I. A Patient’s Milestone: Six Years No Evidence of Disease in Stage IV Cutaneous Melanoma
Dr. Brad (“Tex”) Evans recently informed us that he had received his sixth annual “all clear” scan—meaning no evidence of disease (NED)—from MD Anderson Cancer Center (MDACC), Provectus’s Phase 1b/2 trial for cutaneous melanoma (CM) (NCT02557321). He also said that he was enrolled in MDACC’s survivorship program.
Tex participated in the first of three cohorts: patients in this cohort #1 had Stage IV disease naïve to checkpoint inhibitors (CIs—first-line treatment).1 The trial combined intralesional (IL) PV-10 with standard-of-care (SOC) CI Keytruda (pembrolizumab).
We’ve written about Tex before on Provectus’s Substack. See, for example, Stage IV Melanoma: “…the company that saved my life” (April 6, 2024).
His story is emblematic of the durable responses that we believe PV-10 can induce in patients with metastatic CM and continues to reinforce our belief in PV-10 as an immunotherapy that can work synergistically with approved agents and potentially lead to long-term remission.2
The recipe for the cure for cancer will have a few ingredients and we believe PV-10 will be a key ingredient.
Tex concluded, “A huge thanks to all of you at Provectus (again) and hopefully a reminder of why you all do what you do! Just arrived in Indianapolis for round 4 of the Ferrari Challenge series. Forza Ferrari and Forza Provectus!”
Forza Tex!
II. Penile SCC: Initiating a New Trial in a Rare Disease
Moffitt Cancer Center signed off on the final version of the clinical trial protocol that we provided to them for the Phase 1 study of IL PV-10 in penile squamous cell carcinoma (SCC).
Penile SCC—also PSCC and squamous cell carcinoma of the penis—is a rare disease (i.e., ORPHA:398058).3 According to Barnholtz-Sloan et al., there were 5.8 new cases of penis cancer per million men per year on average between 1993 and 2002 in the U.S.4 (i.e. ~2,000 per year).
This clinical study of 6 to 9 patients is designed for IL PV-10 to be a neoadjuvant therapy—meaning PV-10 will be administered before surgery. The goals of treatment are to reduce or eliminate tumor burden to potentially delay or avoid surgery and to demonstrate immunologic activation to potentially prevent metastatic spread.
Should Phase 1 trial results meet these goals, our hope would be to follow-up with a Phase 2 trial that could support a defined regulatory approval pathway.
Key Phase 1 study aspects include:
Primary objective: Safety and tolerability. Since this is the first time Provectus will treat tumors in this organ system, careful evaluation of injection site and post-procedure pain is critical. In previous IL PV-10 trials, injection-site pain, which was transient, ranged from Grade 1 to 3 adverse events and typically was Grade 1 or 2.5
Efficacy tracking: We will collect data on tumor response using imaging and photographs, and measure response along with photo-documentation. Notably, the clinical trial protocol allows for additional IL PV-10 injections over time if the principal investigator (PI) believes a patient is benefitting (unlike past Provectus Phase 1 clinical trial protocols).
Immune system data: We will also collect innate and adaptive immune response data and compare it to our prior clinical immune correlative data in melanoma and liver metastases. We expect the same immune response and the same details of this response to manifest.
The penile SCC trial revives a key topic from Provectus’s CM program: how best to measure—and then prove—IL PV-10 treatment response. In the 2010s, Provectus was criticized (demonstrably unfairly6) for modifying RECIST criteria to better assess tumor response7, especially when RECIST clearly didn’t then and doesn’t now fully capture the therapeutic effect of IL PV-10. The design of the new penile SCC trial gives us the opportunity to use both traditional and photographic measurement methods to tell a complete efficacy story to regulators.
Moffitt’s site administration and activation steps, Provectus’s CRO onboarding, and the Company’s regulatory steps for PV-10’s IND amendment submission and seeking FDA trial clearance are underway.
We’ll announce when the first patient is treated. We should have a good perspective of how each patient is responding within the first few weeks of treatment.
III. Metastatic Pancreatic Cancer: Redefining the Trajectory
We’ve discussed IL PV-10 in pancreatic ductal adenocarcinoma metastatic to the liver (mPDAC) since 2018, spurred by a deeply engaged Moffitt PI, a growing clinical rationale, and a comprehensive treatment approach (and thus comprehensive clinical trial protocol). Over time, we’ve moved from concept to execution.
Unlike locally present cancer (i.e., non-metastatic)8, mPDAC represents a complex metastatic cancer challenge that we have no fears of taking on and strongly believe we can conquer.
Our focus has been to determine whether IL PV-10, administered repeatedly to hepatic tumors over time, can change the patient’s disease trajectory. Frankly, we asked ourselves: could patients reasonably achieve NED?
Our emerging model for mPDAC includes:
Multiple cycles of IL PV-10 injections to liver tumors,
Use of comprehensive imaging (CT/RECIST, PET-CT/PERCIST) to capture potential hepatic and extra-hepatic disease resolution, and
Assessing whether IL PV-10 can drive systemic response that could lead to NED.
A key challenge has been to organize and present the data in a form that comprehensively communicates this model to the FDA, especially in terms of IL PV-10 dosing, comparisons to systemically administered SOC drugs, response, and long-term outcomes. As an example, the early portion of Provectus’s Phase 1 trial of IL PV-10 for cancers metastatic to the liver (NCT00986661):
Demonstrated safety and tolerability (including for liver enzymes),
Established pharmacokinetics (IL PV-10 treatment was in the body, compared to on the body for CM),
Highlighted treated tumor diversity (e.g., six hepatic tumor types to that point), and
Focused on long-term patient outcomes, with no discussion about tumor responses.
The later portion of this Phase 1 study, (i) which was post-2017, (ii) arguably should have been labeled a Phase 2 trial to establish that its primary objectives were response, durability of response, and survival, and (iii) primarily focused on metastatic uveal melanoma patients at MDACC:
Confirmed safety and tolerability,
Collected response data by modified RECIST, 2D-EASL, and PERCIST, and
Hypothesized that complete metabolic response (by PERCIST) was prognostic of (i.e., a surrogate endpoint for) overall survival.
We’ve made progress, but thoughtful and detailed framing with comprehensive supporting information has taken time.
IV. VisiRose (Ophthalmology): Regulatory Steps for RB-PDAT
VisiRose, Provectus’s ophthalmology-focused subsidiary, is continuing to prepare its pre-IND submission meeting package to send to the FDA for rose bengal photodynamic antimicrobial therapy (RB-PDAT) for infectious keratitis (corneal ulcers).
Our regulatory consultants have needed additional time to access longstanding non-clinical in vitro and ex vivo data and clinical data (~140 patients treated with RB-PDAT after SOC failed) from Bascom Palmer Eye Institute (BPEI) at the University of Miami (UM), University of California, San Francisco (UCSF) (the REAGIR trial sponsor, and 330 patients treated in the randomized controlled trial), and Stanford University (a former UCSF trial clinician now works here; UCSF owns the data). Data use agreements (DUAs) are required to access the clinical data,; these specifically have taken time to put in place.9
At the World Cornea Congress IX meeting in March 2025, where the REAGIR study data were first presented, the lead Indian PI reportedly said: “After today, the next ulcer I see that is fusarium, I will recommend RB-PDAT.” We have since learned that he now reportedly advocates for RB-PDAT as a potential first-line therapy for both fungal and parasitic (acanthamoeba) keratitis. SOC for fungal keratitis still is natamycin, which was the first anti-fungal agent approved by the FDA in 1978.
This endorsement underscores the importance of making RB-PDAT widely available—not only through FDA pathways but also with affordability and accessibility in global markets such as India. We are exploring the feasibility of incorporating Indian clinical sites at Aravind Eye Hospitals and/or L V Prasad Eye Institute (both of whom have used RB-PDAT in clinical settings) into a bridging study to support initial FDA approval.
V. Dermatology: PH-10 Immunologic Insights
Non-clinical research on our topical investigational agent PH-10 continues at The Rockefeller University (TRU).
James G. Krueger, MD, PhD and the Laboratory for Investigative Dermatology at TRU has completed various in vitro experiments and recently received tissue samples from the pig study conducted at the University of Texas Medical Branch (UTMB) for wound healing. TRU will be performing RNA sequencing to analyze PH-10’s effect on skin for dermatological diseases and disorders.
Importantly, TRU—along with Aru Narendran, MD, PhD at the University of Calgary Cumming School of Medicine—have helped to correct earlier misconceptions and lack of conception from pre-2017 leadership: the original Provectus founders said the core mechanism of action of Provectus’s rose bengal sodium (RBS) was concentration-dependent—the high concentration of RBS in PV-10 made it a stimulatory agent (i.e., a co-stimulatory agonist), whereas the low concentration of RBS in PH-10 made it an anti-inflammatory agent). Wrong.
New research from TRU—and prior research from Narendran—show PH-10 exerts both broad and targeted immunomodulatory effects across many multiple key pathways and PV-10 also inhibits targets (i.e., a co-inhibitory antagonist). In fact, TRU’s research results are rather absurd in their magnitude.
We believe that the totality of TRU’s work—post-2017 leadership greenlit the original clinical mechanism research on PH-10 in early-2017—together with this new TRU research and Provectus’s available clinical data in dermatology (such as it is)—is necessary to begin to monetize this clinical stage asset.
If TRU’s data are as good and comprehensive as we believe that they could be, we could try to create a dermatology-focused spinout company majority owned by Provectus with initial outside investment, leverage Dr. Krueger’s reputation and relationships and confidence in the PH-10 data his team has generated to secure a co-development partnership, or pursue another path.
VI. Wound Healing: Large Animal Study Nears Completion
The wound healing research at UTMB is concluding a large animal study in pigs. The data generated will support an initial and broader wound healing applications for PH-10 and expand our understanding of its healing and regenerative potential.
These data, along with UTMB’s non-clinical in vitro and in vivo (in mice) data, should allow for a Phase 3 clinical trial to be designed for an initial wound healing application. We would leverage PH-10’s existing IND to do so.
VII. Oral PV-10 for Cancer: Compassion Inspires Innovation
We are finalizing plans for new cancer research involving oral PV-10. We also plan to expand PV-10’s IND to include oral administration of PV-10.
This non-clinical research will be financially supported by a shareholder who personally used oral reagent-grade rose bengal for his bladder cancer and reported significant benefit. Deeply moved by his experience, the shareholder offered to help fund studies to accelerate development of an oral PV-10 cancer drug product candidate.
This situation parallels the case of David, a stage IV pancreatic cancer patient who was told, among other things, to seek hospice care. Under physician supervision, he took oral reagent-grade RB and SOC chemotherapy. He is now NED, sharing his story at our 2025 Annual Stockholder Meeting on June 18th in Knoxville, Tenn.
This planned non-clinical cancer research includes:
Oral and intra-vesicular (i.e., “intra-bladder”) PV-10 in vivo studies for bladder cancer,
Additional combination studies involving anti-PD-1 treatment (e.g., oral PV-10 versus oral PV-10 + anti-PD-1), and
Collaboration with clinicians at an NCI-designated comprehensive cancer center and Dr. Narendran’s lab at the University of Calgary.
We believe that oral PV-10 has the potential to transform treatment for many cancers and for many other diseases.
VIII. Platform Expansion: Unlocking New Disease Areas
We are conducting non-clinical mechanistic studies aimed at a pivotal disease cluster.
If successful, this work could justify broader use of oral PV-10 in certain diseases, potentially establishing a new therapeutic paradigm.
IX. Annual Meeting Feedback
Several shareholders shared their feedback with us that the audio and video quality of the Zoom webinar of the annual stockholder meeting on June 18th was suboptimal.
We sincerely apologize.
Going forward, we will improve communications and ensure better delivery of quarterly and annual investor updates.
Forward-Looking Statements
The information provided in this Provectus Substack Post may include forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, relating to the business of Provectus and its affiliates, which are based on currently available information and current assumptions, expectations, and projections about future events and are subject to a variety of risks and uncertainties and other factors that could cause actual events or results to differ materially from those projected in the forward-looking statements. Such statements are made in reliance on the safe harbor provisions of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Forward-looking statements are often, but not always, identified by the use of words such as “aim,” “likely,” “outlook,” “seek,” “anticipate,” “budget,” “plan,” “continue,” “estimate,” “expect,” “forecast,” “may,” “will,” “would,” “project,” “projection,” “predict,” “potential,” “targeting,” “intend,” “can,” “could,” “might,” “should,” “believe,” and similar words suggesting future outcomes or statements regarding an outlook.
The safety and efficacy of Provectus’s drug agents and/or their uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated or that such agents as products will achieve any revenue levels.
Due to the risks, uncertainties, and assumptions inherent in forward-looking statements, readers should not place undue reliance on these forward-looking statements. The forward-looking statements contained in this Provectus Substack Post are made as of the date hereof or as of the date specifically specified herein, and the Company undertakes no obligation to update or revise any forward-looking statements, whether because of new information, future events, or otherwise, except in accordance with applicable securities laws. The forward-looking statements are expressly qualified by this cautionary statement.
Risks, uncertainties, and assumptions include those discussed in the Company’s filings with the U.S. Securities and Exchange Commission, including those described in Item 1A of Provectus’s Annual Report on Form 10-K for the period ended December 31, 2024 and the Company’s Quarterly Report on Form 10-Q for the period ended March 31, 2025.
Cohort #2 comprised patients with Stage IV disease refractory to CIs. Cohort #3 were Stage III patients naïve to CIs.
The Phase 1b trial protocol for cohorts #1 and #2 did not give enough IL PV-10 treatment to patients. The protocol for cohort #3 was eventually amended to give PV-10 pro re nata (PRN or “as needed”). While response, durability of response, and survival data were compelling in the first two cohorts, data were super compelling in the third because of giving enough drug to patients. As we’ve previously discussed, a pivotal combination therapy study would have required treating many hundreds of patients, lasted several years in order for a survival-based primary endpoint to readout, and costed hundreds of millions of dollars. The time and cost to pursue a registrational study for any of these CM indications appeared to us to be too prohibitive, especially compared to other potential injectable solid tumor clinical programs, trials, and approval pathways for IL PV-10.
At the 2025 Annual Stockholder Meeting, we discussed our use of (i) Provectus’s existing data of IL PV-10-treated patients for in-transit melanoma (ITM), (ii) published literature, and (iii) expert clinician testimony to try to convince Australia’s Therapeutic Goods Administration (TGA) that this cancer indication was a rare disease and therefore deserved an approval pathway. Most patients treated by Provectus since inception had ITM, a subset of Stage III disease. The biomedical literature, however, provided limited incidence and prevalence data for ITM-specific occurrence due to the rare nature of this manifestation of CM. Two publications (Wong et al. 1990 and Read et al. 2015), however, allowed us to estimate an ITM incidence rate of 4.3-4.8% (out of all melanoma incidences per year). In Australia, this means an incidence of up to 30 ITM patients per million people and a prevalence of 4 in 10,000 people, which was below Australia’s prevalence requirement of 5 in 10,000 required for orphan designation. Unlike penile SCC, ITM does not have an official rare disease code. Key opinion leaders (KOLs) in melanoma in Australia, some of whom were and remain global KOLs attested that the unique clinical presentation and course of ITM are what made it a distinct disease and that ITM presented distinct challenges for disease management. TGA countered that IL PV-10 could plausibly treat melanoma as a whole, with a prevalence of 25 in 10,000 Australian. TGA also would not meet with the KOLs to hear their testimony in person. Post-2017 leadership simply and smartly used what data they inherited to ascertain whether a time- and cost-effective approval pathway existed for ITM; none did.
Barnholtz-Sloan JS, Maldonado JL, Pow-sang J, Giuliano AR. Incidence trends in primary malignant penile cancer. Urol Oncol. 2007 Sep-Oct;25(5):361-7. doi: 10.1016/j.urolonc.2006.08.029. Erratum in: Urol Oncol. 2008 Jan-Feb;26(1):112. Guiliano, Anna R [corrected to Giuliano, Anna R]. PMID: 17826651.
CTCAE grades are classified into five severity grades: 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, and 5 = death.
Such modified RECIST was based on Therasse et al., Journal of the National Cancer 2000. The focus of this modification of RECIST was anticancer cytotoxic agents like IL PV-10.
You can read about this approach in Company’s journal article of its Phase 2 clinical trial of IL PV-10 for metastatic melanoma (Thompson et al., Ann Surg Oncol 2015). Provectus believed that a modified version of RECIST would better capture deflation (i.e., the reduction in height of an injected tumor) to assess and define tumor shrinkage, even when the injected tumor’s diameter(s), and primary means of measurement assessment, may not have changed.
Such as, ITM (most of the patients treated with IL PV-10 since Provectus’s inception), pre-operative breast cancer (a few treated patients in a poorly designed trial in the mid-2000s; NCT00237354) or pre-operative penile SCC
A DUA is an agreement that is required under the HIPAA Privacy Rule and must be entered into before there is any use or disclosure of a limited data set to an outside party. A limited data set is a data set that is stripped of certain direct identifiers specified in the Privacy Rule. A limited data set is still protected health information. Covered entities like the UM (which governs BPEI), UCSF, and Stanford must enter into a data use agreement with any recipient of a limited data set from them.