BEDFORD, Mass.--(BUSINESS WIRE)--Stoke Therapeutics, Inc. (Nasdaq: STOK), a biotechnology company pioneering a new way to treat the underlying cause of genetic diseases by precisely upregulating protein expression, today reported financial results for the third quarter of 2020 and provided business updates.

“We have made important progress in recent months that includes the continued enrollment and dosing of children and adolescents in our MONARCH study, reaching agreement with the FDA to evaluate an additional higher dose of STK-001 in this study and submitting a plan to the Agency that also would allow us to evaluate multiple ascending doses. We remain on track for preliminary data from this Phase 1/2a study in 2021,” said Edward M. Kaye, M.D., Chief Executive Officer of Stoke Therapeutics. “In addition, based on new preclinical data, we are announcing today the expansion of our pipeline with the nomination of OPA1 as our next preclinical target. Consistent with our strategy, we believe our approach has the potential to be a first-in-class, disease modifying treatment for autosomal dominant optic atrophy, the most common inherited optic nerve disorder. There are currently no treatments available for this disease, which causes progressive and irreversible vision loss in both eyes starting in the first decade of life.”

The nomination of OPA1 as the Company’s next preclinical target is supported by preclinical data that demonstrated in vitro and in vivo target engagement and protein upregulation in OPA1 protein-deficient cells. In these studies, TANGO antisense oligonucleotides (ASOs) demonstrated:

• Dose-dependent decreases in non-productive OPA1 mRNA and increases in OPA1 protein expression in vitro and in vivo.
• An increase in OPA1 protein expression to approximately 75% of wild-type levels in an OPA1 haploinsufficient (OPA1 +/-) cell line.
• In vivo increases in OPA1 protein levels in the retina of wild-type rabbits that correlated with increases in the level of the test ASO.
• The test ASO was well tolerated for up to 29 days (maximum days evaluated) after intravitreal injection.

Recently completed preclinical studies have now demonstrated the ability of TANGO ASOs targeting the OPA1 gene to upregulate adenosine triphosphate production (ATP) levels in the mitochondria. These new data showed that in haploinsufficient cells where half the amount of OPA1 is present and mitochondrial function is impaired, our ASOs demonstrated an ability to increase OPA1 protein levels and also partially restore mitochondrial function as measured by an increase in ATP production. OPA1 expression is essential to retinal ganglion cell survival and visual signal transmission. Retinal ganglion cells have high energy needs making them particularly susceptible to losses in ATP production due to OPA1 haploinsufficiency.

“The ATP finding is significant because in patients with autosomal dominant optic atrophy (ADOA), the retinal ganglion cells are not producing enough ATP and have defective mitochondrial function, which leads to cell death and progressive vision loss. These new data suggest that our ASO approach can restore mitochondrial function to potentially address the underlying cause of autosomal dominant optic atrophy,” said Gene Liau Ph.D., Executive Vice President, Head of Research and Preclinical Development of Stoke Therapeutics. “Our goal is to advance an ASO that would delay, or potentially even prevent, vision loss for people living with ADOA. We aim to complete our lead optimization studies by the end of 2021 so that we can advance the most promising potential new medicine into human studies.”

OPA1 protein deficiency is the primary cause of ADOA, the most common inherited optic nerve disorder. ADOA typically presents in the first decade of life and affects approximately one in 30,000 people globally with a higher incidence in Denmark of one in 10,000 due to a founder effect. An estimated 65% to 90% of cases are caused by loss of function mutations in one allele (haploinsufficiency) in the OPA1 gene. There are over 400 different mutations reported to date in ADOA patients. Similar to Stoke’s Dravet syndrome program, Stoke’s approach for ADOA leverages upregulation of the wild-type allele and can potentially be used to treat ADOA due to loss of OPA1 activity in a mutation-independent manner.

Third Quarter 2020 Business Highlights and Recent Developments

• On October 7, the Company announced plans to move forward with dosing of STK-001 in its ongoing Phase 1/2a MONARCH study for Dravet syndrome. The FDA will allow the Company to add an additional higher dose level to the single ascending dose portion of the study, which will now include a total of three dose levels (10 mg, 20 mg and 30 mg). In addition, the Company has submitted an amendment to the MONARCH protocol to add a multiple ascending dose portion to the study, pending FDA review.
• On August 26, the journal Science Translation Medicine published preclinical data from studies of STK-001 that demonstrated significant improvements in survival and reductions in seizure frequency in a mouse model of Dravet syndrome.
• On August 17, the Company appointed Gary E. Menzel, Ph.D., to both its Board of Directors and Compensation Committee. Dr. Menzel brings more than 25 years of executive management experience in the global healthcare sector and currently serves as President and Chief Executive Officer of TCR2 Therapeutics Inc.
• On July 9, the journal Nature Communications published data that support the Company’s proprietary TANGO approach to addressing severe genetic diseases by precisely upregulating protein expression.
• The BUTTERFLY observational study is ongoing. Despite experiencing a slowing in new patient enrollment earlier this year due to the impact of COVID-19, new patient enrollment continues, and we believe we have achieved sufficient participation in the study to provide informative data about the natural progression of Dravet syndrome.

Upcoming Anticipated Milestones

• Preliminary safety and pharmacokinetic data from the MONARCH study are still expected in 2021.
• Several abstracts related to Stoke’s work in Dravet syndrome have been accepted for presentation at the American Epilepsy Society (AES) Annual Meeting, December 4-8, 2020.
• The Company expects to complete lead optimization for TANGO ASOs directed at OPA1 in 2021.

Third Quarter and Year-to-Date Results

• Net loss for the three months ended September 30, 2020 was $13.7 million, or $0.41 per share compared to $8.6 million or $0.26 per share for the same period in 2019.
• Research and development expenses for the three months ended September 30, 2020 were $8.1 million, compared to $6.5 million for the same period in 2019.
• General and administrative expenses for the three months ended September 30, 2020 were $5.6 million, compared to $3.3 million for the same period in 2019.
• Net loss for the first nine months of 2020 was $37.7 million or $1.14 per share, compared to net loss of $22.2 million or $1.71 per share for the same period in 2019.
• Research and development expenses for the nine months ended September 30, 2020 were $23.3 million, compared to $16.7 million for the same period in 2019.
• General and administrative expenses for the nine months ended September 30, 2020 were $15.2 million, compared to $7.9 million for the same period in 2019.
• The increase in expenses for the three and nine month periods in 2020 over the same periods in 2019 primarily relate to increases in costs associated with personnel, third party contracts, consulting, facilities and others associated with development activities for STK-001, research on additional therapeutics and growing a public corporation.
• As of September 30, 2020, Stoke had approximately $191.7 million in cash, cash equivalents and restricted cash, which is anticipated to fund operations into 2023.

About TANGO

TANGO (Targeted Augmentation of Nuclear Gene Output) is Stoke’s proprietary research platform. Stoke’s initial application for this technology are diseases in which one copy of a gene functions normally and the other is mutated, also called haploinsufficiencies. In these cases, the mutated gene does not produce its share of protein, so the body does not function normally. Using the TANGO approach and a deep understanding of RNA science, Stoke researchers design antisense oligonucleotides (ASOs) that bind to pre-mRNA and help the target genes produce more protein. TANGO aims to restore missing proteins by increasing – or stoking – protein output from healthy genes, thus compensating for the non-functioning copy of the gene.

About STK-001

STK-001 is an investigational new medicine for the treatment of Dravet syndrome currently being evaluated in a Phase 1/2a clinical trial. Stoke believes that STK-001, a proprietary antisense oligonucleotide (ASO), has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome. STK-001 is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities. Stoke has generated preclinical data demonstrating proof-of-mechanism and proof-of-concept for STK-001. STK-001 has been granted orphan drug designation by the FDA as a potential new treatment for Dravet syndrome.

About Phase 1/2a Clinical Study (MONARCH)

The MONARCH study is a Phase 1/2a open-label study of children and adolescents ages 2 to 18 who have an established diagnosis of Dravet syndrome and have evidence of a pathogenic genetic mutation in the SCN1A gene. The primary objectives for the study will be to assess the safety and tolerability of STK-001, as well as to characterize human pharmacokinetics. A secondary objective will be to assess the efficacy as an adjunctive antiepileptic treatment with respect to the percentage change from baseline in convulsive seizure frequency over a 12-week treatment period. Stoke also intends to measure non-seizure aspects of the disease, such as quality of life, as secondary endpoints. Enrollment and dosing are ongoing in MONARCH and Stoke plans to enroll approximately 48 patients in the study across 20 sites in the United States. Additional information about the MONARCH study can be found at https://www.monarchstudy.com/.

About Dravet Syndrome

Dravet syndrome is a severe and progressive genetic epilepsy characterized by frequent, prolonged and refractory seizures, beginning within the first year of life. Dravet syndrome is difficult to treat and has a poor long-term prognosis. Complications of the disease often contribute to a poor quality of life for patients and their caregivers. The effects of the disease go beyond seizures and often include severe intellectual disabilities, severe developmental disabilities, motor impairment, speech impairment, autism, behavioral difficulties and sleep abnormalities. Compared with the general epilepsy population, people living with Dravet syndrome have a higher risk of sudden unexpected death in epilepsy, or SUDEP. Dravet syndrome affects approximately 35,000 people in the United States, Canada, Japan, Germany, France and the United Kingdom, and it is not concentrated in a particular geographic area or ethnic group.

About Autosomal Dominant Optic Atrophy (ADOA)

Autosomal dominant optic atrophy (ADOA) is the most common inherited optic nerve disorder. It is a rare disease that causes progressive and irreversible vision loss in both eyes starting in the first decade of life. Symptoms typically begin between the ages of 4 and 6 years old, affecting males and females equally. The severity of the condition by adolescence reflects the overall level of visual function to be expected throughout most of the individual’s adult life. Roughly half of people with ADOA fail driving standards and up to 46% are registered as legally blind. ADOA is considered a haploinsufficiency, as most people living with ADOA have genetic mutations in the OPA1 gene that result in only half the necessary OPA1 protein being produced. More than 400 OPA1 mutations have been reported in people diagnosed with ADOA. Currently there is no approved treatment for people living with ADOA.

About Stoke Therapeutics

Stoke Therapeutics (Nasdaq: STOK) is a biotechnology company pioneering a new way to treat the underlying causes of severe genetic diseases by precisely upregulating protein expression to restore target proteins to near normal levels. Stoke aims to develop the first precision medicine platform to target the underlying cause of a broad spectrum of genetic diseases in which the patient has one healthy copy of a gene and one mutated copy that fails to produce a protein essential to health. These diseases, in which loss of approximately 50% of normal protein expression causes disease, are called autosomal dominant haploinsufficiencies. Stoke is headquartered in Bedford, Massachusetts with offices in Cambridge, Massachusetts. For more information, visit https://www.stoketherapeutics.com/ or follow the company on Twitter at @StokeTx.