worldwide, respectively.

We believe our GLP-1R programs have demonstrated qualities that offer the potential to differentiate them versus current approved and in development programs.

Metabolic Diseases

We are initially advancing our GLP-1R franchise as a treatment for obesity and T2DM , conditions affecting approximately 764 million and 537 million people worldwide, respectively.

We believe our GLP-1R programs have demonstrated qualities that offer the potential to differentiate them from current approved and development stage programs.

● Selective GLP-1R Program.

GSBR-1290 is a biased GLP-1R agonist which has demonstrated dose-dependent activation of the G-protein pathway.

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The product candidate is designed to be orally administered, without restrictions on diet or concomitant therapy .

We submitted an IND in the United States for our dose escalation Phase 1b study in T2DM and obesity.

In September 2022, we received FDA allowance to proceed with the Phase 1b MAD study, which we initiated in January 2023, and completed dosing in March 2023.

We plan to submit a protocol amendment to the FDA to transition to a Phase 2a proof-of-concept study in T2DM and obesity with the expected initiation in the second half of 2023.

We expect to report topline data for the Phase 1b study and Phase 2a study in the second half of 2023.

We will initially focus development of GSBR-1290 on T2DM with a secondary focus on obesity.

● Next generation.

Our next generation small molecule program is focused on GLP-1R/GIPR modulation with the potential for enhanced metabolic control.

Pulmonary and Cardiovascular

Our APJR agonist program is being evaluated for IPF and PAH.

In another program, we are evaluating LTSE-2578 for IPF.

Our APJR product candidate, ANPA-0073, is a G-protein biased APJR agonist for which we completed a Phase 1 SAD and MAD study, in which it was generally well tolerated as a single dose from 2mg to 600 mg, and at doses from 75 mg to 500 mg once daily dosing for seven days, with no serious adverse events (“SAEs”) reported.

● GLP-1R Combination.

Our combination and next generation small molecule program is focused on GLP-1R candidates, including GLP-1R/GIPR agonists and amylin agonists, each designed with customized properties to achieve additional benefits like enhanced metabolic control .

Our APJR agonist, ANPA-0073, is being evaluated for selective or muscle-sparing weight loss.

ANPA-0073, is a G-protein biased APJR agonist for which we completed a Phase 1 SAD and MAD study, in which it was generally well tolerated as a single dose from 2mg to 600 mg, and at doses from 75 mg to 500 mg once daily dosing for seven days, with no SAEs reported.

Pulmonary and Cardiovascular Diseases

We are evaluating our LPA1R program, LTSE-2578 for IPF and PPF .

Our LPA1R program, LTSE-2578, is an investigational oral small molecule LPA1R antagonist.

We believe LTSE-2578 is a differentiated molecule because it demonstrated potent in vitro and in vivo activity in preclinical IPF models and dose dependent inhibition of histamine release as the PD marker.

We plan to initiate a first-in-human study in the second quarter of 2024.

GPCRs as a Therapeutic Target Family

GPCRs form the largest human membrane protein family, consisting of approximately 800 identified members as illustrated below.

GPCRs are involved in several vital physiological functions, such as immune system

regulation and inflammation, autonomic nervous system transmission, behavioral and mood regulation, sensory transmission, and maintenance of homeostasis, making them important targets for numerous therapeutics.

GPCRs are involved in several vital physiological functions, such as immune system regulation and inflammation, autonomic nervous system transmission, behavioral and mood regulation, sensory transmission, and maintenance of homeostasis, making them important targets for numerous therapeutics.

To date, there are approximately 475 drugs on the market acting at over 100 unique GPCRs.

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● GPCRs are involved in diverse downstream signaling pathways which can result in side effects:

GPCRs interact with a range of molecules, including G-protein and non-G-protein transducers including β-arrestin.

GPCRs interact with a range of molecules, including G-protein and non-G-protein

transducers including β-arrestin.

Signaling pathway selectivity results from agonist-induced specific receptor conformation and when targeting GPCRs involved in multiple signaling pathways, both therapeutic benefits and side effect issues may arise.

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GPCRs are known to signal not only through G-proteins, but also through β-arrestins, intracellular proteins that “arrest” the signal and stop the receptor from becoming over-stimulated through a receptor internalization mechanism.

Using the three-dimensional structures of GPCRs and selection methods, we can potentially design highly selective “biased” molecules that preferentially activate G-protein and not β-arrestin pathways, which could lead to enhanced clinical activity as well as an improved safety profile due to lower dosage requirements.

Using the three-dimensional structures of GPCRs and selection methods, we can potentially design highly selective “biased”

molecules that preferentially activate G-protein and not β-arrestin pathways, which could lead to enhanced clinical activity as well as an improved safety profile due to lower dosage requirements.

GPCR Experience

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Partnership with Schrödinger Leveraging its Cutting-Edge Computational Chemistry Capability

We have a collaboration with Schrödinger on the iteration and optimization of GPCR lead compounds using various next-generation physics-based computational technologies.

We have collaborations with Schrödinger on the iteration and optimization of GPCR lead compounds using various next-generation physics-based computational technologies.

Schrödinger is a scientific leader in chemical simulation, accurate physics-based methods, which includes among many technologies, Free Energy Perturbation (“FEP”) and in silico drug discovery.

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Structure Therapeutics Integrated Platform

As shown above, our collaboration with Schrödinger in our computational and chemistry module enables us to accelerate our lead optimization drug discovery process and reduce development costs.

As shown above, our collaborations with Schrödinger in our computational and chemistry module enables us to accelerate our lead optimization drug discovery process and reduce development costs.

In our partnership with Schrödinger on GPCR drug discovery, we retain the full product rights on the compounds under development.

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We completed a Phase 1 SAD study for GSBR-1290 in healthy volunteers in September 2022.

We initiated the Phase 1b MAD study in January 2023 and completed dosing in healthy overweight subjects in March 2023.

We plan to submit a protocol amendment to the FDA to transition to a Phase 2a proof-of-concept study in T2DM and obesity with the expected initiation in the second half of 2023.

Based on our preclinical data, we believe that GSBR-1290 and our next-generation product candidates have the potential to have highly differentiated profiles versus currently approved therapies and those in development.

We initiated the Phase 1b MAD study in January 2023 and completed dosing in otherwise healthy overweight subjects in March 2023.

In May 2023, we submitted a protocol amendment to the FDA and initiated dosing of the Phase 2a proof-of-concept study in T2DM and obesity.

We reported topline data for the 28-day Phase 1b MAD study in September 2023, in which GSBR-1290 was generally well-tolerated with no adverse event-related discontinuations and demonstrated an encouraging safety profile and significant weight loss of up to 4.9% placebo-adjusted, supporting once-daily dosing.

In December 2023, we reported clinically meaningful topline data from our Phase 2a T2DM cohort, interim results from our Phase 2a obesity cohort and topline data from our Japanese ethno-bridging study of GSBR-1290.

These data demonstrated

that GSBR-1290 was generally well-tolerated, with no treatment-related SAEs over 12 weeks, with only one participant discontinuing the study due to adverse events in the T2DM cohort and none in the obesity cohort.

GSBR-1290 also showed significant reduction in weight in the obesity cohort, and significant reductions in HbA1c and weight in the T2DM cohort.

We expect to report the full 12-week Phase 2a obesity data in the latter half of the second quarter of 2024 with additional 24 participant data.

We also fully enrolled a formulation bridging and titration optimization study to evaluate capsule versus tablet PK and explore different titration regimens of GSBR-1290.

This study is expected to be completed in the latter half of the second quarter of 2024, in preparation for the global Phase 2b study for obesity which we expect to initiate in the fourth quarter of 2024.

A Phase 2 study in T2DM is also planned for the second half of 2024.

Based on our preclinical and clinical data, we believe that GSBR-1290 and our next-generation product candidates have the potential to have highly differentiated profiles versus currently approved therapies and those in development.

Diabetes Disease Background

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Obesity affects nearly one third of all adults in the United States and is associated with a range of comorbidities, such as T2DM, cardiovascular disease, obstructive sleep apnea, and cancer.

Importantly, even modest weight reduction, on the order of five to ten percent, can significantly reduce comorbidities and improve health-related outcomes and has been recently recommended by the major scientific societies (European Association of the Study of Diabetes (“EASD”) and ADA).

Importantly, even

modest weight reduction, on the order of five to ten percent, can significantly reduce comorbidities and improve health-related outcomes and has been recently recommended by the major scientific societies (European Association of the Study of Diabetes (“EASD”) and ADA).

Obesity therefore represents an immense commercial opportunity with very few approved therapies on the market.

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Observed increases in the prevalence of T2DM are related to the increasing prevalence of obesity and multiple mechanisms have been proposed through which they may be linked pathophysiologically.

body and visceral fat are associated with T2DM, metabolic syndrome and cardiovascular disease.

Upper body and visceral fat are associated with T2DM, metabolic syndrome and cardiovascular disease.

Obesity is a major contributor to poor metabolic control in patients with T2DM.

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Given this information, a therapy that can both lower blood glucose and help with weight management in T2DM could have near-term benefits in glycemic control and longer-term benefits in increased insulin sensitivity and reduction of cardiovascular risk.

Current Treatments for T2DM

Current Treatments for T2DM and Obesity

First-line treatment for patients with T2DM involves lifestyle modifications and metformin.

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(“Sanofi”), have captured significant market share in the approximately $65.4 billion market for glucose-lowering agents in 2023, which is projected to grow to $115.4 billion by 2027 as depicted below.

Historical and projected global type-2 diabetes drug sales by class

Historical and projected global obesity and type-2 diabetes drug sales by class

Overview of GLP-1R Signaling Pathway and Target Biology

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The development of GLP-1R agonists for the treatment of diabetes and obesity has involved modifications to the GLP-1 peptide and/or conjugation to carrier compounds or matrices that delay degradation after subcutaneous administration.

The five marketed GLP-1R agonists are synthetic peptides and include liraglutide and semaglutide marketed by Novo Nordisk;

dulaglutide marketed by Eli Lilly;

The six marketed GLP-1R and GLP-1R/GIPR agonists are synthetic peptides and include liraglutide and semaglutide marketed by Novo Nordisk;

dulaglutide and tirzepatide marketed by Eli Lilly;

exenatide marketed primarily by AstraZeneca plc (“AstraZeneca”);

and lixisenatide marketed by Sanofi.

According to Global Data, these five GLP-1R peptides approved for T2DM and/or obesity collectively generated approximately $13.2 billion in worldwide sales in 2020, which is projected to reach $36.4 billion by 2026.

According to Global Data, these six GLP-1R and GLP-1R/GIPR peptides approved for T2DM and obesity collectively generated approximately $65.4 billion in worldwide sales in 2023, which is projected to reach $115 billion by 2027.

Rybelsus is an oral formulation of semaglutide co-formulated with sodium N-8-(2-hydroxybenzoyl) amino caprylate to limit degradation and improve oral absorption.

To date, there are no approved oral small molecule therapies targeting this pathway.

Common side effects of GLP-1R agonists include nausea, vomiting, and diarrhea, which are most pronounced when starting therapy or increasing the dose.

Common side effects of GLP-1R and GLP-1R/GIPR agonists include nausea, vomiting, and diarrhea, which are most pronounced when starting therapy or increasing the dose.

Generally, these effects correlate with times of maximum drug concentrations and ameliorate with continued therapy.

Typically, slow up-titration to the desired dose can mitigate these side effects.

However, once-weekly injectable GLP-1R agonists typically require a long titration period to achieve an optimal dose, potentially delaying therapeutic benefit.

However, once-weekly injectable GLP-1R and GLP-1R/GIPR agonists typically require a long titration period to achieve an optimal dose, potentially delaying therapeutic benefit.

Once-daily therapy with an oral small molecule may provide flexibility in titration and allow a combined approach with other oral therapies.

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Each molecule is designed to have a different tissue penetration profile and other incretin activities in order to maximize the value and/or realize the full potential offered by our in-house platform.

GSBR-1290 Selective GLP-1R Agonist Program

We are developing GSBR-1290, a biased orally-available small molecule GLP-1R agonist, initially as a treatment for T2DM and obesity.

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In a repeat food intake study in NHPs, GSBR-1290 showed a significant decrease in body weight relative to the placebo and surpassed that seen with liraglutide.

Preclinical Data, Pharmacology, and Biomarker Data

GSBR-1290 Preclinical Data, Pharmacology, and Biomarker Data

In NHP ivGTT studies, glucose was injected five minutes following intravenous administration of either GSBR-1290 (0.05 mg/kg) or liraglutide (0.1 mg/kg).

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A p-value of less than or equal to 0.05 is a commonly used criterion for statistical significance, and may be supportive of a finding of efficacy by regulatory authorities.

GSBR-1290 was demonstrated to be generally well tolerated based on its 28-day GLP toxicology studies with no-observed-adverse-effect level (“NOAEL”) dose at 1000 mg/kg/day in rats.

The estimated therapeutic window is more than 1000-fold based in rats based on its 28-day GLP toxicology studies.

In addition, we conducted a preclinical comparison study of GSBR-1290 and PF-06882961, a clinical stage compound in development by Pfizer.

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In an experiment conducted in-house, GSBR-1290 demonstrated comparable in vivo activity to PF-06882961 at a lower exposure.

In the acute ivGTT studies, GSBR-1290 achieved similar activity to liraglutide at average concentration around 34 nanomolar (“nM”) (0.05 mg intravenous), comparing to a similar activity achieved by PF-06882961 in an in-house experiment at an

average concentration around 442 nM (0.3 mg intravenous).

This suggests that the concentration needed to achieve full activity for GSBR-1290 is at a level much lower than that for PF-06882961.

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GSBR-1290 was inactive in this assay, suggesting reduced risks with long-term use.

In addition, GSBR-1290 also did not show activity as a time dependent inhibitor (“TDI”) for cytochrome P450 3A4, or CYP3A4.

In addition, GSBR-1290 also did not show activity as a time dependent inhibitor (“TDI”) for cytochrome P450 3A4 (“CYP3A4”).

PF-06882961 was reported as a CYP3A4 TDI, which, if confirmed in clinical trials, suggests the potential for interactions with the 30–50% of marketed drugs metabolized through this pathway.

Phase 1 Healthy Volunteer Trial

GSBR-1290 Phase 1 Healthy Volunteer Trial

In September 2022, we completed a first-in-human Phase 1 SAD study for GSBR-1290 in 48 healthy adult volunteers between the ages of 18 and 55.

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Schema of our GSBR-1290 Phase 1 SAD study in healthy volunteers

Phase 1 PK and PD Data in Healthy Volunteers

GSBR-1290 Phase 1 PK and PD Data in Healthy Volunteers

In the study, PK parameters of systemic exposure, C max and AUC, increased with doses of GSBR-1290 across the dose range from 1 mg to 90 mg GSBR-1290.

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The 30mg dose AUC provided more than double the effective AUC0-24h required for glycemic control, derived from non-human primate PK/PD data.

Food intake (high fat meal) was associated with a ~36%

decrease in the geometric mean C max but no significant change in mean AUC value, with 80% relative bioavailability, based on AUC compared with the fasted state.

Phase 1 Safety Data in Healthy Volunteers

Food intake (high fat meal) was associated with a ~36% decrease in the geometric mean C max but no significant change in mean AUC value, with 80% relative bioavailability, based on AUC compared with the fasted state.

GSBR-1290 Phase 1 Safety Data in Healthy Volunteers

GSBR-1290 was shown to be generally well tolerated at all dose levels administrated in this Phase 1 SAD study.

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Across the various dose levels, there were apparent dose-related trends in the overall incidence of common TEAEs.

The incidence of the TEAEs described above was notably higher following fasted administration of the high dose GSBR-1290 treatments (30 mg, 60 mg, 90 mg) than the low dose GSBR-1290 treatments (1 mg, 10 mg, 15 mg) and placebo, with a similar observation in treatment-related AEs of nausea, vomiting, dehydration, and headache of at least moderate severity.

The incidence of the TEAEs described above was notably higher following fasted administration of the high dose GSBR-1290 treatments (30 mg, 60 mg, 90 mg) than the low dose GSBR-1290 treatments (1

mg, 10 mg, 15 mg) and placebo, with a similar observation in treatment-related AEs of nausea, vomiting, dehydration, and headache of at least moderate severity.

We believe all TEAEs observed during the study are in line with the proposed treatment mechanism and typically derive from impacts on appetite, nausea, and vomiting.

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PK parameters of systemic exposure increased with dose of GSBR-1290 across the dose range from 1 mg to 90 mg GSBR-1290.

Non-clinical Safety Pharmacology and Toxicology Studies

GSBR-1290 Non-clinical Safety Pharmacology and Toxicology Studies

A standard battery of nonclinical safety pharmacology studies (central nervous system, cardiovascular and respiratory) has been completed with GSBR-1290 with no findings anticipated to be of clinical relevance.

Genotoxicity assessments demonstrated an absence of genotoxicity potential.

In the 4-week and 13-week GLP toxicology study in rats, the NOAEL dose was considered to be 1000 mg/kg/day, the highest dose tested.

In the 4-week and 13-week GLP toxicology study in rats, the no-observed-adverse-effect level (“NOAEL”) dose was considered to be 1000 mg/kg/day, the highest dose tested.

In the 4-week and 13-week GLP toxicology study in NHPs, GSBR-1290 showed pharmacologically related events such as inappetence and bodyweight loss, which were reversible with sufficient recovery periods.

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In nonclinical animal models, GSBR-1290 demonstrated statistically significant decreases in blood glucose concentration and increases of insulin secretion.

We have initiated the 26-week chronic toxicology studies in rats and 39-week studies in NHP and embryo-fetal development studies that we believe will be required by regulatory agencies to continue dosing beyond 13 weeks in Phase 2b.

Phase 1b MAD study

We submitted an IND to the FDA to support initiation of a GSBR 1290 Phase 1b MAD study and received FDA allowance in September 2022.

After initiation in January 2023, we enrolled 24 healthy overweight or obese subjects between the ages of 18 and 55.

The primary objective is to assess drug safety and tolerability.

The secondary objectives are to evaluate PK and PD and determine the starting dose for titration and help define the titration scheme including the dose level and duration of steps.

The study enrolled three cohorts of eight participants who received multiple ascending doses of GSBR 1290 or placebo in a 6:2 ratio.

We completed dosing of Cohorts 1 through 3 in March 2023.

Cohort 1 doses started at 5 mg daily and escalated up to 60 mg weekly over four weeks.

Cohort 2 doses started at 10 mg and escalated up to 90 mg daily over four weeks.

Cohort 3 doses started at 10 mg for two weeks and escalated to 30 mg for an additional two weeks.

A schema of our Phase 1b MAD study is presented below:

Schema of our GSBR-1290 Phase 1b MAD study in healthy overweight/obese subjects

Phase 2a proof-of-concept study

We plan to submit a protocol amendment to initiate a Phase 2a proof-of-concept portion of the study in T2DM and healthy overweight or obese subjects and expect to report initial data in the second half of 2023.

The primary objective is to assess safety and tolerability of GSBR 1290 in healthy obese subjects and T2DM subjects.

Secondary objectives include assessing changes in body weight, HbA1c and other PD measures in T2DM subjects as well as changes in body weight in healthy overweight or obese subjects.

The exploratory objectives are to assess metabolite formation.

The Phase 2a part of the study will enroll at least 69 subjects, which number may increase based upon the final study design.

Approximately 54 T2DM subjects will be randomized in three groups to receive GSBR 1290 45 mg or 90 mg or placebo.

There will be a four week titration period followed by eight weeks of daily treatment at the target dose.

In addition, at least 15 healthy overweight or obese subjects will receive GSBR 1290 or placebo or, after a four week titration period, GSBR 1290 90 mg daily for two to four weeks followed by 120 mg daily for four to

six weeks, depending on the final study design.

We may make additional modifications to the initial study design when we submit our final protocol amendment to the FDA.

We also anticipate initiating a Phase 2b study in 2024, subject to favorable results in the Phase 2a study.

A schema of our Phase 2a proof-of-concept study is presented below:

Schema of our GSBR-1290 Phase 2a proof-of-concept study in T2DM and healthy overweight/obese subjects

Next Generation GLP-1R Program

In our next generation GLP-1R program, we have identified hits for small molecule dual GLP-1R/GIPR modulation and we are planning to select a development candidate in 2024.

In a recent 6-month GLP toxicology study in rats, GSBR-1290 demonstrated a NOAEL dose at 1000 mg/kg/day, which supports an estimated more than 100 fold safety window up to 120 mg human dose.

We also conducted a 9-month non-human primate (NHP) GLP toxicology study and found no test article-related change in heart rates or QTc intervals.

No meaningful increases in the liver enzymes, ALT/AST, were observed in either the rat or NHP study.

There were no significant findings in embryo-fetal developmental toxicology studies in rats and rabbits.

GSBR-1290 Phase 1b MAD study

The Phase 1b MAD study focused on the safety and tolerability of GSBR-1290 in 24 healthy overweight or obese individuals.

Participants were randomized 3:1 to GSBR-1290 or placebo across three dose cohorts with target doses of 30mg, 60mg or 90mg.

GSBR-1290 demonstrated reductions in mean body weight ranging up to 4.9 kg compared to baseline, and up to 4.9% placebo-adjusted.

Percent Weight Change from Baseline to Day 28

% weight change from baseline

% weight change placebo-adjusted

(-3.8 to 1.7)

(-6.6 to -2.7)

(-7.8 to -1.9)

Exploratory p-value vs.

GSBR-1290 demonstrated an encouraging safety and tolerability profile following once-daily dosing.

No participants discontinued the study drug due to adverse events.

The majority of adverse events reported were mild, with no severe or serious adverse events observed.

As expected for this class, leading adverse events were gastrointestinal-related, with the two most common gastrointestinal adverse events being nausea and diarrhea, with higher incidences observed in all three cohorts compared to placebo.

There were no clinically meaningful changes in liver function tests.

Summary of Treatment Emergent Adverse Events

Placebo pooled

Any TEAE by maximum severity

Any Serious Adverse Events

GSBR-1290 Phase 2a study in diabetes and obesity

The randomized, double-blind, 12-week placebo-controlled Phase 2a clinical trial has enrolled a total of 94 participants to date, including 60 participants randomized to GSBR-1290.

The T2DM cohort enrolled 54 participants, randomized to GSBR-1290 at 45 mg (n=10) or 90 mg (n=26), or placebo (n=18), dosed once daily.

The obesity cohort initially enrolled 40 participants randomized to GSBR-1290 at 120 mg (n=24) or placebo (n=16), dosed once-daily.

An additional 24 participants have been enrolled in the obesity arm as previously announced in September 2023 to replace those for whom 12-week weight data was not collected as a result of a data collection omission.

These replacement participants have also been randomized 3:2 to GSBR-1290 or placebo.

The primary endpoints of the Phase 2a study are safety and tolerability of GSBR-1290.

Key secondary endpoints include reduction in weight for both obesity and T2DM cohorts, as well as reduction in HbA1c for the T2DM cohort.

GSBR-1290 Safety and tolerability results

GSBR-1290 demonstrated an encouraging safety and tolerability profile following repeated, daily dosing for all doses studied (up to 120 mg) in the obesity and T2DM cohorts, with results summarized as follows:

● The majority (88 to 96%, depending on study arm) of AEs reported were mild to moderate.

● There were no SAEs related to study drug.

● As expected for this mechanism of action, leading AEs were gastrointestinal-related.

The two most common AEs were nausea and vomiting.

● There were no cases of elevated liver enzymes in the obesity cohort.

One participant in the T2DM treatment group experienced an event of elevated liver enzymes without an increase in bilirubin initially at day 8 while receiving 5 mg of study drug.

This participant was diagnosed with fatty liver disease while in the study.

● Of the 60 participants dosed with GSBR-1290, only one participant discontinued the study due to AEs related to study drug (none in the obesity cohort and one (2.8%) in the T2DM cohort).

Summary of Treatment Emergent Adverse Events (TEAEs)

Phase 2a TDM Cohort

Phase 2a Obesity Cohort

(12-week data)

(12-week interim data)

Any TEAE by maximum severity

Any SAEs related to study drug

GSBR-1290 Efficacy result s

GSBR-1290 demonstrated clinically meaningful activity in both T2DM and obesity cohorts, with results summarized as follows:

● In the T2DM cohort, there was a statistically significant HbA1c reduction (-1.01 to -1.02%, placebo-adjusted) at Week 12 (Table 1 ).

The study demonstrated a statistically significant and clinically meaningful reduction in weight at Week 12 (-3.26% to -3.51%, placebo-adjusted) (Table 2).

Weight loss continued to decrease through Week 12.

● Results of the interim analysis in the obesity cohort showed a statistically significant and clinically meaningful decrease in weight at Week 8 (-4.74%, placebo-adjusted) (Table 3 ).

Weight loss continued to decrease throughout the eight weeks of treatment.

Diabetes cohort least square means difference (LSM) change in HbA1c from baseline to 12 weeks (%)

LSM HbA1c change from baseline (%)

% HbA1c change placebo-adjusted (LSM,

95% confidence interval (CI))

(-1.73, -0.29)

(-1.59, -0.44)

* LSM, CI and p - value from Mixed Model for Repeated Measures

Diabetes cohort LSM change in weight from baseline (%)

LSM weight change from baseline (%)

% weight change placebo-adjusted (LSM,

(-5.58, -1.43)

(-5.17, -1.36)

* LSM, CI and p - value from Mixed Model for Repeated Measures

Obesity Cohort LSM change in weight from baseline (%) 8 week interim results

LSM weight change from baseline (%)

% weight change placebo-adjusted (LSM, 90%

(-6.74, -3.10)

GSBR-1290 Phase 1 Japanese Bridging Study

The 4-week Phase 1 Japanese ethnobridging study included healthy lean Japanese participants randomized to GSBR-1290 (n=9) and placebo (n=3), and healthy lean non-Japanese participants receiving GSBR-1290 (n=6).

GSBR-1290 demonstrated a substantial weight reduction in Japanese participants (-3.91% on GSBR-1290 vs -1.67% placebo) and in non-Japanese participants (-5.13% not placebo-adjusted), with no discontinuations or dose reductions, and no SAEs.

These data will be used for regulatory interactions in Japan in preparation for potential future global studies of GSBR-1290.

GSBR-1290 Six- and Nine-Month Toxicology Studies

In preparation for Phase 2b development with longer durations of treatment, we have completed six-month (rodent) and nine-month (non-human primate) toxicology studies to evaluate the safety of GSBR-1290.

No major findings were observed in either study, with no test article-related changes observed in the liver, including ALT/AST, at all doses, and a more than 100 fold safety window at the 120 mg therapeutic dose.

Amylin Receptor Agonist - Combination GLP-1R Program

Amylin is co-secreted with insulin from β pancreatic cells upon nutrient delivery to the small intestine as a satiety signal, acts upon sub-cortical homeostatic and hedonic brain regions, slows gastric emptying, and

suppresses post-prandial glucagon responses to meals.

Therefore, new pharmacological amylin analogues can be used as potential anti-obesity medications in individuals who are overweight or obese.

Amylin tool compound showed add-on effects when used with semaglutide

In collaboration with Schrödinger, we are taking a structure-based drug discovery approach to identify oral small molecule amylin agonists for daily use either alone or in combination with GLP-1R agonists to treat obesity and T2DM.

We have identified two novel lead series with promising potency and PK profiles.

We have obtained multiple high quality Cryo-EM structures and established in-house in vivo animal models, which enable us to advance our lead optimization effort with high efficiency.

In an in-house proof-of-concept study in rats, our small molecule amylin tool compound (ACCG-0184) showed additional beneficial effects when used as an add-on treatment to a GLP-1R agonist.

We are planning to select a development candidate in the second half of 2024.

GenerationGIPR Modulator - Combination GLP-1R Program

In our GIPR program, we have identified multiple GIPR agonist, dual GLP-1R/GIRP agonist and GIPR antagonist hits for small molecule GIPR modulation.

We believe GLP-1R/GIPR modulation has the potential to provide a differentiated treatment in diabetes and obesity.

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While displaying different GIPR activity, both compounds still maintained certain levels of GLP-1R activities.

Next generation dual incretin GLP-1R/GIPR agonist hits identified

We are planning to select a development candidate in the first half of 2025.

GIPR agonist/dual agonist/antagonist hits identified for potential GLP-1R combinations

Our LPA1R and APJR Program for the Treatment of IPF

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We have completed IND-enabling studies including 28 day GLP-toxicology studies in dogs and rats.

We are planning to initiate a first-in-human Phase 1 single and multiple ascending dose study in healthy volunteers in the second quarter of 2024.

In addition, we are developing ANPA-0073, an investigational oral small molecule APJR agonist, for the treatment of IPF.

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In September 2022, we completed a Phase 1 SAD and MAD study evaluating ANPA-0073, in which it was generally well tolerated in healthy human volunteers.

We expect to conduct additional preclinical studies to be followed by a Phase 1 formulation bridging PK study in Australia.

We also plan to initiate a Phase 2 study in 2024 in the United States.

We expect to conduct additional preclinical studies and are evaluating plans to initiate a Phase 2 study in IPF.

IPF Disease Background

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After conducting additional toxicology investigations, BMS reported that hepatobiliary toxicity was likely caused by inhibition of bile acids efflux transporters such as Bile Salt Export Pump (“BSEP”).

Second generation LPA1R antagonists (BMS-986278) with minimal BSEP inhibition by BMS are currently in clinical development.

generation LPA1R antagonists (BMS-986278) with minimal BSEP inhibition by BMS are currently in clinical development.

We believe that LPA1R can also be used to treat progressive pulmonary fibrosis (“PPF”), which is defined as the presence of at least two of the three criteria, which are worsening respiratory symptoms, functional decline, and radiological progression in patients with interstitial lung disease with radiological pulmonary fibrosis for known or unknown reasons other than IPF, within the previous year.

A conditional recommendation has been made for nintedanib in the treatment of PPF, and further studies are needed for pirfenidone.

As illustrated below, we utilized the available protein structural information to collaborate with Schrödinger.

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Iterative LPA1R Structure-Based Drug Discovery

Preclinical Data

LTSE-2578 Preclinical Data

In an in vivo PK and PD study, mice were orally dosed with LTSE-2578 and challenged by LPA at one hour and at 12 hours after dosing.

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LTSE-2578 showed limited inhibition (IC50 > 50 μ M) of efflux transporters including BSEP, MRP3 and MRP4, potentially reducing the likelihood of hepatobiliary toxicity caused by efflux transporter inhibition.

IND-enabling studies of LTSE-2578 are ongoing with data expected in the second half of 2023.

One month GLP toxicity studies of LTSE-2578 in rats and dogs have been completed to enable the upcoming first time in human study.

Overview of APJR Pathway and Target Biology

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Since an APJR agonist mainly targets endothelial cells, we believe it could be easily combined with the current standard of care, pirfenidone and ninetedanib, which do not target the anti-fibrosis pathway from endothelial cells.

We are developing ANPA-0073, an investigational, oral, small molecule APJR agonist, for the treatment of IPF.

Our APJR Program for the Treatment of Obesity

APJ is expressed in human and murine skeletal muscles.

Apelin and APJ are widely distributed in the body and are involved in various physiological functions as blood pressure regulation.

Depending on the cell type studied, APJ activation enhances extracellular signal-regulated kinases, AMPK, AKT, and p70S6 kinases and the inhibition of cyclic AMP (cAMP) production.

Activation of these pathways would result in worthwhile increases in the protein content of skeletal muscles.

Apelin has in fact proved beneficial in maintaining muscle and could potentially counteract age-associated atrophy.

We are evaluating ANPA-0073 which is Phase 2 ready, to be used in combination with weight loss medicines for selective or muscle-sparing weight loss.

We are also developing ANPA-0073, an investigational, oral, small molecule APJR agonist, for the treatment of IPF.

ANPA-0073 is designed to suppress cAMP production through activation of a G-protein-mediated signaling without significant activation of the β-arrestin pathway in order to avoid APJ internalization, and thereby potentially avoid any desensitization effects of an unbiased APJR agonist.

We conducted preclinical in vitro studies on our compounds and third-party compounds to assess arrestin signaling and internalization.

As shown below, apelin peptide and clinically tested competitor compounds including AMG-986 and BMS-986224 are all non-biased APJR agonists in these in vitro studies, with low β-arrestin/cAMP and internalization/cAMP ratios.

As shown below, apelin peptide and clinically tested competitor compounds including AMG-986 and

BMS-986224 are all non-biased APJR agonists in these in vitro studies, with low β-arrestin/cAMP and internalization/cAMP ratios.

Our molecules, such as ANPA-0073 and ANPA-137, are designed to be biased with much higher β-arrestin/cAMP and internalization/cAMP ratios than apelin peptide and the competitor compounds shown below.

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Apelin Peptide

Preclinical Data

ANPA-0073 Preclinical Data

In an in vitro study, ANPA-0073 demonstrated high potency in suppressing cAMP production through the G-protein-mediated signaling pathway with a half maximal excitatory concentration (EC50) value of less than 10 nM (n=15), but less potency in triggering the β-arrestin pathway and APJR internalization respectively.

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Furthermore, ANPA-137 also demonstrated anti-fibrotic activity in an in vivo bleomycin-induced rat lung fibrosis model.

Similar to mouse bleomycin study design, seven days after bleomycin challenges, rats received 15 mpk of oral ANPA-137 for two weeks.

Similar to mouse bleomycin study design, seven days after bleomycin challenges, rats

received 15 mpk of oral ANPA-137 for two weeks.

ANPA-137 significantly reduced lung fibrosis as quantified by Ashcroft score as shown below.

APJR agonist demonstrated anti-fibrosis efficacy in therapeutic IPF rat model

Phase 1 Healthy Volunteer Trial Design

ANPA-0073 Phase 1 Healthy Volunteer Trial Design

In September 2022, we completed a two-part, 96 subject, first-in-human Phase 1 SAD and MAD study for ANPA-0073 in 48 healthy adult volunteers between the ages of 18 and 55.

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Doses from 2 mg to 600 mg across the eight cohorts were evaluated.

The second part of the trial was a MAD study, including four cohorts of

eight subjects receiving sequential ascending doses of ANPA-0073 daily for seven days, increasing from 75 mg to 500 mg once daily.

The second part of the trial was a MAD study, including four cohorts of eight subjects receiving sequential ascending doses of ANPA-0073 daily for seven days, increasing from 75 mg to 500 mg once daily.

A schema of our Phase 1 study is presented below:

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ANPA-0073-01 Part B MAD Schema

Phase 1 Safety Data in Healthy Volunteers

ANPA-0073 Phase 1 Safety Data in Healthy Volunteers

ANPA-0073 was generally well tolerated at all dose levels administrated in the SAD and MAD parts of this Phase 1 study.

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AEs did not result in any early terminations or subject discontinuations from participation in this study.

No trial stopping criteria were met and no significant changes or trends in hematology, blood chemistries, vital signs or electrocardiogram (“ECG”) measurements were noted.

No trial stopping criteria were met and no significant changes or trends in hematology, blood

chemistries, vital signs or electrocardiogram (“ECG”) measurements were noted.

The following table shows all TEAEs that were reported:

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AEs did not result in any early terminations or subject discontinuations from participation in this study.

No trial stopping criteria were met and no significant changes or trends in hematology, blood

chemistries, vital signs or ECG measurements were noted.

No trial stopping criteria were met and no significant changes or trends in hematology, blood chemistries, vital signs or ECG measurements were noted.

The following table shows all TEAEs that were reported:

ANPA-0073 Phase 1 MAD Treatment Emergent Adverse Events

A Phase I, Open-label Study to Evaluate the Relative Bioavailability of ANPA-0073 Capsule versus Tablet

We are planning to conduct a Phase 1 study to evaluate the relative oral bioavailability of two formulations of ANPA-0073 (tablet and capsule) using a 2-period, 2-sequence, 2-way crossover design.

We expect this study to be an open-label study in 16 healthy male and female volunteers, aged 18 to 55 in Australia.

After screening, we plan for subjects to be confined in the clinical unit from Day-1 to Day 10, and that each study subject will be enrolled and randomized into one of two treatment arms (n=8 per arm).

Capsule and tablet formulations of ANPA-0073 will be administered as a single 200 mg (2 x 100 mg) dose in a fasted manner in two separate treatment periods:

Day 1 (Period 1) and Day 7 (Period 2).

We expect the sequence of administration (capsule → tablet vs.

tablet → capsule) will differ between each treatment arm and that each treatment period will be separated by a 6-day washout interval.

Our APJR Program for the Treatment of PAH

We are evaluating ANPA-0073 for the treatment of PAH.

Despite existing treatment options for PAH, five-year mortality remains high.

In a third-party clinical proof-of- concept study an acute infusion of an apelin agonist intravenously was shown to improve cardiac output.

In our preclinical rat models, ANPA-0073 has shown increased cardiac output and mitigated the vascular remodeling that is characteristic of PAH.

We believe that oral ANPA-0073 has the potential to provide therapeutic benefit through its novel mechanism of action, infrequent dosing, and lack of stringent administration requirements.

PAH Background

Pulmonary hypertension (“PH”) is a group of diseases characterized by remodeling of the pulmonary vasculature that leads to a progressive elevation of blood pressure in the pulmonary circulation from a variety of causes.

The World Health Organization (“WHO”) has divided PH into five groups based on similarities in pathophysiology, clinical presentation, and therapeutic options as shown below.

WHO classification of pulmonary hypertension

Pulmonary arterial hypertension

Pulmonary hypertension secondary to left heart disease

Pulmonary hypertension from chronic lung diseases and/or hypoxia

Pulmonary hypertension due to pulmonary artery obstruction

Pulmonary hypertension from unexplained or multifactorial mechanisms

PAH is a rare, progressive life-threatening disease characterized by elevated pressures in the pulmonary arteries, the blood vessels responsible for carrying deoxygenated blood from the heart to the lungs.

This increase in pressure results from disordered proliferation of endothelial cells lining the lumen of pulmonary arteries, which causes a narrowing in blood vessel diameter and a consequent slowing of blood flow to the lungs.

Over time, recruitment of inflammatory cells and cytokines stimulates fibrosis and further blood vessel remodeling, ultimately causing severe restrictions in blood flow.

To overcome increased pulmonary arterial pressures, the right side of the heart must work harder in order to circulate blood through the lungs, causing excessive strain on the right ventricle.

Left untreated, this leads to right ventricular hypertrophy and ultimately right heart failure, which can present with symptoms such as breathlessness, fatigue, chest pain, and abdominal distension.

Right ventricular hypertrophy and pulmonary arterial hypertension

As shown in the schematic of PAH pathology above, increased pulmonary vascular resistance is caused by cell proliferation in the pulmonary vessels that obstructs blood flow.

Ultimately, this disease leads to right heart failure, resulting eventually in death.

Therefore, treatments that can increase right heart contractility may have benefit.

In addition to the above classification based on physiologic mechanisms of PH, the WHO has also developed a functional classification of PH patients, including those with PAH, as shown below.

Four functional classes categorize patient symptom severity and ability to carry out physical activity.

Higher numbered functional classes indicate worsening symptoms and are associated with higher mortality.

As patients in Class I are asymptomatic and generally not diagnosed and also cannot show clinical improvement, patients in Classes II–IV are generally studied in clinical trials of new therapeutic agents.

WHO functional classification of pulmonary hypertension

Patients with pulmonary hypertension but without resulting limitation of physical activity.

Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope.

Patients with pulmonary hypertension resulting in a slight limitation of physical activity.

They are comfortable at rest.

Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope.

Patients with pulmonary hypertension but without resulting limitation of physical activity.

Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope.

Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms.

These patients manifest signs of right heart failure.

Dyspnea and/or fatigue may even be present at rest.

Discomfort is increased by any physical activity.

Prevalence of PAH and Unmet Medical Need

It is estimated that between 40,000 and 100,000 patients suffer from PAH worldwide, though the actual number is likely higher given underdiagnosis in developing countries.

In the United States, the prevalence of PAH is 12 to 30 per million, and incidence is approximately 2.3 per million diagnosed annually.

Combined global sales for approved drugs for the treatment of PAH totaled approximately $5.4 billion in 2020.

While advances in the treatment of PAH have markedly improved median survival over the past two decades, patients still face significant disease burden and premature death.

Patient survival of PAH remains poor at five years despite treatment advances and there is unmet medical need for new therapies beyond the standard of care.

Our current and future pipeline candidates could have broad applicability in other PH groups as well as more broadly in heart failure, which is estimated to affect approximately 26–64 million people worldwide.

Limitations of Current Treatments and Unmet Medical Need

The current standard of care for patients with PAH consist of three classes of vasodilators including phosphodiesterase 5 (“PDE5”) inhibitors, endothelin receptor antagonists, and prostanoids.

PDE5 inhibitors are often used in combination with ERAs as an early treatment strategy.

In patients who fail to respond to combination therapy of an ERA and a PDE5 inhibitor, it is common practice to add a prostanoid which is also commonly used to treat patients with evidence of right heart failure.

While existing treatments have led to significant improvements in time to clinical worsening and other composite endpoints in PAH patients, none directly alter the underlying disease process.

The effect of vasodilation, while improving blood flow through the lungs, may eventually be overtaken by the worsening cellular proliferation and arterial remodeling underlying the condition.

Accordingly, we believe there is unmet medical need for therapies that are disease modifying and address more fundamental aspects of the disease.

Apelin Receptor is a Clinically Validated and Highly Druggable Target

APJR is a GPCR with wide distribution throughout the human body.

The expression patterns of apelin and APJR are consistent with their importance in cardiovascular and pulmonary diseases such as PAH.

Apelin and APJR are expressed in several tissues, including those in the heart, lung, and blood vessels with expression observed in endothelial cells lining the blood vessels.

Activation of APJR pathways by its cognate peptide ligand, apelin, exerts pleiotropic effects in human biology, including inducing diverse physiological effects such as strengthening of cardiac contractility, vasodilation, angiogenesis, reducing vascular remodeling and regulation of energy metabolism and fluid homeostasis as shown below.

We believe that the apelinergic signaling pathway will provide disease modifying effects in PAH through right ventricular protection and anti-pulmonary vessel remodeling.

Apelin Biology in human makes APJR an attractive target for PAH

Apelin mRNA and protein levels in control and PAH lung samples

As shown above, the apelin expression level in the lung of PAH patients (IPAH) was dramatically reduced compared to the non-PAH (C) lung samples.

Apelin signaling is implicated in PAH which can be induced in animal models by hypoxia, a condition which temporarily induces apelin expression.

Apelin peptide reduced PVR and increased cardiac output without a change in

heart rate or mean arterial pressure

As shown above, apelin has a role in cardiac function.

In a published third-party clinical proof-of-concept study, intravenous infusion of apelin peptide in PAH patients provided a significant reduction in pulmonary vascular resistance and an increase in cardiac output without a change in heart rate or systemic vascular resistance.

It was also observed that the effect was most prominent in the subgroup of patients receiving concomitant PDE5 inhibition.

Both biased and non-biased apelin analogs could increase cardiac contraction, while biased apelin analogs have limited effects on vasorelaxation and systemic blood pressure reduction.

These suggest that the inotropic efficacy mainly signals through G-protein pathway, while β-arrestin signaling pathway correlates with hypotensive effect as shown below.

APJR agonist activity on β-arrestin recruitment and its correlation with hypotensive effect.

We believe that a biased APJR agonist as compared to a non-biased agonist has the potential to maintain long-term cardiac output and stroke volume improvement while avoiding β-arrestin related hypotensive effect and mechanical stress induced cardiac hypertrophy.

Our Solution:

Small Molecule Biased APJR Agonist

As described above, we are developing ANPA-0073, a novel orally-available biased APJR agonist which is designed to suppress cAMP production through activation of a G-protein-mediated signaling without significant activation of the β-arrestin pathway in order to avoid APJR internalization.

We believe that ANPA-0073 has the potential to be a differentiated and disease-modifying therapeutic agent and it is designed to provide the following potential advantages:

● Orally-available with improved cardiac contractility, increased stroke volume and right ventricular cardiac output leading to increased survival;

● Biased agonism that avoids down regulation due to APJR internalization;

● Disease-modifying effect through decreased vascular remodeling;

● Limited effect on systemic blood pressure, avoiding hypotension.

ANPA-0073 did not change mean arterial blood pressure in a rat telemetry study

One way ANOVA analysis;

**** p<0.0001 compared to vehicle

As shown above, in a rat telemetry model, a non-biased apelin peptide demonstrated an acute decrease in mean arterial pressure as expected, whereas the biased molecule, ANPA-0073, did not.

ANPA-0073 has demonstrated promising activity in multiple animal models.

In five different studies using monocrotaline (“MCT”) induced rat models of PAH, daily oral doses of ANPA-0073 reduced right ventricular systolic pressure, right ventricular hypertrophy index, and percentage of pulmonary artery wall thickness (“PAWT”), but increased right ventricular ejection fraction.

As shown below, ANPA-0073 treatment resulted in reduced pulmonary artery pressure and increased cardiac function.

Treatment with sildenafil or an ANPA-0073 in an MCT rat model of PAH

One way ANOVA analysis;

*p<0.05, **p<0.01, **** p<0.0001 compared to vehicle

In summary, in a published third-party clinical proof-of-concept study, an intravenous infusion of apelin has demonstrated increased cardiac output, especially in combination with the PAH standard of care therapy, sildenafil.

In the MCT rat model of PAH, our biased apelin agonists showed increased cardiac stroke volume and cardiac output without impacting heart rate, and also mitigation of PAH-induced vascular remodeling.

Together, these data suggest that an orally-available, biased apelin agonist, such as ANPA-0073, may have potential as a treatment for PAH, providing benefits differentiated from current standard of care therapies.

We will initiate the 26-week chronic GLP-toxicology studies in rats and 39-week studies in dogs that we believe will be required by regulatory agencies to continue dosing beyond 13 weeks in Phase 2.

We are also evaluating ANPA-0073 for selective or muscle-sparing weight loss.

Intellectual Property

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Our success also depends in part on our ability to operate without infringing the proprietary rights of others, and in part on our ability to prevent others from infringing our proprietary rights.

A comprehensive discussion on risks relating to intellectual property is provided under Part I.

A comprehensive

discussion on risks relating to intellectual property is provided under Part I.

“Risk Factors—Risks Related to Our Intellectual Property.”

For our GLP-1R program, as of December 31, 2023, our wholly-owned subsidiary Gasherbrum Bio, Inc., is the sole owner of one granted U.S.

patent and five pending U.S.

patent applications, 16 Patent Cooperation Treaty (“PCT”) applications, and 42 pending foreign patent applications in Argentina, African Regional Intellectual Property Organization (“ARIPO”) Australia, Brazil, Canada, Chile, the People’s Republic of China (“PRC”), Colombia, Costa Rica, Dominican Republic, Egypt, Eurasian Patent Office (“EAPO”), European Patent Office (“EPO”), Guatemala, Indonesia, Israel, India, Japan, South Korea, Mexico, Malaysia, New Zealand, Panama, Peru, Philippines, Saudi Arabia, Singapore, Thailand, Taiwan, Ukraine, Vietnam, and South Africa.

patent and 11 pending U.S.

patent applications, 14 Patent Cooperation Treaty (“PCT”), applications, and 94 pending foreign patent applications in Argentina, the African Regional Intellectual Property Organization (“ARIPO”), Australia, Brazil, Canada, Chile, the People’s Republic of China (“PRC”), Colombia, Costa Rica, Dominican Republic, Egypt, the Eurasian Patent Office (the “EAPO”), the European Patent Office (the “EPO”), Guatemala, Hong Kong, Indonesia, Israel, India, Japan, South Korea, Mexico, Malaysia, New Zealand, Panama, Peru, Philippines, Saudi Arabia, Singapore, Thailand, Taiwan, Ukraine, Vietnam, and South Africa.

These patent applications, to the extent they issue (or in the case of priority applications, if issued from future non-provisional applications that we file), are expected to expire between 2041 and 2044, without accounting for potentially available patent term adjustments or extensions.

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We intend to strengthen the patent protection of our product candidates and other discoveries, inventions, trade secrets and know-how that are critical to our business operations through additional patent application filings.

For our APJR program, as of December 31, 2022, our wholly-owned subsidiary Annapurna Bio, Inc.

is the sole owner of one granted U.S.

patent and two pending U.S.

patent applications, one PCT, application, and 22 pending foreign patent applications in Argentina, Australia, Brazil, Canada, the PRC, EAPO, EPO, Hong Kong, Israel, India, Japan, South Korea, Mexico, New Zealand, Singapore, Taiwan and South Africa relating to compounds and compositions of matter for treating conditions associated with Apelin receptor activity, including ANPA-0073 and its analogs, solid forms and methods of treating conditions associated with Apelin receptor activity.

For our oral small molecule APJR program, as of December 31, 2023, our wholly-owned subsidiary Annapurna Bio, Inc.

is the sole owner of two granted U.S.

patents and three pending U.S.

patent applications, one PCT application, one granted European patent and 24 pending foreign patent applications in Argentina, Australia, Brazil, Canada, the PRC, the EAPO, the EPO, Hong Kong, Israel, India, Japan, South Korea, Mexico, New Zealand, Singapore, Taiwan, and South Africa relating to compounds and compositions of matter for treating conditions associated with Apelin receptor activity, including ANPA-0073 and its analogs, solid forms and methods of treating conditions associated with Apelin receptor activity.

Any patents issuing from these patent applications (or in the case of priority applications, if issued from future non-provisional applications that we file) are expected to expire between 2039 and 2043, without accounting for potentially available patent term adjustments or extensions.

For our LPA1R program, as of December 31, 2023, our wholly-owned subsidiary Lhotse Bio, Inc.

(“Lhotse”) is the sole owner of four PCT applications and two pending foreign patent applications in Argentina and Taiwan relating to compounds and compositions of matter for treating conditions associated with LPA receptor activity, including LTSE-2578 and their analogs, and methods of treating conditions associated with LPA receptor activity.

(“Lhotse”) is the sole owner of three pending U.S.

patent applications, four PCT applications and seven pending foreign patent applications in Argentina, the PRC, the EPO, Japan, and Taiwan relating to compounds and compositions of matter for treating conditions associated with LPA receptor activity, including LTSE-2578 and its analogs, and methods of treating conditions associated with LPA receptor activity.

Any patents issuing from these patent applications (or in the case of priority applications, if issued from future non-provisional applications that we file) are expected to expire between 2041 and 2044, without accounting for potentially available patent term adjustments or extensions.

For our oral small molecule Amylin program, as of December 31, 2023, our wholly-owned subsidiary Aconcagua Bio, Inc.

(“Aconcagua”) is the sole owner of two PCT applications relating to compounds and compositions of matter for treating conditions associated with Amylin receptor activity and methods of treating conditions associated with Amylin receptor activity.

Any patents issuing from these patent applications (or in the case of priority applications, if issued from future non-provisional applications that we file) are expected to expire in 2044, without accounting for potentially available patent term adjustments or extensions.

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

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Unless terminated earlier, the Lhotse-Schrödinger Agreement will continue for three years, subject to extension by mutual written agreement of the parties.

Either party may terminate the Lhotse-Schrödinger

Agreement for the other party’s uncured material breach, subject to certain notice and cure periods, or for the other party’s bankruptcy or insolvency.

Either party may terminate the Lhotse-Schrödinger Agreement for the other party’s uncured material breach, subject to certain notice and cure periods, or for the other party’s bankruptcy or insolvency.

Lhotse’s obligation to make milestone and royalty payments (subject to the Royalty Term) to Schrödinger continues after the expiration or termination of the Lhotse-Schrödinger Agreement.

Aconcagua Collaboration Agreement with Schrödinger

In November 2023, Aconcagua, our wholly-owned subsidiary, entered into a collaboration agreement (the “Aconcagua-Schrödinger Agreement”) with Schrödinger to discover and develop novel, small molecule modulators of a specific target.

Under the Aconcagua-Schrödinger Agreement, Schrödinger is obligated to provide computational modeling and design support, including by using its technology platform to perform virtual screens, and Aconcagua is obligated to provide day-to-day chemistry and biology support.

Pursuant to the Aconcagua-Schrödinger Agreement, a joint steering committee comprised of representatives from both parties oversees the research performed under the agreement.

During the term of the Aconcagua-Schrödinger Agreement or if longer, for a specified number of years after the effective date of the Aconcagua-Schrödinger Agreement, Schrödinger is obligated, subject to certain exceptions, to work exclusively with Aconcagua on the design, research, development and commercialization of compounds that inhibit the target.

Aconcagua will solely own the research results, work product, inventions and other intellectual property

generated under the Aconcagua-Schrödinger Agreement other than improvements to Schrödinger’s background intellectual property.

During the term of the Aconcagua-Schrödinger Agreement, Aconcagua is obligated to pay Schrödinger a monthly active program payment in the low six digits, which payment includes fees payable for certain Schrödinger software employed in the Collaboration, and as of December 31, 2023, we have paid to Schrödinger an aggregate of $0.3 million.

If Aconcagua develops and commercializes a product containing a compound (“Aconcagua Collaboration Compound”) that is discovered or developed under the Aconcagua-Schrödinger Agreement or a derivative thereof (“Aconcagua Collaboration Product”), Aconcagua is obligated to pay Schrödinger development, regulatory and commercialization milestone payments of up to an aggregate of $89.0 million for the first Aconcagua Collaboration Product to achieve a particular milestone event, regardless of the number of Aconcagua Collaboration Products that reach such milestones.

Aconcagua will also be obligated to pay Schrödinger tiered royalties in the low single digit range on aggregate worldwide net sales of all Aconcagua Collaboration Products, subject to specified reductions and offsets.

Aconcagua’s obligation to pay royalties to Schrödinger will expire on a Aconcagua Collaboration Product-by- Aconcagua Collaboration Product and country-by-country basis on the later of (i) the expiration of the last-to-expire Aconcagua owned patent claim covering the composition of matter of the Aconcagua Collaboration Compound contained in such Aconcagua Collaboration Product in such country and (ii) ten years after the first commercial sale of such Aconcagua Collaboration Product in such country (“Aconcagua Royalty Term”).

Unless terminated earlier, the Aconcagua-Schrödinger Agreement will continue for three years, subject to extension by mutual written agreement of the parties.

Either party may terminate the Aconcagua-Schrödinger Agreement for convenience after a specified period or for the other party’s uncured material breach.

Aconcagua’s obligation to make milestone and royalty payments (subject to the Aconcagua Royalty Term) to Schrödinger continues after the expiration or termination of the Aconcagua-Schrödinger Agreement, unless the Aconcagua-Schrödinger Agreement is terminated under specified circumstances.

Manufacturing

We do not own or operate manufacturing facilities for the production of our product candidates and currently have no immediate plans to build our own clinical or commercial scale manufacturing capabilities.

We currently engage with third-party contract manufacturing organizations (“CMOs”) for the manufacture of our product candidates.

We currently engage with third-party contract manufacturing organizations (“CMOs”) in multiple geographies for the manufacture of our product candidates.

We rely on and expect to continue to engage third-party manufacturers for the production of both drug substance and finished drug product.

We currently obtain our supplies from these manufacturers on a purchase order basis and do not have long-term supply arrangements in place.

Should any of these manufacturers become unavailable to us for any reason, we believe that there are a number of potential replacements, although we may incur some delay in identifying and qualifying such replacements.

Should any of these manufacturers become unavailable to us for any reason, we believe that there are a number of potential replacements.

The biotechnology and pharmaceutical industries are characterized by rapid evolution of technologies, fierce competition and strong defense of intellectual property.

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Despite significant biopharmaceutical industry investment, no oral small molecule therapy targeting GLP-1R has been approved for the treatment of diabetes or obesity.

We are aware of GLP-1R small molecules in development by Pfizer, Eli Lilly, and Qilu Regor Therapeutics Inc.

We are aware of GLP-1R small molecules in

development by Eccogene (licensed by Astrazeneca in November 2023) Carmot Therapeutics (acquired by Roche in January 2024), Terns Pharmaceuticals, Pfizer, Eli Lilly, and Qilu Regor Therapeutics Inc.

There are currently approved GLP-1R peptides for the Pfizer, Eli Lilly, and Qilu Regor Therapeutics Inc.

There are currently approved GLP-1R peptides for the treatment of diabetes and obesity marketed by Novo Nordisk, Eli Lilly, AstraZeneca, and Sanofi.

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In addition, there are a number of companies developing product candidates for PAH utilizing approaches with different mechanisms of action, including but not limited to FibroGen, Inc., Galapagos NV, Galecto, Inc., Pliant Therapeutics, Inc., Gilead Sciences, Inc., Roche Holding AG and Boehringer Ingelheim.

We are aware of LPA1R targeted product candidates in development for IPF by BMS, Horizon Therapeutics plc, and DJS Antibodies Ltd;

We are aware of LPA1R targeted product candidates in development for IPF by BMS, Horizon Therapeutics plc (acquired by Amgen in October 2023), and DJS Antibodies Ltd;

and myelin restoration and neuroinflammation by Pipeline Therapeutics.

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Data Privacy and Security Laws

Numerous state, federal and foreign laws, regulations and standards govern the collection, use, access to, confidentiality and security of health-related and other personal information, and could apply now or in the future to our operations or the operations of our partners.

Numerous state, federal and foreign laws, regulations and standards govern the collection, use, access to, confidentiality and security of health-related and other personal or sensitive information, and could apply now or in the future to our operations or the operations of our partners.

In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws and consumer protection laws and regulations govern the collection, use, disclosure, and protection of health-related and other personal information.

In addition, certain foreign laws govern the privacy and security of personal data, including health-related data.

For example, the European Union General Data Protection Regulation (“EU GDPR”) imposes strict requirements for processing the personal data of individuals within the European Economic Area (“EEA”).

For example, the European Union General Data Protection Regulation (“EU GDPR”) imposes strict requirements for processing the personal data of individuals within

the European Economic Area (“EEA”).

Companies that must comply with the EU GDPR face increased compliance obligations and risk, including more robust regulatory enforcement of data protection requirements and potential fines for noncompliance of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater.

Further, from January 1, 2021, companies have had to comply with the GDPR and also the United Kingdom GDPR (“UK GDPR”) which, together with the amended UK Data Protection Act 2018, retains the GDPR in UK national law.

Further, from January 1, 2021, companies have had to comply with the GDPR and also the United Kingdom (“UK”) GDPR (“UK GDPR”) which, together with the amended UK Data Protection Act 2018, retains the GDPR in UK national law.

The UK GDPR mirrors the fines under the GDPR relating to fines up to the greater of £17.5 million or 4% of global turnover.

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The process of obtaining marketing approvals and the subsequent compliance with appropriate federal, state and local rules and regulations requires the expenditure of substantial time and financial resources.

Our drug candidates must be approved by the FDA through the New Drug Application (“NDA”) process before they

may be legally marketed in the United States.

Our drug candidates must be approved by the FDA through the NDA process before they may be legally marketed in the United States.

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

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Preclinical Studies and Clinical Trials

The preclinical development stage generally involves synthesizing the active component, developing the formulation and determining the manufacturing process, evaluating purity and stability, as well as carrying out non-human toxicology, pharmacology and drug metabolism studies in the laboratory, which support subsequent clinical testing.

non-human toxicology, pharmacology and drug metabolism studies in the laboratory, which support subsequent clinical testing.

The conduct of the preclinical tests must comply with federal regulations, including GLPs where applicable.

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GCPs also include the requirement that all research subjects provide their informed consent in writing for their participation in any clinical trial.

Clinical trials are conducted

under written study 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.

Clinical trials are conducted under written study 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.

Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND.

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Clinical trials are generally conducted in three sequential phases that may overlap or be combined, known as Phase I, Phase II and Phase III clinical trials.

The drug is initially introduced into a small number of healthy volunteers or patients with the target disease or condition who are initially exposed to a single dose and then multiple doses of the drug candidate.

The drug is initially introduced into a small number of healthy volunteers or patients with the target disease or condition who are initially exposed to a single dose and then multiple doses of

the drug candidate.

These studies are designed to assess the metabolism, pharmacologic action, dosage tolerance, side effects associated with increasing doses, and safety of the drug, and if possible, to gain early evidence on effectiveness.

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The FDA, the IRB, or the clinical trial 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, or an

institution it represents, 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.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, 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.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the drug in commercial quantities in accordance with cGMP requirements.

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Once filed, the FDA has a goal of ten months from the filing date to complete a standard review of an NDA for a drug that is a new molecular entity.

This review typically takes twelve 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.

This review typically takes twelve 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 reviews the NDA to determine, among other things, whether the proposed drug is safe and effective for its intended use, and whether the drug is being manufactured in accordance with cGMP to assure and preserve the drug’s identity, strength, quality and purity.

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After the FDA evaluates the application, manufacturing process and manufacturing facilities where the drug product and/or its API will be produced, it may issue an approval letter or a Complete Response Letter (“CRL”) An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.

A CRL indicates that the review cycle of the application is complete and the

application is not ready for approval.

A CRL indicates that the review cycle of the application is complete and the application is not ready for approval.

A CRL usually describes all of the specific deficiencies in the NDA identified by the FDA.

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Under the Pediatric Research Equity Act, an NDA or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the drug product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

A sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must also submit an initial Pediatric Study Plan (“PSP”) within sixty days of an end-of-Phase II meeting or as may be agreed between the sponsor and the FDA.

meeting or as may be agreed between the sponsor and the FDA.

The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.

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

exclusivity, meaning that the FDA may not approve any other applications for the same product for the same indication for seven years, including a full NDA, except in certain limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated.

If a product that has orphan drug designation subsequently receives the first FDA approval for a particular active ingredient for the disease for which it has such designation, the product is entitled to orphan product exclusivity, meaning that the FDA may not approve any other applications for the same product for the same indication for seven years, including a full NDA, except in certain limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated.

Orphan drug exclusivity does not prevent the FDA from approving a different drug for the same disease or condition, or the same drug for a different disease or condition.

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NDA holders using contract manufacturers, laboratories or packagers are responsible for the selection and monitoring of qualified firms, and, in certain circumstances, qualified suppliers to these firms.

These manufacturers must comply with cGMP regulations that require, among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

deviations from cGMP.

Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws.

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A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance.

During the exclusivity period, the FDA may not accept for review an abbreviated new drug application (“ANDA”), or an NDA submitted under Section 505(b)(2), or 505(b)(2) NDA, submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original reference drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval.

During the exclusivity period, the FDA may not accept for review an abbreviated new drug application (“ANDA”), or

an NDA submitted under Section 505(b)(2), or 505(b)(2) NDA, submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original reference drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval.

However, an application may be accepted for review after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA for the reference drug.

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Depending on the circumstances, failure to meet applicable regulatory requirements can result in criminal prosecution, fines, civil monetary or other penalties, injunctions, recall or seizure of drugs, total or partial suspension of production, denial or withdrawal of product approvals, additional regulatory oversight and integrity monitoring, exclusion from participation in government healthcare programs or refusal to allow a firm to enter into supply contracts, including government contracts.

In addition, even if a firm complies with FDA and other requirements, new information regarding the safety or efficacy of a product could lead the FDA to modify or withdraw product approval.

In addition, even if a firm complies with

FDA and other requirements, new information regarding the safety or efficacy of a product could lead the FDA to modify or withdraw product approval.

Prohibitions or restrictions on sales or withdrawal of future products marketed by us could materially affect our business in an adverse way.

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Under the Innovation Opinion and other recent reforms, the expedited programs and other advantages encourage drug manufacturers to seek marketing approval in China first and to develop drugs in high priority disease areas, such as oncology or rare disease.

To implement the regulatory reform introduced by the Innovation Opinion, the Standing Committee of the National People’s Congress of the PRC (“SCNPC”) and the National Medical Products Administration (“NMPA”) have recently revised the fundamental laws, regulations and rules governing pharmaceutical products and the pharmaceutical industry, including the amendment of the framework law known as the People’s Republic of China Drug Administration Law (“PRC Drug Administration Law”), which became

effective on December 1, 2019.

To implement the regulatory reform introduced by the Innovation Opinion, the Standing Committee of the National People’s Congress of the PRC (“SCNPC”) and the National Medical Products Administration (“NMPA”) have revised the fundamental laws, regulations and rules governing pharmaceutical products and the pharmaceutical industry, including the amendment of the framework law known as the People’s Republic of China Drug Administration Law (“PRC Drug Administration Law”), which became effective on December 1, 2019.

The State Administration for Market Regulation (“SAMR”) has promulgated two key implementing regulations for the PRC Drug Administration Law:

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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;

● federal false claims laws, including the False Claim Act and the Civil Monetary Penalties Law, which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, information or claims for payment from Medicare, Medicaid, or other third-party payers that are false or fraudulent.

In addition, a claim including items or services resulting from a violation of the U.S.

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● federal laws that require pharmaceutical manufacturers to report certain calculated product prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under government healthcare programs;

doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;

● the federal Physician Payments Sunshine Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually to the CMS, information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;

● HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (“HITECH”), and their implementing regulations, imposes obligations, including mandatory contractual terms, on “covered entities,” including certain healthcare providers, health plans, healthcare clearinghouses, and their respective “business associates,” and their subcontractors that create, receive, maintain or transmit individually identifiable health information for or on behalf of a covered entity, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;

● state law equivalents of the above federal laws, such as anti-kickback and false claims laws, which may apply to items or services reimbursed by any third-party payer, including private insurers, state transparency laws, state laws limiting interactions between pharmaceutical manufacturers and members of the healthcare industry, and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by federal laws, thus complicating compliance efforts.

● state law equivalents of the above federal laws, such as anti-kickback and false claims laws, which may apply to items or services reimbursed by any third-party payor, including private insurers, state transparency laws, state laws limiting interactions between pharmaceutical manufacturers and members of the healthcare industry, and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by federal laws, thus complicating compliance efforts.

We may also be subject to federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers.

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Additionally, there has been heightened governmental scrutiny in the United States of pharmaceutical pricing practices in light of the rising cost of prescription drugs and biologics.

Such scrutiny has resulted in several recent Congressional inquiries, presidential executive orders and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products.

Such scrutiny has resulted in several recent Congressional inquiries, presidential executive orders and proposed and enacted federal and state

legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products.

For example, in July 2021, the Biden administration released an executive order with multiple provisions aimed at prescription drugs.

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In addition, the IRA, among other things, (1) directs the HHS to negotiate the price of certain single-source drugs and biologics covered under Medicare and (2) 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.

Further, 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.

These provisions will take effect progressively starting in fiscal year 2023.

On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges.

In response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.

It is unclear whether the models will be utilized in any health reform measures in the future.

Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act.

On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.

While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework.

Other Significant Chinese Regulation Affecting Our Business Activities in China

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Pursuant to the PRC Company Law, where laws on foreign investment have other stipulations, such stipulations shall prevail.

The most recent amendment of the PRC Company Law was adopted in December 2023 and will come into effect on July 1, 2024, which introduced multiple updates to the current PRC Company Law with regard to, among others, the capital contribution liability, corporate governance structure and responsibilities of directors, supervisors, senior managers, controlling shareholders and actual controllers.

Investment activities in China by foreign investors are governed by the Guiding Foreign Investment Direction, which was promulgated by the State Council on February 11, 2002 and came into effect on April 1, 2002, and the latest Special Administrative Measures (Negative List) for Foreign Investment Access (2021) (the “Negative List”), which was promulgated by the Ministry of Commerce of the People’s Republic of China (“MOFCOM”), and National Development and Reform Commission (“NDRC”), on December 27, 2021 and took effect on January 1, 2022.

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The Negative List covers 12 industries, and any field not falling in the Negative List shall be administered under the principle of equal treatment to domestic and foreign investment.

The Foreign Investment Law of the People’s Republic of China (the “Foreign Investment Law”) was promulgated by the National People’s Congress (“NPC”) in March 2019 and become effective in January 2020.

After the Foreign Investment Law came into force, the Law on Wholly Foreign-Owned Enterprises of the People’s Republic of China, the Law on Sino-foreign Equity Joint Ventures of the People’s Republic of China and the Law on Sino-foreign Contractual Joint Ventures of the People’s Republic of China have been repealed simultaneously.

The Foreign Investment Law of the People’s Republic of China (the “Foreign Investment Law”) was promulgated by the National People’s Congress (“NPC”) in March 2019 and became effective in January 2020.

have been repealed simultaneously.

The investment activities of foreign natural persons, enterprises or other organizations (hereinafter referred to as foreign investors) directly or indirectly within the territory of China shall comply with and be governed by the Foreign Investment Law, including:

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A pharmaceutical company will not be penalized by the relevant Chinese government authorities merely by virtue of having contractual relationships with distributors or third-party promoters who are engaged in bribery activities, so long as such pharmaceutical company and its employees are not utilizing the distributors or third-party promoters for the implementation of, or acting in conjunction with them in, the prohibited bribery activities.

In addition, a pharmaceutical company is under no

legal obligation to monitor the operating activities of its distributors and third-party promoters, and it will not be subject to penalties or sanctions by relevant Chinese government authorities as a result of failure to monitor their operating activities.

In addition, a pharmaceutical company is under no legal obligation to monitor the operating activities of its distributors and third-party promoters, and it will not be subject to penalties or sanctions by relevant Chinese government authorities as a result of failure to monitor their operating activities.

Chinese Regulation of Product Liability

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In China, a patent must have novelty, creativity and practical applicability.

Under the PRC Patent Law, novelty means that before a patent application is filed, no identical invention or utility model has been publicly disclosed in any publication in China or overseas or has been publicly used or made known to the public by any other means, whether in or outside of China, nor has any other person filed with the patent authority an application that describes an identical invention or utility model and is recorded in patent application documents or patent documents published after the filing date.

Under the PRC Patent Law, novelty means that before a patent application is filed, no

identical invention or utility model has been publicly disclosed in any publication in China or overseas or has been publicly used or made known to the public by any other means, whether in or outside of China, nor has any other person filed with the patent authority an application that describes an identical invention or utility model and is recorded in patent application documents or patent documents published after the filing date.

Creativity means that, compared with existing technology, an invention has prominent substantial features and represents notable progress, and a utility model has substantial features and represents any progress.

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Failure to comply with this requirement will result in the denial of any Chinese patent for the relevant invention.

This added requirement of confidential examination by the CNIPA has raised concerns by foreign companies who conduct research and development activities in China or outsource research and development activities to service providers in China.

The PRC Patent Law also sets up the framework and adds the provisions for patent linkage and patent term extension.

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Manufacturers not meeting relevant legal requirements are not permitted to commence their manufacturing activities.

safety and labor protection measures in connection with the operation of their manufacturing equipment and manufacturing process.

Pursuant to the Administrative Measures Governing the Production Quality of Pharmaceutical Products effective on March 1, 2011, manufacturers of pharmaceutical products are required to establish production safety and labor protection measures in connection with the operation of their manufacturing equipment and manufacturing process.

Pursuant to applicable Chinese laws, rules and regulations, including the Social Insurance Law which became effective on July 1, 2011 and amended on December 29, 2018, the Interim Regulations on the Collection and Payment of Social Security Funds, which became effective on January 22, 1999 and amended on March 24, 2019, Interim Measures concerning the Maternity Insurance of Employees, which became effective on January 1, 1995, and the Regulations on Work-related Injury Insurance, which became effective on January 1, 2004 and was subsequently amended on December 20, 2010, employers are required to contribute, on behalf of their employees, to a number of social security funds, including funds for basic pension insurance, unemployment insurance, basic medical insurance, work-related injury insurance and maternity insurance.

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In July 2014, the State Administration of Foreign Exchange (“SAFE”), issued SAFE Circular 37 and its implementation guidelines.

Pursuant to SAFE Circular 37 and its implementation guidelines, residents of China (including Chinese institutions and individuals) must register with local branches of SAFE in connection with their direct or indirect offshore investment in an overseas special purpose vehicle (“SPV”), directly established or indirectly controlled by Chinese residents for the purposes of offshore investment and financing with their legally owned assets or interests in domestic enterprises, or their legally owned offshore assets or interests.

Pursuant to SAFE Circular 37 and its implementation guidelines, residents of

China (including Chinese institutions and individuals) must register with local branches of SAFE in connection with their direct or indirect offshore investment in an overseas special purpose vehicle (“SPV”), directly established or indirectly controlled by Chinese residents for the purposes of offshore investment and financing with their legally owned assets or interests in domestic enterprises, or their legally owned offshore assets or interests.

Such Chinese residents are also required to amend their registrations with SAFE when there is a change to the basic information of the SPV, such as changes of a Chinese resident individual shareholder, the name or operating period of the SPV, or when there is a significant change to the SPV, such as changes of the Chinese individual resident’s increase or decrease of its capital contribution in the SPV, or any share transfer or exchange, merger, division of the SPV.

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SAFE promulgated the Notice of the State Administration of Foreign Exchange on Reforming and Standardizing the Foreign Exchange Settlement Management Policy of Capital Account (“SAFE Circular 16”), effective on June 9, 2016, which reiterates some of the rules set forth in SAFE Circular 19, but changes the prohibition against using RMB capital converted from foreign currency-denominated registered capital of a foreign-invested company to issue RMB entrusted loans to a prohibition against using such capital to issue loans to unassociated enterprises.

Violations of SAFE Circular 19 or SAFE Circular 16 could result in administrative penalties.

On December 4, 2023, SAFE promulgated the Notice of the State Administration of Foreign Exchange on Further Deepening the Reform and Promoting Facilitation of Cross-border Trade and Investment (“SAFE Circular 28”), which further updates the restrictions on use of RMB converted from the foreign currency- denominated capital.

Violations of SAFE Circular 19, SAFE Circular 16 or SAFE Circular 28 could result in administrative penalties.

The Circular of Further Improving and Adjusting Foreign Exchange Administration Policies on Foreign Direct Investment was promulgated by SAFE in November 2012 and amended in May 2015, which substantially amends and simplifies the current foreign exchange procedure.

Pursuant to this circular, the opening of

various special purpose foreign exchange accounts ( e.g.

Pursuant to this circular, the opening of various special purpose foreign exchange accounts ( e.g.

, pre-establishment expenses accounts, foreign exchange capital accounts and guarantee accounts), the reinvestment of lawful incomes derived by foreign investors in China ( e.g.

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In addition, SAFE promulgated the Circular on Printing and Distributing the Provisions on Foreign Exchange Administration over Domestic Direct Investment by Foreign Investors and the Supporting Documents in May 2013, which specifies that the administration by SAFE or its local branches over direct investment by foreign investors in China shall be conducted by way of registration and banks shall process foreign exchange business relating to the direct investment in China based on the registration information provided by SAFE and its branches.

In February 2015, SAFE promulgated the Circular on Further Simplifying and Improving the Policies Concerning Foreign Exchange Control on Direct Investment (“SAFE Circular 13”), which took effect on June 1, 2015.

June 1, 2015.

SAFE Circular 13 delegates the authority to enforce the foreign exchange registration in connection with the inbound and outbound direct investment under relevant SAFE rules to certain banks and therefore further simplifies the foreign exchange registration procedures for inbound and outbound direct investment.

Regulations on Securities Offering and Listing Outside of China

On February 17, 2023, the CSRC promulgated a new set of regulations consisting of the Trial Administrative Measures of Overseas Securities Offering and Listing by Domestic Companies (the “Trial Measures”) and five supporting guidelines which will come into effect on March 31, 2023 to regulate overseas securities offering and listing activities by domestic companies either in direct or indirect form.

On February 17, 2023, the CSRC promulgated a new set of regulations consisting of the Trial Administrative Measures of Overseas Securities Offering and Listing by Domestic Companies (the “Trial Measures”) and five supporting guidelines which came into effect on March 31, 2023 to regulate overseas securities offering and listing activities by domestic companies either in direct or indirect form.

The Trial Measures and supporting guidelines apply to overseas offerings by domestic companies of equity shares, depositary receipts, convertible corporate bonds, or other equity-like securities, and overseas listing of the securities for trading.

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(ii) the majority of the senior management in charge of business operation and management of the issuer are Chinese citizens or habitually reside in China, or its main places of business operation are located in China or main parts of its business activities are conducted in China.

Under the Trial Measures and supporting guidelines, a filing-based regulatory system would be implemented covering both direct and indirect overseas offering and listing.

Under the Trial Measures and supporting guidelines, a filing-based regulatory system was implemented covering both direct and indirect overseas offering and listing.

For an indirect initial public offering and listing in an overseas market, the issuer shall designate a major domestic operating entity to submit the filing documents to the CSRC, including but not limited to the prospectus within three working days after such application of overseas offering and listing is submitted.

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If domestic companies fail to fulfill the above-mentioned filing procedures or offer and list in an overseas market against the prohibited circumstances, they would be warned and fined up to RMB 10 million.

The controlling shareholders and actual controllers of such domestic companies that organize or instruct the aforementioned violations would be fined up to RMB10 million and directly liable persons-in-charge and other directly liable persons would be each fined up to RMB 5 million.

Other Chinese National- and Provincial-Level Laws and Regulations.

The controlling shareholders and actual controllers of such domestic companies that organize or instruct the

aforementioned violations would be fined up to RMB10 million and directly liable persons-in-charge and other directly liable persons would be each fined up to RMB 5 million.

Other Chinese National- and Provincial-Level Laws and Regulations

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Of these 93 employees, 66 were engaged in research and development activities and 27 were engaged in business development, finance, information systems, facilities, human resources or administrative support.

Five of the non-research and development-based employees were based in Shanghai, China while the other 18 resided in the United States.

Four of the non-research and development-based employees were based in Shanghai, China and one based in the UK, while the other 22 resided in the United States.

None of our employees are represented by labor unions or covered by collective bargaining agreements.

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Our principal executive office is located at 601 Gateway Blvd., Suite 900, South San Francisco, California 94080 and our telephone number is (628) 229-9277.

The principal executive office of our research and development operations is located at Unit 02, F5, No.

1, Lane 2889, Jinke Road, China (Shanghai) Free Trade Zone, Shanghai, People’s Republic of China, 201203.

The principal executive office of our research and development operations is located at Unit 01, 11th floor, Lane 2889, Jinke Road, Pudong New Area, Shanghai, People’s Republic of China, 201203.

Our telephone number at this address is 86 21 61215839.

Our current registered office in the Cayman Islands is located at the offices of International

Corporation Services Ltd., P.O, Box 472, 2nd Floor, Harbour Place, 103 South Church Street, George Town, Grand Cayman KY1-1106, Cayman Islands.

Our current registered office in the Cayman Islands is located at the offices of International Corporation Services Ltd., P.O, Box 472, 2nd Floor, Harbour Place, 103 South Church Street, George Town, Grand Cayman KY1-1106, Cayman Islands.

Our website is www.structuretx.com.

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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