Yes its been interesting to reflect on the 'lets not do a deal...

Yes its been interesting to reflect on the 'lets not do a deal too early' approach, and as you said we may be near 'certain milestones' which make dealing more attractive. In that light it got me going back over our recent trails and in particular the strong drive to get a "lookthrough" into the P3 results before we get them.....

005 (our phase 2)
2x2 versusplacebo with KOOS pain score the primary endpoint.

008 (biomarker)
Mainlyabout disease modification and biomarker response, but also designed togive valuable data on pain and function. Started the trial with 2x2,and had WOMAC as primary endpoint, ie. the same dose as 005 but using the sameendpoint that would be used in our P3 (WOMAC). Manycomments by PAR at the time about how this will provide a "Lookthrough"of the P3 result and what an incredible bargaining position this gives us, as apartner will be able to significantly derisk a P3 failure. The protocol wasalmost identical as our desired P3 - results before the exam!

008 - update

008was paused halfway, and an additional arm was added (1x2), among otherchanges. Maybe they did this on the back of FDA feedback that we'd need adosing arm in the P3 and we wanted to mirror the trial to maintain a lookthrough? Doesn't really matter. End of the day, 008 then comprised........... 2x2 and 1x2.

002 IND
Westarted our application with 2x2 and 1x2 (ie. exactly the same as 008 for the lookthrough obviously), and a fixed dose arm which I'm ignoring. Multiplefrustrating interactions with FDA later, the 2x2 was moderated down and theprotocol was changed to 2x1.5 and 1x2 dueto the infamous rat adrenal issue. Thisput us in a spot as we no longer had an exact 'lookthrough' which was theoriginal leveraging strategy. We had no data on 2x1.5 at all, but perhapsthere was some hope that 1x2 might have given a significant proportional response? This would be read out in 008 so there would be a preview of the data for that arm.

008Readout
The 2x2group achieved statistical significance in WOMAC pain function and stiffnessafter 56 days (the intended P3 endpoint) with an n of 20. Awesome result. The 1x2 did not reach significance. Furthermore, the 12 month pain data in 008 released later clearly showed 1x2 did no better than placebo, nailing the coffin on 1x2. (Mozz, there is some research here to do on 'loading doses' and non-linear drug responses!)

002 dosing safety check, DMC
At exactly the same time we got a peek into the 002 data where the DMC could see we werenice and safe but we weren't getting a huge efficacy response. This isall a bit fuzzy to me but I think we then said, lets unveil thedosing data and see what it really means. The only common arm leftwas 1x2, but this was probably a non-starter from the 008 readout (smaller n admittedly). The 2x1.5 was also discardedwithout much quant detail given.
“Thedoses (less than 2 mg/kg twice weekly) included in the dose determination partof phase 3 trial did not meet the prespecified performance threshold, which wasbased on prior outcome data produced with the 2mg/kg twice weekly dosingregimen.”
Thatcomment is from our latest 4C, which does not say 2x1.5 didn'twork, it just didn't meet 'prespecified criteria' based on 2x2 whatever that means. Perhaps 75% of the benefit of the 2x2 defines an equivalent bang for buck or minimum effective dose? Anyway it was unceremoniously discarded (felt a little quick at the time).

I am thinking now that perhapsthe 2x1.5 was a hoop we had to jump through but we were unlikely to proceed with forstage 2 in any event because we have no data we can leverage a deal on? (Maybe not?). Maybe we were more than happy to ditch it quickly and stick with 2x2 on which we have a lot of data, were confident we would get through FDA, and highly likely to pass the trial.Anyway,I find this all quite interesting especially the ease and surety with which wethrew away the stage 1 data and are now pushing ahead with 2x2 which the FDAdid not want initially. It makes some sense because there is a huuuugecarrot for us as we will simply be redoing 008 for which we already havestatistical significance on a tiny population as well as greater numbers from 005. This carrot could makedeal-making a lot easier and more lucrative you would think, as we can present the results of an exact replica trial (008) as soon as our protocol is accepted.

So whenit comes to why we haven't done a deal yet, partners mustn't beinterested, surely someone would have jumped by now, we're entering adeath spiral.. maybe we just don’t want to deal until we have a 2x2protocol approved and we can exploit the "lookthrough" benefits we spoke about years ago.