Data-driven

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When Provectus presented data on its liver Phase 1 trial (A Study to Assess PV-10 Chemoablation of Cancer of the Liver, cancer metastatic to the liver, hepatocellular carcinoma) in July 2015 [1], it was the first time since November 2010 (Phase 2 Study of Intralesional PV-10 for Metastatic Melanoma, [2]) that the company released meaningful clinical oncology data [3], a period of nearly five years.

Key pre-clinical oncology data also was presented during this 2010-2015 timeframe by Provectus, and medical research organizations Moffitt Cancer Center and the University of Illinois at Chicago) [4] that, among other things, independently reproduced PV-10's tumor ablation and systemic, anti-tumor specific, immune response in multiple solid tumor cancers.

Key clinical data also was presented by Moffitt during this time period that began to elucidate PV-10's mechanism of action and mechanism of immune action. [5]

But the lack of additional, germane, clinical data aimed towards traversing the pathway to an initial approval of PV-10 undermined management's position that their greatest obstacle was overcoming pharmaceutical industry skepticism of a local (intralesional [IL]) agent being sufficiently capable of defeating the systemic disease that is cancer. You cannot overcome skepticism of clinical relevance if you have don't have enough clinical data.

Revisiting history, in January 2012 Provectus announced what appeared to receipt of sufficient guidance from the FDA regarding the design of a pivotal melanoma Phase 3 trial. [6] In January 2014 the company announced agreement with the Agency on the appropriate melanoma patient population. [7] In May 2014, in the aftermath of the FDA's denial of Provectus' breakthrough therapy designation request, we learned three additional contributory factors were (i) not enough clinical data, (ii) insufficient intellectual property protection of Rose Bengal's therapeutic use [8] and (iii) inadequate supply chain for the production of both drug substance (Rose Bengal) and drug product (PV-10). [9]

In the intervening time (2015-), intralesional agent T-Vec (Imylgic) was approved by the FDA. Overlapping both time periods has been a growing appreciation for the key role certain local therapies (e.g., radiation or radiotherapy) and therapeutics (e.g., targeted therapies, chemotherapy, IL agents) play in generating immunogenic cell death and initiating the cancer immunity cycle to the added benefit of therapeutics offered in subsequent steps of the cycle (e.g., immune checkpoint inhibitors).

Provectus also ramped up its clinical data generation processes:

• In April 2015 the company commenced its pivotal melanoma Phase 3 trial (PV-10 Intralesional Injection vs Systemic Chemotherapy for Treatment of Locally Advanced Cutaneous Melanoma) [10],

• As noted above, Provectus released initial data from its liver Phase 1 trial in July 2015, and

• In September 2015 the company initiated its melanoma combination therapy Phase 1b trial (PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma) [11].

All of which bring us to 2016, when and where management (Provectus' CFO/COO Peter Culpepper) has guided the year would be comprised of several clinical data generation opportunities (in no particular order) from trials and studies, and in medical conferences and biomedical publications:

• Interim readout of the pivotal melanoma Phase 3 trial,

• Data readout from the melanoma combination Phase 1b study,

• More data from the liver Phase 1 trial,

• Data description(s) from the compassionate use/expanded access program,

• Data description of clinical mechanism of action work in melanoma, and

• The potential or possible starts of liver Phase 1b and/or Phase 2/3 studies and trials, a Phase 1b study of another solid tumor indication, and pivotal Phase 3 trials for psoriasis and/or atopic dermatitis.

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Takeaways:

• Time taken from 2010-2015 comprised, it would seem:

• Not enough clinical data,

• Skepticism of a local agent being capable of delivery a systemic clinical benefit,

• Insufficient IP protection of Rose Bengal's therapeutic use, and 

• An inadequate supply chain.

• 2015: Finally, more clinical data, and the commencement of clinical trial generation (and the growing appreciation of IL agents and their roles in treating cancer)

• 2016: The year of even more clinical data generation?

[1] Data on PV-10 for Chemoablation of Liver Cancers Presented at ESMO 17th World Congress on Gastrointestinal Cancer, Phase 1 PV-10 Data on Liver Cancer Presented at 6th Asia-Pacific Primary Liver Cancer Expert Meeting

[2] Reports Full Phase 2 Study Data on PV-10 for Metastatic Melanoma

[3] Top line clinical data from Provectus' Randomized Study of PH-10 for Psoriasis was press released by the company in March 2012, Announces Top Line Phase 2 Data For PH-10 in Its First Randomized Controlled Psoriasis Study.

[4] Various, see below:

1. Intralesional PV-10 Treatment Leads to the Induction of Anti-Tumor Immunity (Moffitt),
2. Presents Nonclinical Data on Antitumor Immune Response to PV-10 Immuno-Chemoablation (Provectus),
3. Presents Data on PV-10 Combination Therapy at American Association of Cancer Research Annual Meeting (Provectus),
4. PV-10 Data Presented by Moffitt Cancer Center Researchers Examines Induction of Systemic Immune Response in Multiple Tumor Types,
5. Provectus' Intralesional PV-10 and Co-Inhibitory Blockade Data to Be Presented at SITC 29th Annual Meeting (Moffitt), and
6. Abstract on Provectus Biopharmaceuticals' PV-10 in Colon Cancer Models Published by Society of Surgical Oncology (UIC).

[5] Various, see below:

• Induction of Systemic Immunity Following Treatment of Tumors with PV-10 Reported by Moffitt Cancer Center Researchers at American Association for Cancer Research Annual Meeting,
• PV-10 Data Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting Defines Path Forward for Provectus Biopharmaceuticals, Inc. (Moffitt), and
• Reports Immune Mechanism of Action Data for PV-10 Presented at Society for Immunotherapy of Cancer Annual Meeting Authored by Researchers at Moffitt Cancer Center.

[6] Receives Guidance From FDA On Pathway to Approval for Phase 3 Trial of PV-10 For Metastatic Melanoma

[7] PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes

[8] Novel Synthesis Patent Issued by United States Patent and Trademark Office

[9] Connecting the dots: May 30, 2014 blog post "Why did it take four years...to arrive at this point?"

[10] Opens Patient Enrollment; Begins Phase 3 International FDA Comparative Clinical Trial of PV-10 for Melanoma

[11] Announces Initiation of Phase 1b/2 Clinical Trial to Study PV-10 in Combination with Immune Check Point Inhibitor Pembrolizumab