−Removed: We are a biotechnology company developing novel small molecule therapeutics to treat diseases across, several therapeutics areas, including, lysosomal storage disorders (“LSDs”), central nervous system disorders (“CNS”), metabolic disorders, and oncology.
−Removed: We use our exclusively in-licensed computational target and drug discover 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.
−Removed: These binding sites, distinct from the protein’s active site, are called allosteric sites.
−Removed: We believe that targeting an allosteric binding site instead of the active binding site of a protein provides numerous advantages:
+Added: 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.
+Added: 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.
+Added: 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.
+Added: Targeting an allosteric binding site instead of the active binding site of a protein provides numerous advantages, including:
the ability to regulate proteins implicated in disease through several different mechanisms of action covering both functional and conformational effects, including stabilization, destabilization, targeted degradation, allosteric inhibition, and allosteric activation of the targeted protein;
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and the ability to identify small molecules with more favorable drug-like properties.
−Removed: The SEE-Tx® platform has been used to identify novel allosteric sites and small molecules for all of our internal and partnered programs.
−Removed: Discovering and targeting novel allosteric sites with our platform not only collapses 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.
−Removed: We have filed four patent applications for our novel small molecule drug candidates that are Structurally Targeted Allosteric Regulators (“STARs”).
−Removed: In June 2021, the Company announced the publication of two PCT patents.
−Removed: The first was directed at compounds targeting misfolded beta-glucocerebrosidase (GBA) addressing CNS diseases such as Parkinson’s disease, Gaucher disease, Alzheimer’s disease, and Lewy body dementia.
−Removed: The second was directed at compounds targeting galactosylceramidase (GALC), addressing demyelinating disorders such as Krabbe disease and multiple sclerosis.
−Removed: We have identified two different STARs as the lead compounds for our Parkinson’s disease program and our Gaucher disease program and are currently developing these product candidates through preclinical studies.
−Removed: In September 2021, the Company announced positive topline data of an in vitro study evaluating the two STARs for the treatment of Gaucher and Parkinson’s disease in neuronal cells derived induced pluripotent stem cells (“iPSCs”) of a a patient with Gaucher disease that contained the disease-causing mutation of the GBA1 gene and from iPSCs of a healthy donor with a normal GBA1 gene, so called wild-type cells.
−Removed: The results of the study, conducted at the University of Maryland School of Medicine, demonstrate a significant increase in beta-glucocerebrosidase (“GCase”) protein levels, improved trafficking of GCase to the lysosome, and a significant decrease of toxic substrates glucosylceramide and alpha-synuclein p129 levels in both the neuronal cells that contained the mutated GBA1 gene as well as the wild-type cells.
−Removed: Alpha synuclein is consididered to be the hallmark of Parkinson’s disease.
−Removed: In addition, these data provides further evidence that these product candidates have the potential to treat Gaucher disease and Parkinson’s disease and slow or stop the progression of GBA Parkinson’s disease.
−Removed: We expect to complete the preclinical development and submit the regulatory dossier to the Human Research Ethics Committee in Australia to initiate a first-in-human Phase 1 clinical trial in our Parkinson’s disease program, and to initiate the preclinical toxicology studies for our Gaucher program in the second half of 2022.
−Removed: In addition, we plan to continue to advance research programs and initiate additional programs targeting allosteric binding sites identified with the SEE-Tx® platform.
+Added: The SEE-Tx® platform has been used to identify novel allosteric sites and small molecules for all of our internal programs and partnered programs.
+Added: 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.
+Added: Our Lead Product Candidate:
+Added: GT-02287 for the Treatment of GBA1 Parkinson’s disease
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: Our Research Programs Using SEE-Tx® Platform
+Added: 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.
−Removed: Since our inception in 2017, we have devoted substantially all of our resources to identify and develop next-generation brain-penetrant allosteric small molecules for the treatment of devastating diseases with high-unmet medical needs using our in-licensed SEE-Tx® platform.
−Removed: To date, we do not have any product candidates approved for sale and have not generated any revenue from product sales.
−Removed: We have primarily financed our operations through a combination of sales of our securities and research grants.
−Removed: On March 17, 2021, we completed our IPO and issued and sold approximately 4.1 million shares of our common stock at a public offering price of $11.00 per share, including approximately 0.5 million shares in connection with the full exercise of the underwriters’ option to purchase additional
−Removed: shares, resulting in net proceeds of approximately $40.5 million, after deducting the underwriting discounts and commissions and offering expenses.
−Removed: Our operations have consisted primarily of organizing and expanding the Company’s operation, securing financing, performing research, conducting preclinical studies and developing licensed technology.
−Removed: We face risks associated with early-stage biotechnology companies whose product candidates are in development.
−Removed: Product candidates currently under development will require significant additional research and development efforts, including extensive preclinical and clinical testing and regulatory approval prior to commercialization.
−Removed: These efforts require significant amounts of additional capital for us to complete our research and development, achieve our research and development objectives, defend our intellectual property rights, and recruit and retain skilled personnel, and key members of management.
−Removed: Even if our product development efforts are successful, it is uncertain when, if ever, we will realize significant revenue from product sales.
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.
−Removed: Our exclusively in-licensed platform, SEE-Tx® was designed to address this problem.
+Added: Our exclusively in-licensed SEE-Tx® 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.
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The graphic below provided an overview of SEE-Tx®.
−Removed: Allosteric Buinding Site Identification
−Removed: Using the three-dimensional structure of proteins that have been experimentally derived or generated or that predictive protein structures from the Alphafold database and our computational technology, our SEE-Tx® platform applies various computational methods and proprietary algorithms to identify and map previously uncharacterized binding sites on the proteins called “binding hotspots or allosteric binding sites.” These are key points on the protein surface where a small molecule can potentially bind.
−Removed: The amount, density, nature and quality of these hotspots determine the druggability of the protein, that is, if a drug-like small molecules can effectively bind to the particular site with an appropriate potency.
+Added: Allosteric Binding Site Identification
+Added: 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.
+Added: 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
−Removed: 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 substrate that binds to the active binding site,
−Removed: and the ability to identify small molecules with more favorable drug-like properties.
+Added: 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.
−Removed: Identification of Structurally Targeted Allosteric Regulatotrs (“STARs”) – Our Molecular Hypothesis
+Added: 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.
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.
−Removed: We believe our process for identifying STARs is a more efficient and effective drug discovery tool than traditional drug discovery approaches such as random high-throughput screening because we use a validated-target approach.
+Added: We believe our process for identifying STARs provides several advantages over traditional drug discovery approaches such as random high-throughput screening.
In high-throughput screening, very large libraries of randomly selected molecules are tested for their ability to perform a specific function such as binding to a target protein.
−Removed: This approach typically results in a large number of positive responses that must then be laboriously analyzed to identify compounds with relevant properties and effect.
−Removed: In contrast, 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.
−Removed: Compared to high throughput screening, our validated-target approach is significantly less expensive, significantly faster and significantly more effective.
+Added: This approach typically results in a large number of positive hits that must then be laboriously analyzed to identify compounds with relevant properties and effect.
+Added: A high-throughput screening campaign may take up to two years or more to complete , and, on average, only 0.1% of all compounds tested in this manner bind to the targeted protein with the desired effect.
+Added: 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.
−Removed: Our average hit rate for validated compounds is 14%, which represents a greater than 1000-fold enrichment compared to traditional high throughput screening methods.
−Removed: In addition, traditional screening methods takes months to years to complete.
+Added: Our average hit rate for validated compounds is 14%, a greater than 100-fold higher success rate compared to traditional high throughput screening methods.
+Added: 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.
Allosteric Regulators Cover Several Mechanisms of Action
Another benefit of targeting allosteric sites is that it allows for several different mechanisms of action.
−Removed: In our LSD and Parkinson’s disease programs, we have identified STARs that are designed to bind to a misfolded protein, stabilize that protein and restore protein function.
−Removed: However, in areas such as oncology, we have identified STARs that are designed to destabilize normal proteins by binding to a non-native or mutant form of the protein and render it inactive.
−Removed: 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
−Removed: by the natural ligand of the active site of the protein.
+Added: In our LSD and Parkinson’s disease programs, we have identified STARs that are designed to bind to a protein with a tendency to misfold, stabilize that protein in its correctly folded state and restore protein function.
+Added: 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.
+Added: 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.
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Therapeutic small molecules that facilitate the folding of enzymes into their correct shape can restore function and the proper processing of substrate.
−Removed: As illustrated below, in LSDs, the gene that codes for an enzyme is mutated and results in a misfolded enzyme.
−Removed: The misfolded enzyme cannot traffic through the cell resulting in toxic protein accumulation.
+Added: As illustrated below, in LSDs, the gene that codes for an enzyme is
+Added: mutated and results in a misfolded enzyme.
+Added: 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.
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Current therapeutic approaches to address misfolded enzymes have inherent limitations.
−Removed: 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
−Removed: selectivity issues.
−Removed: Other treatments such as enzyme replacement therapy (“ERT”), in which new functional enzymes are infused into the patient, are not optimal for treating neurological conditions because currently available ERTs cannot cross the blood-brain barrier and do not address the root cause of the disease.
−Removed: Gene therapy, which aims to create new, 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.
−Removed: Given these limitations on current therapies, we believe patients would benefit from a new therapeutic approach both on its own and, potentially, in combination with existing therapies.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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.
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.
−Removed: Additionally, our approach enables the less-invasive and more convenience of oral administration.
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.
−Removed: The initial focus of the development pipeline was on several LSDs with high unmet medical need, but has since expanded to include CNS disorders, metabolic diseases, and oncology.
−Removed: The platform is disease agnostic and provides us with the ability to expand our pipeline as we continue to discover new targets.
−Removed: We have entered into a number of collaborations to advance the development of our programs, such as with the Michael J.
−Removed: Fox Foundation for Parkinson’s Research, The Silverstein Foundation, University of Illinois, Chicago and the University of Maryland;
−Removed: these collaborations are understandings to work together in the research of potential therapies for the treatment of specific diseases.
−Removed: Neither we, nor the institutions we collaborate with, are under contractual obligations to continue the collaboration and all parties retain their respective intellectual property.
−Removed: Additionally, we have a multi-target drug development and commercialization partnership with Zentalis Pharmaceuticals for the development of novel small molecules for the treatment of cancers.
−Removed: We believe that the STARs we have selected for our product pipeline programs have high specificity to their allosteric binding site and do not interact with the active site of the enzyme target, which is designed to enhance both tolerability and response.
−Removed: Our technology allows us to identify STARs that have the ability to bind to both mutant and wild-type enzymes.
−Removed: Because they are small molecules, STARs can be administered orally, have the ability to cross the blood-brain barrier and enter hard-to-treat tissues such as bone and cartilage.
−Removed: We believe the ability to cross the blood-brain barrier is essential to effectively treating diseases with neurological symptoms.
−Removed: In addition, we believe our STARs could be used in combination with ERT or gene therapy approaches to more completely address the patient’s needs.
−Removed: Programs in Preclinical Development
+Added: The platform is disease agnostic and provides us with the ability to expand our pipeline, quickly, efficiently and at low cost.
+Added: We are currently focusing on progressing our programs in Parkinson’s and Gaucher disease.
+Added: 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.
+Added: We are seeking non-dilutive funding in order to progress our other research programs in additional lysosomal storage disorders and metabolic diseases.
+Added: Our Product Pipeline
GCase Enzyme-Related Disorders:
GBA1 Parkinson’s Disease and Neuronopathic Gaucher Disease
−Removed: We are investigating the restoration of GCase enzymatic function as a treatment for Parkinson’s Disease (PD) and neuronopathic Gaucher disease (nGD), an LSD.
+Added: 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.
−Removed: Homozygous mutations of the GBA1 gene lead to the misfolding of GCase and associated degradation, which in turn can lead to accumulation of these substrates to toxic levels in the liver, spleen, bone marrow and nervous system and can result in lysosomal storage and neurodegenerative diseases.
+Added: 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.
−Removed: The GBA1 gene mutation most commonly associated with nGD is also found in the most pathogenic form of Parkinson’s disease (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 the toxic substrate alpha-synuclein, a pathological hallmark of Parkinson’s disease.
−Removed: Decreased GCasse activity is also observed in idiopathic PD (PD that occurs in patients without GBA1 mutuations) and Lewy Body Dementia.
−Removed: Currently, there is no cure for nGD or PD, and there are very limited treatment options.
+Added: 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.
+Added: Decreased GCase activity is also observed in idiopathic PD (PD that occurs in patients without GBA1 mutations) and Dementia with Lewy Bodies.
+Added: 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.
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Parkinson’s disease is a disorder of the central nervous system that affects movement, often including tremors.
−Removed: Nerve cell damage in the brain causes dopamine levels to drop, leading to the symptoms of Parkinson's disease.
−Removed: 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 severe debilitating disease that eventually require full-time home care or a transfer to a skilled nursing facility.
−Removed: GBA1 Parkinson’s disease is caused by mutations in the GBA1 gene, which are among the most pathogenic risk factors for the development of Parkinson’s disease and related neurodegenerative disorders characterized by the accumulation of alpha-synuclein in cell bodies of neurons.
+Added: Damage to dopaminergic neurons in the brain causes dopamine levels to drop, leading to the symptoms of Parkinson's disease.
+Added: 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.
+Added: 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.
It is widely accepted that GCase deficiency has a biological role as a modifier or facilitator of Parkinson’s disease pathogenesis in the brain.
−Removed: Brain autopsy studies have shown that even some cases of idiopathic Parkinson’s disease (without GBA1 mutations) exhibit decreased levels of GCase.
−Removed: Reduced GCase activity may enhance the risk for Parkinson’s disease by facilitating a pathological hallmark, namely alpha-synuclein accumulation.
+Added: Brain autopsy studies have shown that decreased levels of GCase are also found in patients with idiopathic Parkinson’s disease (without GBA1 mutations).
+Added: Reduced GCase
+Added: 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.
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At present, there is no effective cure for Parkinson’s disease.
−Removed: Treatment options or potential treatments, such as ERT, are limited due to their inability to cross the blood-brain barrier and are therefore unable to prevent neurodegeneration.
Current approved therapies for Parkinson’s disease are limited to symptomatic treatments such as levodopa, dopaminergic receptor agonists and inhibitors of enzymes related to dopamine metabolism such as monoamine oxidase inhibitors and catechol-O-methyltransferase inhibitors.
These therapies aim to improve overall dopaminergic function.
−Removed: The benefits of these types of treatments diminish over time as the disease progresses, and these therapies do not impact the non-motor symptoms or the progression of the disease.
+Added: The benefits of these types of treatments diminish over time as the disease progresses, and these therapies do not impact the non-motor symptoms such as cognitive decline or the progression of the disease.
As the disease progresses, the non-motor symptoms, such as dementia and cognitive impairment, can lead to severe morbidity and mortality.
−Removed: Preclinical Characterization of Lead Compound GT-02287 for the Treatment of PD
−Removed: Biological Activity
−Removed: We have identified the lead compound GT-02287 targeting GCase for the treatment of GBA1 and idiopathic PD.
−Removed: Biophysical assay results have demonstrated that our STAR compound can bind to GCase protein and increase its thermal stability.
−Removed: We observed a dose-dependent increase in GCase activity in normal and GCase mutant cells when
−Removed: treated with our STAR molecule.
−Removed: Additionally, GT-02287 has shown cell type and mutation specific GCase enzyme enhancement in an extended panel of patient derived cells representative of the most frequent and pathogenic GBA1 mutations related to GBA1 Parkinson’s and neuronopathic Gaucher’s disease.
−Removed: To assess GCase delivery into the lysosomes upon treatment with GT-02287, HEK293 were transfected with either GBA WT, GBA L444P and GBA N370S with HaloTag, thirty hours later, compounds and a fluorescent Halo ligand that covalently binds to a pocket in the tag were added for 17 hours.
−Removed: Once the protein reaches the lysosome, the tag is cleaved off GCase but is resistant to lysosomal hydrolases enabling the detection of a 31 kDa fluorescent fragment that corresponds to the protein that reached the lysosome.
−Removed: Full length protein and lysosomal fragment were measured by western blot.
−Removed: Treatment with GT-02287 of transfected cells both with WT and mutated GBA1 (N370S, L444P) leads to enhanced GCase lysosomal delivery.
−Removed: The efficacy of GT-02287 was assessed in an in vitro model of rat primary mesencephalic neurons where GD was chemically induced by inhibiting GCase using the irreversible inhibitor CBE.
−Removed: Cells were cultured, at day 6, GT-02287 was applied and after 24 hours, CBE (400 µM) was added to the culture medium for 48 hours.
−Removed: On day 8, the culture was fixed and stained with tyrosine hydroxylase (TH), a marker for dopaminergic neurons.
−Removed: Neuronal survival, neurite network was evaluated.
−Removed: GT-02287 was assessed at 100 nM, 500 nM, 1 µM and 12.5 µM and dose-dependently improved neuronal survival, neurite network and decreased CBE-induced a-synuclein accumulation in TH neurons.
−Removed: We used an in vitro model based on patient-derived iPSCs differentiated into cortical neurons to assess the efficacy of GT-02287 in enhancing GCase enzyme activity, protein levels, translocation into the lysosomes, as well as the ability of GT-02287 in reducing toxic substates (GlcCer and a-synuclein).
−Removed: 45-day cortical human neurons were incubated with GT-02287 for 48 hrs.
−Removed: The cell pellets were washed once with 1xPBS and stored at -80°C.
−Removed: Sphingolipids were extracted from pelleted cells and analyzed by LC-MS and data was collected form three independent experiments.
−Removed: We reported that GT-02287 increased GCase enzyme levels, co-localization of GCase with lysosomes, reduced both phosphorylated and aggregated a-synuclein as well as reduced GlcCer accumulation in L444P/RecNcil and L444P/L444P patients (see figure below).
−Removed: Toxicology and Safety
−Removed: GT-02287 was administered in mice with IV (3 mice per dose group) and oral administration (12 mice per dose group).
−Removed: GT-02287 was safe up to 60 mg/kg IV and was well tolerated up to 120mg/kg PO BID following sub-chronic twelve days treatment.
−Removed: Additional non-clinical studies, which include toxicology, safety and pharmacology studies are currently ongoing for GT-02287.
−Removed: Pharmacokinetics
−Removed: We examined promising STAR molecules in neuro-PK studies to evaluate their brain penetration properties.
−Removed: GT-02287 showed high brain exposure with a brain-to-plasma ratio level greater than one.
−Removed: Additional PK studies will be performed as part of the regulatory non-clinical study package.
−Removed: A preclinical rotenone-induced Parkinson’s disease model in rats demonstrated that oral administration of GT-02287 leads to a dose-dependent depletion of total and phosphorylated alpha-synuclein, increase in tyrosine hydroxylase, reduction of microgliosis as well as improvement in rearing behavior.
−Removed: GT-02287 was administered orally, twice a day for 7 days, to ten rats per group and samples were collected one day after final administration.
−Removed: Rearing behavior and locomotion assessment has been performed at day 8.
−Removed: Overview of GBA Gaucher Disease
−Removed: Gaucher disease is an inherited LSD caused by homozygous mutations of the GBA1 gene that result in the misfolding and subsequent dysfunction of beta-glucocerebrosidase (GCase), an enzyme that breaks down fatty chemicals in the body.
+Added: Overview of Gaucher Disease
+Added: 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 traditionally classified according to one of three types.
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Current ERT and gene therapy treatments are unable to address the onset of type 1 neurological symptoms because these treatments are unable to cross the blood-brain barrier.
−Removed: Unlike Gaucher disease type 1, Gaucher disease types 2 and 3 have early onset brain degeneration that gets progressively worse over time.
+Added: Unlike Gaucher disease type 1, Gaucher disease types 2 and 3 have early onset brain degeneration that worsens over time.
For this reason, Gaucher disease types 2 and 3 are known as neuronopathic Gaucher disease (nGD).
−Removed: Currently, there is no effective treatment for the severe brain degeneration associated with Gaucher disease types 2 and 3.
+Added: Currently, there is no effective treatment for nGD.
In type 2 Gaucher disease, there is neurological impairment that presents before birth through the first months of life, progresses rapidly, and is typically fatal within two years.
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Additionally, infants with Gaucher disease may have abnormally large organs, deficiency in growth, seizures and compromised swallow and airway problems.
−Removed: Gaucher disease type 3 (also known as chronic neuronopathic Gaucher disease) is thought to be the most common type worldwide.
−Removed: later and more gradual onset compared with type 2.
+Added: Gaucher disease type 3 (also known as chronic neuronopathic Gaucher disease) has a later and more gradual onset compared with type 2.
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.
−Removed: Gaucher disease is caused by alterations in the GBA1 gene that encodes GCase, an enzyme which catalyzes a key step in breaking down glucosylceramide and glucosylsphingosine.
−Removed: 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 within the CNS can result in neurological symptoms.
+Added: 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.
+Added: 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.
The prevalence of Gaucher disease type 1 (non-neuronopathic Gaucher disease) is reported as 1:57,000 to 75,000 people worldwide.
Type 1 is the most common form in Western countries (around 95%).
−Removed: The prevalence of type 2 and type 3 Gaucher disease (so called neuronopathic Gaucher disease, or nGD) is approximately 1:100,000 people worldwide, and these forms are the most common in non-Western countries, especially in Asian countries where they make up more than 50% of the Gaucher disease patient population.
+Added: The prevalence of type 2 and type 3 Gaucher disease, or nGD, is approximately 1:100,000 people worldwide, and these forms are the most common in non-Western countries, especially in Asian countries where they make up more than 50% of the Gaucher disease patient population.
At present there are no available treatment options for neuronopathic Gaucher disease, but ERT is still used to address organ enlargement, hematological manifestation and bone disease, as well as to improve the quality of life for these patients.
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 .
−Removed: Preclinical Characterization of GT-02329 for the Treatment of Gaucher Disease
−Removed: We have identified the lead compound GT-02329 targeting GCase for nGD.
−Removed: Biophysical assay results have demonstrated that our STAR compound can bind to GCase protein and increase its thermal stability.
−Removed: We observed a dose-dependent increase in GCase activity in normal and GCase mutant cells when treated with our STAR molecule.
−Removed: The efficacy of GT-02329 in depleting GlcSph (Lyso-Gb1) was assessed in dopaminergic neurons BE(2)-M17 carrying either wild-type or L444P GBA1 mutation after treatment for 10 days with 25 μM of compound.
−Removed: As shown in the figures below, treatment with GT-02329 of cells bearing wild-type and L444P GCase leads to a decrease of glucosylsphingosine.
−Removed: Media exchange with compound was performed after 3 days, then after 4 days and finally cells were harvested after 3 additional days.
−Removed: GlcSph (Lyso-Gb1) levels were quantified by LC-MS.
−Removed: STAR compounds decrease glucosylsphingosine levels in the neuronal cell model
−Removed: Supported by a grant from the Michael J.
−Removed: Fox Foundation and the Silverstein Foundation, the promising compounds were further evaluated in a neuronal cell model developed by the Vall d’Hebron Research Institute.
−Removed: These neuronal cell lines express either normal or mutated GCase and display alpha-synuclein accumulation.
−Removed: Since accumulation of alpha-synuclein is the pathological hallmark of Parkinson’s disease, the use of these cell lines is important to determine the capacity of STAR compounds to decrease accumulation of the most pathogenic form of alpha-synuclein, namely phosphorylated alpha-synuclein (p-synuclein) through enhancement of GCase activity.
−Removed: In a study with patient-derived iPSCs, 45-day cortical human neurons were incubated with GT-02329 for 48 hrs.
−Removed: The cell pellets were washed once with 1xPBS and stored at -80°C.
−Removed: Sphingolipids were extracted from pelleted cells and analyzed by LC-MS and data was collected form three independent experiments.
−Removed: In this study, GT-02329 was shown to enhance GCase levels and co-localization with lysosomes, and to decrease phosphorylated a-synuclein.
−Removed: Pharmacokinetics
−Removed: We examined STAR molecules in neuro-PK studies to evaluate their brain penetration properties.
−Removed: GT-02329 showed high brain exposure with a brain-to-plasma ratio level greater than one.
−Removed: Additional PK studies will be performed as part of the regulatory non-clinical study package.
−Removed: A preclinical mouse model demonstrated that oral administration of GT-02329 significantly enhances WT GCase activity both in striatum and plasma and the effect is dose-dependent.
−Removed: GT-02329 was administered orally, twice a day for 12 days, to ten mice per group and samples were collected one hour after the final administration.
−Removed: Pipeline Programs in Research Phase
−Removed: In addition to our preclinical stage programs for PD and nGD, we have a range of programs in LSDs and a program in a metabolic disease that are in various stages of research.
−Removed: GLB Enzyme-Related Disorders:
−Removed: GM1 Gangliosidosis
−Removed: GLB is an enzyme found in lysosomes, which are compartments within cells that degrade and recycle different types of molecules, including toxic molecules.
−Removed: GLB is essential for the breakdown of GM1 and keratan sulfate, which serve important functions in the brain and other tissues.
−Removed: Misfolding of GLB allows these substrates to build up to toxic levels and leads to the diseases GM1 Gangliosidosis.
−Removed: GM1 gangliosidosis is a rare and often life-threatening LSD in infants (type 1), juveniles (type 2) and adults (type 3).
−Removed: It manifests in a continuum of clinical severity by type.
−Removed: In type 1 or the infantile form, the onset is observed earlier and is a more severe and rapidly progressive disease.
−Removed: Type 2 and 3 are less severe manifestations and have slower progression with a juvenile or adult onset.
−Removed: The infantile form of the disease is characterized by onset in the first year of life with symptoms including hypotonia (reduced muscle tone), progressive CNS dysfunction that can lead to deafness, blindness, enlarged liver and spleen rigidity, and progressive skeletal dysplasia that can result in restrictive lung disease and aspiration pneumonia.
−Removed: The disease rapidly progresses, with a life expectancy of two to four years.
−Removed: Juvenile GM1 manifests between 18 months and five years of age with a slower progression compared to infants.
−Removed: The average life expectancy for type 2 GM1 is typically 10 years.
−Removed: Adult GM1 has an onset age between three and 30.
−Removed: While it is less severe and progresses at a slower rate than infantile or juvenile GM1, adult GM1 causes debilitating symptoms, including muscular atrophy, corneal clouding and dystonia.
−Removed: The prevalence of GM1 is approximately 1:100,000 to 200,000 live births worldwide.
−Removed: Currently, there is no effective cure for GM1, and symptomatic treatment options, including substrate reduction therapy, ERT, bone marrow transplantation, stem cell transplantation and gene therapy are limited or still under development.
−Removed: Existing 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.
−Removed: In Vitro and In Vivo Characterization of STARs for the Treatment of GM1 Gangliosidosis
−Removed: We have identified novel STAR molecules targeting GLB through our SEE-Tx® platform and conducted our initial studies on these compounds.
−Removed: Binding of two of these compounds to the GLB target has been confirmed using a biophysical assay.
−Removed: Preclinical studies indicate that our STARs help mutated GLB escape premature degradation and travel to the lysosome where it can perform its catalytic activity.
−Removed: These preliminary studies were conducted in vitro using cells that carried the GLB1 mutation.
−Removed: In addition, one compound showed clearance of the toxic GM1 ganglioside accumulation in GM1-affected canine cells.
−Removed: We also tested the GLB-targeting compounds in an acute toxicity study in mice after oral administration.
−Removed: No abnormal clinical signs were observed and there were no mortalities at the tested dose levels.
−Removed: As such, we have not yet established a maximum tolerable dose in mice.
−Removed: Further, we performed preliminary pharmacokinetic (PK) studies with the GLB-targeting compounds in mice confirming that the compounds showed positive brain-penetrating properties.
−Removed: In oral bioavailability studies in mice, we found no central or peripheral clinical abnormalities, and the brain to plasma ratio was greater than one at each dose tested while the bone to plasma ratio increased approximately 3-fold over time from one hour to eight hours.
−Removed: The pharmacokinetic profile was completed with PK studies of one compound after repeated treatments to obtain safety information and exposure in tissues including brain and bone, showing that it was generally well-tolerated after seven days of treatment without showing clinical signs.
−Removed: Comparable plasma exposure was observed at oral doses at two dose levels, and accumulation was not observed after seven days of treatment.
−Removed: Brain concentrations were quantifiable up to eight hours following the last dose showing brain and bone exposure.
−Removed: After conducting initial pharmacological studies in 2021, we are currently testing additional compounds in in vitro assays to provide the basis for a decision on the lead series selection.
−Removed: IDUA Enzyme-Related Disorders:
−Removed: Mucopolysaccharidosis Type 1 (MPS1)
−Removed: IDUA is an enzyme in lysosomes needed to breakdown large sugar molecules called glycosaminoglycans (GAGs), especially heparan sulfate and dermatan sulfate.
−Removed: The misfolding of IDUA can allow substrate to build up to toxic levels in the bone and cartilage and can result in MPS1.
−Removed: There is no cure for MPS1, and treatment options to address symptoms such as enzyme replacement therapy or ERT, laronidase®, and bone marrow transplants are limited.
−Removed: We have identified a STAR targeting IDUA and are applying medicinal chemistry approaches to generate proprietary compounds.
−Removed: Preclinical studies of this compound have shown that in healthy cells, this STAR can stabilize recombinant IDUA and increase its activity.
−Removed: Additionally, when this STAR is co-administrated with laronidase, there is a dose-dependent increase in IDUA activity levels in vitro and in mice.
−Removed: Overview of MPS1
−Removed: MPS1 is a rare LSD that presents as a spectrum of symptoms that can include severe impairment of the CNS.
−Removed: Because there is no clear delineation between the syndromes, patients are best described as having one of two subtypes, severe MPS1 or attenuated MPS1.
−Removed: Patients with severe MPS1 typically have earlier onset of symptoms and experience a decline in intellectual function and a more rapid disease progression.
−Removed: Symptoms include abnormal formation of the soft tissue of the face, enlarged vocal cords, enlarged liver and spleen, heart valve defects, short stature, joint deformities, corneal clouding, macrocephaly, hydrocephalus, hearing loss, development delays and regression.
−Removed: Children with severe MPS1 usually do not live past the age of 10.
−Removed: Patients with attenuated MPS1 make up approximately 55% of all MPS1 cases and present a variety of symptoms that tend to be less acute than in those seen in severe MPS1.
−Removed: Due to their longer life span, attenuated MPS1 patients also make up a larger fraction of the patient population.
−Removed: MPS1 results from mutations in the gene encoding IDUA, an enzyme responsible for the hydrolysis of glycosidic bonds in terminal α-L-iduronic acid residues of complex glycosaminoglycans (GAGs), such as heparan sulfate and dermatan sulfate.
−Removed: Impaired degradation of these molecules can lead to their accumulation within lysosomes and triggers a complex cascade of intracellular events ultimately leading to multisystem morbidity caused by tissue damage and organ dysfunction.
−Removed: The prevalence of severe MPS1 is reported as affecting about 1 in 100,000 live births.
−Removed: Attenuated MPS1 is less common and occurs in about 1 in 500,000 live births.
−Removed: At present, there is no effective cure for MPS1 and there are limited treatment options to address symptoms such as enzyme replace therapy or ERT, laronidase, and bone marrow transplants.
−Removed: These approaches, however, do not cross the blood-brain barrier or penetrate the hard to treat tissues like cartilage.
−Removed: Preclinical Characterization of IDUA Compounds
−Removed: Biological Activity
−Removed: We have identified certain compounds that bind to an allosteric site on IDUA with functional effect.
−Removed: We plan to use this compound as a starting point to generate proprietary compounds.
−Removed: These compounds have been shown to stabilize IDUA and protect the enzyme against denaturation in physiological conditions.
−Removed: Preclinical cell-based studies indicate that stability and cellular uptake of IDUA is enhanced when co-administered with these compounds in MPS-affected fibroblasts.
+Added: Preclinical Characterization of Lead Compound GT-02287 for the Treatment of GBA1-related Diseases
+Added: 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.
+Added: 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.
+Added: 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-
+Added: up compound to GT-02287.
+Added: This decision resulted in a reduction of projected development costs of our GBA1 program of approximately $8.4 million.
+Added: Activity in Biophysical and Cell-based Assays
+Added: Biophysical assay results have demonstrated that GT-02287 binds to the GCase protein and increases its thermal stability.
+Added: 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.
+Added: 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.
+Added: 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
−Removed: The acute toxicity of these preliminary test compounds was investigated after acute intravenous administration to mice to provide information on the maximum tolerated dose to be used in pharmacology studies and determined the maximum tolerable dose for intravenous administration in mice.
+Added: 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.
+Added: The GLP toxicology study with repeated administrations of GT-02287 in male and female dogs and rats is currently ongoing.
+Added: 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).
+Added: 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
−Removed: We performed a neuro-PK study in mice after intravenous administration and determined the compound was not detected in the brain.
−Removed: However, these compounds showed tissue distribution in bone and cartilage, the relevant tissues for MPS1, after oral administration in mice, which is critical for a potential treatment of MPS1 as current treatments are ineffective at penetrating bone and cartilage.
−Removed: Additionally, at higher doses limited brain penetration was observed and the low brain penetration of this compound was confirmed from a pharmacology study performed.
−Removed: Combination therapy of STARs with pharmacological chaperones and ERT can improve tissue uptake and reduce ERT’s immunogenicity by stabilizing the enzyme in its properly folded and active form in vivo .
−Removed: In preclinical studies, one of our STAR compounds was co-administered with laronidase (Aldurazyme®), an approved enzyme replacement therapy, intravenously to mice.
−Removed: Data show the combination treatment stabilized the recombinant enzyme, increasing enzymatic activity levels in plasma, liver, bone and cartilage in a dose-dependent manner.
−Removed: Bone and cartilage represent the most critical medical need due to poor ERT uptake in these tissues.
−Removed: The benefit of combination therapy is particularly noticeable at longer times.
+Added: Studies in mice, rats and dogs have shown that GT-02287 is quickly absorbed following oral administration, reaching the maximal concentration in plasma (Tmax) between 0.5 and 2 hours with a plasmatic half-life (t1/2) of about 2 hours in mice, 3 hours in rats and 5 hours in dogs.
+Added: We examined GT-02287 in neuro-PK studies to evaluate its brain penetration properties, and we observed high brain exposure with a brain-to-plasma ratio level greater than one.
+Added: In-Vivo Pharmacology in PD Animal Models
+Added: 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.
+Added: GT-02287 was orally administered once a day, at doses of 30, 60 and 90 mg/kg.
+Added: 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.
+Added: In the same animal model, GT-02287 improved the survival of dopaminergic neurons in the substantia nigra.
+Added: Notably, these biological effects resulted in a dose-dependent behavioral effect shown by improved neuromotor strength as measured by the “wire-hang” test.
+Added: 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 .
+Added: 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.
+Added: In addition GT-02287 improved the survival of dopaminergic neurons along with an increased level of dopamine in the striatum.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: In addition, GT-02287 was shown to reduce tumor necrosis factor alpha (TNF-alpha), a biomarker for
+Added: 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).
+Added: Results of the CBE/PFF Mouse Model
+Added: GCase Activity (plasma) Glucosylceremide (brain) Glucosylspingosine (brain) Motor (wire hang)
+Added: Results of the Rotenone Rat Model
+Added: In Vivo Pharmacology in GD Animal Models
+Added: 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.
+Added: 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.
+Added: 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.
+Added: Results of the CBE Mouse Model
+Added: Iba-1 levels in brains of CBE-injected mice treated with GT-02329 Motor Function
+Added: Pipeline Programs in Research and Discovery Phases
+Added: 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.
+Added: We are also seeking non-dilutive funding in order to continue additional research programs in additional lysosomal storage disorders and metabolic diseases.
GALC Enzyme-Related Disorders:
3 unchanged sentences
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.
−Removed: 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.
+Added: The misfolding of GALC can
+Added: 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.
4 unchanged sentences
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.
−Removed: Myelin is the protective covering around neurons that ensures the rapid
−Removed: transmission of neural signals.
+Added: Myelin is the protective covering around neurons that ensures the rapid transmission of neural signals.
The most common form of Krabbe disease, the infantile form, usually begins before the age of one.
12 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.
−Removed: Preclinical Characterization of GALC STAR Lead Compounds
+Added: Preclinical Characterization of GALC Lead Compounds
Biological Activity
6 unchanged sentences
We showed that the tested compounds showed significant reduction in psychosine levels in glial cultures.
−Removed: ARSA Enzyme-related Disorders:
−Removed: Metachromatic Leukodystrophy (MLD)
−Removed: We are investigating the restoration of ARSA function as a treatment for Metachromatic Leukodystrophy.
−Removed: ARSA is an enzyme in lysosomes needed to breakdown sulfatides and sulfate-containing lipids, which are critical constituents in the nervous system comprising approximately 5% of the myelin lipids.
−Removed: The misfolding of ARSA can result in the toxic accumulation of sulfatide in the nervous system, which eventually leads to myelin breakdown (leukodystrophy) and a progressive neurologic disorder.
−Removed: We have identified two potential allosteric sites and have selected 133 virtual hits obtained from virtual screening with whom to start experimental hit confirmation.
−Removed: Overview of MLD
−Removed: Metachromatic leukodystrophy is an autosomal recessive hereditary neurodegenerative disease caused by mutations in the ARSA gene, which encodes the lysosomal enzyme arylsulfatase A.
−Removed: At least 280 ARSA pathogenic variants have been reported, mostly missense mutations.
−Removed: Impaired breakdown of sulfatides and sulfate-containing lipids due to ARSA deficiency in the nervous system eventually leads to myelin breakdown (leukodystrophy) and a progressive neurologic disorder.
−Removed: The exact molecular pathogenic processes of demyelination in MLD are poorly understood.
−Removed: The clinical presentation of MLD is heterogeneous with respect to the age of onset, the rate of progression, and the initial symptoms.
−Removed: The clinical manifestations and a degree of neurodegeneration depend on the type of mutation and the level of enzyme deficiency.
−Removed: Three clinical subtypes of MLD are primarily distinguished by age of onset:
−Removed: ● Late-infantile MLD, comprising 50%-60% of affected individuals
−Removed: ● Juvenile MLD, approximately 20%-30%
−Removed: ● Adult MLD, approximately 15%-20%
−Removed: Although the presenting symptoms and age of onset vary, all individuals eventually develop complete loss of motor, sensory, and intellectual functions.
−Removed: The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms.
−Removed: Death most commonly results from pneumonia or other infection.
−Removed: Life span correlates roughly with the age of onset but can be quite variable, particularly in the later-onset forms.
−Removed: Current management is still mostly symptomatic and/or relies on HSCT;
−Removed: however, Libmeldy® ( ex vivo gene therapy) has been the first disease-modifying treatment to be approved to date (Dec 2020 in the EU, Ph III in US ) and is administered to patients with :
−Removed: ● late infantile or early juvenile forms of the disease who have not yet developed symptoms;
−Removed: ● early juvenile forms who have initial symptoms but can still walk independently and have not yet developed mental deterioration.
−Removed: There are still limitations and unmet medical needs connected to ex vivo gene therapy.
−Removed: First, it cannot be administered to patients with manifested clinical symptoms therefore it is not ideal for late-onset forms.
−Removed: Moreover, it is very expensive and must be performed in specialized centers since autologous HSCs are transduced ex vivo with ARSA-encoding lentiviral vector and reinfused after the patients had been treated with a myeloablative regimen.
−Removed: Moreover, there is no data yet available on how effective this cross-correction is in the long-term (>15 y).
−Removed: The overall prevalence has been reported at between 1:40,000 and 1:160,000 worldwide.
−Removed: The disorder is pan ethnic;
−Removed: however, most data come from European and North American populations, where prevalence ranges from 1:40,000 to 1:100,000.
−Removed: Incidence is estimated to be 1:40,000 births in the United States of America.
−Removed: Males and females are affected equally and there is no difference in survival.
−Removed: Primary Screening
−Removed: Hit identification was completed with two orthogonal techniques:
−Removed: hit confirmation was obtained for 8 of 35 compounds (23% hit rate) with consistent K d -range in the two-digit μM.
−Removed: Hit analoging was completed with 82 analog compounds tested in dose-response assay.
−Removed: A positive signal was obtained for 22 of 82 compounds (27% hit rate) with consistent K d -range in the two-digit µM.
−Removed: Rare Metabolic Liver/Lung Disorder
−Removed: We are investigating the stabilization of an undisclosed enzyme to avoid its gain of function in the liver and provide a treatment for a rare lung/liver disease.
−Removed: We have identified one allosteric site and have selected 146 virtual hits obtained from virtual screening with whom to start experimental hit confirmation.
+Added: 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.
+Added: GLB Enzyme-Related Disorders:
+Added: GM1 Gangliosidosis
+Added: GLB is an enzyme found in lysosomes, which are compartments within cells that degrade and recycle different types of molecules, including toxic molecules.
+Added: GLB is essential for the breakdown of GM1 and keratan sulfate, which serve important functions in the brain and other tissues.
+Added: Misfolding of GLB allows these substrates to build up to toxic levels and leads to the diseases GM1 Gangliosidosis.
+Added: GM1 gangliosidosis is a rare and often life-threatening LSD in infants (type 1), juveniles (type 2) and adults (type 3).
+Added: It manifests in a continuum of clinical severity by type.
+Added: In type 1 or the infantile form, the onset is observed earlier and is a more severe and rapidly progressive disease.
+Added: Type 2 and 3 are less severe manifestations and have slower progression with a juvenile or adult onset.
+Added: The infantile form of the disease is characterized by onset in the first year of life with symptoms including hypotonia (reduced muscle tone), progressive CNS dysfunction that can lead to deafness, blindness, enlarged liver and spleen rigidity, and progressive skeletal dysplasia that can result in restrictive lung disease and aspiration pneumonia.
+Added: The disease rapidly progresses, with a life expectancy of two to four years.
+Added: Juvenile GM1 manifests between 18 months and five years of age with a slower progression compared to infants.
+Added: The average life expectancy for type 2 GM1 is typically 10 years.
+Added: Adult GM1 has an onset age between three and 30.
+Added: While it is less severe and progresses at a slower rate than infantile or juvenile GM1, adult GM1 causes debilitating symptoms, including muscular atrophy, corneal clouding and dystonia.
+Added: The prevalence of GM1 is approximately 1:100,000 to 200,000 live births worldwide.
+Added: Currently, there is no effective cure for GM1, and symptomatic treatment options, including substrate reduction therapy, ERT, bone marrow transplantation, stem cell transplantation and gene therapy are limited or still under development.
+Added: 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.
+Added: In Vitro Characterization of STARs for the Treatment of GM1 Gangliosidosis
+Added: We have identified novel STAR molecules targeting GLB through our SEE-Tx® platform and conducted our initial studies on these compounds.
+Added: Binding of two of these compounds to the GLB target has been confirmed using a biophysical assay.
+Added: Preclinical studies indicate that our STARs help mutated GLB escape premature degradation and travel to the lysosome where it can perform its catalytic activity.
+Added: These preliminary studies were conducted in vitro using cells that carried the GLB1 mutation.
+Added: In addition, one compound showed clearance of the toxic GM1 ganglioside accumulation in GM1-affected canine cells.
+Added: Based on the data generated to date, we have selected a lead series for further characterization and development.
+Added: Serpina related disorder:
+Added: alpha-1 Antitrypsin (A1AT) Deficiency
+Added: We are investigating the stabilization of alpha-1 antitrypsin (A1AT) as a potential treatment for rare lung and/or liver disorder.
+Added: 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.
+Added: 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
3 unchanged sentences
Positive signal was observed for 4 of 85 compounds.
−Removed: The biotechnology and pharmaceutical industries, including the rare disease field, are characterized by rapidly changing technologies, intense competition and a strong emphasis on intellectual property.
−Removed: We are not aware of any other companies that are taking the therapeutic approach to protein folding disorders similar to the one we are pursuing.
−Removed: However, we are aware of companies developing gene therapy approaches for our target indications.
−Removed: For example, Axovant Gene Therapies, Ltd., recently began clinical trial for its gene therapy treatment for juvenile GM1, and Lysogene, S.A.
−Removed: is expected to initiate a clinical trial for its gene therapy treatment for GM1.
−Removed: Additionally, other companies are developing product candidates for the treatment of Krabbe disease such as Chiesi, Ranedis, Passage Bio, MediciNova and Polaryx, which are in the discovery and preclinical stages, and Magenta which is developing a cell-based approach for various inherited metabolic disorders, including Krabbe disease, which is in clinical trials.
−Removed: Companies such as Prevail Therapeutics and Apollo Therapeutics are developing candidates targeting GCase and GBA1 to address type 2 and type 3 Gaucher’s disease and are in the preclinical and clinical stage for certain candidates.
+Added: We have now identified a hit chemical series that inhibits polymerization of A1AT protein, and a priority patent application was filed in February 2023.
+Added: 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.
+Added: This grant supports a research project to develop novel small molecule allosteric regulators against Alpha-1 Antitrypsin (AAT) Deficiency, a rare genetic condition that can result in serious lung and liver diseases.
+Added: Allosteric Regulators in Oncology
+Added: Allosteric regulators are molecules able to modify the activity of a protein binding to a site topographically distinct from the site of the protein, called the active site, in which the activity characterizing the protein is carried out and in oncology usually involves the binding of receptors.
+Added: Targeting allosteric sites may provide greater specificity and selectivity of activity and allow for a better efficacy and safety profile.
+Added: An allosteric site is more specific to an individual protein, potentially leading to safer and more efficacious medicines.
+Added: The allosteric-targeted therapies also introduce the possibility of fine-tuning a protein’s activity in new ways—one modulator may shift a protein into a conformation that shuts it down entirely, while another might under the right condition potentiate activity, and others may result in activity levels in between.
+Added: Allosteric drugs open the door to identifying drug targets that are inaccessible to traditional active-site inhibitors.
+Added: 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.
+Added: Target Selection Strategy
+Added: 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.
+Added: Our Oncology Programs
+Added: 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.
+Added: 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.
+Added: 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.
+Added: We believe that our SEE-Tx® platform, our scientific capabilities, know-how and experience provide us with competitive advantages.
+Added: 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.
+Added: Many of our competitors, either alone or with their collaborations, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, and marketing approved products than we do.
+Added: Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.
+Added: 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.
+Added: As a result, our competitors may discover, develop, license, or commercialize products before or more successfully than we do.
+Added: We are not aware of any other companies that are taking the same therapeutic approach to protein folding disorders similar to the ones we are pursuing.
+Added: However, we are aware of companies developing products for the same target indications.
+Added: For example, companies targeting GBA-PD using small molecules include Vanqua Bio and Caraway Therapeutics.
+Added: 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.
+Added: There are also a number of companies targeting GBA-PD through other modalities such as cell/gene therapies and monoclonal antibodies.
+Added: These companies include, among others:
+Added: Prevail Therapeutics, which is evaluating a potential gene therapy candidate in a Phase 1/2 clinical trial, Apollo Therapeutics and Voyager Therapeutics.
+Added: 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.
+Added: 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.
We may also face competition from large pharmaceutical and biotechnology companies, academic research institutions, government agencies and public and private research institutions with genetic medicine and other therapeutic approaches.
−Removed: Many of our potential competitors, alone or with their strategic partners, may have substantially greater financial, technical and other resources than we do.
−Removed: These may include larger research and development, clinical, marketing and manufacturing organizations and resources.
−Removed: Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated among a smaller number of competitors.
−Removed: Our commercial opportunity could be reduced or eliminated if competitors develop and commercialize products that are safer, more effective, more convenient or less expensive than any product candidates that we may develop.
−Removed: Competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.
Additionally, new or advanced technologies developed by our competitors may render our current or future product candidates uneconomical or obsolete, and we may not be successful in marketing our product candidates against competitors.
−Removed: For more information about the risks and challenges we face, see "Risk Factors"
−Removed: under Item 1A of this Annual Report on Form 10-K.
Strategic Transactions;
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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.
−Removed: Sumitomo Dainippon Pharma Co.
−Removed: In September 2020, we entered into a strategic research collaboration agreement with Sumitomo for the research and development of structurally targeted allosteric regulators to restore functional activity of defective lysosomal enzymes in rare genetic and demyelinating diseases.
−Removed: While the goals of the first phase of the research project have been achieved, Sumitomo determined not to continue the research collaboration, and informed the Company on March 22, 2022, that it will send a formal notice letter in due course.
Zentalis Pharmaceuticals, Inc.
−Removed: On April 20, 2021, the Company entered into a multi-target collaboration agreement with Zentalis Pharmaceuticals, Inc.
−Removed: (“Zentalis”) to discover new product candidates for the treatment of cancer.
−Removed: Under the terms of the agreement, the Company will use its 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 their prospective therapeutic use in oncology.
−Removed: Pursuant the terms of the agreement, Zentalis agreed to pay the Company, on a program-by-program basis, a non-creditable, non-refundable, program initiation fee and reimburse of expenses incurred by the Company in accordance with the agreed-upon research budget.
−Removed: With respect to any development program, and subject to the delivery of the data package, the Company granted to Zentalis an option to obtain an exclusive, transferable worldwide license, with the right to sublicense, under relevant intellectual property rights and know-how of the Company arising from the collaboration to develop, manufacture and commercialize any products resulting from the development program.
−Removed: Zentalis may exercise the option, at its reasonable discretion, and shall use commercially reasonable efforts to develop and obtain market approval for products developed from the applicable programs.
−Removed: Unless terminated earlier, the agreement expires at the expiration of the last valid claim of the licensed patents, subject to certain surviving rights and obligations.
−Removed: Zentalis and the Company can each terminate the agreement in the event of the bankruptcy or insolvency of the other party, or a material breach by the other party and failure to cure such breach within a certain period of time.
−Removed: Zentalis shall have the right, at its sole discretion, exercisable at any time to terminate the agreement on a program-by-program basis, upon ninety (90) days’ prior written notice to the Company or, at any time, if a safety concerns arises with respect to any development program or product.
−Removed: In May 2021, the first target development program was identified, and the estimated development cost were approved and collected in July 2021.
−Removed: The transaction price of this first target development program includes (i) $50 thousand of fixed consideration as program initiation fee, (ii) up to $272 thousand as reimbursement for employee and external research and development cost, (iii) $250 thousand subject to the exercise of a research program option, (iv) up to $41.5 million of variable consideration in the form of event-based milestone payments, if goals will be met in the future, and (v) other royalty-based payments based on future net sales.
−Removed: The research project is progressing in accordance with the agreed upon research plans.
+Added: 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.
+Added: 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.
+Added: During the course of 2022, Zentalis informed us of its desire to wind down the collaboration.
+Added: 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.
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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.
−Removed: Minoryx’s IP includes the Site-Directed Enzyme Enhancement Therapy (SEE-Tx®) discovery platform for identification of non-competitive pharmacological chaperones, 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.
+Added: 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.
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.
Under the Minoryx License Agreement, products include any product in the field that would infringe the UB/ICREA IP or the Minoryx IP in the absence of the license provided therein.
−Removed: Also, field encompasses any field of use and commercialization of the UB/ICREA IP or the Minoryx IP.
+Added: Also, the field encompasses any field of use and commercialization of the UB/ICREA IP or the Minoryx IP.
Unless earlier terminated, the Minoryx License Agreement expires upon expiration of the royalty term, which occurs ten years after the first product covered by the licensed IP is commercialized.
2 unchanged sentences
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.
−Removed: In addition to royalties, we will pay Minoryx certain milestones payments of 1.25% of any consideration received by us in the event of a sale of our company or substantially all of our assets, including by merger, change of control, or reorganization.
The Minoryx License Agreement will terminate upon expiration of the royalty term (which is the 10th anniversary of the commercialization of the first product covered by the licensed IP) or by mutual agreement.
In addition, each party has the right to terminate the Minoryx License Agreement upon a material breach by the other party that remains uncured.
−Removed: 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.
+Added: 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
+Added: such abandonment or unlawful use.
We may terminate the Minoryx License Agreement at any time upon 90 days’ written notice.
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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.
−Removed: As of February 2022, our patent portfolio consisted of five pending European patent applications and related national stage applications.
−Removed: In regards 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.
+Added: As of February 2023, our patent portfolio consisted of six pending European patent applications and related national stage applications.
+Added: 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.
This patent is expected to expire in 2032.
−Removed: In regards 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 8 foreign patent applications pending in such jurisdictions such as Canada, Australia, Japan, Europe, and China.
+Added: 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.
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.
−Removed: In regards to our GBA 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 8 foreign patent applications pending in such jurisdictions such as Canada, Australia, Japan, Europe, and China.
+Added: In regard to our GBA 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 patent 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.
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In addition, our trade secrets may otherwise become known or be independently discovered by competitors.
−Removed: To the extent that our
−Removed: collaborators, employees and consultants use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.
+Added: To the extent that our collaborators, employees and consultants use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.
Our success will also depend in part on not infringing upon the proprietary rights of third parties.
−Removed: 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.
+Added: It is uncertain whether the issuance of any third-party patent would require us to alter our development or commercial
+Added: 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.
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Clinical trials to evaluate therapeutic indications to support NDAs for marketing approval are typically conducted in three sequential phases, which may overlap.
−Removed: ● Phase I —Phase I clinical trials involve initial introduction of the investigational product into healthy human volunteers or patients with the target disease or condition.
+Added: ● Phase 1 —Phase 1 clinical trials involve initial introduction of the investigational product into healthy human volunteers or patients with the target disease or condition.
These studies are typically designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, excretion the side effects associated with increasing doses, and, if possible, to gain early evidence of effectiveness.
−Removed: ● Phase II —Phase II clinical trials typically involve administration of the investigational product to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.
−Removed: ● Phase III —Phase III clinical trials typically involve administration of the investigational product to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical
−Removed: efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites.
+Added: ● Phase 2 —Phase 2 clinical trials typically involve administration of the investigational product to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.
+Added: ● Phase 3 —Phase 3 clinical trials typically involve administration of the investigational product to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites.
These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval and physician labeling.
−Removed: Post-approval trials, sometimes referred to as Phase IV clinical trials, may be conducted after initial marketing approval.
+Added: Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.
These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication and are commonly intended to generate additional safety data regarding use of the product in a clinical setting.
−Removed: In certain instances, the FDA may mandate the performance of Phase IV clinical trials as a condition of approval of an NDA.
+Added: In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.
Progress reports detailing the results of the clinical trials, among other information, must be submitted at least annually to the FDA.
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An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.
−Removed: 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 IV 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.
+Added: 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.
The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs.
18 unchanged sentences
In addition, a new drug may be eligible for Breakthrough Therapy designation if it is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
−Removed: 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 I, and FDA organizational commitment to expedited development, including involvement of senior managers and experienced review staff in a cross-disciplinary review, where appropriate.
+Added: 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.
14 unchanged sentences
The FDA may impose a number of post-approval requirements as a condition of approval of an NDA.
−Removed: For example, the FDA may require post-market testing, including Phase IV clinical trials, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.
+Added: For example, the FDA may require post-market testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.
In addition, drug manufacturers and their subcontractors 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 ongoing regulatory requirements, including cGMP, which impose certain procedural and documentation requirements upon us and our contract manufacturers.
22 unchanged sentences
Since its enactment, there have been judicial, administrative, executive and Congressional legislative challenges to certain aspects of the ACA, and we expect there will be additional challenges and amendments to the ACA in the future.
−Removed: For example, various portions of the ACA are currently undergoing constitutional challenges in the U.S.
−Removed: Supreme Court, the Trump Administration has issued various Executive Orders eliminating cost sharing subsidies and various provisions that would impose a fiscal burden on states or a cost, fee, tax, penalty or regulatory burden on individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices, and Congress has introduced several pieces of legislation aimed at significantly revising or repealing the ACA.
−Removed: It is unclear whether the ACA will be overturned, repealed, replaced, or further amended, and we cannot predict what affect further changes to the ACA would have on our business.
+Added: For example, on June 17, 2021 the U.S.
+Added: Supreme Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed by Congress.
+Added: In addition, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022 (“IRA”) into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.
+Added: The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and creating a new manufacturer discount program.
+Added: It is unclear how any additional challenges and healthcare reform measures of the Biden administration will impact the ACA and our business.
Other federal health reform measures have been proposed and adopted in the U.S.
3 unchanged sentences
These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and, due to subsequent legislative amendments to the statute, including the BBA, will remain in effect through 2031, unless additional Congressional action is taken.
−Removed: These Medicare sequester reductions have been suspended from May 1, 2020 through December 31, 2020 due to the COVID-19 pandemic.
+Added: Under current legislation the actual reduction in Medicare payments will vary from 1% in 2022 to up to 4% in the final fiscal year of this sequester.
● The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
1 unchanged sentence
● 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.
−Removed: 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 products.
+Added: 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.
−Removed: government, state legislatures, and foreign governments have shown significant interest
−Removed: in implementing cost containment programs, including price-controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs to limit the growth of government paid healthcare costs.
+Added: government, state legislatures, and foreign governments have shown significant interest in implementing cost containment programs, including price-controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs to limit the growth of government paid healthcare costs.
For example, the U.S.
government has passed legislation requiring pharmaceutical manufacturers to provide rebates and discounts to certain entities and governmental payors to participate in federal healthcare programs.
−Removed: Further, Congress and the Trump administration have each indicated that it will continue to seek new legislative and/or administrative measures to control drug costs, and the current administration recently released a “Blueprint,” or plan, to reduce the cost of drugs.
−Removed: The Blueprint contains certain measures that the U.S.
−Removed: Department of Health and Human Services is already working to implement.
−Removed: Individual states in the U.S.
−Removed: have also increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
−Removed: Congress and the Trump administration have each indicated that it will continue to seek new legislative and/or administrative measures to control drug costs.
−Removed: Additionally, we may face competition in the United States for our development candidates and investigational medicines, if approved, from therapies sourced from foreign countries that have placed price controls on pharmaceutical products.
−Removed: In the United States, the Medicare Modernization Act, or MMA, contains provisions that call for the promulgation of regulations that expand pharmacists’ and wholesalers’ ability to import cheaper versions of an approved drug and competing products from Canada, where there are government price controls.
−Removed: Further, the MMA provides that these changes to U.S.
−Removed: importation laws will not take effect, unless and until the Secretary of the HHS certifies that the changes will pose no additional risk to the public’s health and safety and will result in a significant reduction in the cost of products to consumers.
−Removed: On September 23, 2020, the Secretary of the HHS made such certification to Congress, and on October 1, 2020, the FDA published a final rule that allows for the importation of certain prescription drugs from Canada.
−Removed: Under the final rule, States and Indian Tribes, and in certain future circumstances pharmacists and wholesalers, may submit importation program proposals to the FDA for review and authorization.
−Removed: On September 25, 2020, CMS stated drugs imported by States under this rule will not be eligible for federal rebates under Section 1927 of the Social Security Act and manufacturers would not report these drugs for “best price” or Average Manufacturer Price purposes.
−Removed: Since these drugs are not considered covered outpatient drugs, CMS further stated it will not publish a National Average Drug Acquisition Cost for these drugs.
−Removed: Separately, the FDA also issued a final guidance document outlining a pathway for manufacturers to obtain an additional National Drug Code, or NDC, for an FDA-approved drug that was originally intended to be marketed in a foreign country and that was authorized for sale in that foreign country.
−Removed: The market implications of the final rule and guidance are unknown at this time.
−Removed: Proponents of drug reimportation may attempt to pass legislation that would directly allow reimportation under certain circumstances.
−Removed: Legislation or regulations allowing the reimportation of drugs, if enacted, could decrease the price we receive for any products that we may develop and adversely affect our future revenues and prospects for profitability.
+Added: Further, in July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at prescription drugs.
+Added: In response to Biden’s executive order, on September 9, 2021, the U.S.
+Added: Department of Health and Human Services (“HHS”), released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles.
+Added: In addition, the IRA, among other things, (i) directs HHS to negotiate the price of certain high-expenditure, single-source drugs and biologics covered under Medicare, and subject drug manufacturers to civil monetary penalties and a potential excise tax by offering a price that is not equal to or less than the negotiated “maximum fair price” for such drugs and biologics under the law, and (ii) imposes rebates with respect to certain drugs and biologics covered under Medicare Part B or Medicare Part D to penalize price increases that outpace inflation.
+Added: The IRA permits HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.
+Added: These provisions will take effect progressively starting in fiscal year 2023, although they may be subject to legal challenges.
+Added: It is currently unclear how the IRA will be implemented but is likely to have a significant impact on the pharmaceutical industry.
+Added: Further, the Biden administration released an additional executive order on October 14, 2022, directing HHS to submit a 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.
+Added: It is unclear whether this executive order or similar policy initiatives will be implemented in the future.
Individual states in the U.S.
9 unchanged sentences
Violations of the federal Anti-Kickback Statute can result in significant civil monetary and criminal penalties, per kickback plus three times the amount of remuneration and a prison term per violation.
−Removed: Further, violation of the federal
−Removed: Anti-Kickback Statute can also form the basis for False Claims Act liability (discussed below).
+Added: Further, violation of the federal Anti-Kickback Statute can also form the basis for False Claims Act liability (discussed below).
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.
4 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.
−Removed: 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.
+Added: 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.
5 unchanged sentences
Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.
−Removed: We may also be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business.
−Removed: HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and its implementing regulations, including the final omnibus rule published on January 25, 2013, imposes certain requirements relating to the privacy, security and transmission of individually identifiable health information.
−Removed: Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to “business associates,” defined as independent contractors or agents of covered entities that create, receive, maintain or transmit protected health information in connection with providing a service for or on behalf of a covered entity.
−Removed: HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions.
−Removed: Many states also have 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 HIPAA, thus complicating compliance efforts.
−Removed: California recently enacted the California Consumer Privacy Act, or CCPA, which creates new individual privacy rights for California consumers (as defined in the law) and places increased privacy and security obligations on entities handling personal data of consumers or households.
−Removed: The CCPA will require covered companies to provide certain disclosures to consumers about its data collection, use and sharing practices, and to provide affected California residents with ways to opt-out of certain sales or transfers of personal information.
−Removed: The CCPA went into effect on January 1, 2020, and the California Attorney General commenced enforcement actions against violators beginning July 1, 2020.
−Removed: While there is currently an exception for protected health information that is subject to HIPAA and clinical trial regulations, as currently written, the CCPA may impact our business activities.
−Removed: The California Attorney General has proposed draft regulations, which have not been finalized to date, that may further impact our business activities if they are adopted.
−Removed: The uncertainty surrounding the implementation of CCPA exemplifies the vulnerability of our business to the evolving regulatory environment related to personal data and protected health information.
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.
−Removed: physicians and teaching hospitals, as well as physician ownership and investment interests in the manufacturer.
−Removed: Effective January 1, 2022, these reporting obligations will extend to include transfers of value made to certain non-physician providers such as physician assistants and nurse practitioners.
+Added: 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.
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.
−Removed: 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.
+Added: Ensuring business arrangements comply with applicable healthcare
+Added: 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.
+Added: Data Privacy and Security
+Added: In the ordinary course of business, we collect, receive, store, process, generate, use, transfer, disclose, make accessible, protect, secure, dispose of, transmit, and share (collectively, process) personal information, such as clinical trial data and other health data.
+Added: Accordingly, we may be subject to numerous data privacy and security obligations, including federal, state, local, and foreign laws, regulations, guidance, industry standards, external and internal privacy and security policies, contractual requirements and other obligations related to data privacy and security.
+Added: These frameworks are evolving and may impose potentially conflicting obligations.
+Added: Such obligations may include, without limitation, the Federal Trade Commission Act, the California Consumer Privacy Act of 2018, as amended by the California Privacy Rights Act of 2020 (“CPRA”) (collectively, “CCPA”), the European Union’s General Data Protection Regulation 2016/679 (“EU GDPR”), the EU GDPR as it forms part of United Kingdom law by virtue of section 3 of the European Union (Withdrawal) Act 2018 (“UK GDPR”), the ePrivacy Directive, and wiretapping laws.
+Added: HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and its implementing regulations, imposes certain requirements relating to the privacy, security and transmission of protected health information.
+Added: Many states also have laws governing the privacy and security of health information and other personal information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.
+Added: For example, the CCPA applies to personal information of consumers, business representatives, and employees who are California residents, places increased privacy and security obligations on entities handling personal information of such California residents or households, requires covered companies to provide certain disclosures to such California residents about its data collection, use and sharing practices, and requires covered companies to provide such California residents with ways to opt-out of certain sales or transfers of personal information.
+Added: In addition, the CPRA expanded the CCPA’s requirements.
+Added: Additionally, European data privacy and security laws (including the EU GDPR and UK GDPR) impose significant and complex compliance obligations on companies that are subject to those laws, notably with respect to the processing of health-related data from EEA or UK-based individuals.
+Added: Coverage and Reimbursement
+Added: Market acceptance and sales of approved products depends in part on the extent to which reimbursement for these drugs and related treatments will be available from third-party payors, including government health administration authorities, managed care organizations and other private health insurers.
+Added: Third-party payors decide which therapies they will pay for and establish reimbursement levels.
+Added: Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own coverage and reimbursement policies.
+Added: Additionally, a third-party payor’s decision to provide coverage for a therapy does not imply that an adequate reimbursement rate will be approved.
+Added: Even if favorable coverage and reimbursement status is attained for any product candidate, less favorable coverage policies and reimbursement rates may be implemented in the future.
+Added: Patients are unlikely to use our drugs unless coverage is provided and reimbursement is adequate to cover a significant portion of the cost of our drugs.
+Added: A primary trend in the U.S.
+Added: healthcare industry and elsewhere is cost containment.
+Added: Third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications.
+Added: If coverage and adequate reimbursement are not available, or are available only at limited levels, we may not be able to successfully commercialize our current and any future product candidates that we develop.
Government Regulation of Drugs Outside of the United States
−Removed: To market any product outside of the U.S., we would need to comply with numerous and varying regulatory requirements of other countries regarding safety and efficacy and governing, among other things, clinical trials, marketing authorization or identification of an alternate regulatory pathway, manufacturing, commercial sales and distribution of our products.
−Removed: For instance, in the United Kingdom and the European Economic Area, or the EEA (comprised of the 27 EU Member States plus Iceland, Liechtenstein and Norway), medicinal products must be authorized for marketing by using either the centralized authorization procedure or national authorization procedures.
−Removed: ● Centralized procedure —If pursuing marketing authorization of a product candidate for a therapeutic indication under the centralized procedure, following the opinion of the European Medicines Agency’s Committee for Medicinal Products for Human Use, or, CHMP, the European Commission issues a single marketing authorization valid across the EEA.
−Removed: The centralized procedure is compulsory for human medicines derived from biotechnology processes or advanced therapy medicinal products (such as gene therapy, somatic cell therapy and tissue engineered products), products that contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases and other immune dysfunctions, viral diseases, and officially designated orphan medicines.
−Removed: For medicines that do not fall within these categories, an applicant has the option of submitting an application for a centralized marketing authorization to the European Medicines Agency, or EMA, as long as the medicine
−Removed: concerned contains a new active substance not yet authorized in the EEA, is a significant therapeutic, scientific or technical innovation, or if its authorization would be in the interest of public health in the EEA.
−Removed: Under the centralized procedure the maximum timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP.
−Removed: Accelerated assessment might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation.
−Removed: The timeframe for the evaluation of an MAA under the accelerated assessment procedure is 150 days, excluding clock stops.
−Removed: ● National authorization procedures —There are also two other possible routes to authorize products for therapeutic indications in several countries, which are available for products that fall outside the scope of the centralized procedure:
−Removed: ● Decentralized procedure —Using the decentralized procedure, an applicant may apply for simultaneous authorization in more than one EU country of medicinal products that have not yet been authorized in any EU country and that do not fall within the mandatory scope of the centralized procedure.
−Removed: ● Mutual recognition procedure —In the mutual recognition procedure, a medicine is first authorized in one EU Member State, in accordance with the national procedures of that country.
−Removed: ● Following authorization through either procedure, additional marketing authorizations can be sought from other EU countries in a procedure whereby the countries concerned recognize the validity of the original, national marketing authorization.
−Removed: In the EEA, new products for therapeutic indications that are authorized for marketing (i.e., reference products) qualify for eight years of data exclusivity and an additional two years of market exclusivity upon marketing authorization.
−Removed: The data exclusivity period prevents generic or biosimilar applicants from relying on the preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization in the EU during a period of eight years from the date on which the reference product was first authorized in the EU.
−Removed: The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until ten years have elapsed from the initial authorization of the reference product in the EU.
−Removed: The ten-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.
+Added: To market any product outside of the U.S., we would need to comply with numerous and varying regulatory requirements of other countries regarding safety and efficacy and governing, among other things, clinical trials, marketing authorization, manufacturing, commercial sales and distribution of our products.
+Added: To obtain a Marketing Authorization, or MA, for a product in the European Economic Area, or the EEA (comprised of the 27 EU Member States plus Iceland, Liechtenstein and Norway), for example an applicant must be established within the EEA.
+Added: The applicant must submit a Marketing Authorization Application, or MAA, either under a centralized procedure administered by the EMA or one of the procedures administered by competent authorities in the EEA countries
+Added: (decentralized procedure, national procedure or mutual recognition procedure).
+Added: An MA may be granted only to an applicant established in the EEA.
+Added: The centralized procedure provides for the grant of a single MA by the European Commission that is valid for all EEA countries.
+Added: Pursuant to Regulation (EC) No 726/2004, the centralized procedure is compulsory for specific products, including for (i) medicinal products derived from biotechnological processes, (ii) products designated as orphan medicinal products, (iii) advanced therapy medicinal products, or ATMPs, and (iv) products with a new active substance indicated for the treatment of HIV/AIDS, cancer, neurodegenerative diseases, diabetes, auto-immune and other immune dysfunctions and viral diseases.
+Added: For products with a new active substance indicated for the treatment of other diseases and products that are highly innovative or for which a centralized process is in the interest of patients, authorization through the centralized procedure is optional on related approval.
+Added: Under the centralized procedure, the EMA’s Committee for Medicinal Products for Human Use, or CHMP, conducts the initial assessment of a product.
+Added: The CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing MA.
+Added: Under the centralized procedure in the EEA, the maximum timeframe for the evaluation of an MAA is 210 days, excluding clock stops when additional information or written or oral explanation is to be provided by the applicant in response to questions of the CHMP.
+Added: Accelerated assessment may be granted by the CHMP in exceptional cases, when a medicinal product targeting an unmet medical need is expected to be of major interest from the point of view of public health and, in particular, from the viewpoint of therapeutic innovation.
+Added: If the CHMP accepts a request for accelerated assessment, the time limit of 210 days will be reduced to 150 days (excluding clock stops).
+Added: The CHMP can, however, revert to the standard time limit for the centralized procedure if it considers that it is no longer appropriate to conduct an accelerated assessment.
+Added: Unlike the centralized authorization procedure, the decentralized MA procedure requires a separate application to, and leads to separate approval by, the competent authorities of each EEA country in which the product is to be marketed.
+Added: This application is identical to the application that would be submitted to the EMA for authorization through the centralized procedure.
+Added: The reference Member State prepares a draft assessment and drafts of the related materials within 120 days after receipt of a valid application.
+Added: The resulting assessment report is submitted to the concerned EEA countries who, within 90 days of receipt, must decide whether to approve the assessment report and related materials.
+Added: If a concerned EU Member State cannot approve the assessment report and related materials due to concerns relating to a potential serious risk to public health, disputed elements may be referred to the Heads of Medicines Agencies’ Coordination Group for Mutual Recognition and Decentralised Procedures – Human, or CMDh, for review.
+Added: The subsequent decision of the European Commission is binding on all EEA countries.
+Added: The mutual recognition procedure allows companies that have a medicinal product already authorized in one EEA country to apply for this authorization to be recognized by the competent authorities in other EEA countries.
+Added: Like the decentralized procedure, the mutual recognition procedure is based on the acceptance by the competent authorities of the EEA countries of the MA of a medicinal product by the competent authorities of other EEA countries.
+Added: The holder of a national MA may submit an application to the competent authority of an EEA country requesting that this authority recognize the MA delivered by the competent authority of another EEA country.
+Added: An MA has, in principle, an initial validity of five years.
+Added: The MA may be renewed after five years on the basis of a re-evaluation of the risk-benefit balance by the EMA or by the competent authority of the EEA country in which the original MA was granted.
+Added: To support the application, the MA holder must provide the EMA or the competent authority with a consolidated version of the eCTD (Common Technical Document) providing up-to-date data concerning the quality, safety and efficacy of the product, including all variations introduced since the MA was granted, at least nine months before the MA ceases to be valid.
+Added: The European Commission or the competent authorities of the EEA countries may decide on justified grounds relating to pharmacovigilance, to proceed with one further five year renewal period for the MA.
+Added: Once subsequently definitively renewed, the MA shall be valid for an unlimited period.
+Added: Any authorization which is not followed by the actual placing of the medicinal product on the EU market (for a centralized MA) or on the market of the authorizing EEA country within three years after authorization ceases to be valid (the so-called sunset clause).
+Added: Innovative products that target an unmet medical need and are expected to be of major public health interest may be eligible for a number of expedited development and review programs, such as the Priority Medicines, or PRIME, scheme, which provides incentives similar to the breakthrough therapy designation in the U.S.
+Added: PRIME is a voluntary scheme aimed at enhancing the EMA’s support for the development of medicinal products that target unmet
+Added: medical needs.
+Added: Eligible products must target conditions for which there is an unmet medical need (there is no satisfactory method of diagnosis, prevention or treatment in the EU or, if there is, the new medicinal product will bring a major therapeutic advantage) and they must demonstrate the potential to address the unmet medical need by introducing new methods of therapy or improving existing ones.
+Added: Benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and potentially accelerated MAA assessment once a dossier has been submitted.
+Added: In the EEA, a “conditional” MA may be granted in cases where all the required safety and efficacy data are not yet available.
+Added: The European Commission may grant a conditional MA for a medicinal product if it is demonstrated that all of the following criteria are met:
+Added: (i) the benefit-risk balance of the medicinal product is positive;
+Added: (ii) it is likely that the applicant will be able to provide comprehensive data post-authorization;
+Added: (iii) the medicinal product fulfils an unmet medical need;
+Added: and (iv) the benefit of the immediate availability to patients of the medicinal product is greater than the risk inherent in the fact that additional data are still required.
+Added: The conditional MA is subject to conditions to be fulfilled for generating the missing data or ensuring increased safety measures.
+Added: It is valid for one year and must be renewed annually until all related conditions have been fulfilled.
+Added: Once any pending studies are provided, the conditional MA can be converted into a traditional MA.
+Added: However, if the conditions are not fulfilled within the timeframe set by the EMA and approved by the European Commission, the MA will cease to be renewed.
+Added: An MA may also be granted “under exceptional circumstances” where the applicant can show that it is unable to provide comprehensive data on efficacy and safety under normal conditions of use even after the product has been authorized and subject to specific procedures being introduced.
+Added: These circumstances may arise in particular when the intended indications are very rare and, in the state of scientific knowledge at that time, it is not possible to provide comprehensive information, or when generating data may be contrary to generally accepted ethical principles.
+Added: Like a conditional MA, an MA granted in exceptional circumstances is reserved to medicinal products intended to be authorized for treatment of rare diseases or unmet medical needs for which the applicant does not hold a complete data set that is required for the grant of a standard MA.
+Added: However, unlike the conditional MA, an applicant for authorization in exceptional circumstances is not subsequently required to provide the missing data.
+Added: Although the MA “under exceptional circumstances” is granted definitively, the risk-benefit balance of the medicinal product is reviewed annually, and the MA will be withdrawn if the risk-benefit ratio is no longer favorable.
+Added: Upon grant of a MA in the EEA, innovative medicinal products generally benefit from eight years of data exclusivity and an additional two years of market exclusivity.
+Added: If granted, data exclusivity prevents generic or biosimilar applicants from referencing the innovator's pre-clinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization during a period of eight years from the date on which the reference product was first authorized in the EEA.
+Added: During the additional two year period of market exclusivity, a generic or biosimilar marketing authorization can be submitted, and the innovator's data may be referenced, but no generic or biosimilar product can be marketed until the expiration of the market exclusivity period.
+Added: The overall ten year period will be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to authorization, is held to bring a significant clinical benefit in comparison with existing therapies.
+Added: In the EEA, there is a special regime for biosimilars, or biological medicinal products that are similar to a reference medicinal product but that do not meet the definition of a generic medicinal product.
+Added: For such products, the results of appropriate preclinical or clinical trials must be provided in support of an application for marketing authorization.
+Added: Guidelines from the EMA detail the type of quantity of supplementary data to be provided for different types of biological product.
+Added: EU Post-Approval Requirements
+Added: Where an MA is granted in relation to a medicinal product in the EEA, the holder of the MA is required to comply with a range of regulatory requirements applicable to the manufacturing, marketing, promotion and sale of medicinal products.
+Added: Similar to the United States, both MA holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA, the European Commission and/or the competent regulatory authorities of the individual EEA countries.
+Added: The holder of an MA must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance who is responsible for oversight of that
+Added: Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports, or PSURs.
+Added: All new MAAs must include a risk management plan, or RMP, describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks associated with the product.
+Added: The regulatory authorities may also impose specific obligations as a condition of the MA.
+Added: Such risk-minimization measures or post-authorization obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies.
+Added: In the EEA, the advertising and promotion of medicinal products are subject to both EU and EEA countries’ laws governing promotion of medicinal products, interactions with physicians and other healthcare professionals, misleading and comparative advertising and unfair commercial practices.
+Added: Although general requirements for advertising and promotion of medicinal products are established under EU legislation, the details are governed by regulations in individual EEA countries and can differ from one country to another.
+Added: For example, applicable laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics, or SmPC, as approved by the competent authorities in connection with an MA.
+Added: The SmPC is the document that provides information to physicians concerning the safe and effective use of the product.
+Added: Promotional activity that does not comply with the SmPC is considered off-label and is prohibited in the EEA.
+Added: Direct-to-consumer advertising of prescription medicinal products is also prohibited in the EEA.
+Added: Orphan designation in the EU
The criteria for designating an “orphan medicinal product” in the EEA are similar in principle to those in the U.S.
4 unchanged sentences
During this ten-year orphan market exclusivity period, no marketing authorization application shall be accepted, and no marketing authorization shall be granted for a similar medicinal product for the same indication.
−Removed: An orphan product can also obtain an additional two years of market exclusivity in the EU for pediatric studies.
−Removed: The ten-year market exclusivity may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.
+Added: An orphan product can also benefit from an additional two years of market exclusivity in the EU for pediatric studies.
+Added: The ten-year market exclusivity period may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.
Additionally, marketing authorization may be granted to a similar product for the same indication at any time if (i) the second applicant can establish that its product, although similar, is safer, more effective or otherwise clinically superior;
2 unchanged sentences
Similar to the United States, the various phases of non-clinical and clinical research in the European Union are subject to significant regulatory controls.
−Removed: The Clinical Trials Directive 2001/20/EC, the Directive 2005/28/EC on GCP and the related national implementing provisions of the individual EU Member States govern the system for the approval of clinical trials in the European Union.
−Removed: Under this system, an applicant must obtain prior approval from the competent national authority of the EU Member State in which the clinical trial is to be conducted.
−Removed: Furthermore, the applicant may only start a clinical trial at a specific trial site after the competent ethics committee has issued a favorable opinion.
−Removed: The clinical trial application must be accompanied by, among other documents, an investigational medicinal product dossier (the Common Technical Document) with supporting information prescribed by Directive 2001/20/EC, Directive 2005/28/EC, where relevant the implementing national provisions of the individual EU Member States and further detailed in applicable guidance documents.
−Removed: In April 2014, the new Clinical Trials Regulation, (EU) No 536/2014 (Clinical Trials Regulation) was adopted.
−Removed: It is expected that the new Clinical Trials Regulation (EU) No 536/2014 will apply following confirmation of full functionality of the Clinical Trials Information System, or CTIS, the centralized European Union portal and database for clinical trials foreseen by the regulation, through an independent audit.
−Removed: The regulation becomes applicable six months after the European Commission publishes notice of this confirmation.
−Removed: The Clinical Trials Regulation will be directly applicable in all the EU Member States, repealing the current Clinical Trials Directive 2001/20/EC.
−Removed: Conduct of all clinical trials performed in the European Union will continue to be bound by currently applicable provisions until the new Clinical Trials Regulation becomes applicable.
−Removed: The extent to which ongoing clinical trials will be governed by the Clinical Trials Regulation will depend on when the Clinical Trials Regulation becomes applicable and on the duration of the individual clinical trial.
−Removed: If a clinical trial continues for more than three years from the day on which the Clinical Trials Regulation becomes applicable the Clinical Trials Regulation will at that time begin to apply to the clinical trial.
−Removed: The new Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the European Union.
−Removed: The main characteristics of the regulation include:
−Removed: a streamlined application procedure via a single-entry point, the “EU portal”;
−Removed: a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors;
−Removed: and a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts.
−Removed: Part I is assessed by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned).
−Removed: Part II is assessed separately by each Member State concerned.
−Removed: Strict deadlines have been established for the assessment of clinical trial applications.
−Removed: The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the concerned EU Member State.
−Removed: However, overall related timelines will be defined by the Clinical Trials Regulation.
−Removed: The collection and use of personal health data in the European Union, previously governed by the provisions of the Data Protection Directive, is now governed by the General Data Protection Regulation, or the GDPR, which became effective on May 25, 2018.
−Removed: While the Data Protection Directive did not apply to organizations based outside the EU, the GDPR has expanded its reach to include any business, regardless of its location, that provides goods or services to residents in the EU.
−Removed: This expansion would incorporate any clinical trial activities in EU members states.
−Removed: The GDPR imposes strict requirements on controllers and processors of personal data, including special protections for “sensitive information” which includes health and genetic information of data patients residing in the EU.
−Removed: GDPR grants individuals the opportunity to object to the processing of their personal information, allows them to request deletion of personal information in certain circumstances, and provides the individual with an express right to seek legal remedies in the event the individual believes his or her rights have been violated.
−Removed: Further, the GDPR imposes strict rules on the transfer of personal data out of the European Union to the U.S.
−Removed: or other regions that have not been deemed to offer “adequate” privacy protections.
−Removed: Failure to comply with the requirements of the GDPR and the related national data protection laws of the European Union Member States, which may deviate slightly from the GDPR, may result in fines of up to 4% of global revenues, or €20,000,000, whichever is greater.
−Removed: As a result of the implementation of the GDPR, we may be required to put in place additional mechanisms ensuring compliance with the new data protection rules.
−Removed: There is significant uncertainty related to the manner in which data protection authorities will seek to enforce compliance with GDPR.
−Removed: For example, it is not clear if the authorities will conduct random audits of companies doing business in the EU, or if the authorities will wait for complaints to be filed by individuals who claim their rights have been violated.
−Removed: Enforcement uncertainty and the costs associated with ensuring GDPR compliance are onerous and may adversely affect our business, financial condition, results of operations and prospects.
+Added: Conduct of clinical trials in the EU
+Added: In the EU, clinical trials are governed by the Clinical Trials Regulation (EU) No 536/2014, or CTR, which entered into application on January 31, 2022 repealing and replacing the former Clinical Trials Directive 2001/20, or CTD, and related national implementing legislation of EU Member States.
+Added: 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.
+Added: 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;
+Added: a single set of documents to be prepared and submitted for the application;
+Added: as well as simplified reporting procedures for clinical trial sponsors.
+Added: A harmonized procedure for the assessment of applications for clinical trials has been introduced and is divided into two parts.
+Added: Part I assessment is led by the competent authorities of a reference Member State selected by the trial sponsor and relates to clinical trial aspects that are considered to be scientifically harmonized across EU
+Added: Member States.
+Added: This assessment is then submitted to the competent authorities of all concerned Member States in which the trial is to be conducted for their review.
+Added: Part II is assessed separately by the competent authorities and Ethics Committees in each concerned EU Member State.
+Added: Individual EU Member States retain the power to authorize the conduct of clinical trials on their territory.
+Added: The extent to which on-going clinical trials will be governed by the CTR will depend on the duration of the individual clinical trial.
+Added: For clinical trials in relation to which application for approval was made on the basis of the CTD before January 31, 2022, the CTD will continue to apply on a transitional basis for three years.
+Added: If authorized, those clinical trials will be governed by the CTD until January 31, 2025.
+Added: By that date, all ongoing trials will become subject to the provisions of the CTR.
+Added: The CTR will apply to clinical trials from an earlier date if the clinical trial has already transitioned to the CTR framework.
+Added: Since January 31, 2023 all new requests for approval of clinical trials must be based on the CTR.
Should we utilize third-party distributors, compliance with such foreign governmental regulations would generally be the responsibility of such distributors, who may be independent contractors over whom we have limited control.
+Added: The position in the United Kingdom
+Added: Following the result of a referendum in 2016, the United Kingdom (UK) left the European Union on January 31, 2020, commonly referred to as Brexit.
+Added: The UK and the European Union have signed an EU-UK Trade and Cooperation Agreement, or TCA, which became provisionally applicable on January 1, 2021 and entered into force on May 1, 2021.
+Added: The Annex provides a framework for the recognition of Good Manufacturing Practice, or GMP, inspections and for the exchange and acceptance of official GMP documents.
+Added: The regime does not, however, extended to procedures such as batch release certification.
+Added: As part of the TCA, the European Union and the UK will recognize Good Manufacturing Practice inspections carried out by the other party and the acceptance of official GMP documents issued by the other party.
+Added: The TCA also encourages, although it does not oblige, the parties to consult one another on proposals to introduce significant changes to technical regulations or inspection procedures.
+Added: Among the areas of absence of mutual recognition are batch testing and batch release.
+Added: The UK has unilaterally agreed to accept European Union batch testing and batch release However, the European Union continues to apply European Union laws that require batch testing and batch release to take place in the European Union territory.
+Added: This means that medicinal products that are tested and released in the UK must be retested and re-released when entering the European Union market for commercial use.
+Added: As regards marketing authorizations, Great Britain has a separate regulatory submission process, approval process and a national marketing authorization.
+Added: Northern Ireland will, however, continue to be covered by the marketing authorizations granted by the European Commission.
+Added: Since January 1, 2021, an applicant for a centralized procedure marketing authorization can no longer be established in the UK.
+Added: Since this date, companies established in the UK cannot use the centralized procedure and instead must follow one of the UK national authorization procedures to obtain an MA to market products in the UK.
+Added: The MHRA has been updating various aspects of the regulatory regime for medicinal products in the UK.
+Added: These include:
+Added: introducing the Innovative Licensing and Access Procedure to accelerate the time to market and facilitate patient access for innovative medicinal products;
+Added: updates to the UK national approval procedure, introducing a 150-day objective for assessing applications for marketing authorizations in the UK, Great Britain and Northern Ireland and a rolling review process for marketing authorization applications (rather than a consolidated full dossier submission).
+Added: Orphan designation in Great Britain following Brexit is, unlike in the EU, not available pre-marketing authorization.
+Added: Applications for orphan designation are made at the same time as an application for a marketing authorization.
+Added: The criteria to be granted an orphan medicinal product designation or essentially identical to those in the EU but based on the prevalence of the condition in Great Britain.
+Added: The UK regulatory framework in relation to clinical trials is derived from existing EU legislation (as implemented into UK law, through secondary legislation).
+Added: However, it is currently unclear to what extent the UK will seek to align its regulations with the EU following entry into application of the Clinical Trials Regulation on January 31, 2022.
Patent Term Restoration and Marketing Exclusivity
17 unchanged sentences
Employees and Human Capital Resources
−Removed: As of December 31, 2021, we had twenty-five full-time employees and four part-time employees.
−Removed: Twelve employees are based in Barcelona, Spain, fourtheen employees are based in Lugano, Switzerland and three employees are based in Bethesda, Maryland.
−Removed: Of these twenty-nine employees, twenty are engaged in research and development activities and nine are engaged in finance, investor relations, business developments and general management.
−Removed: Our employees in Spain are subject to a national collective labor agreement, Convenio General de la Industria Quimica.
+Added: As of December 31, 2022, we had twenty-eight full-time employees and three part-time employees.
+Added: Fourteen employees are based in Barcelona, Spain, eleven employees are based in Lugano, Switzerland, two employees are based in the U.K.
+Added: and four employees are based in Bethesda, Maryland.
+Added: 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.
+Added: Our employees in Spain are subject to a national collective labor agreement, the “ Convenio General de la Industria Quimica” .
National agreements are negotiated collectively between the national associations of companies within a given industry and the respective national unions.
We consider our relationship with our employees to be good and have not experienced any work stoppages.
−Removed: 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 the five outside members of our Scientific Advisory Board.
−Removed: Corporate Governance and Public Information
−Removed: The address of Gain Therapeutics’ website is http://www.gaintherapeutics.com/.
−Removed: Stockholders can access a wide variety of information on Gain’s website, under the "Investor Relations"
−Removed: tab, including corporate governance information, news releases, SEC filings, information Gain is required to post online pursuant to applicable SEC and Nasdaq rules, and online links.
−Removed: Gain makes available via its website all filings it makes under the Securities and Exchange Act of 1934, as amended, including Forms 10-K, 10-Q, and 8-K, as well as any related amendments as soon as reasonably practicable after they are filed with, or furnished to, the SEC.
−Removed: All such filings are available free of charge.
−Removed: Neither the content of Gain’s website nor any other website referred to in this report are incorporated by reference into this report unless expressly noted.
+Added: 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.
+Added: Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees.
+Added: We maintain our equity incentive plan in order to attract, retain and incentivize our workforce through the granting of stock-based compensation.
+Added: We also provide cash bonus awards based on Company progress toward key annual goals and employee performance.
+Added: Available Information
+Added: 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.
+Added: We make these reports available through our website as soon as reasonably practicable after we
+Added: electronically file such reports with, or furnish such reports to, the Securities and Exchange Commission, or the SEC.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: Our website address is included in this Annual Report as an inactive technical reference only.
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.