Ganaxolone
Scientific and Clinical Information

Ganaxolone (3a-hydroxy-3b-methyl-5a-pregnan-20-one), is the 3b-methylated synthetic analog of the neurosteroid allopregnanolone (3a,5a-P), a metabolite of progesterone. Importantly, ganaxolone does not have significant classical nuclear steroid hormone activity and, unlike 3a,5a-P, cannot be converted to metabolites with such activity. Phase I and Phase II human trials indicate that ganaxolone is well tolerated and that it may be efficacious in the treatment of diverse forms of epilepsy in children and adults.

Pharmacology – A new class of anti-convulsant

Ganaxolone is a powerful positive allosteric modulator of GABA_A receptors with potency and efficacy comparable to its endogenous analog 3a,5a-P (Carter et al., 1997). As with 3a,5a-P, Ganaxolone potentiation of the GABA_A receptor occurs at a site distinct from the benzodiazepine site. Ganaxolone has protective activity in diverse rodent seizure models, including clonic seizures induced by pentylenetetrazol (PTZ) and bicuculline (BIC), limbic seizures in the 6 Hz model, and amygdala kindled seizures (Carter et al., 1997; Rogawski and Reddy, 2004; Kaminski et al., 2004).

Nonclinical toxicology

Acute ganaxolone treatment is associated with reversible, dose-related sedation as expected for a positive modulator of GABA_A receptors. Ganaxolone showed less of an interaction with ethanol than did VPA in mice (Marinus Pharmaceuticals, data on file). Ganaxolone affected cognitive function in an animal passive-avoidance paradigm only at ataxic doses. Studies of organ toxicity and initial studies in pregnancy were unremarkable (Bialer et al., 1999). In chronically treated rats, tolerance does not occur to the anticonvulsant activity of ganaxolone (Reddy and Rogawski, 2000). Non-teratogenicity is an important safety characteristic of the drug, distinguishing ganaxolone from other anticonvulsants.

Pharmacokinetics

Pharmacokinetic studies in healthy human volunteers were carried out in diverse single- and multiple-dose regimens (Monaghan et al., 1997). Ganaxolone was administered in a variety of paradigms, including rising dose tolerance, and using several oral formulations (single doses 1,600 and 750 mg t.i.d.). Ganaxolone showed predictable linear and dose proportional pharmacokinetics with single doses in the range of 50 to 600 mg.

Safety in Humans

Doses up to 500 mg t.i.d. were generally well tolerated in volunteers. Plasma levels over 300 ng/ml were usually associated with somnolence although some subjects with levels as high as 612 ng/mL did not report any treatment-related AEs. Ganaxolone is primarily metabolized by CYP 3A4.

Drug interactions

In vitro drug-drug interaction studies have revealed no significant interactions with other AEDs. Ganaxolone, while having high plasma protein binding (> 99%), did not demonstrate any protein binding interactions with VPA.

Formal in vivo drug-drug interaction studies have not yet been carried out. Analyses of available pharmacokinetic data from the pediatric add-on studies revealed no or limited drug-drug interactions between ganaxolone and concomitant AEDs. Subjects receiving known CYP 3A4 inducers such as phenobarbital (PB), carbamazepine (CBZ) and phenytoin (PHT) had similar response rates as those subjects not receiving these drugs.

Clinical efficacy

Six-hundred-thirty one adults (males and females, age 18–69 years old) and 79 pediatric subjects (males and female, age 6 months to 15 years) have been exposed to ganaxolone.

In 11 phase II studies (8 in epilepsy), 421 adults received ganaxolone. In an 8-day treatment-refractory presurgical trial, ganaxolone monotherapy (1,875 mg/day) was well tolerated and the AEs reported by ganaxolone-treated subjects (N=24) were similar to those on placebo (N=28; Laxer et al., 2000). Two serious AEs were reported: one ganaxolone-treated subject experienced severe agitation and depression after day 1 of treatment, and one placebo-treated subject exhibited moderate post-ictal psychosis. Efficacy of ganaxolone compared to placebo was supported by an intent-to-treat survival analyses showing a trend toward significance (p= 0.0795; log-rank test).  Lack of statistical significance was attributed to insufficient power and a higher than usual placebo response rate.

In 5 phase II open-label, adjunctive therapy studies, 79 pediatric subjects (ages 6 months to 15 years) received ganaxolone. All subjects experienced refractory seizures despite concurrent AEDs (3 or fewer) and the majority of the subjects had a history of infantile spasms. On average, each subject had been previously treated with 7 AEDs, including ACTH, vigabatrin (VGB), valproate (VPA) and benzodiazepines.

In one of the pediatric studies, 20 patients aged 0.6–7 years with refractory infantile spasms or with continuing seizures after a history of spasms received ganaxolone for up to 12 weeks at a dose titrated up to a 36 mg/kg/day or the maximally tolerated dose (Kerrigan et al., 2000).  The responses of the 15 infantile spasms patients who completed were considered substantial (>50% reduction in spasms) in 5 (one of whom became spasm free), and moderate (25–50% reduction) in 5. Five patients were considered nonresponders (< 25% reduction), although one nonresponder was spasm-free from weeks 2 through 7.

In two additional refractory pediatric epilepsy studies, 59 patients, aged 2–15 years, some with persistent spasms, were dosed for up to 17 weeks.  In the first study, the responses of the 13 patients evaluated at maintenance week 4 after a 16-day inpatient dose titration period were considered substantial in 4 (one whom became seizure free), moderate in 3 and insufficient in 6 patients. Of the 8 patients who were evaluated at maintenance week 8, the responses were considered substantial in 4 (one of whom was a nonresponder at maintenance week 4, moderate in 2 and insufficient in 2 patients.  In the second study of similar design, 45 patients were enrolled. Of the 27 patients whose seizure frequency was available for both baseline and maintenance week 8, responses were considered substantial in 12 (one who stayed seizure free since maintenance week 4), moderate in 4, and insufficient in 11 patients.

Of the 48 pediatric subjects eligible for open-label extension treatment for whom ganaxolone was available, 29 continued on ganaxolone therapy. Eleven subjects discontinued within 1 year. Of the 18 subjects exposed to ganaxolone for over 1 year, 4 received the drug for over 4 years (stopped when ganaxolone was no longer available), 2 over 3 years, 1 over 2 years, and 11 over 1 year. Nine subjects also showed behavioral improvement.

Tolerability and side effects

Safety and tolerability in the clinical program have been generally good. No fatal or life threatening adverse events (AE) attributed to the drug were reported. The majority of AEs in phase I studies were judged mild (74%) or moderate (18%) in intensity, and all resolved spontaneously. The safety and tolerability of ganaxolone has also been demonstrated in epilepsy and adult migraine patient populations. As with the healthy volunteer subjects, the majority of AEs were mild to moderate. The principal dose-limiting AE observed in clinical studies has been somnolence, which is consistent with the mechanism of action and nonclinical study data.

In 14 Phase I studies, 210 healthy adult volunteers received ganaxolone. There were 34 reports of severe somnolence (14 following 900 mg, 15 following 750 mg, 3 following 300 mg, 1 following 250 mg, and 1 following placebo). No serious AEs were reported. 

Planned studies

Separate Phase IIb studies of the newly improved Marinus ganaxolone formulation in both adult (partial complex seizures) and pediatric (infantile spasms) populations are ongoing. More>>

References

Bialer, M., Johannessen, S.I., Kupferberg, H.J., Levy, R.H., Loiseau, P., Perucca, E., 1999. Progress report on new antiepileptic drugs: a summary of the fourth Eilat conference (EILAT IV). Epilepsy Res 34, 1-41.

Carter, R.B., Wood, P.L., Wieland, S., Hawkinson, J.E., Belelli, D., Lambert, J.J., White, H.S., Wolf, H.H., Mirsadeghi, S., Tahir, S.H., Bolger, M.B., Lan, N.C., Gee, K.W., 1997. Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3a-hydroxy-3b-methyl-5a-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid_A receptor. J Pharmacol Exp Ther 280, 1284-1295.

Kaminski, R.M., Livingood, M.R., Rogawski, M.A., 2004. Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice. Epilepsia 45, 864-867.

Kerrigan, J. F., Shields, W. D., Nelson, T. Y., Bluestone, D. L., Dodson, W. E., Bourgeois, B. F., Pellock, J. M., Morton, L. D., Monaghan, E. P., 2000. Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial. Epilepsy Res 42, 133-139.

Laxer, K., Blum, D., Abou-Khalil, B. W., Morrell, M. J., Lee, D. A., Data, J. L., Monaghan, E. P. and the Ganaxolone Presurgical Study Group. 2000. Assessment of ganaxolone's anticonvulsant activity using a randomized, double-blind, presurgical trial design. Epilepsia 41, 1187-1194.

Monaghan, E.P., Navalta, L.A., Shum, L., Ashbrook, D.W., Lee, D.A., 1997. Initial human experience with ganaxolone, a neuroactive steroid with antiepileptic activity. Epilepsia 38, 1026-1031.

Reddy, D.S., Rogawski, M.A., 2000. Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself. J Pharmacol Exp Ther 295, 1241-1248.

Rogawski, M.A., Reddy, D.S., 2004. Neurosteroids: endogenous modulators of seizure susceptibility. In: Rho, J.M., Sankar, R., Cavazos, J. (Eds.), Epilepsy: Scientific Foundations of Clinical Practice. Marcel Dekker, New York, pp. 319–355.

Ganaxolone Bibliography