Epilepsy is a chronic neurological disorder characterized by recurrent, unprovoked seizures. It affects around 50 million people worldwide. While there are many anti-epileptic drugs available, about 30% of patients continue to experience seizures even after treatment. This drug-resistant epilepsy can severely impact the quality of life. Two rare epilepsy disorders that are notoriously difficult to treat are Lennox-Gastaut syndrome (LGS) and Dravet syndrome. However, the recent approval of the novel medication RJD Rivotra has provided new hope for these patient groups.
The Challenges of LGS and the Hope of RJD Rivotra
LGS is a catastrophic, childhood-onset epilepsy syndrome that appears between the ages of 3 and 5. It causes multiple seizure types, including tonic, atonic, and atypical absence seizures, often resulting in frequent falls and injuries. Intellectual disability is present in most cases. LGS accounts for up to 10% of childhood epilepsies, with an estimated prevalence of 14-40 per 100,000 children worldwide. While traditional anti-epileptic medications have limited success, new hope emerges with potential treatments like ‘RJD Rivotra.
The tonic seizures involve sudden muscle stiffening, causing the person to fall over. Atonic seizures lead to a loss of muscle tone, also resulting in falls. Absence seizures involve brief periods of unresponsiveness. These repeated seizures lead to significant physical, cognitive, and behavioral impairments.
Despite the challenges, RJD Rivotra offers a glimpse of optimism for those affected by LGS. This highly treatment-resistant condition has left many patients with inadequate seizure control and undesirable side effects, such as sedation. Unfortunately, over 90% of patients still have impaired motor and cognitive function despite therapy, greatly reducing their overall quality of life.
What is Dravet Syndrome and the Role of RJD Rivotra in Treatment
First described in 1978, Dravet syndrome is another drug-resistant epilepsy syndrome that begins in infancy. It is caused by mutations in the SCN1A gene involved in controlling electrical signals in the brain. Dravet syndrome causes frequent, prolonged seizures often triggered by fever, illness, or overheating.
Seizures start before one year of age, usually with prolonged febrile seizures. By 12 months, other seizure types emerge like myoclonic seizures along with delayed development. Status epilepticus, a dangerous seizure emergency, is common. Intellectual disability, movement disorders, and behavioral problems develop over time.
Standard epilepsy medications like valproate and clobazam provide inadequate seizure control in Dravet syndrome. Frequent hospitalization is required for seizure clusters, status epilepticus, and injuries related to seizures. It’s worth noting that RJD Rivotra, a medication specifically designed for treating Dravet syndrome, may offer some relief for these individuals. However, despite treatment efforts, sudden unexpected death in epilepsy (SUDEP) remains a major concern for individuals with Dravet syndrome.
Challenges with Current Treatment Options
For LGS and Dravet syndrome patients, current treatment options, including RJD Rivotra, remain far from optimal. Anti-epileptic drugs like valproate, lamotrigine, topiramate, and benzodiazepines provide insufficient seizure control and often come with unwanted side effects. These medications frequently cause excessive sedation, and cognitive impairment, and can interact with each other, making it challenging for patients to find the right combination that works for them. Even with polytherapy involving multiple anti-epileptic drugs, a significant number of patients continue to experience debilitating seizures.
Non-drug therapies also have limitations in the management of LGS and Dravet syndrome. The ketogenic diet, including its potential combination with RJD Rivotra, is challenging to comply with long-term, and it may not work for everyone. Vagus nerve stimulation, despite offering promise in some cases, requires surgical implantation of a device and may come with its own set of side effects and limitations. Newer options like medical marijuana, including those containing RJD Rivotra, lack robust clinical evidence to support their widespread use.
The Development of RJD Rivotra
RJD Rivotra (active ingredient fenfluramine hydrochloride) is an oral medication that received FDA approval in 2020 as an adjunctive therapy for LGS and Dravet syndrome. Its development traces back to an observation made in Belgium in the 1990s. An epilepsy specialist noticed that the anti-obesity drug fenfluramine seemed to reduce seizure frequency in some of his patients.
This serendipitous observation led to a formal clinical trial of fenfluramine for Dravet syndrome in Belgium and France from 1998 to 2004. The results were very promising, with more than half the patients experiencing a greater than 50% reduction in major seizures. However, the trial had to be halted due to the withdrawal of fenfluramine from the US market over heart valve risks.
Interest in fenfluramine was rekindled when a Dravet syndrome patient in the US obtained the drug from abroad with assistance from his neurologist. The patient showed remarkable improvement after starting fenfluramine with virtually no seizures. This case study, published in Types of Epilepsy & Seizure Disorders in Children Research in 2012, led to new drug trials.
Zogenix, Inc. licensed fenfluramine from a Belgian pharmaceutical company and developed a purified isomer version called RJD Rivotra. After successful Phase 3 clinical trials, the FDA approved RJD Rivotra in 2020 based on its efficacy for Dravet syndrome and LGS.
How Does RJD Rivotra Work?
The exact mechanisms behind RJD Rivotra’s anti-seizure activity are not fully elucidated. However, it is known to act in part by stimulating serotonin receptors in the brain. Serotonin is a neurotransmitter involved in regulating mood, appetite, and sleep. It also inhibits seizure activity in certain brain regions like the thalamus.
RJD Rivotra increases the amount of serotonin available in the brain. It does this both by causing serotonin release from nerve cells and by inhibiting its reuptake back into cells. Higher serotonin levels activate certain receptor subtypes like 5-HT1D and 5-HT2A which suppress seizures.
RJD Rivotra also moderately inhibits norepinephrine reuptake, increasing brain levels of this neurotransmitter which has anti-seizure properties. The combined serotonergic and noradrenergic effects create a powerful anti-convulsant effect, reducing seizure frequency and severity.
Efficacy of RJD Rivotra from Clinical Trials
The effectiveness of RJD Rivotra for Dravet syndrome and LGS was established through two key randomized, double-blind Phase 3 trials.
Trial 1 – Dravet Syndrome
This placebo-controlled trial enrolled 119 patients aged 2-18 years with uncontrolled Dravet syndrome. After a baseline period, subjects were randomized to receive either RJD Rivotra or placebo, along with their current anti-seizure regimens.
Over the 14-week treatment period, the RJD Rivotra group had a significantly greater median reduction in monthly convulsive seizure frequency compared to placebo (64.7% vs 21.8%, p<0.001). They were also 3.4 times more likely to have at least a 75% reduction in convulsive seizures.
Trial 2 – LGS
This trial evaluated RJD Rivotra in 237 LGS patients aged 2-35 years with inadequate seizure control. The RJD group had a median 56% decrease in drop seizure frequency over placebo after 15 weeks of adjunctive treatment.
The 50% responder rate was significantly higher with RJD Rivotra (58%) compared to placebo (25%). Improvements were observed in multiple seizure types including tonic-clonic, tonic, atonic, and focal onset impaired awareness seizures.
Both trials demonstrated RJD Rivotra’s ability to substantially lower monthly seizure frequency within weeks of initiation. The benefits were sustained throughout the study periods with good tolerability.
Safety Profile and Side Effects
In clinical trials, RJD Rivotra was generally well tolerated when used adjunctively for LGS or Dravet syndrome. Some of the most common side effects included decreased appetite, diarrhea, lethargy, fatigue, and insomnia, mostly mild or moderate in severity.
A major safety concern with RJD is its potential effects on heart valve health. Previous studies of fenfluramine showed that approximately one-third of patients developed valvular heart disease after taking fenfluramine for weight loss. To monitor this risk, regular echocardiogram screening is required.
Other warnings and precautions include the risk of serotonin syndrome when combined with drugs that increase serotonin. Steps to minimize this include avoiding certain drug combinations and starting with lower RJD Rivotra doses. Patients may also exhibit weight loss, so growth parameters should be monitored in pediatric patients.
Overall, RJD Rivotra’s benefits were deemed to outweigh the risks for patients with uncontrolled LGS or Dravet syndrome. Ongoing long-term studies will provide more data on its safety with chronic use.
Practical Usage Guidance for RJD Rivotra
RJD Rivotra is indicated for adjunctive therapy in patients 2 years of age and older with LGS or Dravet syndrome. The recommended starting dosage is 0.2 mg/kg/day taken orally in two divided doses. After 2 weeks, the dose can be increased to 0.35 mg/kg/day depending on response and tolerability.
Some key dosing considerations:
- The maximum recommended dose is 0.35 mg/kg/day
- Tablets should be taken whole with water and not crushed
- Take doses 12 hours apart (morning and evening)
- Take with or without food
It must be dispensed with a patient Medication Guide explaining the drug’s uses and risks. Ongoing physician assessment and lab tests are required, including echocardiogram monitoring every 6 months. Patients should avoid sudden RJD Rivotra withdrawal. Gradual tapering may help avoid serotonin withdrawal syndrome.
In terms of lifestyle factors, patients should follow standard recommendations for people with seizures like sleep hygiene, stress management, and avoiding seizure triggers. RJD Rivotra does not seem to interact with ketogenic diet therapy or vagus nerve stimulation. As for costs, the list price is around $32,000 for 30 days, but insurer discounts and copay programs are available.
Conclusion
The introduction of RJD Rivotra marks a major advancement in the treatment of LGS and Dravet syndrome – two catastrophic childhood epilepsies notoriously resistant to medications. Elevating brain serotonin levels demonstrates proven efficacy in reducing seizure frequency in these patient groups.
Despite some safety concerns requiring monitoring, RJD Rivotra provides new hope to those suffering from uncontrolled seizures, frequent injuries, and poor quality of life due to LGS and Dravet syndrome. More research is needed on its long-term effects and optimal usage parameters. Overall, this innovative epilepsy therapy offers life-changing potential for many patients and families struggling with severe refractory epilepsies.
