2B3-201

to-BBB's second internal product is glutathione pegylated liposomal methylprednisolone (2B3-201) for the treatment of patients with acute and chronic neuroinflammation associated with several CNS disorders.

Clinical need

Neuroinflammation is associated with a wide range of CNS diseases, such as Multiple Sclerosis, Epilepsy, Amyotrophic Lateral Sclerosis, Parkinson's Disease, Lysosomal Storage Diseases, and many more. Without treatment, an uncontrolled inflammatory response in the CNS can be devastating due to the limited regenerative capacity of neurons and other brain cells. Treatment with 2B3-201 aims to limit the damaging effect of neuroinflammation and thereby to safely modify the course of these diseases.

Existing treatment

Methylprednisolone, a steroidal (glucocorticoid) drug, is the standard treatment for acute MS flares, spinal cord injury, CNS lupus and childhood epilepsy.

The use of glucocorticoids is however limited by their many dose-related side effects in both body and brain. Short-term side effects include sodium retention-related weight gain and fluid accumulation, hyperglycemia and glucose intolerance, gastrointestinal side effects, and psychiatric symptoms. Chronic administration may further lead to decreased bone density, diabetes and susceptibility to infectious diseases due to immunosuppression.

Benefits of the G-Technology^®

Based on a comparison of efficacy and safety parameters, methylprednisolone is to-BBB's preferred treatment option with proven use in neuroinflammation. By incorporating methylprednisolone into liposomes, a lower total dose can be given and the dosing frequency could be reduced, resulting in at least the same efficacy and a reduced toxicity. to-BBB is extending this benefit even further by using the G-Technology to safely enhance the delivery of methylprednisolone to the brain, without the acute psychiatric side effects caused by peak concentrations associated with administration of the free drug.

In preclinical proof-of-concept studies in a model of MS, 2B3-201 was shown to be more effective when compared to non-targeted pegylated liposomal methylprednisolone, while free methylprednisolone at the same dose was completely ineffective. Compared to free methylprednisolone, 2B3-201 had a favorable pharmacokinetic profile and optimal distribution to the brain.

This cryo-electron microscopy picture of 2B3-201 is prepared by Vironova. Unilamellar liposomes (approximately 100 nm) with precipitated methylprednisolone in the water core are visible (the precipitate is visible as a dark shade in the core of the liposomes).

Development

Currently, 2B3-201 is in lead optimization heading towards preclinical development. As a follow-up of the positive proof-of-concept data in a model of MS, to-BBB is currently investigating 2B3-201 for its efficacy in models of epilepsy, several lysosomal storage diseases, ALS and other relevant diseases. Furthermore, NOTOX will investigate the safety of 2B3-201 versus free methylprednisolone in a multiple-dose toxicity study. DeltaPhenomics is quantifying the acute behavioral side effects of free methylprednisolone versus 2B3-201 at therapeutic dose levels. As for 2B3-101, manufacturing of 2B3-201 will be performed by TTY Biopharm (Taipei, Taiwan, R.O.C.).