February 18, 2015

The Early Obsolescence of Checkpoint Inhibitors

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Take as a starting point Inman et al.’s 2007 article entitled Costimulation, coinhibition and cancer, and their statement therein: (underlined emphasis is mine):
If sufficient co-stimulation is provided in the presence of adequate tumor-associated antigenic stimulation, the immune system will act against tumor antigen and, thus, destroy early tumors before they become fully established. Contrarily, if co-inhibitory signaling dominates, the immune system will be tolerized to tumor antigens, and the tumor will be permitted to grow unfettered and unmolested by the immune system. If neither co-stimulatory nor co-inhibitory signals dominate, the adaptive immune system may remain in a tenuous state of equilibrium, militating against tumor outgrowth with varying degrees of success.
The essence of the authors’ view might be that the immune system is capable of decisively acting against cancer only in the situation where or circumstance that co-stimulation dominates co-inhibition. Take also as context to this starting point, however, that what we don’t know about the immune system probably dwarfs what we know about it.

The notion of “releasing the brakes” in the medical literature and mainstream press describes the approach of inhibiting cancer’s ability to suppress or block the body’s immune system from acting, and thus to evade attack. Although possibly coined in the early-2000s (see, for example, Tirapu et al.’s 2002 article entitled Effective tumor immunotherapy: start the engine, release the brakes, step on the gas pedal,...and get ready to face autoimmunity), use of the releasing-the-brakes phrase may have grown more widespread starting in the late-2000s and around the time of Dr. James Allison, Ph.D’s seminal work of blocking (inhibiting) the CTLA-4 protein receptor (using Bristol-Myers’ ipilimumab) and, later, the follow-up scientific exploration of blocking (inhibiting) PD-1 and PD-L1 ligands too (and associated PD-1 therapeutics pembrolizumab and nivolumab, for example, from Merck and Bristol-Myers, respectively).

Medical literature has more sparsely touched on, and mainstream press much less so, the other two components of the get-the-car-moving analogy (where the car is the immune system), “starting the engine” and “stepping on the gas pedal,” where these phrases relate to different aspects of stimulating the body’s immune system.

Possibly over-using the car analogy further, with the potential risk of over-simplifying it inappropriately, consider T cell immunity as a car at rest. More immunogenic tumors and their associated cancers like melanoma are like a car sitting on a slight incline. Release its brakes by treating the tumors (and thus the cancer) with checkpoint inhibitors, and the car may roll forward move some distance, notable or otherwise. With other less or non-immunogenic cancers, think of the car as sitting on a flat surface. Releasing the brakes does not enable the car to move any meaningful distance, if at all.

If you want to get the car to really move, you have to start its engine, and then step on its gas pedal. Releasing the brakes might help the car move farther and faster, but it also is quite possible the car may be able to move sufficiently without the need for further action other than to start its engine and/or stepping on its gas pedal.

The continued use of get-the-car-moving analogy of course requires the assumption the car can drive by itself; that is, the immune system can handle its own business once it has been started, and is appropriately up and running from stepping on the gas pedal.

Now consider Winograd et al.’s 2015 article entitled Induction of T cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. In particular, note the underlined sentences (my emphasis) from the article’s abstract:
Disabling the function of immune checkpoint molecules can unlock T cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4 resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFN-γin this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with PD-1 mAb, with or without CTLA-4 mAb, failed in well-established tumors, recapitulating clinical results. Agonist CD40 mAb with chemotherapy induced T cell immunity and reversed the complete resistance of pancreatic tumors to PD-1 and CTLA-4. The combination of αCD40/chemotherapy plus PD-1 and/or CTLA-4 induced regression of subcutaneous tumors, improved overall survival, and confered curative protection from multiple rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers although no cures were observed. Our findings suggest that in pancreatic carcinoma, a non-immunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T cell response with αCD40/chemotherapy.”
CD40 is a co-stimulatory protein, while chemotherapy has been understood to act in a stimulatory fashion through the subsequent release of cancer antigens.

Achieving T cell immunity almost if not actually by definition should mean overcoming resistance to cancer, thus overcoming checkpoint blockade and mitigating the need to artificially release the brakes.

Should stimulation via stimulatory therapeutics and therapies start the engine and enables the gas pedal to be stepped on sufficiently and appropriately (i.e., with minimal or manageable side effects or adverse events) so as to achieve T cell immunity, brakes may not be necessary once the car is moving (in context, and given the car [the immune system] can drive itself and not careen off the road because it then should know what it is doing).

Over time, however, road friction may start slowing the car down to the point where waning immunosurveillance (the immune system recognizing and eliminating continuously arising cancerous cells) no longer can protect the patient from relapse (analogous to how waning varicella zoster antibody titers may result in a bout of shingles). Keeping the brakes disengaged, especially with non-immunogenic tumors, should have some role going forward, making Merck, Bristol-Myers, Roche, AstraZeneca, Pfizer and other companies’ checkpoint inhibitors not necessarily obsolete as much as persnickety.

February 12, 2015

Hazard ratio, and other stat stuff

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I have written about hazard ratio in the context of Provectus's pivotal Phase 3 trial. For example, see:

The projected hazard ratio of Provectus' upcoming pivotal Phase 3 trial (a registration study) for locally advanced cutaneous melanoma is unknown.

Assumption: Let's assume this number is 0.545 or thereabouts, which derives from past Phase 3 trial design information publicly provided by the company. See below from 2013:
Click to enlarge. Provectus corporate presentation, March 15, 2013
This figure of 0.545 could be traced back further, such as to 2012:
Click to enlarge. June 2012 blog post Pivotal MM Phase 3 Trial Design: Study Size Dramatically Reduced.
Note: While the above company slides are from 2012-2013, Eric presented preliminary metastatic melanoma Phase 2 trial results at SMR 2010, and final results at ESMO 2012.

Wikipedia notes about hazard ratio: "If the analogy of a race is applied, the hazard ratio is equivalent to the odds that an individual in the group with the higher hazard reaches the end of the race first. The probability of being first can be derived from the odds, which is the probability of being first divided by the probability of not being first: HR = P/(1 − P); P = HR/(1 + HR)."

In the case of Provectus' pivotal trial, and using the race analogy above, race entrant number 1 is PV-10 (the trial's treatment arm), and entrant number 2 is chemotherapy (the comparator or control arm). Hazard ratio, or HR, is the probability of PV-10 being first — an event or hazard (i.e., progression of disease) occurring in the treatment arm before it occurs in the control one.

Calculation: The probability of PV-10 being first is 0.545 / (1 + 0.545), or ~35%.

Another way of putting it, "...hazard ratio compares two treatments. If the hazard ratio is 2.0, then the rate of [events or hazards] in one treatment group is twice the rate in the other group." In the case of Provectus' pivotal trial, if the projected hazard ratio is 0.545, the rate of events or hazards in PV-10 treatment arm is projected to be about half the rate in the chemotherapy control arm.

Progression-free survival for chemotherapy (dacarbazine ["DTIC"] or temozolomide ["TMZ"] in Provectus' Phase 3 trial) is approximately 2-3 months (e.g., Middleton et al. (2000), Patel et al. (2011) [see footnote 13], Hauschild et al. (2012) [see reference 1], etc.). According to Eric, "[t]he performance of DTIC and TMZ are well documented and generally yield a normal distribution of events (for example, refer to Middleton et al.)."

 Let's assume most patients in the company's Phase 3 trial's chemotherapy comparator or control arm have their disease progress after 2-3 months (about 8-13 weeks). PFS assessments will be made every 12 weeks (i.e., t = 12 weeks, 24 weeks, etc.) up to 18 months.

Provectus observed (see the ESMO 2012 poster) Stage 3 patients in the company's Phase 2 trial achieved PFS of 9.7+ months (mean) as measured by modified RECIST (9.8 months (mean) on the ESMO 2014 poster). Eric reported PFS as measured by RECIST 1.1 (according to Peter), which is the approach or convention by which tumor progression will be measured in the Phase 3 trial, on ClinicalTrials.gov as 3.7 months (median). PFS was measured for 12 months (or 52 weeks).

Eric has not disclosed PFS for the subset of patients in the Phase 2 trial who had all of their disease treated. This all disease treated subgroup formed the basis of Provectus' denied breakthrough therapy designation application), and the Phase 3 trial solely will comprise these patients. Stage 3 patients as a group appear to have achieved a 37% complete response ("CR") and an objective response rate ("ORR") of 63%, while all disease treated Stage 3 patients achieved 50% and 71%, respectively (an improvement of 35% and 13%, respectively). See original data, and 95% confidence intervals on the ESMO 2014 poster.

 Let's assume the Phase 3 trial's PFS for PV-10 is at least 3.7 months (as reported for all Stage 3 patients from the Phase 2 trial). Or perhaps it is higher, like 4.2 months (13% above 3.7) or 5.0 months (35% above 3.7). Or perhaps it is much higher, like there is no event because there is no progression because (i) all of their disease is treated with PV-10 and (ii) PV-10 will be injected until the tumors achieve CR (or progress, and thus an event or hazard occurs).

So, at the first assessment period of 12 weeks:
  • Most if not all patients receiving chemotherapy would have progressed: 2-3 months ~< 12 weeks, and
  • Most if not all patients receiving PV-10 would have not: 3.7 to 4.2-5.0 to never > 12 weeks.
Assumption: Let's assume the probability of chemo patients progressing after 12 weeks is 80-90%, and the probability of PV-10 patients progressing after 12 weeks is 0-10%.

Calculation: The actual hazard ratio of the Phase 3 trial — the probability of an event in the PV-10 treatment arm divided by the probability of an event in the chemotherapy control arm — may range from 0 (0% / 90%: not going to happen) to 0.13 (10% / 80%).

A projected trial hazard ratio of 0.545 and an 80-90% probability of progression in the control arm would imply a 44-49% probability of progression in the PV-10 treatment arm. Provectus likely expects the actual hazard ratio (on the order of .13'ish) to handily beat the projected hazard ratio (of 0.545).

Provectus' focus may not be on whether the Phase 3 trial outcome is successful, but rather on how many enrolled and treated patients (and their presumed successful outcomes) are needed for the outcome to reach clinical (statistical) significance as quickly as possible.

February 9, 2015

PV-10, Phase 3, Provectus: Almost [but not quite] there

Almost there (image source)
Provectus issued press release Provectus Biopharmaceuticals Met with FDA on Operational Aspects of PV-10 Phase 3 Melanoma Study today, with the byline FDA allows Provectus to go forward on Phase 3, and filed an associated 8-K.

Previously, on December 22, 2014, the company issued press release Provectus Biopharmaceuticals to Meet with FDA on Operational Aspects of PV-10 Phase 3 Melanoma Study with Aim to Maximize Speed of Enrollment regarding its Type C meeting with the FDA.

I imagine management's talking points are:
  • Provectus met with the FDA,
  • Eric has effectively managed his/the company's interactions with the Agency,
  • The FDA allowed Provectus to move forward with the company's Phase 3 trial, and
  • There are no more changes to the trial design.
My additional takeaways include:

1. While we're continuing to see and read about the making of more sausage, Eric continues to make progress towards kicking-off the company's Phase 3 trial. This meeting result should enable Provectus to commence patient enrollment and treatment following completion of various/certain procedural trial-related items. The Phase 3 trial after all is a registration study that successful completion of which should lead to drug approval.

2. We'll need to see the final version of and thus the changes in the trial protocol posted on ClinicalTrials.gov to draw what (if any) conclusions about how much (if anything) Eric was able to positively change of the trial's operational aspects. If he did effectively manage the FDA, he should have got a lot of what he wanted.

3. I imagine the elapsed time between the dates of the meeting (January 29th) and today's press release (February 9th) primarily if not exclusively comprised waiting for the Agency to confirm in writing Eric's understanding of the meeting's results.

4. Eric was being Eric in issuing a useful but overall poorly written press release from a stock market perspective. He approves (and also may write or mostly write), I believe, all releases related to Provectus' clinical development program. His statement in the PR, among other things, that "[t]he outcome of the review does not affect the fundamental design of the study nor the patient population, but does affect certain details concerning some secondary end points and statistical analysis matters, such as the treatment of missing data" (underlined emphasis is mine) is his way of communicating, I believe, that he endeavored to cover as many of his trial bases as he could, in this case as an example discussing with the FDA a potential scenario in which data is missing from the trial, and how to handle such a situation from among other things a data reporting and analysis perspective. Eric is a process- and detail-oriented (i.e., anal retentive) individual, a character trait I value in his clinical development program role and given his responsibilities, albeit taken in the context of his inexperience entering the role and his experience set now.

5. Although Eric has repeatedly missed timelines and deadlines he has set for himself (and thus Provectus) and despite prior expectations for an earlier start to this trial that repeatedly changed — 3Q 2014 in June at ASCO, 4Q 2014 in September at ESMO, 4Q via the corporate website presentation prior to the December 22nd press release, 1Q 2015 via an updated version of the presentation in January and potentially imputed from today's press release — the 6-month delay from 3Q14 to 1Q15 on the front-end (pre-Phase 3 trial start) may save time and improve outcome on the back-end (drug approval).

6.  I find it hard to believe there were no discussions related to PV-10's label, which would be finalized or put into place should the trial be successful. Eric being Eric, however, means his press release would not discuss the topic because the label was in-process; that is, publicly discussing the label before the trial had an outcome would be premature.

January 27, 2015

"Provectus Biopharmaceuticals' Novel Synthesis Patent Application Allowed by Chinese Patent Office"

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Provectus issued press release Provectus Biopharmaceuticals' Novel Synthesis Patent Application Allowed by Chinese Patent Office on Monday, noting the company "...received notification of allowance from the Chinese Patent Office for its patent application protecting the synthetic process used to produce the small molecule Rose Bengal, the active pharmaceutical ingredient (API) in PV-10, the Company's lead oncology drug candidate."

The synthesis patent, according to Provectus, "...covers the process under which pharmaceutical grade Rose Bengal and related xanthenes are produced, reducing the formation of certain previously unknown transhalogenated impurities that currently exist in commercial grade Rose Bengal in uncontrolled amounts. The requirement to identify and control related substances is in accordance with International Conference on Harmonisation (ICH) guidelines for manufacture of API suitable for clinical trial material and commercial pharmaceutical use."

A screenshot of the allowance is below:
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The joint Provectus-Pfizer combination patent application filed in China also is below and, according to Provectus, "...covers a method of treatment of cancer that comprises administering a therapeutically effective amount of an intralesional chemoablative pharmaceutical composition in combination with a therapeutically effective amount of a systemic immunomodulatory anticancer agent. The systemic immunomodulatory anticancer agent comprises anti-CTLA-4 antibodies including ipilimumab and tremelimumab." Claims not yet made public purportedly include anti-PD-1 and anti-PD-L1 antibodies.
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Both patent applications were submitted at the same time to their respective geographic regulatory agencies. That is, the synthesis patent was filed on September 17, 2010 with both the U.S. and Chinese patent offices, and the combination patent was filed with both agencies on March 9, 2012. According to Eric (paraphrasing), Provectus files Patent Cooperation Treaty ("PCT") versions of the company's PTO patent applications simultaneously in designated jurisdictions within their respective PCT deadlines. Such filings may be made months after the U.S. case is filed. This allows management to obtain initial input from U.S. examination before the process commences in earnest in other jurisdictions, and to fine tune claims before international prosecution starts. Additionally, Provectus also typically elects to file first in certain key jurisdictions the company has learned are both important and rigorous, which allows management to further refine their international claims before proceeding with other jurisdictions. See IP & China (December 26, 2014) on the blog's Archived News II page.

Protecting intellectual property around the world is good process, and a valuation driver for Provectus. An important component of the company's upcoming pivotal Phase 3 trial for locally advanced cutaneous melanoma would be clinical sites in international locations, such as Australia (a given based on prior participation in Provectus' metastatic melanoma Phase 1 and 2 trials), Western Europe, and so-called emerging market/developing countries.

A China site, and its associated investigator, should be on the roster when the trial starts, or shortly thereafter. The site, at least one of them in the country, should be the Peking University Cancer Hospital (also known as, or having the other titles of, the Beijing Cancer Hospital, the Beijing Institute for Cancer Research, and Peking University School of Oncology). Clinical studies registered on ClinicalTrials.gov for the Beijing Cancer Hospital may be found here (there are 3 that are recruiting).

The investigator should be  Professor and Dr. Jun Guo, M.D., Ph.D (Vice President of Clinical Oncology, Peking University; Deputy Director, Beijing Institute for Cancer Research; Director of Department of Melanoma & Renal Cancer, Peking University School of Oncology). Clinical studies registered on ClinicalTrials.gov for Dr. Gou may be found here (there are 102 of them of various statuses). See also The Asia Melanoma Group (November 26, 2014) on the blog's Archived News II page.

St. Luke's University Health Network's and Provectus' lead melanoma Phase 2 trial investigator Dr. Sanjiv Agarwala spoke at Dr. Guo's October 17th-19th Beijing melanoma conference (2014 Beijing International Melanoma Congress), which was co-chaired by Dana-Farber/Harvard Cancer Center's Professor and Dr. Keith Flaherty, M.D. See 2014 Beijing International Melanoma Congress (October 7, 2014) on the blog's Archived News II page.

Dr. Guo is the head of the Asia Melanoma Group, the establishment of which was announced at above mentioned Beijing conference. See China Daily article New group offers hope to melanoma sufferers:
"The new group consists of 17 leading melanoma experts from countries including China, Singapore, Korea and Hong Kong. "Given Asian patients' differences in genetic background and disease types to Europeans, it is high time Asian experts stand together to form a group that will break down barriers in research on melanoma," said Guo Jun, deputy director of the Beijing Cancer Hospital and head of the newly-established group. The incidence of melanoma is higher among white people than Asians but Asian people have a much higher probability of mucous melanoma than Caucasians, which usually has a poorer prognosis than melanoma on the skin, Guo explained."
Dr. Guo also is a member of Melanoma International Foundation's Scientific Advisory Board, which is co-chaired by Dr. Flaherty.

Amgen's pivotal metastatic melanoma Phase 3 trial for T-Vec did not include any clinical trial sites in China. International locations included sites in Canada, South Africa, and the United Kingdom

January 18, 2015

Dr. Weber

An interview of Moffitt Cancer Center's Dr. Jeffrey Weber, M.D., Ph.D. by OncLive's Andrew Roth, Expert Discusses Integration of PD-1 Inhibitors Into Clinical Practice, was published last week. I found several of Weber's answers to Roth's questions separately notable by themselves and germane to PV-10 (when viewed in the context of his involvement with the drug).

Dr. Weber's public positions on intralesional therapies and PV-10 are interesting, as has been his work with Provectus' drug when one considers his other clinical work. I have not been able to find disclosure statements for him that included Provectus—if you find any, let me know. Into November 2014 sample Weber disclosures included:
Click to enlarge. ESMO 2014-related (i.e., September)

Click to enlarge. November 6, 2014
Moffitt and Dr. Weber's work with PD-1s pembrolizumab and nivolumab are:
  • Moffitt Cancer Center Plays Pivotal Role in FDA Approval of New Anti-PD-1 Inhibitor Keytruda for Metastatic Melanoma (Moffitt press release, September 2014): "Jeffrey S. Weber, M.D., Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at Moffitt Cancer Center, was one of the lead investigators of the PD-1 clinical trial which led to the drug receiving breakthrough status from the FDA. “Pembrolizumab is the first PD-1 drug to be approved by the FDA, and it is a clearly effective drug that will prolong survival for many patients with metastatic melanoma.  This approval is a real advance, and a major milestone in the treatment of the disease,” Weber said."
  • Bristol-Myers Squibb Receives Accelerated Approval of Opdivo (nivolumab) from the U.S. Food and Drug Administration (Bristol-Myers press release, December 2014): "“The approval of Opdivo gives patients and physicians an important new treatment option for a population where they were once very limited,” said Jeffrey S. Weber, MD, Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center. “For the first time, a PD-1 blocking antibody has shown a response rate of 32% in a Phase 3 randomized clinical trial of patients with unresectable or metastatic melanoma, who have progressed following first line therapy.”"
Click to enlarge. Source link
Moffitt and Dr. Weber also have been involved in three other melanoma approvals, ipilimumab, vemurafenib, and the combination of dabrafenib and trametinib:
  • (2011) "Researchers at several NCI-designated cancer centers were lead investigators in the pivotal phase III clinical trial that ultimately led to FDA approval in March 2011of ipilimumab as a treatment for advanced melanoma. These researchers included Dr. F. Stephen Hodi Exit Disclaimer of the Dana-Farber/Harvard Cancer Center, Dr. Jeffrey A. Sosman Exit Disclaimer of the Vanderbilt-Ingram Cancer Center, Dr. Jedd D. Wolchok Exit Disclaimer of the Memorial Sloan-Kettering Cancer Center, and Dr. Jeffrey S. Weber Exit Disclaimer of the Moffitt Cancer Center and Research Institute."
  • FDA Approves Personalized Medicine Drug For Melanoma (Moffitt press release, August 2011): From Moffitt's website, "Jeffrey S. Weber, M.D., Ph.D., and others at Moffitt contributed significantly to the approval and testing of the melanoma drug Vemurafenib, including important laboratory work in developing an inhibitor to overcome resistance to the drug that has led to improved outcomes."
  • Moffitt Cancer Center Instrumental in FDA Approval of Revolutionary Two-Drug Combo to Treat Advanced Melanoma (Moffitt press release, January 2014): "“Melanoma is the most aggressive type of skin cancer and the leading cause of death from skin disease,” said Jeffrey S. Weber, M.D., Ph.D., director of Moffitt’s Melanoma Research Center of Excellence. “This new combination therapy is a huge step in the right direction for the treatment of melanoma, and our researchers played a large role in bringing this treatment option to patients.”"
Of seven drugs the FDA has approved for melanoma since 2011, according to Moffitt and Dr. Weber, they have been instrumental or significantly participated in six approvals.

To date Dr. Weber has publicly associated himself (so to speak) with PV-10 two times, both around ASCO 2014 (June).
To add context to the above, however, he:
  • Does not believe intralesional ("IL") therapies have a singular role in treating late-stage melanoma with heavy tumor burden and spread of the disease to visceral organs. See Debating Systemic Intralesional Therapies (April 16, 2014) on the blog's Archived News I, and
In the moment, as it relates to Provectus' upcoming pivotal Phase 3 trial for locally cutaneous advanced melanoma, the company has an initial pathway to licensure. When they finally start their trial, management finally would have advanced their drug candidate to the final clinical stage prior to approval (pending of course a positive outcome for the trial). A "fully FDA-approved" and fully operational Phase 3 protocol should be tantamount to a prospective drug label; that is, who to treat and how to treat them.

Returning to Dr. Weber's OncLive interview:
OncLive interview, Figure 1
Takeaway: He notes three approved drugs (ipi, pembro and nivo), and the IL agent (T-Vec) that has begun testing in combination with ipi and will be combined with pembro. Anti-CTLA-4 and PD-1 drugs do not sufficiently work singularly for late-stage patients. Combinations now are the order of the day for this patient population where drug permutations would be graded based on a combination of safety ("keep toxicity down") and efficacy ("boost the response rate). Combining two checkpoint inhibitors, or drugs that release the brakes of the immune system, does not make sense (you're further releasing the brake?) from safety, efficacy and cost perspectives. Combining a stimulatory agent (starting the engine) with an inhibitory one (i.e., a checkpoint blockade agent) makes more sense in order to garner a better grade.
OncLive interview, Figure 2
Takeaway: The role of chemotherapy is being diminished and presumably eventually eliminated as drugs are approved for different melanoma patient populations as safer and more effective alternatives to chemo. He notes three approved immunotherapies (ipi, pembro and nivo). IL-2, also an immunotherapy, was approved in 1998. If and when T-Vec is approved (for metastatic melanoma), it would be an alternative for certain patients. If and when PV-10 is approved (for locally advanced cutaneous melanoma), it would be an option for another segment of melanoma patients.
OncLive interview, Figure 3
Takeaway: I found this answer interesting because Provectus principal investigator and St. Luke's University Health Network medical oncologist Dr. Sanjiv Agarwala said at ECC 2013, "[d]iscussing the interest in the use of PV-10 by his surgical colleagues, Dr. Agarwala added other potential benefits of pre-surgical intralesional injection—turning unresectable lesions into resectable ones and stimulating the immune system to lower the odds of recurrence." Neoadjuvant therapy refers to treatment given prior to the primary one (i.e., in this context, surgery—turn an unresectable lesion into a resectable one so it may be removed with surgery or excision). PV-10 achieved a 71% objective response and 50% complete response in the subgroup of 28 patients from Provectus' melanoma Phase 2 trial who received PV-10 into all existing melanoma lesions (i.e., no un-injected lesions).
OncLive interview, Figure 4
Takeaway: I don't believe Moffitt has commented on progress it may have made in determining a biomarker for PV-10. At this year's J.P. Morgan Health Care Conference, Roche's Chief Financial Officer Dr. Alan Hippe, Ph.D. said 70% of the company's projects in development have a biomarker hypothesis, which underscores Roche's deal with Foundation Medicine. Provectus's upcoming pivotal Phase 3 trial would include patients with "indolent, low-burden, low bulk with normal LDH."

Should Dr. Weber lend his voice—appropriately and in context—to the process of approving PV-10, his could be an important one to the FDA, and one that could help frame the drug's initial and potential eventual roles in treating advanced melanoma in particular and melanoma in general.

January 9, 2015


Image source
I found the following while monitoring my curated Twitter feed for this project (h/t Tom Silver, ‏@TomSilver39):
"Does anyone have early access to inside information?  There is another way that CytRx’s clinical results are made available to big pharmaceutical companies, and that is CytRx’s “black box” website. This website is designed to provide big pharma with inside information, with the objective of interesting them in possible partnerships, which can enhance shareholder value by providing cash to accelerate and/or expand the pipeline without selling more shares.  Big pharma companies who wish to monitor research results as they occur, can sign a nondisclosure agreement, and are then granted access to this restricted site. There, they can view results at almost the same time that CytRx receives them from the clinical testing centers.  Now, if it is a double-blind study, they will still not know which patients received Aldox, and which received the control drug(s) or placebo. Still, it is not difficult to calculate the therapeutic benefit of Aldox, using known historical data on the control drug, and the ratio by which patients are assigned to each arm of the trial. For example, suppose that Aldox is being compared to Dox, and every 3 patients are randomly assigned in a 2:1 ratio Aldox:Dox. If Dox gives a progression-free survival of 10 months, and the average PFS for all of the patients is 20 months, we can calculate that the PFS for Aldox is 25 months because (25 + 25 + 10) /3 = 20." Source link: CytRx Corporation Overlooked News {Bold emphasis is mine}
There are two topics here. First, there is subject of collecting clinical trial data in real-time, which should come as no surprise to anyone (given the advent of information technology now on its umpteenth wave of progress). It also goes without saying that if you can collect data in real-time, or as clinical sites send these data in, you also can analyze and share it. A sample paper on the topic: Harnessing technology to improve clinical trials: study of real-time informatics to collect data, toxicities, image response assessments, and patient-reported outcomes in a phase II clinical trial, Pietanza et al., J Clin Oncol. 2013 Jun 1;31(16):2004-9. doi: 10.1200/JCO.2012.45.8117. Epub 2013 Apr 29.

Second, there is the subject of sharing the data with third parties. See Pharma Compliance Monitor's December 29, 2014 blog post entitled Clinical Trial Data Sharing: Landscape, Trends, and Risks by Robin Jenkins of Sanofi U.S. and Joe Morrell of Huron Life Sciences:
"The potential benefit of sharing clinical trial data (patient-level data and clinical documentation) has been recognized by various industry groups over the past several years, but the reality of sharing data is emerging...[D]ata sharing initiatives can be categorized into three fairly broad data sharing models[1]; Black Box, Gatekeeper, and Open Access."
[1] refers to Mello, JD, PhD, Michelle, “Potential Models for Data Sharing.” Issues and Case Studies in Clinical Trial Data Sharing: Lessons and Solutions; Cambridge, MA, May 17, 2013. The slides below better inform on the black box reference above in the CytRx blog post, which is the name of one of several models of data sharing noted above in the Pharma Compliance Monitor blog post.
Click to enlarge.
Click to enlarge.
Click to enlarge.
The conference above speaks to a much larger topic about leveraging data sharing to accelerate biopharmaceuticals development.
Click to enlarge.
My blog post is more focused on what I learned:
  • That all companies running any clinical trial and certain pre-clinical ones can share data with third parties,
  • That to gain access to such data, the parties would have to enter into non-disclosure agreements ("NDAs"),
  • That software platforms and packages exist to facilitate sharing. INC Research has such a product, and other large global contract research organizations ("CROs") have proprietary ones as well,
  • That Big Pharma do enter into NDAs with companies when the former are interested in one of latter's trials, and
  • That providing data access to certain melanoma advocacy groups might assist in the effort to bring more visibility to the Stage 3 melanoma patient (progress is gained for constituents when the oncology community is better educated and good public policy is facilitated).
Let's say, merely for the sake of argument of course, that you're Pfizer (or any interested Big Pharma), and you want to look at data generated from Provectus's upcoming pivotal Phase 3 trial for locally advanced cutaneous melanoma. Let's assume:
  • The above mentioned process for clinical trial data sharing with third parties is real, appropriate and indeed happens, etc.,
  • You sign an NDA with Provectus, and
  • Progression-free survival ("PFS") for systemic chemotherapy (dacarbazine or DTIC) is [2-]3 months.
If DTIC gives a progression-free survival of 3 months, and the average PFS for all of the patients is 9 months, we can calculate that the PFS for PV-10 is 12 months because (12 + 12 + 3) /3 = 9. [Randomization is 2-to-1]

Let me frame the analysis another way, using the knowledge gleaned by Eric and Provectus from the compassionate use program ("CUP") and sub-set of the metastatic melanoma Phase 2 trial patients who had all of their disease treated: hit the injectable disease early, often and repetitively until is goes away (i.e., a complete response, or partial response until the complete response is achieved). This approach could (would) suggest a PFS of 1.0 for the pool of suitably treated PV-10 patients (i.e., the PV-10 arm of the upcoming pivotal trial). Let's now assume you re-use the assumption above that the PFS for systemic chemotherapy is 3 months (i.e., the pivotal trial's control arm). A graph of months after treatment vs. PFS in months might look like this:
Click to enlarge.
A graph of months after treatment vs. PFS (as a % or fraction of 1) might look like this:
Click to enlarge.
None of the above graphs are dependent on N, the total number of patients treated at a given point in time. Real-time data collection, or data collection as clinical trial sites provide the data to the CRO running the trial and, thus, the data sharing software sharing package, would simply yield lines, graphs and trends that would change over time as N changes (increases) and the results of treatment on each N changes.

Different thresholds of N would have different meanings for statistical significance and relevance. N-1 might be the number of patients for the divergence of the PV-10 (blue above) and chemo (red above) arms to reach statistical significance. N-2 might be the number of patients for the trial to reach its assigned hazard ratio. N-3 might be the number of patients/responses to trigger the interim analysis.

A Big Pharma with a basic-to-good understanding of PV-10 (e.g., pre-clinical data, prior clinical data, mechanism of action, mechanism of immune response, intralesional therapies, etc.) that also had signed an NDA to access some level of pivotal trial data would observe the trends of the trial's data—positive or negative—before or as the different N thresholds are reached and/or passed.

Then what?

January 4, 2015

The Emergence of PV-10, and Provectus Biopharmaceuticals

Sayaka Ganz, Reclaimed Creations, Silence
In several respects 2014 saw the emergence of Provectus Biopharmaceuticals, much as I as a long-time shareholder would have thought this development could have begun earlier, say in the 2010-2011 time period.

Nevertheless, PV-10's recent emergence reflects growing awareness of the drug—with the FDA, Big Pharma, key opinion leaders ("KOLs") and members of the medical community at large—and the role of dual mechanisms (one ablative, the other immunological) in the approaches to and outcomes of treating cancer, especially given the backdrop of cancer immunotherapy (or "immuno-oncology").

Figure 1
Of course the story is not just about the drug. It's also about the management team and publicly traded company and, thus, the stock and share price. PVCT's' historical performance (see Figure 1) remains the single most contrary point to arguing for the emergence of PV-10 and Provectus, and ostensibly challenges recognition of positive identifiers of progress last year.

The larger argument for the other side of the Provectus trade is that the market is always right ("...any one person can be wrong about the market—indeed, everyone can be—but the market as a whole is always right"). The efficient-market hypothesis ("EMH") "...asserts that financial markets are 'informationally efficient'" (Quote sources: Efficient-market hypothesis, Wikipedia). The price is what it is because the stock, company and drug are what they are, and the share price reflects it.

The larger argument against the argument of the other side of the trade is, "...it is hard to reject the claim that prices are right unless you have a theory of how prices are supposed to behave," which is a quote from an August 2009 article by Richard Thaler in The Financial Times entitled Markets can be wrong and the price is not always right. He also wrote:
"For many years the EMH was “taken as a fact of life” by economists, as Michael Jensen, a Harvard professor, put it, but the evidence for the price is right component was always hard to assess. Some economists took the fact that prices were unpredictable to infer that prices were in fact “right”. However, as early as 1984 Robert Shiller, the economist, correctly and boldly called this “one of the most remarkable errors in the history of economic thought”. The reason this is an error is that prices can be unpredictable and still wrong; the difference between the random walk fluctuations of correct asset prices and the unpredictable wanderings of a drunk are not discernable."
The above is a convenient way of rationalizing my very positive beliefs about the drug and its potential addressable market, positive views of the company and its management team, and extremely upbeat prospects of its stock with the current share price. It's sort of like saying, "I'm right because you can't prove I'm wrong, until I am [right] or you can [prove me wrong]."

When the "other side of the trade" arguers argue the argument in more detail—I have tried to actively curate the other sides since inception of my diligence on Provectus, PV-10 and management, and continue to do so—the intellectual honesty of their veracity ultimately dissolves into fragments I certainly acknowledge. Arguments for PV-10's irrelevance include:
  • The current generation of approved checkpoint blockade therapies (i.e., Merck's pembrolizumab or Keytruda, and Bristol-Myers' nivolumab or Opdivo) will make PV-10 obsolete,
  • Amgen's Talimogene laherparepvec ("T-Vec") is a better intralesional agent than PV-10, or
  • Next generation CAR T cell ("Chimeric Antigen Receptor T cell") companies (i.e., Bluebird Bio, Juno, Kite) will make PD-1s obsolete, which should make PV-10 doubly or squaredly obsolete.
Rather than use PV-10 to talk down these drugs and companies, there are more general counterpoints:
  • While PD-1s clearly have utility, are viable options for cancer patients, and backed by Big Pharma, they are limited (tumor immunogenicity is providing more knowledge about what does and does not work, and where and when it does) and expensive (on both absolute and relative [cost per unit success] bases). The FDA's approval letters for Keytrua and Opdivo (here and here, respectively) are not commensurate with the "excitement" for PD-1s.
  • T-Vec's success and Amgen's marketing muscle ("oncolytic immunotherapy") should help build the category of intralesional cancer agents. Any and all T-Vec success (i.e., approval as a monotherapy, clinical trials and data from combination with checkpoint blockades) is good for PV-10. An oncolytic virus engineered from herpes simplex 1 that is far from simple to store, handle, and use and reuse, however, does not sound like the ideal intralesional agent.
  • CAR T cell companies' multi-billion market capitalizations should be considered in the context of preliminary clinical results, likely high treatment price tags, likely product gross margins that probably will be comparable to if not less than Dendreon's Provenge, more articles about their offerings in the lay press than in scientific literature, and a focus only on T cells (what about NK cells, among other things?).
So, if PV-10 and Provectus management both are bad, well, then we're dealing with that intellectual honesty thingie. If the drug is bad, has no merit or lacks opportunity, it's reasonable to such a position ignores available data and commentary that, while not overly conclusive in some quarters, at the very least speaks to a greater medical and thus financial opportunity than the share price currently reflects. If the drug is good, has merit or presents opportunity but Provectus management is lacking, I would not disagree. They have strengths, weaknesses and blindspots. You may recall my comments about them in my September 2013 investment letter Why I'm Long Provectus Pharmaceuticals):
"Management historically has relied on the input of a stable of high and low quality advisors and consultants in its decision-making, making many good and several questionable decisions and choices along the way. Provectus has eschewed playing Wall Street's game for the most part, and has suffered to some degree because of it. Some company wounds, non-fatal as they are, however, have been self-inflicted. Management possesses a sufficient threshold level of competence and integrity to warrant my support, and seeks to sufficiently protect the economics of Provectus's innovation for shareholders to warrant my continued holding of Company stock."
Until recently, few could dispute management's overall lack of success in properly managing the FDA. Credible people now are entirely focused on the data and clinical development details, and on management's execution and generation of them. Wall Street promotes what it can sell. Provectus has been a difficult promotion for the Street for several reasons, some substantive, some superficial, but none fatal, and thus PVCT has not been sold. Wall Street's interest in the company should change as the immense opportunity of the drug and for the company more fully emerges in 2015. Both sides of the trade also could agree that no one of relevance and substance—neither the FDA, nor Big Pharma nor KOLs—truly spoke up meaningfully about the drug (in word or by action) until 2014.

Entering 2015 I believe my investment thesis not only remains intact, but has grown stronger (below, from my September 2013 investment letter):
"PV-10, a novel oncology compound being developed by Knoxville, Tennessee-based Provectus Biopharmaceuticals, Inc., exemplifies innovation over incrementalism, meaningful over marginal, productized technology over hypothetical, and changing the world over accepting the status quo, with not an insignificant amount of serendipity over contrivance. In sum, these form the quintessential essence of a paradigm shift in the treatment of cancer. 
This is where my investment thesis begins and ends: a novel drug compound with a pristine safety profile, a treatment well tolerated by and easily administered to patients, a readymade product inexpensively produced at scale, and a vast addressable market of unmet need that should be fully and very profitably met over time. 
My thesis comprises compelling clinical, regulatory, business and stock value propositions in a pharmaceutical industry ravenous for safe and effective oncology solutions, with the prospect of annual market growth rates exceeding other therapeutic areas, that following approval(s) should deliver a lucrative monetization for shareholders." {Bold emphasis is mine.}
One simple way to assess emergence merely could be to measure the growth of PV-10's digital awareness over time, in this case by counting visitation to and readership of this blog. See Figures 2 and 3 below.
Figure 2
Figure 3
(Average session duration is measured in seconds.)
Another way to consider emergence would be to assess view points and behavior of key constituencies over time: the regulator, the immune system, KOLs and Big Pharma. See Figure 4 below.
Figure 4, click to enlarge
The Regulator (The FDA): The company seemed be mired in its regulatory trek in 2012, with no agreement with the FDA on indication and patient population, nor clinical trial endpoints. See, for example, Provectus' May 23, 2014 conference call transcript, which in hindsight helped explain Eric's cryptic "oncology presents a moving playing field" comment from the May 2013 annual CEO letter. In 2013, the company seemed to reach an important mile marker towards the end of the year with its December Type C FDA meeting, which established locally advanced cutaneous melanoma as PV-10's initial path to licensure. In 2014 the May BTD denial letter revealed key Agency acknowledgements as well as the need for more data:
"We have reviewed your request and while we have determined that treatment of “locally advanced cutaneous melanoma” meets the criteria for a serious or life-threatening disease or condition, the preliminary clinical evidence you submitted does not indicate that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. Therefore, designation as a Breakthrough Therapy cannot be granted at this time. 
The preliminary clinical data provided in your request for Breakthrough Therapy designation are indicative of drug activity in the treatment of local, satellite or in-transit recurrence of malignant melanoma; however, the preliminary clinical data do not demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. This determination is based on the paucity of data on endpoints indicative of clinical benefit (e.g., pain, infection, significant bleeding) and our inability to determine the clinical significance of the reduction in the size in one to 10 target lesions in patients with locally advanced melanoma, who may have additional untreated cutaneous, subcutaneous, or visceral sites of disease." {Bold emphasis is mine.}
The FDA then announced in October the opportunity for public comment related to the Agency's patient-focused drug development initiative that nominated "Melanoma, specifically unresectable loco-regional disease" to the preliminary list of candidates. In December the Phase 3 trial was accepted by the FDA.

The Immune System (Immuno-Oncology): In 2012 Moffitt Cancer Center began publishing their pre-clinical work on PV-10 that revealed the production of tumor-specific interferon gamma (IFN-γ). In 2013 this work expanded to show T cells played a critical role. In 2014 the cancer center began publishing their clinical work that discerned the involvement of different T cell populations (e.g., CD3+, CD4+ and CD8+), including NK T cells.

Key Opinion Leaders (Moffitt Cancer Center): While Moffitt started their work on PV-10 in 2011, 2013 provided a quizzical press release, quizzical because there has been no comparable public follow-up: Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows. In 2014 Moffitt opined further and nearly as boldly. Dr. Jeffrey Weber, M.D., Ph.D. saying PV-10 might offer the perfect way to prime the immune system (at ASCO). Dr. Vernon Sondak, M.D. said [in a conference presentation] PV-10 was the ideal intralesional agent (at the 4th European Post-Chicago Melanoma Meeting).

Big Pharma (Pfizer)

In 2012 Provectus had one Pfizer executive on its strategic advisory board ("SAB"), who joined in 2011. By 2014 the company had three of them.

Image source

For Provectus' emergence in 2014 to more fully translate into a more reflective share price, there are clear milestones that clearly must be achieved:

1. Commence enrollment of the pivotal Phase 3 trial for locally advanced cutaneous melanoma.

2. Consummate a China regional transaction. If there is a China deal, there will be an Indian one.

3. File the Phase 1b/2 protocol for liver cancer. Enrollment should begin this year; however, a China transaction likely would be a condition precedent to a trial start.

4. File a Phase 1b/2 protocol for a combination therapy of PV-10 and a checkpoint blockade for advanced melanoma. If Pfizer's first touchpoint was its first SAB member, the second was the joint patent application for combination therapies involving PV-10, and the third and fourth were the second and third SAB members, then the fifth could be a co-development arrangement to combine Pfizer's PD-L1 agent with PV-10.

5. File a Phase 1b/2 protocol for triple negative breast cancer. Maybe...?