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Item 1. Business

2021-03-15 compared with 2020-03-11 · 361 added, 1608 removed, 374 unchanged (84% of the section changed)

We are a late-stage clinical biopharmaceutical company focused exclusively on developing impactful medicines for patients and families living with rare neurological disorders.

We believe these disorders represent an attractive area for drug development as the understanding of the underlying biology has grown meaningfully over the last few years and only now is being appreciated by the industry.

Our experienced team began with a vision to integrate the biology and symptomology of rare neurological conditions to employ innovative research and clinical strategies for the development of our drug candidates.

Based on recent scientific advances in genetics and the biological pathways of the brain, we created a proprietary map of disease-relevant pathways and used it to identify and acquire novel compounds for the treatment of rare neurological disorders.

We are also building a deep knowledge of the diseases and the clinically meaningful endpoints required for development of a compound in these rare neurological disorders.

We continue to execute on our strategy by in-licensing and collaborating with leading biopharmaceutical companies and academic institutions.

We have developed a robust pipeline of first-in-class and only-in-class clinical assets with an initial focus on neurodevelopmental disorders and developmental and epileptic encephalopathies, or DEE.

OV101 (gaboxadol)

Our most advanced drug candidate is OV101 (gaboxadol).

Our development plan for OV101 highlights our ability to translate new scientific and clinical insights into drug candidates.

We believe that OV101 modulates tonic inhibition, an important physiological process in the brain that has been identified as a potential central cause of the symptoms seen in a number of disorders of the brain.

Disruption of tonic inhibition can lead to a multiplicity of symptoms including, but not limited to, motor deficiencies, sleep abnormalities, behavioral manifestations, delayed development, intellectual disability and severe speech impairment.

We believe modulating tonic inhibition may have a meaningful clinical impact in patients with Angelman syndrome and Fragile X syndrome.

We have successfully completed a Phase 2 trial of OV101 in adults and adolescents with Angelman syndrome, which we refer to as the STARS clinical trial.

The STARS clinical trial achieved its primary endpoint of safety and tolerability and showed statistically significant improvement in the once-daily OV101 dosing group on the pre-specified physician-rated Clinical Global Impressions-Improvement, or CGI-I, exploratory endpoint as well as improvements in relevant symptoms such as sleep, motor function and behavior.

Following discussion of the STARS clinical trial with the U.S.

Food and Drug Administration, or FDA, and German regulatory authorities, we designed and initiated a pivotal Phase 3 clinical trial in OV101 for Angelman syndrome in June 2019, which we refer to as the NEPTUNE clinical trial.

In September 2019, we announced that the first patient had been randomized in NEPTUNE, and we expect to report topline data from this pivotal trial by mid-2020.

We have also initiated ELARA, an open label extension trial which enrolled its first patient in February 2019 and is open to any patient who has previously been part of an OV101 clinical trial .

There are no other drugs approved, for treatment of Angelman syndrome.

We also are currently conducting a Phase 2 trial evaluating OV101 in adolescent and young male adults with Fragile X syndrome, which we refer to as the ROCKET clinical trial.

The primary endpoint of ROCKET is safety and tolerability of OV101 over 12 weeks of treatment in three different cohorts of either 5mg once daily, 5mg twice daily or 5mg three times daily.

A secondary efficacy endpoint evaluates changes in behavior during 12 weeks of treatment with OV101 using the Activities-specific Balance Confidence Scale that has been used in previous trials for Fragile X syndrome.

We expect to report data from ROCKET early in the second quarter of 2020.

We are also conducting an observational non-drug study, known as SKYROCKET, to assess the suitability of scales for the measurement of behavior, sleep and functioning in individuals with Fragile X syndrome.

W e expect to report data from SKYROCKET early in the second quarter of 2020.

OV935 (soticlestat)

In addition, we have a joint collaboration with Takeda to develop and commercialize TAK-935, which we have licensed from Takeda and refer to as OV935 (soticlestat or TAK-935).

We believe that OV935’s inhibition of a key enzyme in cholesterol metabolism pathway in the brain may modulate the excitatory signals involved in epilepsy, which may suppress seizures.

In addition to these effects on seizures and excitability of the brain, we believe that OV935 may reduce inflammation in and neurotoxic damage to the brain, which may lead to long-term, disease modifying effect.

As a result, we are targeting rare and difficult to treat epilepsies with the goal to develop OV935 not just as a potential medicine to treat the seizures but also one that may have long-term disease-modifying potential.

We are initially studying OV935 for those suffering from severe and often intractable forms of DEE, including Dravet syndrome, Lennox-Gastaut syndrome, CDKL5 Deficiency Disorder, or CDD, and Duplication 15q, or Dup15q, syndrome.

There are limited or no therapeutic options of each of these disorders.

We completed a Phase 1b/2a clinical trial of OV935 in a mixed group of adults with DEE and announced the results in December 2018.

The trial achieved its primary endpoint of safety and tolerability, dose proportional reduction in a potential plasma biomarker called 24HC, and a robust reduction in seizure frequency (61% at day 92), with two patients becoming seizure-free at the end of the treatment period.

Following this trial and as further discussed below, we reported the initial data from the ENDYMION Phase 2 open-label extension study of OV935 in six patients who previously completed our 12-week Phase 1b/2a clinical trial of OV935 in adults with DEE.

OV935 is currently in multiple Phase 2 clinical trials, which we refer to as the ARCADE and ELEKTRA clinical trials.

We expect to report initial data from ARCADE in the

first quarter of 2020 and we expect to report topline data from ELEKTRA in the third quarter of 2020 .

The FDA has granted orphan drug designation for OV935 for the treatment of Dravet syndrome and Lennox-Gastaut syndrome .

Additionally, Takeda elected to initiate a placebo-controlled Phase 2 trial of TAK-935 to treat patients with chronic complex regional pain syndrome, or CRPS.

This trial will look at the efficacy, safety and tolerability of TAK-935 as an adjunctive therapy in participants with CRPS.

Pursuant to our agreement with Takeda, we have a one-time right to opt into this program, but we are not responsible for funding this trial, if we decide to exercise our right to opt in to the CRPS program, the program would become part of the joint collaboration with Takeda and we would become responsible for our share of the program in accordance with terms of the collaboration agreement.

We are a biopharmaceutical company focused on developing impactful medicines for patients and families living with rare neurological disorders.

We believe these disorders represent an attractive area for drug development as the understanding of the underlying biology has grown meaningfully over the last few years and today represent a substantial opportunity medically and commercially.

Based on the rapid increase in scientific understanding of the role of genetics and key biological pathways relevant to diseases of the brain, we aim to identify, discover and develop novel compounds for the treatment of rare neurological disorders.

We have built a deep knowledge of such diseases, how to treat them and how to develop the clinically meaningful endpoints required for development of a compound in these disorders.

As a result of this knowledge, we have developed a pipeline of first-in-class compounds and programs and have demonstrated our model by progressing compounds through to late-stage development.

We continue to execute on our strategy to build this pipeline by discovering, in-licensing and collaborating with leading biopharmaceutical companies and academic institutions.

Rare Neurological Disorders

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We believe that there are at least 100 neurodevelopmental disorders, epileptic encephalopathies and other related rare neurological disorders that we may be able to target.

These disorders are characterized by impairments and pathologies in the growth and development of the brain.

These disorders are characterized by impairments in the growth, development and functioning of the brain.

Due to a historical overwhelming preference in the drug industry to develop drugs for broader neurological indications, many of these disorders have no approved therapies.

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High penetrance linking genetic defect to disorder pathology.

Rare neurological disorders that are genetic in origin typically have a strong correlation, or penetrance, between the presence of a gene and the manifestation of the corresponding disease pathology.

As a result, we believe we can develop drug candidates that will be efficacious in patients with a given genetic profile.

Some rare neurological disorders have a genetic origin and typically have a strong correlation, or penetrance, between the presence of a gene and the manifestation of the corresponding disease pathology.

As a result, we believe in those cases we can develop drug candidates that will be efficacious in patients with a given genetic profile.

Predictive genetic and other models.

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The Ovid Strategy

The Ovid Strategy is to pursue drug development for rare neurological disorders in a manner that is scientifically driven, patient focused and business development oriented.

As we build on our understanding of these rare neurological conditions, we gain an appreciation of the way the different molecular pathways underlying these disorders help drive the symptoms patients suffer.

This, in turn, allows us to transfer the knowledge gained about relevant molecular pathways and clinical endpoints from one disorder to another, which we believe will enable us to build a scalable business model.

Ovid has set out to be a leader in this field, and by keeping our focus on neurology, it is our belief that our model offers us the potential to produce multiple medicines in the future, and thereby succeed in our mission.

Our strategy is to pursue drug discovery and development for rare neurological disorders in a manner that is scientifically driven, patient focused and is coupled with an integrated and discipled approach to research, clinical development and business development.

As we build on our understanding of these rare neurological conditions, we gain an appreciation of the way the different molecular mechanisms and pathways underlying these disorders help drive the symptoms patients suffer.

This, in turn, benefits us with the knowledge gained about genetics, relevant molecular pathways, physiological impact and clinical endpoints from one disorder to another, which we believe will enable us to build a scalable scientific platform and efficient development capabilities.

Ovid has set out to be a leader in this field, and by keeping our focus on neurology, it is our belief that this offers us the potential to produce multiple medicines in the future, and thereby succeed in our mission.

Scientifically Driven

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We are building our portfolio based on the existence of clear biological rationales, including a focus on disorders that have, where possible, a direct genetic linkage.

We use our proprietary map to identify initial drug candidates across all stages of development for potential acquisition or in-licensing.

As we advance our drug candidates into and through the clinical evaluation, we are building on the emerging body of scientific and clinical insights developed by us and others in the biopharmaceutical industry to target these new disease pathways of the brain.

As we evaluate data from previous and ongoing preclinical studies and clinical trials, we intend to refine our scientific approach and apply these insights to continue to build our pipeline and conduct our clinical trials.

Currently our portfolio is focused on inhibitory neuronal signaling pathways mediated by GABA (‘GABA-ergic’ paths) and excitatory neuronal pathways mediated via glutamate signaling (‘glutamatergic’ paths).

Our strategy is therapeutic modality agnostic so that we are pursuing neurology scientific research in high unmet need medical areas, using small molecule or molecular targeted approaches.

In particular, the Ovid approach is driven by the following scientific principles:

map biological pathways that are relevant for rare neurological disorders with significant unmet need;

target biological pathways for which proof-of-concept has been established via in vitro or animal models;

focus on biological pathways that cause the pathology of the disorder and that have common symptoms that we can target;

identify and utilize biomarkers that can provide evidence of the activity of our drug candidates.

We use our deep understanding of the area to identify mechanisms of action, appropriate targets and initial drug candidates.

As we evaluate data from previous and ongoing preclinical studies and clinical trials, we intend to refine and improve our scientific approach and apply these insights to continue to build our pipeline and conduct our clinical trials.

In particular, our approach is driven by the following scientific principles:

identify the genetic origin of the disorder;

develop understanding of gene expression and link to pathophysiology;

target biological pathways or genes for which proof-of-concept has been established via in vitro or animal models;

focus on the pathways and mechanisms that cause the pathology of the disorder and that generate the symptoms that we can target;

target optimal mechanism of action for drug candidates;

utilize biomarkers if present that can provide evidence of the activity of our drug candidates.

Patient Focused

We are highly focused on the patient communities affected by the rare neurological disorders we are addressing.

We believe this aspect of our approach is critical, given that these disorders affect a small population of patients, but carry serious morbidities and require extensive involvement from the patients’ families, caregivers, physicians and patient advocacy groups.

The Ovid Strategy is driven by the following patient-focused principles:

We are focused on the patient communities affected by the rare neurological disorders we address.

We believe this aspect of our approach is critical.

Each of these disorders affect small populations of patients, but carry serious morbidities and require extensive and specialized involvement from the patients’ families, caregivers, physicians and patient advocacy groups.

Our strategy is enhanced by the following patient-focused principles:

develop close relationships with patients, caregivers, families, disease foundations and key opinion leaders, to better understand the history of these disorders, raise awareness, identify patients and facilitate enrollment of clinical trials;

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develop digital capabilities to engage, foster and maintain close relationships with patient communities.

Business Development Oriented

We have built a broad pipeline of potential drug candidates to treat rare neurological disorders through the in-licensing or partnering of drug candidates.

Central to the success of this process is a highly focused and disciplined business development effort aimed at securing relevant assets in each of our selected rare neurological disorders.

We are developing a specialized, scalable and robust infrastructure that we believe will make us a leader in rare neurological disorders and the partner of choice for leading biopharmaceutical companies or academic institutions that wish to maximize the value of their neurology drug candidates in these areas.

This infrastructure spans across critical domains of drug development.

If and when our drug candidates are approved, we also plan to establish a highly focused commercial and distribution network dedicated to rare neurological disorders in the United States and Europe, where we believe the patient populations and medical specialists are sufficiently concentrated to effectively market our drug candidates.

We believe that we are particularly well positioned to execute on our business development strategy because of the extensive network of our Chairman and Chi ef Executive Officer Dr.

Jeremy Levin and the other members of our management team, who collectively have a track record of success in orphan drug development and evaluation.

Research and Development Coupled with Business Development

We have built a broad pipeline of potential drug candidates to treat rare neurological disorders.

Initially we in-licensed or partnered drug candidates.

More recently our pipeline has been built through our internal research and development efforts in collaboration with external leaders in the field.

The intended result is to develop a diversified pipeline to mitigate development risk and provide for scientific and medical opportunity.

Central to the success of this process is coupling a highly focused and disciplined effort to link our research effort in key laboratories around the world aimed at discovering and securing relevant assets in selected rare neurological disorders.

As a result, we have built a specialized, scalable and robust infrastructure that we believe will make us a leader in rare neurological disorders and the partner of choice for leading biopharmaceutical companies or academic institutions that wish to maximize the value of their neurology drug candidates or research platforms in these areas.

This infrastructure spans across critical domains which include but are not exclusive of target discovery, drug delivery and clinical development.

If and when our drug candidates are approved, we also plan to establish over time a focused commercial and distribution network dedicated to rare neurological disorders in the United States and Europe, where we believe the patient populations and medical specialists are sufficiently concentrated to effectively market our drug candidates.

We believe that we are particularly well positioned to execute on our business development strategy because of both the extensive network of our Chairman and Chief Executive Officer Dr.

Jeremy Levin and other members of our management team, as well as our demonstrated success in collaboration with partners including Takeda.

Our efforts have already brought two drug candidates from proof of concept and either through pivotal trials or to the initiation of pivotal trials.

The following table sets forth the status and mechanism of action of our drug candidates:

OV101 (gaboxadol)

We are developing OV101 for the treatment of Angelman syndrome and Fragile X syndrome, two neurodevelopmental disorders that are characterized by similar symptoms due to decreased tonic inhibition, an important mechanism whereby it is believed that the brain distinguishes signal from noise.

Angelman syndrome and Fragile X syndrome have overlapping symptoms, including sleep disorder, aberrant behavior, anxiety and cognitive or intellectual disabilities.

Both of these disorders are typically diagnosable in early childhood and require full-time care for the patients affected.

In September 2016, the FDA granted orphan drug designation for OV101 for the treatment of Angelman syndrome;

in October 2017 the FDA granted orphan drug designation for OV101 for the treatment of Fragile X syndrome;

in December 2017 the FDA granted fast track designation for the treatment of Angelman syndrome;

and in March 2018, the FDA granted fast track designation for the treatment of Fragile X syndrome.

In June 2019, the European Commission granted OV101 orphan drug designation for the treatment of Angelman syndrome based on the results of the STARS clinical trial.

Angelman syndrome – Clinical Development

In July of 2018, we completed the Phase 2 STARS trial, a 12-week, double blind, placebo-controlled study in adults and adolescents with Angelman syndrome that randomized 88 patients aged 13 to 49 years.

The study achieved its primary endpoint of safety and tolerability with a similar incidence of adverse events, or AEs, across the OV101 and placebo treatment arms.

The investigational medicine showed a favorable safety profile and was well tolerated in adults and adolescents with Angelman syndrome through the 12 weeks of treatment.

The most common AEs reported in the trial were vomiting, somnolence, irritability, aggression, and pyrexia.

Serious adverse events, or SAEs, of seizure were reported in two patients with a previous history of seizures:

one patient in the once-daily, QD, dose group experienced a seizure that was deemed unrelated to study drug;

one patient experienced a seizure in the twice-daily, BID, dose group that was assessed as possibly related to study drug by the investigator.

At the prespecified efficacy analysis at 12 weeks of treatment, OV101 QD and BID dose groups showed a statistically significant improvement compared to placebo in the CGI-I.

CGI-I was ranked first in the prespecified hierarchy of the statistical analysis plan.

Data from the full analysis indicate that OV101 positively impacts several relevant clinical features of Angelman syndrome (global functioning, sleep, motor disruption).

We met with the FDA in November 2018 to discuss OV101 as part of our End of Phase 2 Meeting.

Following discussion of the STARS clinical trial with the FDA and German regulatory authorities, we designed and initiated NEPTUNE, a 12-week, two-arm, randomized, double-blind, placebo-controlled trial in OV101 with an estimated enrollment of approximately 60 patients aged 4 to 12 years old with Angelman syndrome, in June 2019.

There are no other drugs approved, for treatment of Angelman syndrome.

have also initiated ELARA , an open label extension trial which randomized its fir st patient in February 2019 and is open to any patient who has previously been part of an OV101 clinical trial .

Fragile X syndrome

In July 2018, we initiated our Phase 2 ROCKET clinical trial, a signal-finding, randomized, double-blind, parallel-group trial evaluating OV101 for the treatment of adolescent and young male adults with Fragile X syndrome.

The trial is currently fully enrolled with males aged 13 to 22 with a confirmed diagnosis of Fragile X syndrome.

The primary endpoint is safety and tolerability of OV101 over 12 weeks of treatment in three different cohorts of either 5mg once daily, 5mg twice daily, or 5mg three times daily.

A secondary efficacy endpoint evaluates changes in behavior during 12 weeks of treatment with OV101 using the Aberrant Behavior Checklist-Community scale, or ABC-C, that has been used in previous trials for Fragile X syndrome .

We anticipate data from this trial early in the second quarter of 2020.

We also initiated the SKYROCKET study in the fourth quarter of 2018.

SKYROCKET is a 12-week, non-drug study to assess the suitability of several behavioral scales in individuals with Fragile X syndrome.

The trial is an observational study designed to provide additional data on the key endpoints that are being explored in the ROCKET trial as well as provide contextual data on the benefit offered by the standard of care.

The study is fully enrolled with males aged 5 to 30 with Fragile X syndrome, and data from SKYROCKET are expected early in the second quarter of 2020.

OV101 and Tonic Inhibition

Tonic inhibition is a critical regulatory mechanism that allows a healthy human brain to decipher excitatory and inhibitory neurological signals correctly without being overloaded.

Defects of this system are thought to play a role in multiple disease states, including Angelman syndrome and Fragile X syndrome.

Because of its unique mode of action, OV101 represents a promising compound targeting this mechanism.

Decreased tonic inhibition results in an imbalance in the ratio of excitation to inhibition.

If tonic inhibition is reduced, the brain becomes inundated with signals and loses the ability to separate background noise from critical information.

This imbalance disrupts normal brain functioning, including sensory processing and integration.

This can lead to symptoms characteristic of neurodevelopmental disorders, including those related to behavior, learning, cognitive development, motor function, sleep disturbances and seizures.

By modulating tonic inhibition, OV101 may have the potential to alleviate important symptoms and provide a meaningful clinical benefit to patients across several neurodevelopmental disorders including Angelman syndrome and Fragile X syndrome.

Tonic Inhibition and Neurodevelopmental Disorders

Neurotransmission

The brain is composed of a vast network of interconnected neurons that facilitate the communication between cells.

These communications are governed by the release of chemical signals, or neurotransmitters, from one neuron to another.

The neuron that releases the neurotransmitter is called the presynaptic neuron.

The neuron that receives the neurotransmitter is called the postsynaptic neuron.

The presynaptic neuron releases a neurotransmitter into a physical gap separating the two neurons, which is called the synaptic gap.

The neurotransmitter then diffuses across the synaptic gap to bind to a receptor on the postsynaptic neuron.

This binding then triggers a signal to stimulate, inhibit or otherwise modulate the activity of the postsynaptic neuron.

The main inhibitory neurotransmitter in the brain is gamma-aminobutyric acid, or GABA.

GABA neurotransmitter plays a major role in regulating sensory, motor, cognitive and other brain functions.

GABA binds to specific synaptic receptors across the synaptic gap on the post-synaptic neuron membrane as well as receptors outside the synapse zone, called extrasynaptic GABA receptors.

The following figure depicts the synaptic gap and extrasynaptic GABA receptors outside the synaptic gap:

The neurotransmitter GABA, released from a presynaptic neuron, diffuses to bind to and activate synaptic GABA A receptors on postsynaptic neurons.

Some of the released GABA diffuses outside of the synapse to bind to and activates extrasynaptic receptors which mediate tonic inhibition.

The above graphic illustrates that in certain diseases like Angelman or Fragile X syndrome where a deficit in extrasynaptic GABA concentrations exists, there is reduced interaction with the extrasynaptic GABA A receptors and decreased tonic inhibition.

Treatment with OV101 helps to restore tonic inhibition by selectively activating extrasynaptic GABA A receptor signaling in the context of low GABA concentrations associated with certain diseases.

The Role of GABA in Phasic and Tonic Inhibition

There is a fine balance between an appropriate and an inappropriate response of the postsynaptic neuron to an incoming stimulus.

Neurons receive both excitatory and inhibitory signals, and their response to excitatory signals is balanced by integrating excitatory input with inhibitory signals that are either short (phasic inhibition) or prolonged (tonic inhibition).

Phasic Inhibition.

Phasic inhibition in neurons is of short duration and takes place on the synaptic membrane through activation of synaptic GABA A receptors (see Figure 1, Synaptic GABA Receptor) by GABA released from the presynaptic neuron, providing for brief inhibitory changes in the neuron’s electrical a ctivity (see Figure 2 , top tracing).

These transient or “phasic” inhibitory changes, mediated by a brief influx of chloride ions, are then integrated with brief excitatory changes that integrate within the neuron on a millisecond time scale.

Collectively, the neurons are organized into feedback systems that allow the brain and body to adjust responses appropriately on a millisecond basis to a constant array of incoming signals.

When the body determines that it should cease responding to a specific signal, it triggers these feedback systems that serve to inhibit the receiving neuron from responding too strongly.

This is effectively accomplished by neurons involved in the feedback system releasing the neurotransmitter GABA which binds to GABA A receptors on th e post-synaptic cell.

Once the receiving postsynaptic neuron has integrated both excitatory and phasic inhibitory signals, balance can be restored, and the receiving neuron can prepare to receive a new stimulus.

Tonic Inhibition.

Tonic inhibition in neurons is a physiologic process of longer duration that sets the overall electrical sensitivity of the post-synaptic neuron membrane to incoming excitatory and inhibitory phasic signals (see Figure 2, bottom tracing).

Tonic inhibition is attributed to stimulation of GABA A receptors on the post-synaptic neuron membrane outside of the synapse that contain specialized δ (delta) subunits.

These extrasynaptic GABA A receptors are activated by GABA that spills out of the synapse, resulting in a prolonged influx of chloride ions and subsequent long-term reduction of the overall post-synaptic neuron membrane’s electrical potential and sensitivity to excitation (see Figure 1, Extrasynaptic GABA A Receptor and Figure 2, bottom tracing), a process known as tonic inhibition.

In certain diseases where GABA concentration deficits occur in various brain regions, there is a reduction in GABA A receptor activation and a corresponding loss of tonic inhibition.

OV101 improves tonic inhibition by acting selectively on these extrasynaptic GABA A receptors even in the face of GABA concentration deficits.

The following figure depicts physiologic levels of phasic inhibition and tonic inhibition, the two levels of signaling between neurons:

Phasic inhibition is rapid and short-lived.

Tonic inhibition is more persistent, longer duration.

Under normal conditions there is sufficient GABA present in and around the synaptic region and both sets of receptors are stimulated.

However, in certain neurodevelopmental disorders, the overall levels of GABA are reduced.

This reduction can lead to a situation in which there is enough GABA in the synapse to maintain normal short-term signaling, but GABA outside the synapse is insufficient to occupy the extrasynaptic receptors and maintain longer-term signaling.

The decline in tonic inhibition triggered by the shortage of extrasynaptic GABA leads to the chronic over-activation/over-excitation of the receiving postsynaptic neurons and disruption of normal brain network activity.

Tonic inhibition is a key mechanism of neural regulation that has not yet, to our knowledge, been specifically addressed by any approved drug.

Tonic inhibition has been shown to be important in helping to discriminate important signals from the “noise” generated by the multitude of sensory signals entering the brain.

In patients with decreased tonic inhibition, the flood of incoming signals overwhelms the ability of the brain to process them.

The clinical manifestations of decreased tonic inhibit ion are seen across several neurodevelopmental disorders, including Angelman syndrome and Fragile X syndrome.

When tonic inhibition is decreased, the body has trouble functioning normally in the presence of this chronic overstimulation of neurons.

The resu lt is profound pathology that is manifested by seizures, anxiety and disturbances in motor function, behavior, sleep, cognition, learning, memory and ability to communicate effectively.

In addition, learning and memory are closely linked to the ability of the brain to establish and maintain connections among nerve cells.

Many brain processes, including tonic inhibition, play a role in the creation and maintenance of these connections.

One of the long-term consequences of decreased tonic inhibition is the disruption of memory.

The restoration of tonic inhibition has been observed to lead to improvements in memory in adult animal models.

OV101 and Tonic Inhibition in Angelman syndrome and Fragile X syndrome

Based on the biological pathway and existing preclinical data, we anticipate developing the orally active extrasynaptic GABA A receptor agonist OV101 to compensate for the loss of tonic inhibition resulting from the deficit in GABA concentrations observed in patients with certain rare neurological disorders.

We believe OV101 is the only drug candidate in development that exerts its biological activity preferentially through selective activation of extrasynaptic GABA A receptors.

We are initially developing OV101 for Angelman syndrome and Fragile X syndrome, and we believe it has the potential to address multiple neurodevelopmental disorders characterized by decreased tonic inhibition.

Angelman Syndrome

Angelman syndrome is a rare genetic disorder that is typically diagnosed in the United States after one year of age when parents notice severe developmental delays or the child suffers seizures.

Characteristic features of this disorder include delayed development, intellectual disability, severe speech impairment, problems with movement and balance, seizures, sleep disorders and anxiety.

Individual patients with Angelman syndrome can have varied symptoms, including the inability to walk or control motor movement, which can limit their ability to handle daily functions such as feeding, dressing or bathing.

These patients are also often hyperactive, leading to various behavioral problems.

Angelman syndrome symptoms, such as poor sleeping patterns, can lead to serious consequences, including increased frequency of seizures and exacerbation of behavioral manifestations.

Different patients with identical genetic defects can show different degrees of these symptoms.

Most Angelman syndrome patients require full-time care and are unable to live independently, which can represent a substantial emotional and financial burden on their families.

In addition, Angelman syndrome has been associated with poor parental sleep and high parental stress.

According to the National Organization for Rare Disorders, the approximate prevalence of Angelman syndrome is between 1 in 12,000 and 1 in 20,000 people.

There are currently no approved therapies in the United States or ex-US specifically for the treatment of Angelman syndrome.

No standard of care exists for Angelman syndrome, and current therapeutic options are symptomatic, suggesting a high unmet clinical need.

Given the likely high burden of Angelman syndrome, new treatments targeting the etiology of the syndrome that result in even small improvements in features of the syndrome may be clinically meaningful for patients and their families.

Tonic Inhibition and Angelman Syndrome.

In 1997, scientists traced the genetic causes of Angelman syndrome to mutations and other disruptions in the UBE3A gene.

The UBE3A gene encodes the UBE3A protein, which plays a central role in protein degradation.

Protein degradation is the breakdown of damaged or unnecessary proteins within the cell, which is an important aspect of maintaining normal cellular function.

The UBE3A protein triggers the attachment of a protein called ubiquitin to other cellular proteins.

These ubiquitin attachments serve as tags that mark the tagged cellular proteins for degradation.

Alterations in the UBE3A gene, and therefore the UBE3A protein, result in deficiencies in the tagging of proteins for degradation, leading to inappropriate protein accumulation within the cell.

One of the proteins that the UBE3A protein normally tags for degradation is GABA A Transporter 1, or G AT1, a protein that is responsible for the uptake of GABA by neurons.

The disruption in the UBE3A gene results in an overabundance of GAT1, leading to an exaggerated uptake of GABA.

This results in low levels of GABA in both the synaptic and extrasynaptic regions.

The deficiency of GABA in the extrasynaptic region culminates in a decrease of tonic inhibition, triggering a chronic activation of downstream neurons.

The following figure depicts the biological pathway by which the UBE3A gene alteration present in Angelman syndrome patients leads to decreased tonic inhibition:

Linkage between UBE3A gene alteration and tonic inhibition.

By adding OV101, a GABA agonist, we believe it is possible to address this decreased tonic inhibition by compensating for the low GABA levels.

Once OV101 is added, the extrasynaptic receptors are activated to transport chloride, or Cl - ions, from outside the cell into the postsynaptic neuron.

Negatively charged CI - ions inside the postsynaptic neuron increase tonic inhibition, reducing the excessive activation of downstream neurons.

Preclinical Data in Angelman Syndrome.

In preclinical studies conducted by independent academic groups in Angelman syndrome mouse models, OV101 was observed to increase tonic inhibition and alleviate the key motor symptoms that are also observed in Angelman syndrome patients.

These results were subsequently confirmed by another academic laboratory.

In 2012, researchers published a study in the journal Science Translational Medicine , reporting that they had created mice that lacked a functional copy of the UBE3A gene.

In these mouse models, the researchers observed several features of Angelman syndrome, including a loss of controlled bodily movements and motor deficits.

The researchers further observed that mice lacking a functional copy of the UBE3A gene had deficiencies in tonic inhibition and that increased GABA could partially restore this deficiency.

In this study, analysis of the activity of individual nerve cells in mice with a defective UBE3A gene demonstrated the effects of decreased tonic inhibition.

Decreased tonic inhibition resulted in excessive neuronal activity, which caused disruption of the normal, tightly coordinated and regulated signaling within the brain.

The direct addition of OV101 to these nerve cells largely restored their activity and regional brain network activity.

Based on these results, we believe that OV101 may have a similar effect in increasing tonic inhibition in Angelman syndrome patients.

The utility of these Angelman syndrome mouse models is also demonstrated by the effects of OV101 on walking gait.

Angelman syndrome patients often have an altered walking gait where the legs are wide-spaced and feet are turned out.

The Angelman syndrome mouse models were obse rved to have an altered gait, involving rotation of the hind paws outward.

In this study, Angelman syndrome mouse models and normal mice were each administered OV101 and a placebo.

Administration of OV101 was observed to result in statistically significant reductions in hind paw rotation in the Angelman syndrome mice, but had no effect in the normal mice.

The following figure depicts the decrease in hind-paw rotation in the Angelman syndrome mice administered OV101 versus those that were administered a plac ebo:

Administration of OV101 led to a reduction in the degree of hind paw rotation.

A p-value of 0.05 or less represents statistical significance, meaning that there is a less than 1-in-20 likelihood that the observed results occurred by chance.

A p-value of 0.01 or less means that there is a less than 1-in-100 likelihood that the observed results occurred by chance.

OV101 administration in Angelman syndrome mouse models was also observed to result in improved overall motor and clasping reflex function as measured by a rotarod test and tail suspension.

In the rotarod test, mice are required to perch atop a rotating cylinder and use their legs and body in a coordinated fashion in order to avoid falling off.

Angelman syndrome mice that were administered OV101 were observed to have an increased time on the rotarod versus those that were administered a placebo.

Administration of OV101 was not observed to have an effect in normal mice.

The experiment showed that the increased amount of time shown on the rotarod after treatment was statistically significant (approximately 20%, p<0.05) relative to the time spent on the rotarod before injection.

In the tail suspension test, Angelman syndrome mice showed a mild to moderate clasping reflex, represented by forelimb clasping and flexion to the body and smaller forelimb flexion.

Angelman syndrome mice treated with OV101 showed improved clasping reflexes and significantly increased forelimb angles (p<0.01).

Fragile X Syndrome

Fragile X syndrome is a genetic condition that results in intellectual disability, anxiety disorders, behavioral and learning challenges and various physical disabilities.

Patients with Fragile X syndrome exhibit autism-like symptoms, including cognitive impairment, anxiety, mood swings, hyperactivity, attention deficit and heightened sensitivity to various stimuli, such as sound.

The severity of an individual patient’s impairment can range from mild learning disabilities to more severe cognitive or intellectual disabilities.

Fragile X syndrome is one of the most commonly inherited intellectual disability disorders.

Children with Fragile X syndrome also often have unusual sleep patterns and may have difficulty with routine activities such as feeding and dressing.

The challenges presented by Fragile X syndrome often extend beyond the patient and can lead to significant hardships on the emotional and financial health of their families.

Fragile X syndrome is caused by mutations in the fragile X mental retardation gene, or FMR1 gene.

FMR1 is a gene that leads to the synthesis of the fragile X mental retardation protein, FMRP, which is needed for normal brain development.

The FMR1 gene normally contains in its sequence between 5 and 44 copies of a short, repeated motif, or recurring pattern in DNA.

In Fragile X syndrome, there are more than 200 copies of this motif in the FMR1 gene, a genetic change that prevents the synthesis of FMRP.

Patients with intermediate numbers of repeats are able to make some FMRP and have milder symptoms.

According to the National Fragile X Foundation, Fragile X syndrome affects approximately 1 in 3,600 to 4,000 males and 1 in 4,000 to 6,000 females.

The average age of diagnosis of Fragile X syndrome is approximately three years.

Currently, there are no approved therapies for the treatment of Fragile X syndrome.

The current standard of care for the psychiatric challenges of Fragile X

syndrome is tailored to each patient and may include antipsychotics, antidepressants and drugs to treat attention deficit and s leep disorders.

Special education and symptomatic treatments for anxiety and irritability are often employed to lessen the burden of illness.

Fragile X syndrome patients also may experience seizures, which are treated with traditional anticonvulsants.

Tonic Inhibition and Fragile X Syndrome.

Due to mutations in the FMR1 gene, patients with Fragile X syndrome have deficiencies in the levels of FMRP, an RNA binding protein that regulates the synthesis of proteins such as the two forms of glutamic acid decarboxylase, or GAD65 and GAD67, which we refer to together as GAD65/67.

GAD65/67 are the key enzymes required for synthesis of GABA.

Knocking out the FMR1 gene results in reduced expression of GAD65/67 in mouse models.

The following figure depicts the reduced expression of GAD65/67 in mice containing a knockout of the FMR1 gene:

Knockout of the FMR1 gene leads to reduced expression of GAD65/67 in mice.

The reduced expression of GAD65/67 in this model results in decreased GABA production and subsequently lower extrasynaptic levels of GABA and decreased tonic inhibition.

Decreased tonic inhibition is believed to be responsible for a number of Fragile X syndrome-related symptoms, such as behavioral and cognitive problems.

The following figure depicts the biological pathway by which an alteration in the FMR1 gene leads to decreased tonic inhibition:

Linkage between FMR1 gene alteration and tonic inhibition.

Preclinical Data in Fragile X Syndrome.

The association between the FMR1 gene and physiological changes observed in Fragile X syndrome patients has been evaluated in preclinical studies conducted by an independent academic group.

Mice containing a knockout of the FMR1 gene exhibit behaviors similar to those observed in Fragile X syn drome patients, such as hyperactivity, anxiety and increased sensitivity to sounds.

In these studies, hyperactivity in FMR1 -deficient mice was assessed by the distance traveled and average speed in an open field test.

FMR1 -deficient mice were significantly more active than normal mice.

It was observed that treatment of these mice with OV101 led to a statistically significant decrease in the distance traveled and average speed.

These results were considered to be indicative of a reduction in hyperactivity, which we believe resulted from increased tonic inhibition.

The following figure depicts the normalization of hyperactivity in mice containing a knockout of the FMR1 gene when administered OV101:

OV101 was observed to reduce signs of hyperactivity in mice containing a knockout of the FMR1 gene.

In these studies, OV101 partially normalized the mice’s response to startling sounds in the pre-pulse inhibition test in which a pre-stimulus is given to suppress the startle response and improve the signal to noise ratio.

Additionally, mice with a knockout of the FMR1 gene were also observed to have higher neuronal activity as compared to normal mice and a lower threshold for action potential, or AP, generation leading to increased AP bursts, which reverted to normal levels with the administration of OV101, as shown in the following figure:

OV101 was observed to reduce levels of neuronal activity in mice with a knockout of the FMR1 gene.

OV101 and its Potential Impact on Neurogenesis and on Learning and Memory

Based on preclinical data, we believe OV101 may facilitate neurogenesis, or the creation and maturation of new neurons, which may lead to cognitive benefits.

In a preclinical study in mice conducted by an independent academic group, OV101 was observed to promote the performance of certain memory behaviors and facilitate neurogenesis.

Extrasynaptic GABA A receptors contain a unique δ subunit, which is a specific domain on extrasynaptic GABA A receptors that is not expressed in synaptic GABA A receptors.

OV101 mediates its pharmacological properties via the activity of this δ subunit and

we believe that is a key differentiating aspect of our drug.

It is believed that GABA A receptor-dependent signaling regulates memory and also facilitates the growth of neurons after birth in the brain.

Long-term administration of OV101 in normal mice, but not in mice deficient in the GABA A receptor delta subunit, was observed to result in significant increases in neurogenesis.

These treated mice also performed better on challenges that were dependent on long-term memory.

We believe that these results in mice suggest that long-term treatment with OV101 in patients with Angelman syndrome and Fragile X syndrome may lead to improvement in cognitive abilities.

Previous Clinical Development of OV101

We acquired worldwide rights to OV101 from H.

Lundbeck A/S, or Lundbeck, in March 2015.

Prior to the acquisition, Lundbeck filed an investigational new drug application, or IND, with the FDA for the treatment of insomnia.

Pursuant to this IND, Lundbeck and Merck & Co., Inc., or Merck, partnered to conduct several Phase 3 trials for primary insomnia between 2004 and 2007.

Over the course of the development of OV101, over 4,000 adults were administered OV101, resulting in an OV101 exposure of approximately 950 patient years.

These trials were primarily randomized, placebo-controlled short-term and long-term safety and efficacy clinical studies, using classic sleep parameters such as total sleep time, time to sleep onset, wakefulness after sleep onset, and number of nocturnal awakenings as clinical endpoints.

The Phase 3 program consisted of three trials:

two 3-month placebo-controlled trials conducted in the United States and one 2-week trial conducted in Europe and Canada, each evaluating OV101 against placebo and the active comparator, zolpidem (Ambien).

The primary endpoints of the trials included total sleep time and time-to-sleep onset and the secondary endpoints included number of nocturnal awakenings, wakefulness after sleep onset and daytime function.

In Phase 3 trials, which were conducted for durations of up to 12 months, OV101 was observed to have efficacy that was largely comparable to zolpidem (Ambien) on several sleep metrics.

In the first 3-month trial, a dose of 15mg of OV101 met both of the primary endpoints as well as the secondary endpoints at week one and month three compared to placebo.

In the second 3-month trial, the same dose met only total sleep time and number of awakenings at week one, but significance was lost after adjusting for multiplicity at month three.

The 2-week trial met all primary endpoints and wakefulness after sleep onset, for 15mg of OV101 at weeks one and two.

Additionally, subjects who were administered OV101 showed no evidence of withdrawal symptoms or rebound insomnia after discontinuation of short-term treatment, whereas transient rebound insomnia was observed in subjects receiving zolpidem.

In addition, clear differences were observed between OV101 and zolpidem from a sleep architecture perspective.

OV101 has shown consistent increases in slow wave sleep compared to zolpidem with no significant effect on stage 2 or REM sleep in healthy adult, elderly subjects.

It is believed that slow wave sleep is important for encoding long-term, fact-based memories.

Slow wave sleep has been associated with physical changes in neuronal connections.

Safety and Tolerability

Overall, OV101 was observed to be well-tolerated in adult patients aged 18-64 years in the Phase 2 and Phase 3 trials at doses of 5mg to 15mg given as evening doses.

Success in these previous trials does not ensure that our clinical trials in OV101 will generate the same results or otherwise provide adequate data to demonstrate the efficacy and safety of OV101.

The most common reported adverse events were headache, nausea, vomiting, somnolence and dizziness.

In general, the adverse events appeared to be dose-related.

The majority of the serious adverse events observed were considered to not be related to treatment with OV101.

One SAE, fatigue, was considered by Lundbeck and Merck as probably related to OV101 treatment.

Among the nine SAEs considered by Lundbeck and Merck to be possibly related to OV101 treatment, there were three cases of fainting and one case each of:

radius fracture, abnormal QRS axis, transient ischemic attack, non-cardiac chest pain, unresponsive to stimuli and atrial fibrillation.

Across trials there were no apparent clinical trends regarding SAEs with respect to frequency, distribution across system organ classes or preferred terms.

Also, there were no apparent clinical differences versus placebo.

In the Phase 3 trials at the 15mg dose, at least one SAE was observed in 1.3% of subjects at two weeks and 3 months and 3.0% of subjects at 12 months versus 0.0% to 1.0% on placebo over the same time frame.

Consistent with the clinical development of other insomnia drugs, the FDA requested that Lundbeck and Merck conduct a series of preclinical and clinical abuse studies as part of their development program.

In preclinical studies, OV101 demonstrated low abuse potential.

In one clinical trial, the abuse potential of OV101 was investigated in doses up to 45mg in male and female subjects with a history of hypnotic/sedative abuse and other drug abuse.

Safety results showed that OV101 administered at doses of 30mg and 45mg in women and 45mg in men was not tolerated in this population of drug abusers, contrary to previous experience with the same doses in healthy volunteers.

This indicated that a history of drug abuse decreased tolerability to OV101 in these subjects.

Adverse events that were associated with a dose-dependent lack of tolerability in this trial included psychiatric, nervous system, musculoskeletal and gastrointestinal disorders.

In 2007, following the completion of all clinical trials for OV101 in insomnia, Lundbeck and Merck discontinued the development program for insomnia, and announced that the overall clinical profile did not support further development of OV101 for insomnia.

Clinical Development Programs

OV101 is a delta selective extrasynaptic GABA A receptor agonist.

An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response.

OV101 specifically exerts its biological activity through the δ subunit of extrasynaptic

GABA A receptors.

Based on the biological pathway and existing preclinical data, we anticipate developing OV101 as an orally active selective extrasynaptic GABA A agonist to compensate for the deficit in GABA concentrations observed in patients with certain rare neurological disorders.

We believe OV101 is the only drug candidate in development that exerts its biological activity preferentially through the δ subunit of extrasynaptic receptors.

We are initially developing OV101 for Angelman syndrome and Fragile X sy ndrome, and we believe it has the potential to address multiple neurodevelopmental disorders characterized by decreased tonic inhibition.

OV101 in Angelman Syndrome

Market Overview and Current Treatments

Angelman syndrome is a severe, lifelong, rare genetic condition that presents in early childhood and results in significant functional limitations in behaviour, motor, sleep, and cognitive functions.

According to the National Organization for Rare Disorders, the approximate prevalence in the general population is 1 in 12,000 to 20,000.

There are currently no approved therapies in the United States or ex-US specifically for the treatment of Angelman syndrome.

No standard of care exists for Angelman syndrome, and current therapeutic options are symptomatic, suggesting a high unmet clinical need.

Our Development of OV101 in Angelman Syndrome

The STARS Trial

STARS was a 12-week, double-blind, placebo-controlled Phase 2 study.

The primary endpoint of the trial was to assess the safety and tolerability of OV101 compared to placebo.

The STARS trial explored the clinical utility of OV101 on improvements in clinical global impressions, maladaptive behavior, sleep, and gross and fine motor skills.

Eighty-eight patients (adults, n=66;

adolescents, n=22) aged 13 to 49 years of age diagnosed with Angelman syndrome were randomized at 13 clinical trial sites in the U.S.

The study randomized patients to o ne of three arms:

QD dose of OV101 at night (15mg), BID dose of OV101 (10mg in the morning and 15mg at night), and placebo.

Details of the trial design are provided below:

Primary Endpoint:

Safety and Tolerability Data

The study met its primary endpoint of safety and tolerability given that the AEs with OV101 treatment were similar to placebo treatment, with the majority of AEs being mild.

OV101 showed a favorable risk profile and was well tolerated through 12 weeks of treatment.

Overall, the data are consistent with the favorable risk profile observed in previous insomnia trials with OV101.

The most common AEs reported in the trial were vomiting, somnolence, irritability, aggression, and pyrexia.

Most Frequent Adverse Events*

Descriptive data

Events occurring in greater than 5 percent (two or more patients) compared to placebo in either treatment arm included pyrexia, rash, seizure, enuresis and myoclonic epilepsy.

Adverse Events Occurring More Frequently in OV101 Arms vs.

Myoclonic epilepsy

Descriptive data

SAEs of seizure were reported in two patients:

one patient in the QD dose experienced a seizure and that was deemed unrelated to OV101;

one patient experienced a seizure in the BID dose group and that was assessed as possibly related to study drug by the investigator.

Treatment discontinuations due to AEs were low.

One patient in the placebo arm discontinued compared to no patients and three patients in the once-daily dose group and twice-daily dose group, respectively.

one patient with irritability

Twice-daily arm:

one patient with myoclonus;

one patient with seizure, and one patient with irritability/anxiety/sleep disorder

Efficacy Endpoint Data

At 12 weeks of treatment, the first prespecified efficacy endpoint of CGI-I demonstrated a robust and statistically significant difference (p=0.0206;

Fisher’s Exact test) between the combined OV101 treatment arms and placebo.

This reflects an improvement in two-thirds of the combined treatment groups versus one-third in placebo.

Response Based on CGI-I at Week 12;

Comparison to Placebo

Pooled treatment groups

(10mg/15mg BID) and

(15mg QD) (n=57)

Absolute number of patients who improved

In the prespecified analysis using the Mixed Model Repeated Measures (MMRM), which evaluated each OV101 treatment arm independently against placebo, the difference in CGI-I mean score at 12 weeks was statistically significant (p=0.0006) in the once-daily OV101 group versus placebo and also in the combined OV101 treatment group versus placebo (p=0.0103).

Mean CGI-I Symptoms Overall Score – by Dose Group at Week 12;

Comparison to Placebo

QD dose (15mg)

BID dose (10mg/15mg) (n=28)

Pooled treatment groups

(10mg/15mg BID) and

(15mg QD) (n=55)

Mean change in CGI-I score (week 6)

Mean change in CGI-I score (week 12)

p-value*** at week 12

MMRM analysis was performed adjusting for fixed effects of visit, treatment, age (adult vs.

adolescent) and visit by treatment interaction.

In a post-hoc analysis of patients who were “much” or “minimally” improved having a CGI-I score of ≤3, the data suggest that younger patients who received a once-daily dose had the greatest response to OV101 compared to older age groups.

Patients Who were ‘Much’ or ‘Minimally’ Improved in CGI-I Score (≤3) (Post-hoc Analysis)

End of Phase 2 Meeting

We met with the FDA in November 2018 to discuss the STARS trial results and plans to move to a phase 3 trial (the NEPTUNE trial).

Pending the outcome of data from this study, it is intended that the NEPTUNE trial data together with the STARS trial data will be the core studies used to support the filing of a New Drug Application (NDA) with the FDA.

Following the End of Phase 2 Meeting, we initiated the NEPTUNE trial with and enrolled our first patient in September 2019.

NEPTUNE is a 12-week, two-arm, randomized, double-blind, placebo-controlled trial with a once-daily, weight-based dose of OV101 versus placebo with an estimated enrollment of approximately 60 patients aged 4 to 12 years.

A few patients aged 2 to 3 years will also be enrolled for pK and safety assessments only.

The primary endpoint is the change in the overall CGI-I adapted for Angelman syndrome score (CGI-I-AS) from baseline to 12 weeks between the OV101 and placebo arms.

Topline data from NEPTUNE is expected in mid-2020.

Based on the STARS trial data, we have initiated ELARA, an open label extension trial which enrolled its first patient in February 2019 and is currently recruiting.

All patients that have been treated in any of our OV101 clinical trials are eligible to enroll.

OV101 in Fragile X Syndrome

Market Overview and Current Treatment

Fragile X syndrome is an inherited form of intellectual disability which manifests as a disruption in behavior, motor, sleep and cognitive functions, and is the most common cause of autism worldwide.

According to the National Fragile X Foundation, Fragile X syndrome affects approximately 1 in 3,600 to 4,000 males and 1 in 4,000 to 6,000 females.

Currently, there are no approved therapies for the treatment of Fragile X syndrome.

The current standard of care for the psychiatric challenges of Fragile X syndrome is tailored to each patient and may include antipsychotics, antidepressants and drugs to treat attention deficit and sleep disorders.

Special education and symptomatic treatments for anxiety and irritability are often employed to lessen the burden of illness.

Fragile X syndrome patients also may experience seizures, which are treated with traditional anticonvulsants.

Our Development of OV101 in Fragile X Syndrome

In July 2018, we initiated our Phase 2 ROCKET clinical trial, a randomized, double-blind, parallel-group trial evaluating OV101 for the treatment of adolescent and young male adults with Fragile X syndrome.

The trial is currently fully enrolled with males aged 13 to 22 with a confirmed diagnosis of Fragile X syndrome.

The primary endpoint is safety and tolerability of OV101 over 12 weeks of treatment in three different cohorts of either 5mg once daily, 5mg twice daily, or 5mg three times daily.

A secondary endpoint evaluates changes in behavior during 12 weeks of treatment with OV101 using the ABC-C, which has been used in previous trials of Fragile X syndrome.

We anticipate data from this trial early in the second quarter of 2020.

We also initiated the SKYROCKET study in the fourth quarter of 2018.

SKYROCKET is a 12-week, non-drug study to assess the suitability of several behavioral scales in individuals with Fragile X syndrome.

The study is fully enrolled with males aged 5 to 30 with Fragile X syndrome, and data from SKYROCKET are expected early in the second quarter of 2020.

OV935 for Epileptic Encephalopathies

We are developing OV935 in a joint collaboration with Takeda for the treatment of rare epileptic encephalopathies.

OV935 (soticlestat)

OV935 is being developed in a joint collaboration with Takeda for the treatment of rare epileptic encephalopathies.

In January 2017, we entered into a license and collaboration agreement with Takeda, or the Takeda collaboration agreement, to develop and commercialize OV935 (soticlestat or TAK-935).

Under the Takeda collaboration agreement, all costs and all profits are shared on a worldwide basis and Ovid leads development and in addition is responsible for commercialization in North America, Europe and Israel.

In March 2021, we entered into a royalty, license and termination agreement, or the Takeda License and Termination Agreement, with Takeda under which Takeda will secure global rights at closing from us to develop and commercialize the investigational medicine OV935 for the treatment of developmental and epileptic encephalopathies, including DS and LGS.

Closing of the Takeda License and Termination Agreement is subject to the satisfaction of customary closing conditions.

See “Business—License and Collaboration Agreements—Agreements with Takeda—2021 Royalty, License and Termination Agreement with Takeda” for a discussion of the terms of the Takeda License and Termination Agreement.

OV935 is a potent, highly selective inhibitor of the enzyme cholesterol 24-hydroxylase, or CH24H.

We believe, if approved, OV935 has the

potential to become a first-in-class i nhibitor of CH24H.

We believe, if approved, OV935 has the potential to become a first-in-class and only-in-class compound targeting the metabolism of cholesterol in the brain.

We believe that OV935 inhibits a key enzyme in cholesterol metabolism pathway in the brain and may modulate the excitatory signals involved in epilepsy, which may suppress seizures .

CH24H is predominantly expressed in the brain, where it plays a central role in cholesterol homeostasis and neuronal physiology.

Recent literature suggests that in addition to its impact on membrane cholesterol homeostasis in the central nervous system, modulation of CH24H may have an impact on over-activation of neurotransmitter pathways that have been implicated in a number of neurological disorders, such as epilepsy.

Preclinical data suggest that inhibition of brain CH24H indirectly re duces glutamatergic signaling via NMDA receptors and modulates glial function and inflammation, which may impact disease pathology and epileptogenesis.

OV935 has completed four Phase 1 trials demonstrating favorable tolerability at doses that are believed to be therapeutically relevant.

The Phase 1b/2a trial of OV935 in adults achieved its primary endpoint of safety and tolerability and showed OV935 was generally well tolerated.

In December 2017, the FDA granted orphan drug designation for OV935 for the treatment of Dravet syndrome and Lennox-Gastaut syndrome.

We believe that OV935 offers the possibility not only to suppress seizures, as was observed in preclinical studies, but also to modulate the underlying biological pathways that lead to the development of seizures.

This may have long-term, disease-modifying potential.

The primary objective of the Phase 1b/2a clinical trial was to characterize the safety and tolerability profile of OV935 in adult patients with a documented DEE.

The secondary objective was to characterize the multiple dose PK profile of OV935 in adult patients with a documented DEE.

Preclinical data suggest that inhibition of brain CH24H indirectly reduces glutamatergic signaling via NMDA receptors and modulates glial function and inflammation, which may impact disease pathology and epileptogenesis.

We believe that because OV935 is an inhibitor of CH24H it may modulate the excitatory signals involved in epilepsy, which may suppress seizures.

As a result, OV935 is being developed in rare and difficult to treat epilepsies with the goal to develop OV935 not just as a potential medicine to treat the seizures but also one that may have long-term disease-modifying potential.

We believe that OV935 if successful in these areas may have utility in other areas as well.

OV935 is initially being studied in those suffering from severe and often intractable forms of DEE, including Dravet syndrome, or DS, Lennox-Gastaut syndrome, or LGS, CDKL5 Deficiency Disorder, or CDD, and Duplication 15q, or Dup15q syndrome.

There are limited or no therapeutic options in each of these disorders.

We have completed multiple trials on OV935 and expect to initiate pivotal phase 3 trials in second quarter of 2021.

Previously w e completed a Phase 1b/2a clinical trial of OV935 in a mixed group of adults with DEE and announced the results in December 2018.

Following this trial and as further discussed below, we reported the initial data from the Phase 2 open-label extension study (which we refer to as the ENDYMION trial) of OV935 in six patients who previously completed our 12-week Phase 1b/2a clinical trial of OV935 in adults with DEE.

On August 25, 2020, we, together with Takeda, announced positive topline results from the ELEKTRA trial which was a phase 2 trial in DS and LGS, along with updated findings from the ENDYMION trial.

Based on the trial results of ELEKTRA and after presentation of the data and review of the phase 3 pivotal trial approach with regulatory authorities in the US ( FDA), EU (CHMP), and Japan (PMDA) , we expect to initiate two separate multinational Phase 3 pivotal registrational trials in Dravet syndrome and LGS with OV935 in the second quarter of 2021.

The FDA has granted orphan drug designation for OV935 for the treatment of Dravet syndrome and LGS .

Dravet Syndrome

26 unchanged sentences

GABAergic promoting antiepileptics are typically ineffective while broad-spectrum antiepileptic medications such as valproic acid and rufinamide provide some relief.

The Role of Cholesterol Metabolism in Epileptic Encephalopathies

The brain is a cholesterol-rich organ, containing about 25% of the total cholesterol in the body.

Cholesterol is an essential component of cellular membranes, including the synaptic membranes that aid in the transmission of signals between cells.

Cholesterol is also a key component of myelin, the protective layer of lipids and proteins that serves as an insulating sheath and facilitates electrical conduction in nerve cells.

Cholesterol in the brain is entirely synthesized and metabolized locally to maintain physiologic levels.

When cholesterol is metabolized in the brain, it is broken down to 24-hydroxycholesterol, or 24HC, by CH24H, an enzyme predominantly expressed in the brain.

Converting cholesterol to 24HC enables it to pass through the blood-brain barrier and enter into the circulatory system, allowing it to be eliminated from the body.

Since CH24H is primarily present in the brain, there is a strong correlation between circulating blood levels and brain levels of 24HC.

The levels of 24HC can therefore serve as a biomarker of CH24H activity in the brain.

24HC levels can profoundly impact key signaling pathways in the brain including glutamatergic signaling, or signaling by the neurotransmitter glutamate.

In one subtype of glutamate recept ors called N-Methyl-D-Aspartate, or NMDA, receptors, elevated levels of 24HC have been shown in various cellular and tissue models to lead to increased activation of the glutamate signaling pathway.

Activation of NMDA receptors has been implicated in a num ber of neurological disorders, including Alzheimer’s disease and epilepsy.

As a result, modulation of cholesterol metabolism has been proposed as a potential therapeutic approach for several neurological disorders.

We believe that decreasing 24HC levels, a nd thereby modulating NMDA receptor activity, represents a sound rationale for addressing the underlying biology of epileptic encephalopathies.

The following figure depicts inhibition of CH24H by OV935 and its impact on excitatory signaling in the brain.

Through inhibition of CH24H, OV935 is believed to reduce brain levels of 24HC, thereby reducing excitatory signaling.

The glutamatergic pathway and NMDA receptors have been the targets of a number of approved drugs.

Many of these approved drugs, including anesthetics such as ketamine, were developed as antagonists of NMDA receptors, thus blocking the receptor.

These drugs have not been used in disorders such as epilepsy, where the goal is not to entirely block the NMDA receptor, but rather to modulate its activity.

The complete blockade of the NMDA receptor with long-term use is frequently associated with poor tolerability.

In some cases, low doses of NMDA receptor antagonists have demonstrated clinical benefit outside their prescribed use, including for treatment of neurological disorders.

For example, memantine, a low affinity NMDA receptor antagonist, has been used to treat moderate to severe Alzheimer’s disease patients because it does not completely block the NMDA receptor.

Modulation of the NMDA receptor, rather than NMDA receptor antagonism, could provide a more effective method for treatment of neurological disorders.

A number of publications by independent academic groups have shown that 24HC is a potent modulator of the NMDA receptor.

These publications describe 24HC as a positive allosteric modulator, a molecule that induces a conformational change within the protein structure of the receptor and increases its activity.

Mice lacking CH24H expression have reduced brain levels of 24HC and decreased NMDA receptor signaling.

Therefore, inhibiting CH24H and reducing 24HC levels in the brain offers an alternate mechanism for modulating NMDA receptor activity without blocking normal receptor function.

We believe that reducing 24HC levels represents an innovative approach to impacting the glutamatergic pathway to treat epileptic encephalopathies.

The potential importance of this target, along with the strength of the data supporting it, is what attracted us to OV935 as a potential treatment for these disorders.

OV935 Preclinical Data

OV935 has been evaluated in multiple preclinical epilepsy and seizure models.

In these studies, OV935 was observed to have anti-convulsive activity in genetic, pharmacologic and inflammation-induced seizure models.

Based on the preclinical data available to us, OV935 may have diverse effects on overall brain function, affecting both seizure intensity and frequency, and potentially modifying the underlying disease biology.

We believe the data provide a rationale to test OV935 in multiple epileptic encephalopathies.

The models are summarized as follows:

Observed OV935 Activity

SCN1A Knock-In Model of DS

Increased temperature threshold for hyperthermia-induced seizures

Pentylenetetrazol (PTZ) Kindling Model

Reduced PTZ-induced seizure progression

Fring’s Audiogenic Seizure Model

Reduced audiogenic seizures

APP/PS1 Transgenic Mouse Model

Prolonged overall survival

TMEV Mouse Model

Decreased seizure activity and duration

SCN1A Knock-In Model of Dravet Syndrome

OV935 was tested in a knock-in model of Dravet syndrome constructed by inactivation of the SCN1A gene.

This gene encodes a voltage-gated sodium channel that plays a critical role in the normal functioning of inhibitory pathways in the brain.

Deficiencies in the functioning of this channel allow brain excitatory pathways to function unchecked, resulting in severe seizures.

The majority of Dravet syndrome cases are caused by mutations in this gene.

Mice containing the SCN1A gene mutation have hyperthermia-induced or high-temperature-induced seizures.

Mice treated with OV935 were observed to have a significantly raised threshold temperature for developing these seizures after seven days of dosing, relative to untreated mice, as depicted below.

RIKEN Brain Science Institute, Neurogenetics laboratory (Lab head;

Kazuhiro Yamakawa).

OV935 increases the threshold for temperature-induced seizures in mice containing the SCN1A gene mutation.

PTZ Kindling Model

OV935 was tested in a preclinical kindling seizure model.

Scientists use kindling models to study the effects of repeat seizures in the brain.

One such kindling model described here is the pentylenetetrazol, or PTZ, model.

As depicted in the figure below, it has been observed that repeat stimulation can increase the likelihood of seizures, presumably because there is a threshold for seizures to occur and the repeat stimulation lowers this threshold.

In this model, PTZ is used to chemically stimulate mice at sub-convulsive levels.

PTZ also increases the density and sensitivity of glutamate receptors in specific regions of the brain.

Mice that were dosed daily with OV935 demonstrated a significant delay in seizure development in this model.

OV935 delayed seizure development in the PTZ-induced kindling mouse model.

Fring’s Audiogenic Seizure Model

OV935 was tested in a preclinical audiogenic seizure model.

The Fring’s audiogenic seizure model is widely used by scientists to investigate the effects of investigational drugs in a model sensitive to sound-induced seizures.

In the experiment, OV935 was dosed once a day for either one or three days.

The effect of OV935 on the duration of seizures was determined after the induction of a seizure either one hour or 24 hours following administration of the last dose.

As depicted in the figure below, it was observed that OV935 treatment resulted in a significant dose-dependent reduction in sound-induced seizures following single and 3-day repeat dosing.

OV935 dose-dependently reduced seizure in the Fring’s audiogenic seizure model.

90 APP/PS1 Transgenic Mouse Model

Other disease models

Presenilin-1 Mice

OV935 was tested in a preclinical Alzheimer’s disease model where an amyloid precursor protein, or APP, overexpressing mouse was crossed with a presenilin-1, or PS1, mutant mouse that is highly prone to developing spontaneous seizures.

We believe that results obtained in this model yield some valuable insights into neurological disorders, and particularly into the biochemistry of the brain.

Mice in this model typically have a high incidence of sudden death with only 50% of them surviving after three months.

As depicted in the figure below, mice treated with OV935 in this model were observed to have a significant increase in overall survival.

While it is unclear if the increase in survival is directly related to reduction in seizures, increase in survival has previously been observed in APP/PS1 mice when one copy of the gene for CH24H is inactivated, suggesting that the survival benefit observed after treatment with OV935 may be due to inhibition of its intended target, CH24H.

OV935 increased survival in APP/PS1 transgenic mouse model.

TMEV Mouse Model

OV935 was tested in a Theiler’s murine encephalomyelitis virus, or TMEV, model to determine the role of OV935 in reducing inflammation-induced seizures.

Infection with TMEV in this model leads to acute seizures and significant elevations in inflammatory signaling molecules, known as cytokines.

A large fraction of the mice develop spontaneous, recurrent seizures and various behavioral co-morbidities weeks later.

As depicted below, treatment with OV935 demonstrated reduction in the overall number and average severity of seizures in the mice in the acute phase.

In addition, long-term benefits were observed, based on significant improvements in anxiety assays such as the open field test.

OV935 reduced the number of seizures and the number of severe (Stage 4/5) seizures in the

OV935 Clinical Data

Phase 1 Trials

OV935 has been tested in 86 healthy volunteers across four Phase 1 trials.

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Both volunteers discontinued the trial at day 11.

One volunteer receiving placebo

reported events of nightmares, spatial disorientation, insomnia and dizziness.

One volunteer receiving placebo reported events of nightmares, spatial disorientation, insomnia and dizziness.

All AEs resolved with continued dosing through day 15.

No SAEs were reported.

Overall, no safety issues of concern were identified in the Phase 1 trials based on assessments of physical examinations, vital sign measurements, clinical laboratory values or 12-lead electrocardiogram findin gs.

The following table summarizes each trial:

The following table summarizes each Phase 1 trial:

Safety and tolerability

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300mg (solution), oral

In the Phase 1 PET imaging trial, following administration of OV935, levels of plasma 24HC decreased as the dose increased, reaching an apparent plateau of a 60% reduction at a dose of 300mg, as depicted in the figure below.

Dose-dependent reduction in plasma 24HC by OV935 in a Phase 1 multiple ascending-dose trial.

OV935 Clinical Development Plan

Phase 1b/2a Trial - 2001

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100 mg, 200 mg twice daily), and treatment period (10 days).

Details of the trial design are provided below:

The target final dose of 300 mg BID could be reached after the 20-day titration period.

Part 2 was a 60-day open-label phase to explore the extent to which OV935 reduces seizure frequency as well as longer-term safety, tolerability, PK, and 24HC plasma levels.

Patients who rolled over to Part 2 started OV935 at 200 mg BID for 10 days (second titration period) and increased to 300 mg BID until Day 85 followed by down titration to Day 92 (end of treatment period).

Patients received OV935 or placebo in addition to their standard antiepileptic treatment regimens.

Primary Endpoint:

Safety and Tolerability Results

OV935 achieved the primary endpoint of safety and tolerability as measured by incidence of AEs.

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Accordingly, changes in seizure frequency data for the Phase 1b/2a trial are now reported with the inclusion and exclusion of the three patients on perampanel, respectively.

Secondary and Exploratory Endpoint Results

PK parameters:

The data reaffirm the PK profile seen in previous studies.

Specifically, OV935 exposure levels were dose-proportional and consistent with levels observed in four prior Phase 1 studies in healthy volunteers.

In Part 1, a dose-dependent reduction of plasma 24HC levels was observed with OV935 treatment compared to placebo.

A similar reduction was observed in Part 2 in both the OV935-treatment arm and patients in the placebo arm who crossed over to receive study drug.

Importantly, there was an association between the reduction of 24HC and the median reduction of seizure frequency with OV935 treatment.

By end of treatment period, 12 of 14 patients had interpretable 24HC data and seizure frequency counts.

Individuals achieving plasma levels of <10 ng/ml (an approximate 80 percent decrease from baseline) at Day 85 (n=7) showed a median seizure reduction of 69 percent compared to 3 percent for those who did not obtain this degree of 24HC reduction (n=5).

Accordingly, 24HC will be further studied as a potential biomarker in OV935 clinical trials.

Exploratory analysis of seizure data:

Median percent reduction from baseline seizure frequency is being reported on patients treated with OV935 during the 60-day open-label Part 2 period for all seizure types (Table 1).

Based on individual patient analysis, three patients on concomitant perampanel had increased seizure frequency during the study, consistent with a potential drug-drug interaction, as described above.

A subset analysis was conducted on 11 patients, who were not taking perampanel.

Overall, seizure frequency reduction was observed with maximal effect in the later part of the treatment period.

Median Seizure Frequency

Full Analysis Set (FAS) Part 2*

FAS Part 2 excluding patients on Perampanel**

Reduction from Baseline in Seizure Frequency

Day 92 (measured from Day 65-92)

Day 85 (measured from Day 58-85)

Day 69 (measured from Day 42-69)

Total Seizure Free Days

Day 92 (measured from Day 65-92)

Responder Analysis – Proportion of Patients with Seizure Reduction from Baseline

100% reduction (seizure free)

≥50% reduction

18 patients randomized to receive OV935 in Part 1 (titration period).

Two withdrew from Part 1 and 16 patients rolled over to Part 2 (treatment period);

14 patients completed the trial.

FAS Part 2 without perampanel:

Excludes 3 patients taking perampanel for a total of 13 patients;

11 patients completed the trial.

Exploratory analysis of OV935 data showed reduction in seizure frequency that was correlated with decreases in plasma 24-hydroxycholesterol (24HC) levels in adults across multiple DEE.

OV935 is a potent, highly-selective first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H) being investigated as a novel approach to treating epilepsy.

Based on the insights gained from the Phase 1b/2a trial, Ovid and Takeda will continue with the dose and titration schedule used in the Phase 2 ELEKTRA trial of OV935 in patients ages 2 to 17 years and the Phase 2 ARCADE trial in patients ages 2 to 55 years.

In addition, Ovid has amended the protocols for these trials to exclude patients being treated with perampanel and, in light of the mode of action of OV935, the duration of treatment has been extended to 20 weeks with the potential to observe the extent of the effects of OV935 on seizure reduction over time.

Ovid and Takeda will continue to enroll eligible patients in the ENDYMION open-label extension study.

ENDYMION is a prospective, multi-center, open-label extension study of OV935 in patients with DEE who have participated in a previous OV935 clinical study.

ENDYMION is a Phase 2 prospective, multi-center, open-label extension study of OV935 in patients with DEE who have participated in a previous OV935 clinical study.

The primary objective is to assess the long-term safety and tolerability of OV935 over four years of treatment in patients with rare epilepsies.

A secondary endpoint evaluates the effect of OV935 on seizure frequency over time.

First Analysis of ENDYMION patients –Adult DEE rollover patients

ENDYMION enrolled eligible patients from the ELEKTRA and ARCADE trials, each discussed below.

In September 2019, we announced initial data from the first six patients in ENDYMION who were previously enrolled in the Phase 1b/2a clinical trial of OV935 in adults with DEE and subsequently ceased taking OV935 for a period of between 6 weeks and 12 months.

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Data from patients who have completed ARCADE, our Phase 2, multi-center, open-label, pilot study evaluating the treatment of OV935 in patients with epileptic seizures associated with CDD or Dup15q syndrome, are not included the above analysis due to their limited treatment duration in ENDYMION.

Data from patients previously treated in ELEKTRA are not included in the above analysis due to the ongoing trial being double-blinded and placebo-controlled.

Data from patients previously treated in ELEKTRA are not included in the above analysis due to the ELEKTRA trial being double-blinded and placebo-controlled at the time of the analysis.

Overall, at 48 weeks, safety observations were consistent with the completed Phase 1b/2a clinical trial in adults with DEE.

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No serious adverse events were observed.

We expect to announce longer-term data from the ARCADE patients that rolled over into ENDYMION in the first quarter of 2020.

ELEKTRA is an international Phase 2, multi-center, randomized, double-blind, placebo-controlled study that will evaluate the treatment of OV935 in 126 pediatric patients, aged two to 17 years, with epileptic seizures associated with Dravet syndrome or Lennox-Gastaut syndrome.

The trial consists of a four- to six-week screening period to establish baseline seizure frequency followed by a 20-week treatment period that includes an eight-week dose titration period and a 12-week maintenance period.

The primary endpoint is the change from baseline in seizure frequency in patients treated with OV935 compared to placebo by disorder (Dravet and Lennox-Gastaut syndrome).

The secondary endpoints include safety, tolerability and PK assessments as well as the percentage of patients considered treatment responders, changes in Clinician’s Clinical Global Impressions of Severity and Change, or CGI-S/C, and correlation of OV935 concentration with plasma 24HC levels.

In September 2019, we announced that enrollment in ELEKTRA has been proceeding at a more rapid rate than anticipated, and we now expect to report topline results from ELEKTRA in the third quarter of 2020, earlier than originally anticipated.

Enrollment in this study is complete, and we attribute the strong enrollment to high interest in the trial from multiple sites across the globe.

Upon the completion of ELEKTRA, patients are eligible to enroll in the ENDYMION open-label extension trial.

ARCADE is a Phase 2, multi-center, open-label, pilot study that will evaluate the treatment of OV935 in patients, aged 2 to 55 years old, with epileptic seizures associated with CDD or Dup15q syndrome.

The primary endpoint is the percent change in motor seizure frequency during maintenance in patients treated with OV935 by disorder type (either CDD or Dup15q syndrome).

The key secondary endpoints include safety and tolerability, including percentage of participants considered treatment responders, assessment in CGI-S/C, and correlation of OV935 concentration and plasma 24HC levels.

ARCADE is enrolling subjects at clinical trial sites in the United States.

This study consists of a four to six-week screening period to establish baseline seizure frequency followed by a 20-week treatment period (8-week dose optimization and 12-week maintenance period).

At the end of treatment, eligible patients can roll over into the ENDYMION study.

We expect to report initial data from ARCADE in the first quarter of 2020 with full data from the trial expected in early 2021.

As discussed below, in August 2020 and September 2020, we announced updated findings from ENDYMION from patients who completed the ELEKTRA and ARCADE studies, respectively, and elected to enroll in ENDYMION.

ELEKTRA was an international, multi-center, randomized, double-blind, placebo-controlled study designed to evaluate treatment with soticlestat in pediatric patients, aged 2 to 17 years, with highly refractory epileptic seizures associated with convulsive seizures (DS) or drop seizures (LGS).

The study consisted of a four- to six-week screening period to establish baseline seizure frequency, followed by a 20-week double-blind treatment period, including an 8-week dose optimization period and a 12-week maintenance period.

During the 8-week dose optimization period, patients were titrated from 100mg twice daily (BID), to 200mg BID to 300mg BID (mg/kg dosing for <60 kg) of orally administered soticlestat.

A total of 141 patients were enrolled in ELEKTRA and 126 completed the study.

A modified intent-to-treat, or mITT, analysis of 139 patients was performed to evaluate the efficacy endpoints, which includes any patient who enrolled in the study and received at least one dose of study drug.

Patients in the study were allowed to be on one to four concomitant anti-epileptic drugs, or AEDs, with the majority of patients concomitantly treated with at least three AEDs.

The most common AEDs taken by the patients were valproate, clobazam, levetiracetam and topiramate.

Further, all patients who completed ELEKTRA enrolled in the ENDYMION open-label extension study.

On August 25, 2020, we, together with Takeda, announced positive topline results from ELEKTRA and updated findings from ENDYMION.

The ELEKTRA study achieved its primary endpoint with high statistical significance, demonstrating a 27.8% median reduction from baseline in convulsive seizure (DS) and drop seizure (LGS) frequency compared to a 3.1% median increase in patients taking placebo during the 12-week maintenance period (median placebo-adjusted reduction=30.5%;

p=0.0007, based on the efficacy analysis set of 120 patients with seizure data in the maintenance period).

In addition, DS and LGS patients treated with soticlestat demonstrated a 29.8% median reduction in convulsive seizure (DS) and drop seizure (LGS) frequency compared to 0.0% change in median seizure frequency in patients taking placebo during the full 20-week treatment period (titration plus maintenance) of the ELEKTRA study (placebo-adjusted reduction=25.1%;

Soticlestat was generally well-tolerated in the ELEKTRA study and demonstrated a safety profile consistent with those of previous studies, with no new safety signals identified.

All patients who completed the ELEKTRA study elected to enroll into the ENDYMION open-label extension study and findings from ENDYMION were also reported on August 25, 2020.

The ENDYMION study data of rolled-over ELEKTRA patients support results in the ELEKTRA study.

The ENDYMION data indicated maintenance of effect over 6 months in those patients originally randomized to soticlestat, and similarly reduced seizure frequency as compared to baseline in those patients previously assigned to the placebo arm.

No new safety signals were identified in ENDYMION.

ARCADE is a Phase 2 open-label, signal-finding pilot study designed to inform the potential for future development of soticlestat in CDD and Dup15q syndrome.

The study enrolled 20 patients, ages 2 to 55 years, with refractory epileptic seizures associated with CDD (n=12) or Dup15q (n=8) and consisted of a four- to six-week screening period to establish baseline seizure frequency, followed by a 20-week treatment period, including an eight-week titration/dose optimization period and a 12-week maintenance period.

Patients in the study were allowed to be on one to six concomitant AEDs, with the majority of patients

concomitantly treated with at least four AEDs, representing a highly refractory patient population.

The primary objective of the ARCADE study was to determine percent change from baseline in motor seizure frequency during the 12-week maintenance period.

Further, all patients who completed ARCADE enrolled in the ENDYMION open-label extension study.

On September 30, 2020, we announced results from ARCADE and updated findings from ENDYMION.

Together, data from the ARCADE and ENDYMION studies showed seizure frequency reduction over time.

In CDD patients (n=12), median motor seizure frequency reduction was 24% during the 12-week maintenance period in the ARCADE study, increasing to a 50% reduction in the ENDYMION long-term extension study in the five CDD patients who reached nine months of continuous treatment.

In Dup15q patients (n=8), there was an increase in median motor seizure frequency in the ARCADE study during the 12-week maintenance period;

however, longer-term data from the four Dup15q patients who reached nine months of continuous treatment showed a 74% reduction in median motor seizure frequency.

Soticlestat was generally well tolerated in both studies and continues to demonstrate a favorable safety profile.

We believe the results are encouraging and next steps are being evaluated with Takeda.

OV101 (gaboxadol)

To date, we have been developing OV101 for the treatment of Angelman syndrome and Fragile X syndrome, two neurodevelopmental disorders that are characterized by similar symptoms.

In December 2020, we reported the primary endpoint of the Pivotal Phase 3 trial in pediatric individuals with Angelman syndrome (the NEPTUNE trial) was not achieved.

Based on the results of the NEPTUNE trial, further development of OV101, other than the ongoing long-term extension study with Angelman syndrome patients who had previously been in a trial for OV101 (the ELARA trial), is currently on hold.

The data from all trials is under review and further development of OV101, if any, will be the subject of full analysis of this data.

Angelman syndrome and Fragile X syndrome have overlapping symptoms, including sleep disorder, aberrant behavior, anxiety and cognitive or intellectual disabilities thought to be caused by decreased tonic inhibition, an important mechanism whereby it is believed that the brain distinguishes signal from noise.

Both of these disorders are typically diagnosable in early childhood and require full-time care for the patients affected.

In September 2016, the FDA granted orphan drug designation for OV101 for the treatment of Angelman syndrome;

in October 2017 the FDA granted orphan drug designation for OV101 for the treatment of Fragile X syndrome;

in December 2017 the FDA granted fast track designation for the treatment of Angelman syndrome;

and in March 2018, the FDA granted fast track designation for the treatment of Fragile X syndrome.

In June 2019, the European Commission granted OV101 orphan drug designation for the treatment of Angelman syndrome based on the results of the STARS clinical trial.

OV101 and Tonic Inhibition

Tonic inhibition is a critical physiological regulatory mechanism that allows a healthy human brain to decipher excitatory and inhibitory neurological signals correctly without being overloaded.

Defects of this system are thought to play a role in multiple disease states, including Angelman syndrome, Fragile X syndrome and insomnia.

Because of its unique mode of action, OV101 represents a promising compound targeting this mechanism.

Decreased tonic inhibition results in an imbalance in the ratio of excitation to inhibition.

If tonic inhibition is reduced, the brain becomes inundated with signals and loses the ability to separate background noise from critical information.

This imbalance disrupts normal brain functioning, including sensory processing and integration.

Disruption of tonic inhibition can lead to a multiplicity of symptoms including, but not limited to, sleep abnormalities, motor deficiencies, behavioral manifestations, delayed development, intellectual disability and severe speech impairment .

By modulating tonic inhibition, OV101 may have the potential to alleviate important symptoms and provide a meaningful clinical benefit to patients across several disorders.

We believe that OV101 modulates tonic inhibition.