I spoke to Babita and Quan from MDA, and Quan verified patients with stage III or IV were eligible for the DCVax-Direct study.
She had already confirmed in a previous conversation that all Meth A activated vaccines were done first, then B, to avoid batch inconsistencies. This was based on her understanding of the manufacturing process as it related to Direct, not that it was done at MDA (obviously). Therefore Meth A still alive 14-18+ months and Meth B alive from 9-14 months.
Babita confirmed ECOG status was changed from 0-2 to 0-1 during the study because patients were getting in the trial that were too sick to allow the vacc time enough to work. Hence, Meth A were in fact enrolled under less strict criteria.
Quan also confirmed that the only reason patients did not receive the full vaccine course was due to progression. I asked her quite a bit about biopsies and "no live tumor cells," and she said ceasing injections had nothing to do with necrosis. The only reason a patient didn't get all their shots if they didn't get them, was due to disease progression.
Another poster demanded over and over that I call MDA to get confirmation of what was already very obvious to me, and that's why I did so.
Notice that NW Bio never broke down Meth A vs B among those alive in their survival chart, just among the dead? What a small cap bio DOESN'T tell is often more important than what they do. That would have told the public Meth A still alive 14-18+ months and Meth B alive from 9-14 months, which isn't nearly as impressive as some of the slides make Meth B vs A appear.
Protocol changed during the study and patient selection "tightened." So those enrolled later were healthier than those enrolled initially. And probably more stage III patients were enrolled and given Meth B than were enrolled and given Meth A (as stage III patients tend more often to be ECOG 0 than stage IV).
Meth A and Meth B are two very different prognostic groups and so any comparison between them is confounded. Meth A is therefore NOT some kind of control that proves Meth B is effective.
The DCVax-Direct data, although selectively presented in bits and pieces by NW Bio management, is not very good at all. No significant shrinkage across any patient's target lesions and 85% of patients experienced progression of disease by week 16. Week 8 stable disease data are basically meaningless. Notice they don't tell us SD rates at 4 or 6 months. Why not? It's because they're horrible, regardless of Method of DC activation. The survival data are also unimpressive being that any number of stage III ECOG 0 patients were enrolled.
Patients looking to potentially enter their P2 studies should be given full information, as well as investors to make informed decisions. This was unfortunately not done by NW Bio.
The P2 studies yet to commence will also be single arm. They will hope to show ORR (significant shrinkage) but that was seen in no patient in the P1 study so it's quite unclear whether or not that will occur. A single, controlled P2 study, enrolled 2:1 with a placebo arm, would be a MUCH better use of investor;s money.
With Direct we're seeing no systemic effect. These DCs just don't seem to be inducing an immune response that can slow progression of disease. Cytokine release goes both ways. IL2,12 = good, IL10 bad. DCs secrete both. Also Tregs may become present inside the tumors as a result of vaccination, which would inhibit apoptosis of tumor cells. 85% of patients progressing in under 16 weeks speaks against any systemic effect.
So far, DCVax-Direct is looking rather impotent.
For the sake of balance I will say there is one case study that is interesting. The ovarian case saw substantial shrinkage of the injected lesion but this did not prevent the emergence of a new lesion. Therefore at that point she was labeled progressive disease (PD). It is possible this patient was a responder and that multiple injects would be effective in her. But apparently the systemic effect with Direct is weak to non-existent, as that new lesion wasn't prevented, despite what PBMC assays may show. Patients are also limited to 3 tumors being injected, and even when only one was injected just 6 times in the P1 many patients failed to produce enough vaccine (according to Babita). These could not enter the study. Direct may therefore only be appropriate as a niche therapy, and only if it can somehow show many more cases of shrinkage like in that one patient.
That case was the only one that showed such a response, however, and they are not testing ovarian in the P2s. The other ovarian cases must have shown evidence to the contrary.
Sarcoma also appears to be more susceptible to cytokines, as the two case studies showed SD out beyond 6 months.
Will that all be enough for approval and significant market share, when checkpoint inhibitors are on a furious clip? No, I do not think so. Direct may have a place in certain indications where patients are ECOG 0, stage II or III, with few lesions and at least one inoperable, who would rather forgo a systemic therapy with many side effects. Who knows how big a market like that would be? The answer may lie in number of patients treated annually with cryoablation. Direct could potentially take some % from that market. Doing a cursory look I would suggest $100mm -$200mm annual sales max. If regulators can be convinced, and IF they can show substantial enough efficacy. However FDA may simply demand randomized, controlled trials testing a survival endpoint.
A very long dilutive road, and one that may never get there if the P3 fails.
The risk here is very high.
