Provectus Fourth Quarter 2024 Investor Update: Q&A Follow-Up
Questions not addressed during the Zoom Webinar
A video recording of Provectus’s Fourth Quarter 2024 Investor Update (Investor Update), held November 14th, is available on the Company’s Business Update webpage. A copy of the Investor Update presentation slide deck may also be found on the same webpage; see here.
In the Company’s First Quarter 2024 Investor Update (conference call) in February, 134 people participated. In Provectus’s Annual Stockholder Meeting in June, 106 people participated (20 in person and 86 by Zoom). For this Investor Update by Zoom, 156 registered/participated, and averaged 55 minutes of participation (actual length was 65 minutes) with a median of 65 minutes (range 1-65).
Some unanswered questions from the Investor Update’s Q&A portion
Questions are lightly edited.
1. What is the status or are the further steps of the mNET, mUM, and cutaneous melanoma indications, clinical trials, and datasets?
Provectus’s Phase 1/1b single-arm trials (SATs) and their different patient cohorts for neuroendocrine tumors metastatic to the liver (mNET), uveal melanoma metastatic to the liver (mUM), and cutaneous melanoma (CM) are ostensibly complete.
The single-site mNET study in Australia (The Queen Elizabeth Hospital) explored single-agent PV-10 use in a third-line setting, where chemotherapy is standard of care (SOC).
The single-site mUM study at MD Anderson Cancer Center (MDACC) investigated PV-10 use:
in first and second-line settings,
as a monotherapy,
in combination with anti-PD-1 (Keytruda), and
in combination with the combination therapy of anti-CTLA-4 (Yervoy) and anti-PD-1 (Opdivo). Yervoy+Opdivo was considered SOC at MDACC.
The multi-site CM study explored the use of PV-10 in combination with SOC Keytruda for:
first-line Stage IV disease,
Stage IV disease where SOC checkpoint inhibition failed, and
first-line Stage III disease.
We considered the strengths, insights, and shortcomings of each study and patient cohort. The overall dataset, which comprises each trial’s respective dataset, supports our colloquial phrase, “a little PV-10 goes a long way, but enough could cure you.”
To us, this phrase and the overall dataset mean:
Enough injection/re-injection of PV-10 into enough injectable tumors on the liver (mNET and mUM; irrespective of extra-hepatic spread) or skin (CM) over enough time (when there are tumors to inject) arguably could put a patient on a trajectory towards no evidence of disease (NED),
Complete metabolic response (CMR) by PERCIST for mNET/mUM or overall patient complete response (CR) by RECIST for CM (although it wouldn’t be a bad idea to do PERCIST for Stage III CM even though by definition Stage III disease has not achieved metastatic spread) from enough PV-10 injection is potentially regularly achievable, and
CMR or patient CR has the potential to be predictive of overall survival (OS).
The mNET, mUM, and CM trials appeared to consistently demonstrate PV-10’s single-agent safety and combination therapy safety profiles, activity, and potentially clinical benefit if actually lined up against an SOC. There are no further development steps for mNET and CM at this time because we decided to focus our PV-10 development efforts on pancreatic ductal adenocarcinoma metastatic to the liver (mPDAC).
After we start the mPDAC program, we may consider a multi-site Phase 2 randomized controlled trial (RCT) for mUM comparing PV-10+Yervoy+Opdivo versus SOC, with a lead site of the University of Colorado Cancer Center, where the principal investigator who led the MDACC mUM work went.
We prioritized seeking an approval pathway in mPDAC over other indications because it potentially provides a more favorable risk-reward:
The typical 5-year NET survival rate, depending on origin, is considerably longer compared to mPDAC,
mUM patient OS is longer compared to mPDAC. Further, SOCs for mUM, such as Kimmtrak (approved specifically for mUM) or checkpoint inhibition, are immunotherapies. A pivotal mUM study could have skeptics (e.g., the “other immunotherapy,” not PV-10, is doing most of the work),
A pivotal CM combination therapy study would very likely require many hundreds of patients and several years for a survival-based primary endpoint to readout. This prospective study’s economics are very prohibitive compared to mPDAC, and
SOCs for mPDAC are chemotherapies. It is unlikely that a successful pivotal trial of PV-10 and SOC would have many skeptics (e.g., chemo is doing most of the work).
2. How would the mPDAC trial data be different from past clinical trial data that Provectus has generated or failed to generate?
First, we feel Provectus has a potentially robust clinical trial protocol that may provide the opportunity for the principal investigator to, finally, administer enough PV-10 to a patient (i.e., enough injection/re-injection into enough injectable tumors over enough time).
Second, we believe the Company’s mPDAC program potentially meets the parameters of the FDA’s Program Optimus to address dose optimization and dose selection in oncology drug development. This would be confirmed or revised through FDA interaction.
Third, we feel Provectus has a potentially comprehensive trial protocol that would collect all appropriate and necessary endpoint (EP) data, such as progression-free survival (PFS) (primary efficacy EP), safety and tolerability, response by RECIST, response by PERCIST, OS, and germane biomarkers.
Fourth, if an initial mPDAC trial is successful for the PFS EP compared to historical SOC, then we may potentially have sufficient data and direction to design and embark on the next clinical trial and regulatory step.
mPDAC potentially provides the best risk-reward for Provectus:
mPDAC patients have a very poor prognosis,
SOC is limited in its effectiveness,
Chemotherapy is not generally viewed as an immunotherapy, and
CMRs are typically not achieved for mPDAC patients.
3. You start lots of trials, but don’t finish anything. You start lots of trials, but don't finish any. What are plans to change that? Etc.
Provectus has finished all the trials (and patient cohorts) the Company has started, but one*, in:
oncology for PV-10: multiple CM indications and multiple hepatic tumor indications,
and dermatology for PH-10: actinic keratosis, psoriasis, atopic dermatitis, respectively
* Provectus’s Phase 3 RCT of intratumoral PV-10 versus investigator’s choice of systemic chemotherapy or intratumoral Imylgic for locally advanced cutaneous melanoma (LACM), a pivotal trial started in 2015, was terminated in 2018 after the Company’s board and management leadership changed in 2017 because we felt some of its design features were inefficient and its economics were prohibitive.
We have gained valuable insights from all the trials Provectus started, finished, and terminated.
The mPDAC program is medically and financially appropriate to pursue and fight for PV-10 drug approval.
4. At this point, you have tried numerous amount of trials without much success, how will you be able to get enough subjects this time to develop enough data this time to see how well RBS works? Also, it does not seem like Provectus has enough money to successfully get through a Phase 3 trial.
Each oncology trial Provectus has undertaken has continued to consistently demonstrate PV-10’s single-agent and combination therapy safety profiles and activity, and potentially its clinical benefit when lined up against SOC.
We address patient accrual in our response to Question 6 below.
As we note in Questions 2 and 3 above, we believe a robust and comprehensive mPDAC program provides the best risk-reward for Provectus.
We feel the Company has investor interest to fund and support the initial mPDAC study.
We understand mPDAC is by far one of the toughest cancer indications to meaningfully treat. If the initial trial is successful, the degree of success measured by PFS, OS, and the potential consistent achievement of CMR will dictate whether and how the opportunities to raise funds for a pivotal RCT or confirmatory study will manifest.
5. Why does Provectus management feel they have the experience and ability to bring rose bengal sodium (RBS) thru a rigorous FDA with preferences towards Big Pharma, when it has been seven years since 2017 and we seem to be in the same place far from any approval here in 2024?
No one on Provectus’s management team or board has taken a drug to approval, yet. It has been 10 years since 2014, when the Company last communicated directly with the FDA: the breakthrough designation application process, and, before that, multiple end-of-Phase 2 meetings, all centered around an LACM indication (which was really in-transit melanoma).
We feel confident about the prospects of our potential prospective meetings with the FDA for (a) Provectus for mPDAC, a Type C meeting, and (b) ophthalmology NewCo (i.e., EyeCo) for infectious keratitis (IK), a pre-IND meeting, because we have engaged who we believe to be two competent, thoughtful, regulatory strategy and affairs advisory firms (one for mPDAC and one for IK) with meaningful experience navigating and interacting with the FDA.
As importantly, we feel Provectus has the proper attitude to engage the FDA, one of humility, listening, and collaboration.
6. What is Provectus doing to improve patient recruitment in clinical trials?
According to Michaeli et al. 2024 in their journal article titled “Patient Enrollment per Month (Accrual) in Clinical Trials Leading to the FDA Approval of New Cancer Drugs,”1, it appears that median patient accrual per month per site ranged from 0.18 (range 0.05-0.62) for SATs to 0.24 (range 0.09-0.54) for RCTs2.
Provectus’s patient accrual rates for its clinical trials involving PV-10 compare favorably to Michaeli et al.’s data, particularly since the Company’s board and management changed in 2017.
We expect an mPDAC patient accrual rate of 1-1.5 patients per month at the trial site.
7. What are the plans for a reverse split?
As we discussed during Provectus’s First Quarter Investor Update and the Company’s Annual Stockholder Meeting, Provectus has no current plans for a reverse stock split (RSS). We will continue to seek stockholder approval each year for such authorization as a tactical option.
An RSS can potentially address the Company’s capital structure and potentially increase Provectus’s stock price, making the Company’s common stock more attractive to a broader range of investors. Such investors, however, would have to be able to buy Provectus’s stock while it currently trades on the mid-level of the lower-tier over-the-counter (OTC) market called OTCQB.
An RSS could be undertaken to facilitate a possible uplist from the lower-tier OTCQB to higher-tier exchanges like the Nasdaq or NYSE, or to further increase the Company’s stock price well after an uplist to improve stock market perception, increase share liquidity, enhance financial metrics, meet index requirements, etc.
Provectus would employ an RSS when the Company’s board believes doing so would be in the best interests of Provectus stockholders.
8. Why hasn’t the financial community recognized any of the potential of Provectus? Clearly the share price performance indicates either non-belief, total skepticism, or too long a time frame for possible success to invest capital in the Company. There are no secrets on Wall Street.
We focus on what we can control. We do not obsess over Provectus’s share price because we understand the Company was left for dead in late-December 2016, when Ed Pershing was asked by the then-chairman to join the board (Ed declined), and has been mostly ignored since, as Provectus’s stock trades on the mid-level lower-tier OTCQB market.
We also understand there are limitations to and realities of one’s stock trading on the OTC, rather than on a well-established, higher-tier, stock market exchange (e.g., transparency, liquidity, investor perception and risk, access and ease of trading, etc.).
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’ Annual Report on Form 10-K for the period ended December 31, 2023 and on Form 10-Q for the period ended September 30, 2024.
Michaeli DT, Michaeli T, Albers S, Michaeli JC. Patient Enrollment per Month (Accrual) in Clinical Trials Leading to the FDA Approval of New Cancer Drugs. Target Oncol. 2024 Sep;19(5):797-809. doi: 10.1007/s11523-024-01081-w. Epub 2024 Jul 31. PMID: 39085451; PMCID: PMC11392992.
Divide patient accrual per month by the number of sites (no. of sites) in Table 1.