All these issues/questions are legit...the challenge is what do you do about sorting out next steps ... and until you do, can you justify going back into humans?

Just a quick and dirty jotting of notes here...in italics, each question raised by Paula (I didn't think they were too analytical) points to areas of need for additional thinking/investment. Which of course means time and money=> delays...very frustrating I know.

1. we don't know if ceregene works well, the trial didn't meet endpoints but does that mean trophic factors aren't worthy of continued emphasis? In my mind, its worth additional work to sort that out and MJFF is working on this. Also, begs the continued emphasis on improving trial design and tools (patient recruitment, biomarkers, etc)--again another priority area for us.

2. there is enough evidence to justify continuing the study ...not continuing the phase II it's done . But, is there a clear path forward and some reasonable probability of success so that Ceregene backers will re-up? That is an important question and a small biotech like Ceregene sometimes doesn't get the luxury of time when the VC clock is ticking.

3. placebo effect - what is real? what is noise? what to do with it? It's real but unpredictable. Some trials see it and others don't...really wasn't there in the Amgen GDNF phase II for instance. Also, its not clear we have to solve the mystery and eliminate placebo (because that could be impossible)...maybe just learn how to predict and structure trials more overtly with placebo in mind. (Just as we recruit 10% additional patients into trials now to account for the fact that we expect noise in the data since we can't definatively diagnose and some trial participants don't actually have PD). But, I believe that this particular connumdrum could be a deterent to investment and that is bad news.

4. target needs to be modified - learned through autopsy Unintended information that is very valuable but still requires a step back to animal models to resolve issues around axonal transport etc. so not immediately back into humans.

5. dosage can be modified [this has been learned concurrent to the trials] Again, back to animals for efficacy and maybe better modelling of volumes/mass difference in primate vs. human brains for better predictability plus dramatic changes in doses might trigger the need for additional safety tests.

6. do less advanced patients need to be used? Phase I and now phase II safety profile will be helpful in making the case but current practice is that high-risk procedure should be reserved for mid to late-stage patients. Certainly the concept of neuron revival makes more sense the earlier in disease process you are able to start the intervention so there is definitely a disconnect here that is hard to resolve.

7. subtypes Not convinced it is particularly glaring in the Ceregene trial / more stage of disease than tremor dominant vs. gait/postural instability but better understanding and validation of subtypes is very important and interesting work continues on many fronts.

8. sham surgery - taking a long hard look at utilities and ethics that can only be productive in this type of conversation? Already covered in this thread.

Anyway, like so many topics...the issues are complex and multifaceted but please know that they are actively discussed at MJFF meetings.

Debi Brooks