This is all getting a little complicated for my old brain. Prana need to get a trial moving and simply look at the effects in humans IMO. Results from DFP trials were being reported back in 2014 and it is sad that Prana did not get into trials earlier than this. This is from DFP early trials. 2014. Without getting into the mechanics of the mechanism of action, the DFP results clearly demonstrate the value of labile iron chelation from a drug which is probably too strong for the purpose. That will have a dose limiting effect. PBT434 has been designed to just chelate labile(free) iron,and perhaps will not have such a dose limitation.
[Abstract Aims: The pathophysiological role of iron in Parkinson’s disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments. Results: For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRIPET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson’s patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30 mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n = 19) compared to DS patients (n = 18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson’s Disease Rating Scale motor indicators of disease progression ( p < 0.03 and p < 0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial. Innovation: A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD. Conclusions: The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or diseasemodifying potential of chelation in PD. ]
I guess MJF wanted too much for further help and Prana was not prepared to spend their own money with PBT2 P3 trials looming. Note DFP trials use the words moderate or conservative dosing. As stated above that is to prevent changes in systemic iron levels, a problem PBT434 was designed to avoid. I expect PBT434 will be able to identify target engagement from labile iron levels, even in healthy volunteers. A-Syn would have been nice.
I guess it is the ethics committee at the Austin holding things up.
The preclinical work for PBT434 is well summarized in this link. IMO it is way past due to begin this trial.
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0456-2
