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A Randomized, Double-Blind, Placebo Controlled, Cross-Over Trial of Quinidine in Genetic Epilepsy Due to KCNT1 Mutations

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A Randomized, Double-Blind, Placebo Controlled, Cross-Over Trial of Quinidine in Genetic Epilepsy Due to KCNT1 Mutations A trial of quinidine in genetic epilepsy A randomized, double-blind, placebo controlled, cross-over trial of quinidine in genetic epilepsy due to KCNT1 mutations Principal Investigator – Dr Saul Mullen Associate Investigators – Prof Ingrid Scheffer, Prof Samuel Berkovic, Dr Patrick Carney, Version 4 19th November, 2014 Page 1 of 14 Version 4, November 2014 A trial of quinidine in genetic epilepsy Introduction Epilepsy is defined by repeated, unprovoked seizures and is a major global health problem with a lifetime incidence of over 3% 1. Epilepsy is not, however, a uniform condition but rather a collection of syndromes with widely variable course, severity and underlying causes. Amongst these causes of epilepsy, inherited factors are prominent. The genetics of most inherited epilepsies is likely complex with multiple genes interacting with environmental factors to produce disease. An increasing number of monogenic epilepsies are however recognised. The majority of genes carrying epilepsy- causing mutations are neuronal ion channel subunits, thus leading to effects on either synaptic transmission or action potential firing. At present, the vast majority of epilepsy therapies take little account of the underlying causes. Anti- epileptic drugs are largely developed and tested in broad cohorts of epilepsy with mixed aetiologies. This has led to drugs each individually usable in most patients but with modest efficacy at best. Tailored drug therapies are starting to emerge for genetic epilepsies. For instance, in tuberous sclerosis complex, genetic abnormalities of the functional cascade associated with Mammalian Target of Rapamycin (mTOR) protein lead to the disease. Treatment with a specific inhibitor of this pathway, everolimus, leads to improved outcomes both in terms of seizures and secondary development of tumours 2. Another example is the use of the orphan drug stiripentol in Dravet Syndrome, a catastrophic epilepsy of early life associated with usually de-novo mutations of the neuronal sodium-channel sub-unit gene SCN1A3, 4. Here we propose a small trial to test a tailored drug therapy in a recently discovered genetic epilepsy, utilising the potassium-channel antagonist quinidine to treat a genetic disease caused by over-active potassium-channels. KCNT1 as an epilepsy gene The gene KCNT1 codes for a potassium channel, variously known as KCNT1, Slo2, SLACK and KCa4.1, expressed mainly in the central and peripheral nervous systems 5, 6. The protein KCNT1, often in hetero-dimers with a related protein KCNT2 (or SLICK), is involved in adjusting the frequency and duration of the firing of neurons in response to a stimulus 7-9. KCNT1 also appears to interact with the Fragile X Mental Retardation Protein (FMRP), the critical protein affected to produce the common Fragile-X mental retardation syndrome 10. KCNT1 and FMRP appear to enhance each other’s function with the loss of FMRP reducing the KCNT1 currents recorded and activation of KCNT1 showing evidence of enhancing the RNA binding and regulation role of FMRP. Recent genetic findings have demonstrated KCNT1 mutations to be a cause of inherited epilepsy. Our group reported in 2012 mutations in KCNT1 in three families with the inherited epilepsy syndrome autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)11. In this dominantly Page 2 of 14 Version 4, November 2014 A trial of quinidine in genetic epilepsy inherited syndrome frequent, often brief, focal seizures occur in sleep at a rate of multiple attacks per night 12. Although seizures in this syndrome are often refractory to treatment, the MRI is normal and intellect is usually preserved. ADNFLE was the first inherited epilepsy for which a gene was conclusively identified, the acetyl choline receptor subunit CHRNA4 13. Subsequently mutations in two other acetyl-choline receptor subunit genes were also identified, CHRNA2 and CHRNA2B 14-16. The families with KCNT1 mutations are notable for more severe phenotypes than individuals carrying acetyl-choline receptor gene mutations. In the 15 reported KCNT1 mutation carriers, penetrance was higher (100% vs. 70%), seizure onset earlier (median 6yrs rather than 10yrs), and additional neuropsychiatric disability was common with 6/15 having intellectual disability and a further 4/12 having psychiatric co-morbidity. In the same issue of the journal, a French group reported de-novo KCNT1 mutations in six patients of the twelve tested with the severe, early-onset epileptic encephalopathy of malignant migrating partial seizures of infancy (MMPSI) 17. MMPSI is characterised by the onset under 12 months of age of focal seizures that are continuous or near continuous in an infant without significant MRI abnormality 18. The foci for these seizures shift over time, migrating across both hemispheres, leading to a long-term status epilepticus that on EEG moves across the brain. The outcome is extremely poor with developmental regression, refractory seizures, mortality under 10 years in up to half of cases and, in those that survive, severe intellectual disability18, 19. The reported mutations in KCNT1 all appeared to be causative as they were de novo, affected conserved amino acids and led to significant changes in the function of the mutant protein 17. All mutations led to significant increase in current; they are gain of function mutations. Mutations in KCNT1 thus lead both to a severe form of focal epilepsy and a catastrophic epilepsy of early childhood. This appears to be due to excess function of the KCNT1 channel. A specific therapy would be of great utility, particularly in MMPSI where the outcome is extremely poor. Quinidine Quinidine is a now uncommonly used Class 1a anti-arrhythmic drug. Derived from a Cincha alkaloid, quinidine leads to slowing of the upstroke of the cardiac action potential as well as prolongation of the action potential duration and effective refractory period. These actions led to its’ use in re- entrant, particularly atrial tachycardias 20, 21. The cardiac action potential duration is the determinant of the ECG measure of QT interval, hence quinidine produces predictable prolongation of the QT interval with the consequent risk of R on T and induction of the ventricular tachycardia Torsade de Pointe 20-23. This prolongation of the QT has led to the main modern application of quinidine, the treatment of genetic short-QT syndromes such as Brugada Syndrome 24. Quinidine and potassium channels Although the original conception of Class 1 antiarrythmic agents was as Na-channel blockers, in fact their action is likely due to blockade of a wide variety of K-channels 25. The cardiac action potential, unlike neuronal action potentials, has a pronged plateau of depolarization following the initial sodium channel dependent upstroke. This leads to sustained muscle contraction and determines the length of the QT interval. This plateau phase is caused by the opposition of depolarising calcium and Page 3 of 14 Version 4, November 2014 A trial of quinidine in genetic epilepsy to a lesser extent sodium currents and re-polarising (or rectifying) potassium currents. Gain-of- function mutations of the relevant K-channels increase this rectifying current leading to short-QT syndrome26. Quinidine acts to prolong the action potential by reducing these rectifying potassium currents 27. Although quinidine has an effect on a variety of K-channels, it is a potent blocker of KCNT1 28. As mentioned above, recent work by our molecular collaborators has demonstrated that increased current is seen in all reported KCNT1 mutations when expressed in xenopus oocytes, with the increase greatest in those mutations associated with the most severe phenotypes29. This work also demonstrated that quinidine functioned as an effective blocker of those pathologically increased currents, reducing them to near-normal (figure 1). There is also at least suggestive, although not well controlled, animal evidence that quinidine reduces susceptibility to induced seizures in animal models overall 30. Thus quinidine is overall likely to be mildly anti-convulsant in effect with a potential to specifically reverse the effects of the faulty KCNT1 gene product. Page 4 of 14 Version 4, November 2014 A trial of quinidine in genetic epilepsy Figure 1 Page 5 of 14 Version 4, November 2014 A trial of quinidine in genetic epilepsy Quinidine pharmacokinetics Quinidine is readily absorbed orally with a half-life in adults of 6-8 hours and 80-90% of blood quinidine being protein bound 22. Serum levels show good correlation with toxicity, particularly cardiac side effects. Excretion is predominantly via hepatic metabolism. Product information is attached. For the use proposed, however, the critical question is the levels reached in brain. Quinidine is clearly measurable in cerebrospinal fluid in humans after a single dose 31. The kinetics of quinidine in the CNS are, however, complex. Efflux of quinidine from the brain is via the multi-drug transporter ATP-binding cassette sub-family B member 1 (ABCB1), also known as multidrug resistance protein 1 (MDR1) or P-glycoprotein 1 (P-gp) 32. Interestingly, quinidine is also regarded as an inhibitor of ABCB1, implying the drug inhibits its own clearance from the central nervous system 33, 34. There is some controversy regarding this inhibition so that even if it is occurring, the strength of inhibition appears small 34, 35. What is clear, however, is that the time-course of brain quinidine levels is different to serum. Microdialysis experiments in rats following a single dose suggest that the peak level is delayed compared to free serum level 32, 35. Also, the total area under the curve of drug level vs. time is 30-50% greater than in the serum. Accurate brain levels are not available during or following chronic dosing. This has two implications for planning a trial of quinidine. Firstly, there is good evidence that quinidine reaches the brain at levels likely to be clinically relevant. Secondly, the clearance of the drug from the brain is delayed compared to serum concentrations. Considerations for trial design Both epilepsy phenotypes associated with KCNT1 mutations are rare but potentially severe.
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