April 11, 2013

$PVCT: London Calling (where else, @starbucks)

My students are doing what they need to do, effectively telling me they don't need me or need me around. I have more time on my hands then I thought...

Some thoughts on the AACR PRs:
  • Per management's approach in the past, the audience for which the PRs were meant was the pharmaceutical industry, domestically and abroad (e.g., potential Chinese, Japanese, Indian and European partners).
  • The PRs certainly weren't designed to inform retail investors. And, I doubt management is expending slightly more than perfunctory effort engaging life sciences fund money on this, other than revisiting the conversation post-AACR. I think the focus, rightly, is on getting regional and/or global license deals done.
  • The PR for Moffitt's data (via Dr. Pilon-Thomas's quote) highlighted a key feature of PV-10's mechanism. For the tumor-specific immunity PV-10 generates, the drug's ablative process is critical for this in situ stimulation of the immune system, which I think is helpful for Big Pharma to better understand. Additionally, the PR reinforces the role T cells play in this response and PV-10's systemic capability, with Moffitt saying they would do more research into the processes that PV-10 induces, stimulates, creates, etc.
  • The essence of the PR from Provectus' data was combination therapy (i.e., PV-10 plus something else, which in this case was anti-CTLA-4 antibody 9H10 (see below).
Provectus' work on combination therapy had several facets to it.

There does not appear to be disagreement that PV-10, as a monotherapy, utilized for locoregional control of cutaneous metastatic melanoma in Stage III patients is singularly dramatically effective. Adjusting for a treatment protocol that allows unlimited frequent injections of the drug for this stage of diseased patient, it's probably not unreasonable to believe efficacy could be near-100%.

Provectus extends this effectiveness by demonstrating themselves and through Moffitt's work that tumor-specific immunity is harnessed, and distant untreated metastases are suppressed  reduced or eliminated because of it. PV-10 successfully battles tumor heterogeneity of accessible injected lesions (tumors).

"...[A]dvanced melanoma patients, particularly those with stage IV disease, have substantial tumor burden in areas that are often non-accessible to injection with PV-10..." (Provectus' AACR PR) How does PV-10 deal with tumor heterogeneity in tumors into which it has not been injected or visceral metastases for these very late stage diseased patients?

Provectus hypothesized combining anti-CTLA-4 agents (like already approved Yervoy (ipilimumab) with PV-10. The thought was to leverage the incremental benefit of the additional systemic agent (i.e., ipi), while ensuring (demonstrating) there were no incremental safety issues or adverse event features resulting from the combination. "...Provectus aimed to ensure that any systemic treatment was potentially safe in combination with PV-10, and that efficacy signals from the combination therapy could be differentiated from those of PV-10 alone." (Provectus' AACR PR) 

The poster and PR showed that "..., as hypothesized, addition of the immunologic effects of an anti-CTLA-4 agent augments the benefits of PV-10." This allows two proofs to be made, in my view. First, the proof of orthogonality -- combination allows for benefit, but no added risk or no greater "un-safety." Second, allowing for the benefit of the combined therapy, in this case the anti-CTLA-4 antibody, to be utilized but at [apparently] lower doses and thus at lower toxicities.

Provectus' work suggests treatment options for very late stage patients can increase markedly by combining a host of other systemic therapies (in potentially less toxic doses) with PV-10 to more effectively defeat tumor burden in inaccessible regions of the body (where injection of PV-10 cannot be done) and visceral metastases (where tumor heterogeneity is more heterogeneous than what PV-10 previously conquered).

Furthermore, management's work suggests
  • Yervoy could (would) be more effective and more safe for very late stage diseased patients when combined with PV-10 in doses lower than currently used, and
  • PV-10 could potentially salvage Pfizer's tremelimumab, a close relative of Yervoy/ipilimumab, by turning the combination of PV-10 and treme into an alternative to Yervoy?

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