Elite Pharmaceuticals Inc (ELTP)

[WeeZuhl]

Isradapine Parkinson’s 3 year $23 million dollar Study

At a cost of $23 million for the Phase 3, not to mention multiple millions $$ more for Phase 2, isradipine was not chosen by accident. The calcium channel sub-type (Cav1.3) that is associated with damage to dopaminergic neurons in Parkinson's Disease has a stronger affinity for isradipine than any other CCB's. Other drugs are weaker inhibitors of Cav1.3, and so the therapeutic cardiovascular effect (lower BP) outweighs the neuro-protective effect. Isradipine was the best of the bunch, and the purpose of the isradipine Phase 2 study was to establish the highest dose of isradipine that could be well-tolerated in PD patients without too many side effects due to low BP. They tested 2.5mg BID, 5mg BID, and 10mg BID, and they found the 5mg dose to be the best. This dose has been well-tolerated in the STEADY-PDIII study, with 98% retention rate despite the long 36-month study.


The tolerability of isradipine in PD patients is now well-established. The only question remaining is if there is enough Cav1.3 inhibitory effect to prevent degeneration of dopaminergic neurons in the substantia nigra pars compacta and slow the progression of Parkinson's Disease. We know the Phase 3 moved through its futility checkpoints, so there is definitely some positive effect. Once the formal results are revealed, the significance of the effect will determine how fast the news will spread through the medical community and interested lay persons. MJFF is an important sponsor of the isradipine studies, and they are an important source of information for PD patients. Even minimal success will very quickly have most PD patients asking their doctors to start them on this drug.







http://n.neurology.org/content/90/15_Supplement/P2.039

https://www.nature.com/articles/ncomms2149#ref-link-section-12

The problem with DHPs from a therapeutic perspective, however, is that they are not selective12. LTCCs are a heterogenous class of multi-subunit ion channels13,14 that can be divided into four classes based on the identity of their pore-forming alpha 1 subunit, CaV1.1-4. This pore-forming subunit governs key features of the channel, including gating and pharmacology. The predominant (~90%) LTCC in the brain has a CaV1.2 subunit; this channel also is abundant in a variety of peripheral organ systems, including the cardiovascular system and is effectively antagonized by DHPs, accounting for their therapeutic efficacy in hypertension15. However, the LTCC responsible for mitochondrial oxidant stress and increased vulnerability in SNc dopaminergic neurons is largely attributable to expression of LTCCs with a CaV1.3 subunit5,6. Among the DHPs, isradipine has the highest relative affinity for CaV1.3 LTCCs, but it is still CaV1.2 LTCC selective14. This diminishes the therapeutic potential of DHPs in PD, as cardiovascular side effects limit the dosing and antagonism of CaV1.3 LTCCs.