What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2024-03-26 compared with 2023-03-23 · 152 added, 175 removed, 558 unchanged (37% of the section changed)

We are a biotechnology company developing novel small molecule therapeutics to treat diseases across several therapeutic areas, including, central nervous system (“CNS”) disorders, lysosomal storage disorders (“LSDs”), metabolic disorders, and other diseases that can be targeted through protein degradation, such as oncology.

We use our exclusively in-licensed computational target and drug discovery platform, Site-Directed Enzyme Enhancement Therapy (“SEE-Tx®”), to discover novel allosteric binding sites on proteins implicated in a disease and to identify proprietary small molecules that bind these sites to modulate protein function and treat the underlying cause of the disease.

We believe that SEE-Tx® is uniquely suited to identify allosteric binding sites on the protein surface, which are different from the protein’s active (or orthosteric) binding site where the natural ligand of the protein binds.

GT-02287 - our lead product candidate:

for the treatment of GBA1 Parkinson’s disease and other synucleinopathies

Our clinical stage product candidate, GT-02287, is being developed for the treatment of GBA1 Parkinson’s disease.

We have generated an extensive preclinical data package providing evidence of the mechanism of action and safety of GT-02287.

In preclinical models of GBA1 Parkinson’s disease, GT-02287 has been shown to restore glucocerebrosidase, or GCase, function in the lysosome, reduce toxic lipid substrates and toxic forms of alpha-synuclein, improve survival of dopaminergic neurons, increase dopamine levels, completely restore locomotor function, and reduce plasma-based neurodegeneration maker, neurofilament light chain, or NfL, back to the level of healthy animals.

In September 2023, we initiated in Australia the first-in-human Phase 1 clinical trial to assess the safety, tolerability, pharmacokinetics, and food effect of GT-02287 in healthy participants.

The study design includes a single ascending dose part during which the study participants receive one dose of GT-02287 at different dose levels, and a multiple ascending dose part during which the study participants receive one daily dose of GT-02287 for 14 days at different dose levels.

In February 2024, we initiated the multiple ascending dose part of this Phase 1 clinical trial, which we anticipate completing in the second quarter of 2024, with the availability of the quality assurance audited interim report in the third quarter of 2024.

We are planning to expand the scope of this Phase 1 clinical trial by amending the study protocol to include a cohort of 12-15 patients with Parkinson’s disease.

These patients will be treated for a period of three months to evaluate safety, tolerability, and pharmacokinetics in patients, as well as to assess the effect of GT-02287 on certain biomarkers of the GCase disease cascade.

In preparation for the treatment of Parkinson’s disease patients, in September 2023, we initiated the sub chronic (13 weeks treatment) preclinical toxicity study.

The in-vivo phase of the preclinical toxicity study was concluded in January 2024 with the final, quality assurance audited, report expected by the beginning of the second quarter of 2024.

In addition, we are planning to initiate the chronic (6 months in rodents and 9 months in non-rodents) preclinical toxicity study in the second half of 2024, enabling the conduct of clinical studies in patients with a GT-02287 treatment duration beyond three months.

Our Magellan™ Platform

We use our computational target and drug discovery platform, Magellan™, to discover novel allosteric binding sites on proteins implicated in a disease and to identify proprietary small molecules that bind these sites to modulate protein function and treat the underlying cause of the disease.

We believe that Magellan™ is uniquely suited to identify allosteric binding sites on the protein surface, which are different from the active (or orthosteric) binding site where the natural ligand of the protein binds.

Targeting an allosteric binding site instead of the active binding site of a protein provides numerous advantages, including:

2 unchanged sentences

and the ability to identify small molecules with more favorable drug-like properties.

The SEE-Tx® platform has been used to identify novel allosteric sites and small molecules for all of our internal programs and partnered programs.

The Magellan™ drug discovery platform is an evolution of its predecessor SEE-Tx®, or Site-Directed Enzyme Enhancement Therapy.

Magellan™ integrates and adds to the foundational models of SEE-Tx® with proprietary AI and machine learning tools that enable the screening of over 50 billion compounds.

Discovering and targeting novel allosteric sites with our platform not only reduces traditional drug discovery timelines but enables rational drug design and offers the potential for superior small molecule drugs that are highly specific and that can penetrate hard to reach tissues and cross the blood-brain barrier.

Our Lead Product Candidate:

GT-02287 for the Treatment of GBA1 Parkinson’s disease

Our lead product candidate, GT-02287, is being developed for the treatment of GBA1 Parkinson’s disease, including restoration of GCase function, reduction of toxic lipid substrates and toxic forms of alpha-synuclein, improved survival of dopaminergic neurons, and increase of dopamine levels and improved locomotor function in animal models.

We have generated an extensive preclinical data package providing evidence of the mechanism of action of GT-02287, and we anticipate completing IND-enabling toxicology studies by the first half of 2023.

We plan to commence a first- in-human, Phase 1 dose escalation clinical trial in Australia of GT-02287 by the second half of 2023.

The primary objectives of the Phase 1 clinical trial in Australia will be to evaluate administration of both single and multiple ascending dose levels of GT-02287 in healthy volunteers to assess safety and pharmacokinetics.

Our Research Programs Using SEE-Tx® Platform

In addition, we plan to continue to advance research programs and initiate additional programs targeting allosteric binding sites identified with the SEE-Tx® platform in various therapeutic areas, mainly oncology.

Through academic partnerships, co-development and licensing arrangements, we intend to develop a broad pipeline of therapeutics, using our novel approach of identifying and targeting previously unknown allosteric sites.

Our Research Programs

We have used the Magellan™ drug discovery platform to identify novel allosteric sites and small molecules for all of our pipeline programs.

We plan to continue to advance our existing research programs and initiate additional programs targeting allosteric binding sites identified with the Magellan™ platform in various therapeutic areas through academic partnerships, co-development and licensing arrangements.

Our Platform for Computational Target and Drug Discovery

A majority of disease-causing proteins (up to 90%) cannot be targeted due to the lack of a known binding site.

Our exclusively in-licensed SEE-Tx® platform was designed to address this problem.

Our Magellan™ platform was designed to address this problem.

We use the platform to discover novel binding sites on proteins implicated in a disease and to identify proprietary small molecules that bind these sites to modulate protein function and treat the underlying cause of the disease.

1 unchanged sentence

We refer to the small molecules we identify that bind to these allosteric sites as structurally targeted allosteric regulators, or STARs, to reflect their mechanism of action and how they are discovered.

The graphic below provided an overview of SEE-Tx®.

The graphic below provides an overview of Magellan™.

Allosteric Binding Site Identification

Using the three-dimensional structure of proteins that have been experimentally derived or generated or predictive protein structures from AI-powered databases such as Alphafold, our SEE-Tx® platform applies various computational methods and proprietary algorithms to identify and map previously uncharacterized clusters of binding hotspots on the protein surface where a small molecule can potentially bind.

Using the three-dimensional structure of proteins that have been experimentally derived or generated or predictive protein structures from AI-powered databases such as Alphafold, our Magellan™ platform applies various computational methods and proprietary algorithms to identify and map previously uncharacterized clusters of binding hotspots on the protein surface where a small molecule can potentially bind.

The number, density, nature and quality of these hotspot clusters determine the druggability of the protein, which refers to whether drug-like small molecules can effectively bind to the particular site on the target protein with an appropriate potency.

Advantages of Targeting Allosteric Binding Sites

We focus on allosteric binding site, which offer a number of advantages compared to targeting the active binding site of a protein, including the ability to regulate proteins implicated in disease through several different mechanisms of action covering both functional and conformational effects, improved specificity of small molecules because binding to an allosteric binding site is non-competitive with the natural ligand that binds to the active binding site, and the ability to identify small molecules with more favorable drug-like properties.

The graphic below provided an overview of the differences and benefits of allosteric binding sites compared to active binding sites.

We focus on allosteric binding sites, which offer a number of advantages compared to targeting the active binding site of a protein, including the ability to regulate proteins implicated in disease through several different mechanisms of action covering both functional and conformational effects, improved specificity of small molecules because binding to an allosteric binding site is non-competitive with the natural ligand that binds to the active binding site, and the ability to identify small molecules with more favorable drug-like properties.

The graphic below provides an overview of the differences and benefits of allosteric binding sites compared to active binding sites.

Identification of Structurally Targeted Allosteric Regulators (“STARs”) – Our Molecular Hypothesis

After an allosteric site has been identified, characterized and selected for targeting, we then use our proprietary structure-based virtual screening methodology to filter a pool of seven to ten million commercially-available compounds to identify those that may potentially bind to the hotspot and have a functional effect.

After an allosteric site has been identified, characterized and selected for targeting, we then use our proprietary structure-based virtual screening methodology to explore virtual chemical libraries of over 50 billion compounds to identify those that may bind to the hotspot and have a functional effect.

Using this information, we develop structural templates to guide the development of a narrowed pool of unique and proprietary small molecules that bind to the newly discovered allosteric sites.

4 unchanged sentences

In contrast, our approach is significantly less expensive, significantly faster and significantly more effective.

We run our SEE-Tx® simulations for target and drug discovery in supercomputer centers where we pay only for time used as and when needed.

We can identify a novel allosteric site in one to two weeks, perform virtual screening in three to four weeks, and validate compounds experimentally in two to three weeks.

Our average hit rate for validated compounds is 14%, a greater than 100-fold higher success rate compared to traditional high throughput screening methods.

Further, every small molecule hit identified by our platform is experimentally tested based on a two-part molecular hypothesis to confirm that (1) the compound has a positive effect on the relevant biomarkers implicated in the disease and (2) binding to the allosteric binding site identified with the SEE-Tx® platform has the intended effect on protein function.

We run our Magellan™ simulations for target and drug discovery in supercomputer centers where we pay only for time used as and when needed.

We can identify a novel allosteric site in one to two weeks, set up and complete virtual screening in three to four weeks, and validate compounds experimentally in two to three weeks.

Our average success rate for experimentally validated compounds is 14%, a greater than 100-fold higher success rate compared to traditional high throughput screening methods.

Further, every small molecule hit identified by our platform is experimentally tested based on a two-part molecular hypothesis to confirm that (1) the compound has a positive effect on the relevant biomarkers implicated in the disease and (2) binding to the allosteric binding site identified with the Magellan™ platform has the intended effect on protein function.

Allosteric Regulators Cover Several Mechanisms of Action

2 unchanged sentences

However, in areas such as oncology, we have identified STARs that are designed to destabilize target proteins by binding to a non-native or mutant form of the protein and render it inactive.

There are several additional potential mechanisms of action including allosteric targeted protein degradation, as well as traditional allosteric inhibition or activation by inducing a conformational change to inhibit or induce binding by the natural ligand of the active site of the protein.

The graphic below provides an overview of the different mechanism of action available through allosteric binding sites.

There are several additional potential mechanisms of action including allosteric targeted protein degradation, as well as traditional allosteric inhibition or activation by inducing a

conformational change to inhibit or induce binding by the natural ligand of the active site of the protein.

The graphic below provides an overview of the different mechanisms of action available through allosteric binding sites.

Enzyme Misfolding and Disease

5 unchanged sentences

Therapeutic small molecules that facilitate the folding of enzymes into their correct shape can restore function and the proper processing of substrate.

As illustrated below, in LSDs, the gene that codes for an enzyme is

mutated and results in a misfolded enzyme.

As illustrated below, in genetic diseases caused by protein misfolding and dysfunction, such as LSDs or GBA1 Parkinson’s disease, the gene that codes for an enzyme is mutated and expresses a misfolded enzyme.

The misfolded enzyme cannot traffic through the cell resulting in toxic substrate accumulation in the lysosome.

We believe that our STARs will have the ability to bind to the allosteric site of the defective enzyme and restore wild type activity and thus serve as potential therapeutic treatments for diseases.

The graphic below provided an overview of the postulated mechanism of action.

The graphic below provides an overview of the postulated mechanism of action .

Limitations of Current Therapies for the Treatment of LSDs

Current therapeutic approaches to address misfolded enzymes have inherent limitations.

In standard chaperone therapy, the drug binds to the active site of the enzyme or other target protein which impairs the protein’s function to some degree by competing with the active substrate, decreasing efficacy and potentially leading to selectivity issues.

Drugs that binds to the active site of the enzyme or other target protein impair the protein’s function to some degree by competing with the active substrate, decreasing efficacy and potentially leading to selectivity issues.

Other treatments such as enzyme replacement therapy, or ERT, in which new functional enzymes are infused into the patient, are not suitable for treating neurological conditions because currently available ERTs cannot cross the blood-brain barrier.

Gene therapy, which aims to replace mutated genes with non-mutated genes that then can express functional enzymes, is not readily accepted for treating neurological conditions because the procedure is invasive in nature and the efficacy of treating neurological conditions remains to be established.

neurological conditions remains to be established.

In addition, clinical development, manufacturing and commercialization of gene therapies remains challenging in light of safety risks, complex manufacturing processes and high production costs, and difficulties in establishing prices acceptable to payors and health care systems.

Given these limitations on current therapies and novel therapeutics approaches, we believe patients would benefit from mall molecules acting as structurally targeted allosteric regulators that offer a new therapeutic approach both on their own and, potentially, in combination with existing therapies.

Given these limitations on current therapies and novel therapeutics approaches, we believe patients would benefit from small molecules acting as structurally targeted allosteric regulators that offer a new therapeutic approach both on their own and, potentially, in combination with existing therapies.

We believe our therapeutic approach represents a potentially significant change from current approaches by addressing protein misfolding using our efficient and proprietary ability to identify previously undiscovered allosteric sites and compounds that avoid the active sites of enzymes and cross the blood-brain barrier or penetrate other hard-to-treat tissues such as bone and cartilage.

Our Pipeline of STARs

We are leveraging our SEE-Tx® technology platform to develop a pipeline of novel small molecule drug candidates to address complex diseases.

We are leveraging our Magellan™ technology platform to develop a pipeline of novel small molecule drug candidates to address complex diseases.

The platform is disease agnostic and provides us with the ability to expand our pipeline, quickly, efficiently and at low cost.

We are currently focusing on progressing our programs in Parkinson’s and Gaucher disease.

We are also continuing to develop our program in Krabbe disease and liver and lung disease, and applying our SEE-Tx® platform to establish new programs in oncology.

We are seeking non-dilutive funding in order to progress our other research programs in additional lysosomal storage disorders and metabolic diseases.

We are currently focusing on progressing our clinical-stage lead program in Parkinson’s disease.

In addition, we plan to continue to advance our existing research programs and initiate additional programs targeting allosteric binding sites identified with the Magellan™ platform in various therapeutic areas through discovery collaborations with industry partners and academic institutions.

Our Product Pipeline

GCase Enzyme-Related Disorders:

GBA1 Parkinson’s Disease and Neuronopathic Gaucher Disease

We are investigating the restoration of GCase enzymatic function as a treatment for Parkinson’s Disease, or PD, and neuronopathic Gaucher disease, or nGD, an LSD.

GCase is an enzyme encoded by the GBA1 gene and found in lysosomes that is needed to breakdown the large molecule glucocerebroside (a component of the cell membrane) into sugar and fat.

Homozygous mutations of the GBA1 gene lead to the misfolding of GCase and associated GCase dysfunction and degradation, which in turn can lead to accumulation of GCase substrates to toxic levels in the liver, spleen, bone marrow and brain and can result in lysosomal storage and neurodegenerative diseases.

Unlike other types of Gaucher disease, none of the existing therapeutics are effective in treating nGD.

GBA1 gene mutations are also found in the most pathogenic form of Parkinson’s disease, or PD, where heterozygous mutations of the GBA1 gene also lead to the misfolding of GCase and reduced GCase activity, which similarly leads to accumulation of toxic levels of lipid substrate as well as alpha-synuclein, a pathological hallmark of Parkinson’s disease.

Decreased GCase activity is also observed in idiopathic PD (PD that occurs in patients without GBA1 mutations) and Dementia with Lewy Bodies.

Currently, there is no cure for nGD or PD, and there are no treatment options that can halt or delay neuronal cell death, the underlying cause of the disease.

Current treatments such as ERT cannot address central nervous system symptoms because they cannot cross the blood-brain barrier.

GCase Enzyme-Related Neurodegenerative Diseases and LSDs

GCase is a lysosomal enzyme encoded by the GBA1 gene that is needed to break down fatty chemicals, in particular glucosylceramide and glucosylsphingosine, into sugar and fat.

If GCase is dysfunctional or not available at sufficient levels, these fatty chemicals start to aggregate and eventual become toxic to the cells, leading to cell death.

Our clinical-stage lead product candidate GT-02287 has been shown to restore enzymatic function of GCase in the lysosome, which may be useful as a treatment for Parkinson’s disease, or PD, neuronopathic Gaucher disease, or nGD, an LSD, and other neurodegenerative diseases, including dementia with Lewy bodies and Alzheimer’s disease.

Overview of GBA1 Parkinson’s Disease

Parkinson’s disease is a disorder of the central nervous system that affects movement, often including tremors.

Damage to dopaminergic neurons in the brain causes dopamine levels to drop, leading to the symptoms of Parkinson's disease.

Parkinson's disease often starts with a tremor in one hand and other symptoms including slow movement, stiffness and loss of balance, and progresses to a severely debilitating disease that eventually requires full-time home care or a transfer to a skilled nursing facility.

GBA1 Parkinson’s disease is caused by mutations in the GBA1 gene, which are the major genetic risk factor for the development of Parkinson’s disease and related neurodegenerative disorders characterized by the accumulation of alpha-synuclein in cell bodies of neurons.

Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease.

Death of dopaminergic neurons in the brain causes dopamine levels to drop, leading to the symptoms of Parkinson's disease, which often start with a tremor in one hand and other symptoms including slow movement, stiffness and loss of balance, and progresse to a severely debilitating disease that eventually requires full-time home care or a transfer to a skilled nursing facility.

GBA1 Parkinson’s disease is associated with heterozygous mutations in the GBA1 gene, which leads to the expression of misfolded and dysfunctional GCase.

It is widely accepted that GCase deficiency has a biological role as a modifier or facilitator of Parkinson’s disease pathogenesis in the brain.

Brain autopsy studies have shown that decreased levels of GCase are also found in patients with idiopathic Parkinson’s disease (without GBA1 mutations).

Reduced GCase

activity may enhance the risk for Parkinson’s disease by facilitating a pathological hallmark, namely alpha-synuclein accumulation.

Alpha-synuclein accumulation and GCase deficiency are thought to act in a debilitating cycle.

GCase deficiency can cause the accumulation of glucosylsphingosine substrate, which has been reported to directly affect the accumulation and aggregation of alpha-synuclein.

In addition, increased alpha-synuclein levels can lead to less GCase activity, which in turn can lead to more alpha-synuclein accumulation.

Parkinson’s disease is reported to affect about 1 in 780 people worldwide or approximately one million worldwide.

Up to 15% of patients with Parkinson’s disease carry GBA1 mutations, making it the major genetic risk factor for the disease and this rate is higher in certain patient populations.

Reduced GCase activity may enhance the risk for Parkinson’s disease by facilitating a pathological hallmark, namely aggregated alpha-synuclein accumulation.

Aggregated alpha-synuclein accumulation and GCase deficiency are thought to act in a debilitating cycle.

GCase deficiency can cause the accumulation of glucosylceramide and glucosylsphingosine substrates, which has been reported to directly affect the accumulation and aggregation of alpha-synuclein.

In addition, increased aggregated alpha-synuclein levels can lead to less GCase activity, which in turn can lead to more aggregated alpha-synuclein accumulation.

Parkinson’s disease is reported to affect more than ten million people worldwide.

Up to 15% of patients with Parkinson’s disease carry GBA1 mutations, making it the largest genetic risk factor for the disease, and this rate is higher in certain ethnic populations.

At present, there is no effective cure for Parkinson’s disease.

4 unchanged sentences

Overview of Gaucher Disease

Gaucher disease is an inherited LSD caused by homozygous mutations of the GBA1 gene that result in the misfolding and subsequent dysfunction of GCase, an enzyme that breaks down fatty chemicals in the body.

Gaucher disease is an inherited LSD caused by homozygous mutations of the GBA1 gene that result in the misfolding and subsequent dysfunction of GCase.

Gaucher disease is traditionally classified according to one of three types.

9 unchanged sentences

People with Gaucher disease type 3 may survive into adulthood with a wide variety of signs and symptoms, including seizures, skeletal irregularities, eye movement disorders, cognitive and coordination problems as well as enlarged liver and spleen, respiratory problems, and blood disorders.

Gaucher disease is caused by mutations of the GBA1 gene that encodes GCase, an enzyme which catalyzes a key step in breaking down glucosylceramide and glucosylsphingosine.

Gaucher disease is caused by mutations of the GBA1 gene, which leads to the expression of misfolded and dysfunctional GCase.

Partial or complete loss of GCase activity can cause the buildup of glucosylceramide and glucosylsphingosine in the lysosomes of macrophages, and the accumulation of these lipid substrates in neuronal cells can result in neurological symptoms.

4 unchanged sentences

ERT does not cross the blood-brain barrier and is not efficient in treating neurological manifestations, therefore creating a significant unmet medical need in this patient population.

Overview of Dementia with Lewy Bodies and Alzheimer’s Disease

Dementia with Lewy bodies (DLB) and Alzheimer’s disease are both dementia types that lead to decline in memory, thinking and behavior.

In DLB, deposits of the protein alpha-synuclein aggregate in neuronal cells and form inclusions called Lewy bodies.

GT-02287 has been shown to reduce alpha-synuclein aggregation in preclinical models.

In Alzheimer’s disease, the main pathophysiology involves the development of amyloid plaques and neurofibrillary tangles.

Lysosomal dysfunction has been shown to play a role in aggregation of Tau and development

of amyloid plaques.

GT-02287 has been shown to reduce tau hyperphosphorylation and neuronal death in response to aggregated amyloid-beta in preclinical models.

Preclinical Characterization of Lead Compound GT-02287 for the Treatment of GBA1-related Diseases

We have continued to assess the performance of our lead compounds GT-02287 and GT-02329 in the various cell-based and animal models of PD and GD that we have performed with these compounds.

As more data have been generated, we determined that both molecules have similar properties and are similarly suitable for the development in GBA1 PD and nGD.

In light of the totality of the data generated with these compounds to date, we have determined to select GT-02287 as the drug candidate for all GBA1-related disease and to maintain GT-02329 as a potential back-

up compound to GT-02287.

This decision resulted in a reduction of projected development costs of our GBA1 program of approximately $8.4 million.

We have assessed the effect of our lead product candidate GT-02287 in various cell-based and animal models of PD and GD.

Activity in Biophysical and Cell-based Assays

Biophysical assay results have demonstrated that GT-02287 binds to the GCase protein and increases its thermal stability.

In cell-based functional assays, we observed a dose-dependent increase in GCase activity in normal and GCase mutant cells when treated with GT-02287 as well as a concomitant depletion of the GCase substrate, glucosyl ceremide.

Our STAR compound also has shown GCase enzyme enhancement in an extended panel of patient derived cells representative of the most frequent and pathogenic GBA1 mutations related to GBA1 PD and nGD.

GT-02287 also has shown GCase enzyme enhancement in an extended panel of patient-derived cells representative of the most frequent and pathogenic GBA1 mutations related to GBA1 PD and nGD.

In addition, we reported that GT-02287 increased GCase enzyme levels, co-localization of GCase with lysosomes, reduced GlcCer accumulation as well as phosphorylated and aggregated a-synuclein accumulation in cells derived from L444P/RecNcil and L444P/L444P patients .

Toxicology and Safety

GLP toxicology studies have shown that GT-02287 is well tolerated following single oral administration of 2000 mg/kg and 1000 mg/kg for male and female rats, respectively, and 1000 mg/kg in male and female dogs.

The GLP toxicology study with repeated administrations of GT-02287 in male and female dogs and rats is currently ongoing.

No severe toxicity has been encountered up to 1000 mg/kg in dog after 14 day administration, corresponding to a human equivalent dose of 33 g per day (based on 60 kg as a standard human subject body weight).

We anticipate completing IND-enabling toxicology studies in the first half of 2023 with the goal of filing the dossier required to commence a first-in-human, Phase 1 clinical trial of GT-02287 in the second half of 2023.

Pharmacokinetics

2 unchanged sentences

In-Vivo Pharmacology in PD Animal Models

In mice administered the GCase inhibitor CBE (conduritol beta epoxide) plus intra-striatal injected alpha-synuclein pre-formed fibrils, or PFF, to simulate the effects of GBA1 Parkinson’s disease.

GT-02287 was orally administered once a day, at doses of 30, 60 and 90 mg/kg.

The data generated in this study showed a statistically significant augmentation of GCase activity, reduction of the accumulation of the toxic substrates glucosylsphingosine and glucosylceramide, a reduction of aggregated alpha synuclein, and a reduction of microgliosis, which is an indicator of reduced neuroinflammation.

In the same animal model, GT-02287 improved the survival of dopaminergic neurons in the substantia nigra.

Notably, these biological effects resulted in a dose-dependent behavioral effect shown by improved neuromotor strength as measured by the “wire-hang” test.

In a rotenone -induced Parkinson’s disease rat model, GT-02287 was administered orally, twice a day for seven days at a dose of 30, 60 and 90 mg/kg bodyweight .

In this study, we observed that GT-02287 showed a reduction of total, aggregated and phosphorylated alpha-synuclein as well as a reduction in microgliosis.

In addition GT-02287 improved the survival of dopaminergic neurons along with an increased level of dopamine in the striatum.

Notably, these biological effects resulted in a dose-dependent behavioral effect shown by an improvement of the motor functionality measured by assessing the rearing behavior.

To verify the potential difference of a twice-a-day and once-a-day dose regimen, the rotenone rat model was repeated administering GT-02287 orally once per day for 10 days at the dose range 60 and 90 mg/kg.

The study provided a similar read-out for aggregated alpha-synuclein and survival of dopaminergic neurons in the substantia nigra thus suggesting that once-a-day oral administration can provide a similar efficacy to twice-a-day administration.

In addition, GT-02287 was shown to reduce tumor necrosis factor alpha (TNF-alpha), a biomarker for

neuroinflammation, in the substantia nigra as well as augment GCase activity in the brain as shown by an increase of GCase activity in cerebrospinal fluid (CSF).

Results of the CBE/PFF Mouse Model

GCase Activity (plasma) Glucosylceremide (brain) Glucosylspingosine (brain) Motor (wire hang)

Results of the Rotenone Rat Model

In Vivo Pharmacology in GD Animal Models

In mice administered the GCase inhibitor CBE to model Gaucher’s disease, our product candidate GT-02329 was orally administered once a day at a doses of 60 and 90 mg/kg.

The data generated in this study showed a statistically significant augmentation of GCase activity in plasma and various different brain regions, reduction of the accumulation of the toxic substrates glucosylsphingosine and glucosylceramide and a reduction of Iba-1 levels, a marker of microgliosis, which is an indicator of reduced neuroinflammation.

In the same animal model, treatment with GT-02329 caused dose-dependent behavioral effect shown by improved motor strength as measured by the “wire-hang” test.

Results of the CBE Mouse Model

Iba-1 levels in brains of CBE-injected mice treated with GT-02329 Motor Function

In mice administered the irreversible GCase inhibitor CBE (conduritol beta epoxide) to simulate the effects of reduced GCase activity seen in GBA1 Parkinson’s disease and GD, GT-02287 was orally administered once a day, at doses of 30, 60 90 and 120 mg/kg.

The data generated in this study showed statistically significant reduction of aggregated alpha-synuclein, reduced microgliosis, or neuroinflammation, as measured by Iba-1 staining, increased survival of dopaminergic neurons in the substantia nigra, as measured by tyrosine hydroxylase staining, increased dopamine levels in the striatum, increased survival of cortical neurons, and decreased levels of NfL (neurofilament light chain), an emerging neurodegeneration biomarker, in the plasma.

These biological effects were accompanied by a dose-dependent behavioral effect shown by improved neuromotor strength as measured by the wire hang test and increased coordination as measured by the beam walk test.

GT-02287 increases dopaminergic and cortical neuronal survival, decreases NfL in plasma, and improves motor function in the CBE Mouse Model

In a therapeutic paradigm in a model in which mice were administered with low levels of CBE every second day and received an injection of alpha-synuclein preformed fibrils directly into the brain to mimic GBA1 Parkinson’s disease, GT-02287 completely restored motor function in the wire hang test even following a delayed administration of the drug candidate after the initial toxic insult.

Rescue of locomotor impairment was reflected in the complete reversal of plasma levels of NfL, the emerging neurodegeneration biomarker, to the level of the control arm in the study, which also suggests a neuroprotective effect of GT-02287.

GT-02287 displays neuroprotection and restores motor function in preclinicaltherapeutic models of Parkinson’s disease.

Nonclinical Toxicology and Safety Studies

The GLP in vivo safety pharmacology and general toxicity studies have been successfully concluded, thus enabling the initiation of the first-in-human clinical trial in September 2023.

In September 2023, we also initiated the 13 weeks GLP toxicology studies, completing the in vivo phase in January 2024.

The final, quality assurance audited report, is expected in the beginning of the second quarter of 2024.

The availability of the 13-weeks GLP study results enables us to continue the clinical development by treating patients with GT-02287 for the same duration, i.e.

To further extend our clinical development plan with GT-02287, we are planning to initiate the chronic toxicity study (6 months in rodents and 9 months in non-rodents) in the second half of 2024, enabling the conduct of clinical studies in patients with a GT-02287 beyond 12 months treatment duration.

Clinical Study

In September 2023, we initiated the first-in-human Phase 1 clinical trial to assess the safety, tolerability, pharmacokinetics, and food effect of GT-02287 in healthy participants.

We are planning to expand the scope of this Phase 1 clinical trial by amending the study protocol to include a cohort of 12-15 patients with Parkinson’s disease.

Pipeline Programs in Research and Discovery Phases

In addition to our preclinical stage programs for PD and nGD, we are progressing additional programs in the research and discovery phases, including our Krabbe disease program, our liver and lung disease program, and two active programs in oncology.

We are also seeking non-dilutive funding in order to continue additional research programs in additional lysosomal storage disorders and metabolic diseases.

In addition to our clinical-stage lead program for Parkinson’s disease, we are planning to progress additional programs in the research and discovery phases, including our programs for alpha-1 antitrypsin deficiency, GM1 gangliosidosis, Krabbe disease, and two active programs in oncology, in conjunction with academic and industry collaborations as well as with non-dilutive grant funding as we have already received under a Eurostars grant for our alpha-1 antitrypsin deficiency program.

GALC Enzyme-Related Disorders:

Krabbe Disease

We are investigating the restoration of GALC function as a treatment for Krabbe disease.

GALC is an enzyme in lysosomes needed to breakdown galactolipids, which are fats primarily found in the nervous system and kidneys.

Among the galactolipids that GALC breaks down are galactosylceramide, which is an essential component of neuronal myelin, and psychosine, which is formed during myelin production and is toxic to cells.

The misfolding of GALC can

result in the toxic accumulation of galactosylceramide, inhibiting myelin production, and of psychosine, leading to demyelination of cells and ultimately to Krabbe disease.

There is no available cure for Krabbe disease.

Current developments in invasive procedures such as bone marrow transplants have not been shown to provide significant neurological improvements, and most developments in gene therapy treatments are still in the preclinical stages.

We have identified compounds that bind to allosteric sites on GALC and stabilize the enzyme in vitro .

We are continuing our development of these promising molecules.

Overview of Krabbe Disease

Krabbe disease is a severe neurological condition that is part of a group of disorders which result from the loss of myelin (demyelination) in the CNS.

14 unchanged sentences

For older individuals, treatment with HSCT is individualized based on disease burden and manifestations, but it serves to delay disease progression and is not an effective cure.

Preclinical Characterization of GALC Lead Compounds

Biological Activity

We have identified several compounds that bind to allosteric sites on GALC and are able to stabilize GALC against thermal denaturation.

STAR molecules were tested in vitro in transfected HEK293 cells bearing different mutations (WT, G286D, T529M).

We examined promising STAR molecules in neuro-PK studies to evaluate their brain penetration properties.

Several of the compounds selected showed enhanced enzyme enhancement and high brain exposure with a brain-to-plasma ratio level greater than one.

In collaboration with Ernesto R.

Bongarzone, Ph.D., Professor in Neuroscience at the College of Medicine at the University of Illinois, Chicago, initial compounds from this program were tested in mouse glial cultures and cell lines with relevant GALC mutations to measure their effect on GALC enzymatic activity and psychosine levels.

We showed that the tested compounds showed significant reduction in psychosine levels in glial cultures.

Further characterization of our compounds is ongoing and we expect to select a lead series for further development based on additional data generated in this program.

We are investigating the restoration of GALC function as a treatment for Krabbe disease.

GALC is an enzyme in lysosomes needed to breakdown galactolipids, which are fats primarily found in the nervous system and kidneys.

The misfolding of GALC can result in the toxic accumulation of galactosylceramide, inhibiting myelin production, and of psychosine, leading to demyelination of cells and ultimately to Krabbe disease.

There is no available cure for Krabbe disease.

GLB Enzyme-Related Disorders:

16 unchanged sentences

We believe current approaches are unable to address both the neuronal and systemic symptoms because current treatment options cannot cross the blood-brain barrier or reach other hard-to-treat organs, such as bone.

In Vitro Characterization of STARs for the Treatment of GM1 Gangliosidosis

We have identified novel STAR molecules targeting GLB through our SEE-Tx® platform and conducted our initial studies on these compounds.

We have identified novel STAR molecules targeting GLB through our Magellan™ platform and conducted our initial studies on these compounds.

Binding of two of these compounds to the GLB target has been confirmed using a biophysical assay.

3 unchanged sentences

Based on the data generated to date, we have selected a lead series for further characterization and development.

A priority patent application was filed in November 2023.

Serpina Related Disorder:

alpha-1 Antitrypsin (A1AT) Deficiency

We are investigating the stabilization of alpha-1 antitrypsin (A1AT) as a potential treatment for rare lung and/or liver disorder.

If A1AT is stabilized, then we believe the molecule would be rendered inactive, thereby preventing the gain of function of the molecule in the lung or liver.

We have identified one allosteric site and have selected 146 virtual hits obtained from virtual screening with which we plan to start experimental hit confirmation.

Primary Screening

Hit identification completed with Surface Plasmon Resonance (SPR) at one concentration and in dose-response.

Binding was confirmed for 23 of 146 compounds (15.6% hit rate).

Hit analoging was completed with 85 analog compounds tested in a SPR dose-response assay.

Positive signal was observed for 4 of 85 compounds.

We have now identified a hit chemical series that inhibits polymerization of A1AT protein, and a priority patent application was filed in February 2023.

We are investigating the stabilization of alpha-1 antitrypsin (AAT) as a potential treatment for rare lung and/or liver disorder.

If A1AT is stabilized, then we believe the molecule would prevent the toxic gain of function of aggregated AAT in the liver and loss of function in the lung.

We have identified one allosteric site and identified a hit chemical series that inhibits polymerization of A1AT protein.

A priority patent application was filed in February 2023.

On March 21, 2023, we announced that that Eurostars with Innosuisse have awarded a grant in the aggregate amount of €1.2 million to a consortium led by Gain Therapeutics which includes the Institute for Research in Biomedicine, Newcells Biotech and the University of Helsinki.

7 unchanged sentences

Allosteric drugs also may provide a new foundation for combining oncolytic agents, to achieve important additive and synergistic effects, and to prevent or overcome drug-resistance to traditional orthosteric anti-cancer agent.

Target Selection Strategy

Targets have been selected based on the potential mechanism of action (with an initial focus on allosteric inhibition), unmet medical needs such as immune resistance, metastatic resistance, non satisfactory response to current standard of care, level of innovation and availability of preclinical tools.

Our Oncology Programs

We have two active oncology projects underway in which we are identifying STARs that are designed to destabilize target proteins by binding to allosteric sites on the proteins and rendering them inactive.

Thus far we have identified allosteric binding sites and run virtual screens to identify virtual hits which are being characterized further in biochemical and cell-based assays.

Thus far we have identified allosteric binding sites and run virtual screens to identify virtual hits which have been characterized further in biochemical and cell-based assays.

The biotechnology and pharmaceutical industries are characterized by the rapid evolution of technologies and understanding of disease etiology, intense competition, and a strong emphasis on intellectual property.

We believe that our SEE-Tx® platform, our scientific capabilities, know-how and experience provide us with competitive advantages.

We believe that our Magellan™ platform, our scientific capabilities, know-how and experience provide us with competitive advantages.

However, we expect substantial competition from multiple sources, including major pharmaceutical, specialty pharmaceutical, and existing or emerging biotechnology companies, academic research institutions and governmental agencies and public and private research institutions worldwide.

1 unchanged sentence

Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient enrollment in clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient

enrollment in clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

As a result, our competitors may discover, develop, license, or commercialize products before or more successfully than we do.

1 unchanged sentence

However, we are aware of companies developing products for the same target indications.

For example, companies targeting GBA-PD using small molecules include Vanqua Bio and Caraway Therapeutics.

While both of these approaches are small molecules hypothesized to increase GCase levels, they differ from our approach because our molecules act as non-competitive pharmacological chaperones, specifically focused on stabilizing and restoring function to misfolded GCase.

There are also a number of companies targeting GBA-PD through other modalities such as cell/gene therapies and monoclonal antibodies.

For example, companies targeting GBA-PD using small molecules include Vanqua Bio, BIAL, and Caraway Therapeutics.

While all of these approaches are small molecules hypothesized to increase GCase levels, they differ from our approach because our molecules act as non-competitive pharmacological chaperones, specifically focused on stabilizing and restoring lysosomal function to misfolded GCase.

There are also companies targeting GBA-PD through other modalities such as gene therapies.

These companies include, among others:

Prevail Therapeutics, which is evaluating a potential gene therapy candidate in a Phase 1/2 clinical trial, Apollo Therapeutics and Voyager Therapeutics.

There are also a number of companies with alpha-synuclein specific approaches ranging from all stages of clinical development but these are distinct from us as they only aim to deplete a specific substrate rather than affecting the root cause of the disease at the start of the disease cascade.

Prevail Therapeutics, which is evaluating a potential gene therapy candidate in a Phase 1/2 clinical trial, and Voyager Therapeutics.

There are also a number of companies with alpha-synuclein specific approaches ranging from all stages of clinical development but these are distinct from us as they only aim to deplete a specific protein rather than affecting the root cause of the disease at the start of the disease cascade.

For Krabbe disease, companies such as Chiesi, Ranedis, Passage Bio, MediciNova and Polaryx are all developing potential therapies, which we believe are in the preclinical stage.

3 unchanged sentences

Collaboration and Licensing Arrangements

In connection with our business development activities, we enter into collaborative and licensing arrangement with third parties, to use our licensed SEE-Tx® computational platform technology to discover novel allosteric sites on misfolded proteins and identify proprietary small molecules that bind these sites, potentially restoring protein folding and treating disease.

In connection with our business development activities, we enter into collaborative and licensing arrangement with third parties to use our Magellan™ drug discovery platform to discover novel allosteric sites on proteins and identify proprietary small molecules that bind these sites to disrupt or restore protein function as may be needed to treat a particular disease.

We expect to continue to identify and evaluate collaboration, co-development and licensing opportunities that may be similar to or different from the collaborations and licenses that we have entered into.

Zentalis Pharmaceuticals, Inc.

On April 20, 2021, we entered into a multi-target collaboration agreement, or the Zentalis Agreement, with Zentalis Pharmaceuticals, Inc., or Zentalis, to discover new product candidates for the treatment of cancer.

Under the terms of the agreement, we used our licensed SEE-Tx computational platform technology to identify binding site on target proteins and determine the potential suitability of these sites as drug targets, as well as the prospective therapeutic use of our technology for treatment of oncology.

During the course of 2022, Zentalis informed us of its desire to wind down the collaboration.

Based on the results generated during the collaboration, we determined to continue the research activities independently (without support of Zentalis) with respect to the applicable target as one of our own internal programs.

Minoryx Therapeutics, S.L.

We have entered into a license agreement, dated December 20, 2017 (the “Minoryx License Agreement”), with Minoryx Therapeutics, S.L., a company organized under the laws of Spain (“Minoryx”), pursuant to which we obtained exclusive worldwide license rights from Minoryx to use and exploit its intellectual property (“IP”), including its SEE-Tx® discovery platform for the identification of non-competitive pharmacological chaperones and exclusive worldwide sublicense rights to certain IP licensed by Minoryx from the University of Barcelona and the Institució Catalana de Recerca i Estudis Avançats.

We have entered into a license agreement, dated December 20, 2017 (the “Minoryx License Agreement”), with Minoryx Therapeutics, S.L., a company organized under the laws of Spain (“Minoryx”), pursuant to which we obtained exclusive worldwide license rights from Minoryx to use and exploit its intellectual property (“IP”), including certain components of its computational drug discovery platform Magellan™ for the identification of non-competitive pharmacological chaperones and exclusive worldwide sublicense rights to certain IP licensed by Minoryx from the University of Barcelona and the Institució Catalana de Recerca i Estudis Avançats.

Under the terms of the Minoryx License Agreement, we have an exclusive, worldwide, royalty-bearing, assignable, transferable license, including the right to license through multiple tiers of sublicense, to Minoryx’s IP to make, have made, use, import, export, offer to sell, have sold, copy, modify, perform, display, create derivative versions of products in the licensed field or otherwise to exploit Minoryx’s IP in the field.

Minoryx’s IP includes the SEE-Tx® discovery platform, certain proprietary Minoryx compounds acting as pharmacological chaperones, all patents and pending applications related thereto and Minoryx’s Know-How and Trademark related to the SEE-Tx® platform.

Minoryx’s IP includes certain components of the Magellan™ drug discovery platform, certain proprietary Minoryx compounds acting as pharmacological chaperones, all patents and pending applications related thereto and Minoryx’s Know-How.

We also have an exclusive, worldwide, royalty-bearing, assignable, transferable sublicense, including the right to sublicense through multiple tiers of sublicense, to the IP of Universitat de Barcelona (UB) and Institucio Catalana de Recerca i Estudis Avancats (ICREA) in EP11380102 and know-how and software related thereto, for the purpose of making, having made, using, importing, offering to sell, selling and having sold, copying, modifying, performing, displaying, and creating derivative versions of products in the field.

3 unchanged sentences

Khalid Islam, the Chairman of our board of directors and one of our founders, is currently the Chairman of the board of directors of Minoryx.

As consideration for the license grant from Minoryx, we have agreed to pay Minoryx royalties on a product-by-product basis based on the licensed IP used by us, ranging from a high single digit to low single digit percentage of net revenues of products during the royalty term commencing on the effective date of the Minoryx License Agreement and continuing until the 10th anniversary of the first product commercialization.

of net revenues of products during the royalty term commencing on the effective date of the Minoryx License Agreement and continuing until the 10th anniversary of the first product commercialization.

Upon the expiration of the royalty term for a product or service in a country, the license with respect to the product or service, as the case may be, shall become royalty-free, fully-paid, irrevocable and perpetual.

1 unchanged sentence

In addition, each party has the right to terminate the Minoryx License Agreement upon a material breach by the other party that remains uncured.

Minoryx has the right to terminate the Minoryx License Agreement on a country-by-country basis if we abandon the technology or use the technology for purposes in violation of law and we fail to cure

such abandonment or unlawful use.

Minoryx has the right to terminate the Minoryx License Agreement on a country-by-country basis if we abandon the technology or use the technology for purposes in violation of law and we fail to cure such abandonment or unlawful use.

We may terminate the Minoryx License Agreement at any time upon 90 days’ written notice.

2 unchanged sentences

Our policy is to seek to protect our proprietary position by, among other methods, pursuing and obtaining patent protection in the United States and in jurisdictions outside of the United States related to our proprietary technology, inventions, improvements, platforms and our product candidates that are important to the development and implementation of our business.

As of February 2023, our patent portfolio consisted of six pending European patent applications and related national stage applications.

In regard to our SEE-Tx® Technology, we in-license a European patent under the Minoryx License Agreement, which is owned by UB/ICREA and has claims directed to a method of binding site and binding energy determination by mixed explicit solvent simulations.

As of February 2024, our patent portfolio consisted of one patent granted in Europe, five international PCT applications in national phase stage and two international PCT applications which will be published in 2024.

In regard to our computational drug discovery platform Magellan™, we in-licensed the European patent under the Minoryx License Agreement, which is owned by UB/ICREA and has claims directed to a method of binding site and binding energy determination by mixed explicit solvent simulations.

This patent is expected to expire in 2032.

In regard to our GLB program, we in-license from Minoryx pursuant to the Minoryx License Agreement, a patent family with a pending European patent application with claims directed to composition of matter and eight foreign patent applications pending in such jurisdictions such as Canada, Australia, Japan, Europe, and China.

In regard to our GLB program, we in-licensed from Minoryx pursuant to the Minoryx License Agreement, a patent family with a pending European patent application with claims directed to composition of matter and eight foreign patent applications pending in such jurisdictions such as Canada, Australia, Japan, Europe, and China.

These patents applications, if issued, are expected to expire in 2037, not giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

16 unchanged sentences

Our success will also depend in part on not infringing upon the proprietary rights of third parties.

It is uncertain whether the issuance of any third-party patent would require us to alter our development or commercial

strategies, or our drugs or processes, obtain licenses or cease certain activities.

It is uncertain whether the issuance of any third-party patent would require us to alter our development or commercial strategies, or our drugs or processes, obtain licenses or cease certain activities.

Our breach of any license agreements or failure to obtain a license to proprietary rights that we may require to develop or commercialize our future drugs may have an adverse impact on us.

9 unchanged sentences

generally involves the following:

● completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with good laboratory practice, or GLP, requirements;

● completion of extensive non-clinical studies in accordance with applicable regulations, including studies conducted in accordance with good laboratory practice, or GLP, requirements;

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

41 unchanged sentences

The sponsor must also notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than seven calendar days after the sponsor’s initial receipt of the information.

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

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

The manufacturing process must be capable of consistently producing quality batches of the product candidate and manufacturers must develop, among other things, methods for testing the identity, strength, quality and purity of the final drug product.

Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

Special Protocol Assessment

The FD&C Act directs FDA to meet with sponsors, pursuant to a sponsor’s written request, for the purpose of reaching agreement on the design and size of clinical trials intended to form the primary basis of an efficacy claim in an NDA or a Biologic Licensing Application (BLA).

If an agreement is reached, the FDA will reduce the agreement to writing and make it part of the administrative record.

This agreement is called a special protocol assessment (SPA).

While the FDA’s guidance on SPAs states that documented SPAs should be considered binding on the review division, the FDA has latitude to change its assessment if certain exceptions apply.

Exceptions include public health concerns emerging that were unrecognized at the time of the protocol assessment, identification of a substantial scientific issue essential to the safety or efficacy testing that later comes to light, a sponsor’s failure to follow the protocol agreed upon, or the FDA’s reliance on data, assumptions or information that are determined to be wrong.

Marketing Approval for Drugs

3 unchanged sentences

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

To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the satisfaction of the FDA.

marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the satisfaction of the FDA.

FDA approval of an NDA must be obtained before a drug may be marketed in the U.S.

3 unchanged sentences

The FDA reviews an NDA to determine, among other things, whether the drug is safe and effective and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, quality and purity.

In most cases, the FDA requires two adequate and well-controlled Phase 3 clinical trials to demonstrate the efficacy of the drug.

A single trial may be sufficient in some instances, including (1) where the study is a large multicenter trial demonstrating internal consistency and a statistically very persuasive finding of a clinically meaningful effect on mortality, irreversible morbidity or prevention of a disease with a potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible or (2) when there is one adequate and well-controlled clinical investigation plus other confirmatory evidence.

Under the goals and polices agreed to by the FDA under the Prescription Drug User Fee Act, or PDUFA, the FDA targets ten months, from the filing date, in which to complete its initial review of a new molecular entity NDA and respond to the applicant, and six months from the filing date of a new molecular entity NDA for priority review.

11 unchanged sentences

The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

Additionally, before approving an NDA, the FDA may inspect one or more clinical trial sites to assure compliance with GCP and other requirements and the integrity of the clinical data submitted to the FDA, and one or more sites where non-clinical testing was conducted to assure compliance with GLP and other requirements.

After evaluating the NDA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter, or, in some cases, a complete response letter.

3 unchanged sentences

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

Even if the FDA approves a product, depending on the specific risk(s) to be addressed it may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product.

drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product.

The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs.

7 unchanged sentences

Competitors, however, may receive approval of different therapeutic agents for the indication for which the orphan product has exclusivity or obtain approval for the same therapeutic agent for a different indication than that for which the orphan product has exclusivity.

Orphan product exclusivity could block the approval of one of our products for seven years if a competitor obtains approval for the same therapeutic agent for the same indication before we do,

unless we are able to demonstrate that our product is clinically superior.

Orphan product exclusivity could block the approval of one of our products for seven years if a competitor obtains approval for the same therapeutic agent for the same indication before we do, unless we are able to demonstrate that our product is clinically superior.

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

8 unchanged sentences

Breakthrough Therapy designation provides all the features of Fast Track designation in addition to intensive guidance on an efficient drug development program beginning as early as Phase 1, and FDA organizational commitment to expedited development, including involvement of senior managers and experienced review staff in a cross-disciplinary review, where appropriate.

Any product submitted to the FDA for approval, including a product with Fast Track or Breakthrough Therapy designation, may also be eligible for additional FDA programs intended to expedite the review and approval process, including Priority Review designation and Accelerated Approval.

process, including Priority Review designation and Accelerated Approval.

A product is eligible for Priority Review if it has the potential to provide a significant improvement in safety or effectiveness in the treatment, diagnosis or prevention of a serious disease or condition.

17 unchanged sentences

There is also a continuing, annual prescription drug product program user fee.

Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information, requirements for post-market studies or clinical trials to assess new safety risks, or imposition of distribution or other restrictions under a REMS.

trials to assess new safety risks, or imposition of distribution or other restrictions under a REMS.

Other potential consequences include, among other things:

9 unchanged sentences

Manufacturing, sales, promotion and other activities of product candidates following product approval, where applicable, or commercialization are also subject to regulation by numerous regulatory authorities in the U.S.

in addition to the FDA, which may include the Centers for Medicare & Medicaid Services, or CMS, other divisions of

the Department of Health and Human Services, the Department of Justice, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency and state and local governments and governmental agencies.

in addition to the FDA, which may include the Centers for Medicare & Medicaid Services, or CMS, other divisions of the Department of Health and Human Services, the Department of Justice, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency and state and local governments and governmental agencies.

Healthcare Reform

19 unchanged sentences

● In addition, effective January 1, 2014, CMS also began bundling the Medicare payments for certain laboratory tests ordered while a patient received services in a hospital outpatient setting.

Further, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which have resulted in several recent Congressional inquiries and proposed and enacted bills 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

In addition, the U.S.

29 unchanged sentences

Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims.

government continues to use the FCA, and the accompanying threat of significant liability, in its investigations and prosecutions of pharmaceutical and biotechnology companies throughout the U.S.

The federal government continues to use the FCA, and the accompanying threat of significant liability, in its investigations and prosecutions of pharmaceutical and biotechnology companies throughout the U.S.

Such investigations and prosecutions frequently involve, for example, the alleged promotion of products for unapproved uses and other sales and marketing practices.

6 unchanged sentences

We may also be subject to federal transparency laws, including the federal Physician Payment Sunshine Act, which was part of the ACA and requires manufacturers of certain drugs and biologics, among others, to track and disclose payments and other transfers of value they make to U.S.

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 in the manufacturer held by such physicians and their immediate family members.

physicians and their immediate family members.

This information is subsequently made publicly available in a searchable format on a CMS website.

9 unchanged sentences

If any of the physicians or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they may be subject to significant criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs.

Ensuring business arrangements comply with applicable healthcare

laws, as well as responding to possible investigations by government authorities, can be time- and resource consuming and can divert a company’s attention from the business.

Ensuring business arrangements comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource consuming and can divert a company’s attention from the business.

Data Privacy and Security

106 unchanged sentences

The CTR is intended to harmonize and streamline clinical trial authorizations, simplify adverse-event reporting procedures, improve the supervision of clinical trials and increasing their transparency.

Specifically, the Regulation, which is directly applicable in all EU Member States, introduces a streamlined application procedure through a single-entry point, the "EU portal", the Clinical Trials Information System, or CTIS;

a single set of documents to be prepared and submitted for the application;

55 unchanged sentences

Employees and Human Capital Resources

As of December 31, 2022, we had twenty-eight full-time employees and three part-time employees.

Fourteen employees are based in Barcelona, Spain, eleven employees are based in Lugano, Switzerland, two employees are based in the U.K.

and four employees are based in Bethesda, Maryland.

Of these thirty-one employees, twenty-two are engaged in research and development activities and nine are engaged in finance, investor relations, business development and general management.

As of December 31, 2023, we had twenty-nine full-time employees and three part-time employees.

Of these thirty-two employees, twenty-three were engaged in research and development activities and nine were engaged in finance, business development, administrative support and general management.

We have a branch office in Barcelona, Spain.

Our employees in Spain are subject to a national collective labor agreement, the “Convenio General de la Industria Quimica”.

1 unchanged sentence

We consider our relationship with our employees to be good and have not experienced any work stoppages.

In addition, we maintain consulting arrangements with a number of scientists at various universities and other research institutions in Europe, Switzerland and the United States, including with the four external members of our Scientific Advisory Board.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees.

3 unchanged sentences

We maintain an internet website at www.gaintherapeutics.com and make available free of charge through our website our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act of 1934, or the Exchange Act.

We make these reports available through our website as soon as reasonably practicable after we

electronically file such reports with, or furnish such reports to, the Securities and Exchange Commission, or the SEC.

We make these reports available through our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the Securities and Exchange Commission, or the SEC.

You can review our electronically filed reports and other information that we file with the SEC on the SEC’s web site at http://www.sec.gov.

In addition, we regularly use our website to post information regarding our business, product development programs and governance, and we encourage investors to use our website, specifically the section titled “Investor Relations” as a source of information about us.

In addition, we regularly use our website to post information regarding our business, product

development programs and governance, and we encourage investors to use our website, specifically the section titled “Investor Relations” as a source of information about us.

The information on our website is not incorporated by reference into this Annual Report and should not be considered to be part of this Annual Report.

1 unchanged sentence

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

What changed 10-K

Item 1. Business