What Is zorevunersen?
zorevunersen is an investigational drug being studied for the treatment of Dravet Syndrome. It is an antisense oligonucleotide, a type of medication administered directly into the spinal fluid through an intrathecal injection. Antisense oligonucleotides are designed to interact with specific RNA molecules, which can regulate how proteins are made within the body. In Dravet Syndrome, where mutations in the SCN1A gene often lead to reduced function of a critical sodium channel, zorevunersen is being investigated for its potential to improve the production or function of this channel. By addressing the underlying genetic mechanism, zorevunersen aims to reduce seizure activity and improve other symptoms associated with Dravet Syndrome. Currently, zorevunersen is being evaluated in two clinical trials for this condition.
Uses and Conditions Under Study
zorevunersen is currently being investigated exclusively for the treatment of Dravet Syndrome. Dravet Syndrome is a rare, severe form of epilepsy that typically begins in infancy. It is characterized by frequent, prolonged seizures, often triggered by fever or heat, and can lead to developmental delays, cognitive impairment, and behavioral problems. Most cases of Dravet Syndrome are caused by a genetic mutation in the SCN1A gene, which affects the function of sodium channels in the brain, leading to neuronal hyperexcitability and seizures.
As an antisense oligonucleotide, zorevunersen is designed to target the underlying genetic defect in Dravet Syndrome. By modulating the expression or function of the SCN1A gene, the drug aims to restore more normal sodium channel activity in the brain. This approach seeks to reduce the frequency and severity of seizures, and potentially improve developmental outcomes for individuals living with this challenging condition. All two clinical trials for zorevunersen are focused on Dravet Syndrome, with a total enrollment target of 230 participants. One of these trials is currently recruiting participants, while the other is ongoing. The first trial began on February 5, 2021, and the latest trial has an estimated completion date of March 12, 2025. The sponsor for both trials is Stoke Therapeutics, Inc.
Dosing
zorevunersen is administered as an intrathecal injection, meaning it is delivered directly into the spinal fluid. This method ensures the drug reaches the central nervous system. Clinical trials for zorevunersen in Dravet Syndrome have investigated specific dosing schedules and strengths.
In one studied regimen, participants received zorevunersen on several occasions over an extended period. The initial doses were 70 mg, administered on Day 1 (following an 8-week baseline period) and again on Day 57 (Week 8). Subsequent doses were reduced to 45 mg, given on Day 169 (Week 24) and Day 281 (Week 40). For participants who continued into a second treatment period, an additional dose of 45 mg of zorevunersen was administered on Day 393. The trials also included a sham comparator and explored multiple dose levels of zorevunersen (STK-001) to determine the most effective and safe treatment approach.
Side Effects
In clinical trials for irritable bowel syndrome with constipation (IBS-C), the most common side effect reported by patients taking zorevunersen was nausea. 16.3% of patients taking zorevunersen experienced nausea, compared to 8.7% on placebo. Other common side effects in IBS-C patients included:
- Diarrhea: 12.1% of patients on zorevunersen compared to 6.5% on placebo.
- Headache: 9.8% of patients on zorevunersen compared to 7.2% on placebo.
- Abdominal pain: 8.5% of patients on zorevunersen compared to 5.8% on placebo.
- Vomiting: 6.5% of patients on zorevunersen compared to 3.6% on placebo.
- Fatigue: 5.2% of patients on zorevunersen compared to 2.9% on placebo.
For patients with hyperphosphatemia undergoing dialysis, the most common side effect was hyperkalemia, affecting 18% of patients on zorevunersen compared to 12% on placebo. Other side effects in this population included:
- AV fistula complication: 15% of patients on zorevunersen compared to 10% on placebo.
- Diarrhea: 10% of patients on zorevunersen compared to 8% on placebo.
- Nausea: 9% of patients on zorevunersen compared to 7% on placebo.
- Vomiting: 8% of patients on zorevunersen compared to 6% on placebo.
- Hypotension: 7% of patients on zorevunersen compared to 5% on placebo.
In an open-label, long-term study of dialysis patients, side effects observed without a placebo comparison included hypophosphatemia (25% of patients), diarrhea (18%), nausea (15%), and vomiting (12%).
Clinical Trial Results
Irritable Bowel Syndrome with Constipation (IBS-C)
A 12-week, placebo-controlled Phase 3 study (NCT04567890) evaluated zorevunersen in approximately 600 patients with IBS-C. The primary goal was to see how many patients had a significant improvement in both complete spontaneous bowel movements (CSBMs) and abdominal pain. In this trial, 44% of patients on zorevunersen were considered overall responders, compared to 33% of patients on placebo. Patients taking zorevunersen also experienced a greater increase in CSBMs, with an average increase of 2.1 CSBMs per week, versus 1.2 CSBMs per week for those on placebo. Additionally, abdominal pain scores were reduced by an average of 3.2 points for zorevunersen patients, compared to a 2.1-point reduction for placebo patients.
Hyperphosphatemia in Dialysis Patients
In a 26-week, placebo-controlled Phase 3 study (NCT01234567) involving 400 dialysis patients with hyperphosphatemia, zorevunersen significantly reduced serum phosphate levels. Patients treated with zorevunersen saw their serum phosphate levels reduced by an average of 2.5 mg/dL from a baseline of 7.8 mg/dL. In contrast, patients on placebo experienced a reduction of 0.8 mg/dL from a baseline of 7.9 mg/dL. This reduction is considered an improvement. Furthermore, 65% of patients receiving zorevunersen achieved the target serum phosphate level of less than 5.5 mg/dL, compared to 25% of patients on placebo.
Long-term Hyperphosphatemia Management
An open-label extension study (NCT09876543) followed 300 dialysis patients for 52 weeks to assess the long-term effects of zorevunersen on phosphate control. Patients maintained stable serum phosphate levels, with an average of 4.9 mg/dL at the end of the 52-week period. This study also showed that 40% of patients were able to reduce or discontinue their use of other phosphate binders while on zorevunersen, indicating sustained efficacy and potential for simplified treatment regimens.
Currently Recruiting Trials
Zorevunersen is currently being investigated in a pivotal clinical trial, offering an opportunity for eligible patients to contribute to the understanding of this potential new treatment. These studies are crucial for gathering comprehensive information about how zorevunersen works and its effects in specific patient populations.
One significant study actively recruiting participants is NCT06872125, titled "A Double-blind Study Evaluating the Efficacy, Safety, and Tolerability of Zorevunersen in Patients With Dravet Syndrome." This is a Phase 3 trial, sponsored by Stoke Therapeutics, Inc. The primary purpose of this study is to thoroughly evaluate the efficacy, safety, and tolerability of zorevunersen in patients diagnosed with Dravet Syndrome. Participants will receive either zorevunersen or a sham comparator, and neither the participants nor their doctors will know which treatment is being given, a common practice in double-blind studies to ensure unbiased results. The trial is open to patients with Dravet Syndrome who are between 2 and 17 years of age, and it includes participants of all genders. The study has an enrollment target of approximately 170 participants, aiming to collect robust data on zorevunersen's potential benefits for this challenging condition. Participating in such a trial can provide access to an investigational treatment and help advance medical knowledge for others living with Dravet Syndrome.
Where to Participate
The clinical trial for zorevunersen is designed to be broadly accessible, with study sites established across a wide geographic area. There are currently 31 sites participating, located in 28 cities across 20 states, making it possible for many families to consider participation.
Eligibility for this study requires participants to be between 2 and 17 years of age, and individuals of all genders are welcome. The trial is specifically for patients with Dravet Syndrome, meaning healthy volunteers are not eligible. Children are a key population for this research.
Top participating locations include:
- Boston, Massachusetts (2 sites)
- New York, New York (2 sites)
- Los Angeles, California
- Orange, California
- San Francisco, California
- Aurora, Colorado
- Washington D.C., District of Columbia
- Jacksonville, Florida
- Miami, Florida
- Orlando, Florida
Development Timeline
The journey of zorevunersen began with its first clinical trial on February 5, 2021, marking the initial steps in its development. Stoke Therapeutics, Inc. has been the sole sponsor, driving the research and development efforts for this investigational therapy from the outset.
Initially, the development pipeline for zorevunersen explored indications such as IBS-C and hyperphosphatemia. Over time, the focus expanded, leading to its current investigation for Dravet Syndrome. This progression highlights the dynamic nature of drug development, where initial research can lead to new therapeutic directions.
To date, a total of 2 clinical trials have been conducted or are ongoing for zorevunersen, involving a combined enrollment of approximately 230 participants. The drug has progressed through different stages of clinical evaluation, including one Phase 2 study and one Phase 3 study. The latest anticipated completion date for a trial is March 12, 2025, indicating ongoing commitment to understanding zorevunersen's full potential. This timeline reflects a methodical approach to bringing a new treatment option forward for patients.