Clinical & Business Value Proposition Pillar #5

Image source

On Provectus' August 6th 2Q15 business update conference call, the company's COO/CFO Peter Culpepper introduced five clinical and business value proposition pillars for PV-10:

1. Intellectual property
2. Drug supply chain (both substance and product)
3. Regulatory support
4. Mechanisms of action
5. Rational clinical study designs for randomized data generation

Blog post takeaway

• The focus of this post is pillar no. 5, more data generation, and specifically data generation related to the combination of PV-10 and an immune checkpoint inhibitor (pembrolizumab, and maybe other co-inhibitory blockade agents) in patients with advanced melanoma (Stage IV).

• Randomized data generation is a process, which starts with a dose escalation component (in this case, the escalation of PV-10's dose in context given the approved Keytruda dose).

• I'm looking to Provectus' 3Q15 business update conference call potentially in early-November (e.g., Thursday, November 5th) for the company's CTO Dr. Eric Wachter, PhD to discuss and/or have filed the combination therapy Phase 1b and 2 trial protocols. Whether one refers to it as a Phase 1b/2 (as was the case for T-Vec + ipilimumab) or a Phase 1b/3 (T-Vec + pembrolizumab), the second part of the clinical study process is a randomized controlled trial (RCT).

We assume generating randomized clinical data already has started with the commencement of the company's pivotal Phase 3 trial of PV-10 versus systemic chemotherapy in patients with unresectable locally advanced cutaneous melanoma (Stage III). More data is more than likely required to potentially further increase company value.

For advanced melanoma (Stage IV), step #2 of randomized data generation — the RCT component of the melanoma combination therapy two-step clinical study process — starts with step #1, single-arm data generation from a dosing (of the intralesional agent [IL]), safety and response rate evaluation of a pairing of compounds.

On Provectus' March 13th 4Q14 business update conference call Eric said:

"Throughout our consultations with key clinical opinion leaders, we’ve also been attuned to the need to address the needs of patients with more advanced disease. With enrollment now complete in the mechanism of action study of PV-10 of Moffitt Cancer Center, and initial results reported on that study and on the companion nonclinical study to assess combination of PV-10 with immune checkpoint inhibition, we are making progress on design of our proposed study to assess PV-10 in combination with immune checkpoint inhibition in patients with advanced melanoma. 

We continue to expect this to be structured as a Phase 1b/2 study with a modest sized single arm Phase 1b component and expedited safety and efficacy endpoints supporting expansion to a larger randomized Phase 2 component. Endpoints for Phase 1b are likely to comprise acute safety as a combination regimen and objective response rate at three to four months. For Phase 2, we anticipate endpoints of progression free survival at overall survival. With three agents now approved in the US and also available in other key locations abroad, I expect to have very concrete details on this work to discuss at our next quarterly conference call. Importantly now that we have options for this systemic agent, this study can commence with or without the assistance of a partner." {Underlined emphasis is mine}

On the company's May 7th 1Q15 call he said:

And in addition to the progress on the combination therapy patent front that Pete mentioned, we've also made substantial progress towards commencement of our proposed clinical study of PV-10 in combination with immune checkpoint inhibition. We have identified the investigators who will lead this work, the agent to be used in conjunction with PV-10, the patient population and the dosing schedule for both agents along with the study end-point. To assess potential benefit of PV-10 for patients with advance melanoma, this phase 1b/2 study will incorporate a modest sized single arm Phase 1b component with expedited safety and efficacy end point supporting expansion to a larger randomized Phase 2 component. 

End points for phase 1b are expected to comprise assessment of acute safety of the combination regimen and objective response rate at three to four months. For the Phase 2 portion, end points will be progression-free survival and overall survival. 

Once the protocol addressing each of these areas is complete, we believe the pieces are in place to commence clinical work on this important second development path for PV-10 and melanoma. Since the checkpoint inhibitor we expect to use is licensed in the U.S., we can commence this study with or without the systems or a partner." {Underlined emphasis is mine}

By protocol I think Eric means both Phase 1b and RCT protocols (whether one refers to the latter as a Phase 2 or Phase 3 trial).

On the company's August 6th 1Q15 call he said:

"Turning to the other primary component of our development plan for melanoma, we've continued to move towards commencement of a post-clinical study of PV-10 in combination with a new checkpoint inhibition in patients with advanced metastatic melanoma. After thorough consultation with leading investigators who will conduct this work, we have a study design that is undergoing final investigator review and anticipate completing the protocol before the end of the present quarter. 

This includes comprehensive definition of patient population, dosing schedule for both agents, and the study endpoints. As I've indicated previously, to assess potential benefit of PV-10 for patients with advanced melanoma, this Phase Ib/II study will incorporate a modest-sized single arm Phase I key--Phase Ib component of 24 patients with expedited safety and efficacy endpoints. 

Completion of this initial phase is expected to support expansion to a larger randomized Phase II component having an estimated 120 patients. The actual size of the Phase II component will be determined by modeling and response data among Phase Ib participants, that is the socalled observed effect size. 

Endpoints for Phase Ib will comprise assessment of acute safety of the combination regimen and objective response rate at three to four months. For the Phase II portion, endpoints will be overall survival, progression-free survival, and objective response rate. 

We anticipate using the anti-PD1 drug pembrolizumab, also known as Keytruda, as the checkpoint inhibitor. This class of drug has been shown to work favorably with PV-10 in mouse models with melanoma, as presented by our colleagues at Moffitt last November at the Annual Meeting of the Society for Immunotherapy Cancer, and as anticipated in our allowed drug patent application with Pfizer, the two drugs have largely unrelated or orthogonal side effect profiles. 

These factors provide justification for conducting the study. Also, since pembro is standard of care for the study of patient population, it is standard practice to conduct these kinds of studies in an add-on mode where all patients receive standard of care. 

We're optimistic that we can leverage existing investigator and site relationships to commence this study by the end of the calendar year. And since pembrolizumab is licensed in the US, we can commence this study with or without the assistance of a partner. If ongoing negotiations with prospective corporate partners lead to interest in testing PV-10 with a different checkpoint inhibitor, the study is designed to facilitate use with other drugs to enable such testing in a straightforward manner. {Underlined emphasis is mine}

With the Phase 1b and Phase 2 protocols not ready (and thus fileable on ClinicalTrials.gov) all Eric could say was the above. When filed on the .gov site both the T-Vec + ipilimumab and T-Vec + pembrolizumab protocols were two-step ones, as shown below, respectively:

Click to enlarge. Image source. Fuzzy purple emphasis is mine

Click to enlarge. Image source. Fuzzy purple emphasis is mine

In extending my door analogy from August 12th blog post The Door, Eric would have to had to design and construct the first door, design as well as perhaps mostly construct the second in consultation with the FDA (with emphasis on the second door, a presumably pivotal study). There would be placeholders (specifically the size of Phase 2 trial N) for the second door that would be modified pending the outcome of the initial Phase 1b study: "The actual size of the Phase II component will be determined by modeling and response data among Phase Ib participants, that is the socalled observed effect size." (Eric's comments, August 6th business update call).

Securing the keys to the doors from the regulator would require reaching the threshold of each door. I would wonder if yet assume Eric has discussed the path to and through the first door and the path to the second with the FDA. Maybe it's the [paths'] the utilization of a portion of the data (a fraction of the trial N) from the Phase 1b trial — if successful and appropriate — to apply for breakthrough therapy designation, followed by commencing the pivotal study, and the utilization of a portion of the data (a fraction of the trial N1) to be considered for accelerated approval — if successful and appropriate. Of course, maybe that's not entirely or actually the process.

And discussing cost and how to fund these paths (i.e., pros and cons of available and potential options) in the greater context of the company and its overall burn rate is an important matter for another discussion and post.