High-Dose Zolpidem Can Improve Motor Activity in CNS Diseases
SELLAS is developing a proprietary formulation of high-dose Zolpidem with potential to treat CNS-related diseases, including Progressive Supranuclear Palsy (PSP) and Parkinson’s disease. Zolpidem in high doses of 25mg – 75 mg per day is a selective agonist of GABA-A-BZ1 receptors that have their highest density in the basal ganglia of the brain. Zolpidem’s effect within the basal ganglia is believed to result in increased activity of motor cortical areas, and clinical studies of high-dose Zolpidem have shown encouraging improvement of motor function in both Parkinson’s and PSP. The International Study Group of PSP has highly endorsed this improvement saying that high-dose Zolpidem in such a 12-24 hour slow release tablet formulation may change the treatment paradigm for PSP.
Through a license with Catalent, SELLAS has applied OptiDose™ technology to create high-dose, slow-release formulations of Zolpidem for use as in monotherapy or combination therapy.
SELLAS expects to initiate a Phase 2b/3 study of high-dose Zolpidem for PSP in 1H 2016, with completion anticipated by 2H 2017. High-dose Zolpidem is eligible for Orphan Designation, Fast-Track Designation and Accelerated Approval for PSP.
High-Dose Zolpidem Mechanism of Action
Zolpidem is a well-known, approved imidazopyridine drug for insomnia. Its mechanism of action and therapeutic effect in CNS-related diseases have already been demonstrated in numerous studies and peer-reviewed publications. SELLAS’ teams have conducted groundbreaking work with a global network of clinical researchers to develop and advance an innovative Zolpidem formulation for basal ganglia disorders, including PSP and Parkinson’s.
As a selective agonist of GABA-A-BZ1 receptors, Zolpidem is thought to exert its effects on two key output inhibitory structures of the basal ganglia:
- internal globus pallidus (GPi)
- substantia nigra pars reticulata (SNr)
These two inhibitory structures (GPi and SNr) are abnormally overactive in diseases such as Parkinson’s, resulting in a reduced activity of motor cortical areas in patients. Zolpidem may produce a selective inhibition of GPi and SNr, resulting in increased activity of motor cortical areas, which may lead to an improvement of motor symptoms.
Zolpidem has shown good tolerability in a Parkinsonian patients. The most frequent adverse event was drowsiness, which became much less frequent when the optimal dosage of this drug was slowly achieved after a titration period.
Need in PSP
Progressive Supranuclear Palsy (PSP) is a rare brain disorder, affecting about 1 in every 100,000 people over the age of 60. PSP is a chronic disease in which increasing damage to brain cells causes serious problems with control of gait and balance, as well as with complex eye movement and cognition. PSP has an average life expectancy of seven to ten years from onset, though there is considerable variation among patients in symptoms and rate of progression. There is no specific test to diagnose PSP, and PET scans are normally used to eliminate all other conditions before arriving at a diagnosis of PSP. Further, patient numbers may be higher due to frequent misdiagnosis of PSP as Parkinson’s disease.