The Immune Checkpoint Inhibitor Global 4 (or 5)

In 2013 Citi equity research analyst Andrew Baum projected cancer immunotherapies "...will generate sales of up to $35 billion (a year) over the next 10 years and be used in some way in the management of up to 60 percent of all cancers" (see Immune system cancer drugs tipped to be a $35 billion market, Ben Hirschler, Reuters, May 22, 2013). The analyst and others in the investment community refer to the next generations of immune checkpoint inhibitors, anti-PD-1 and anti-PD-L1 agents, having moved past approved anti-CTLA-4 agent ipilimumab (Yervoy).

Players (2013 ranking by oncology sales) in the checkpoint inhibitor space include:

• Bristol-Myers (#9): CTLA-4 (approved ipilimumab/Yervoy), and PD-1 (approved internationally nivolumab/Opdivo),

• Merck & Co. (#8): PD-1 (approved pembrolizumab/Keytruda),

• Roche (#1): PD-L1 (investigational MPDL3280A), and

• AstraZeneca (#7): PD-L1 (investigational MEDI4736).

Farther behind, it seems, is Novartis (#3): PD-1 (potential candidates via its CoStim acquisition). It could be late for Novartis to bring a checkpoint inhibitor to market. By the time it gets its version out, Novartis should have four competitors with similarly functioning drugs.

Even before Baum made his bold claim, it was clear the FDA, researchers and industry understood the combination of checkpoint inhibitors and other agents and therapies would be the eventual approach for treating late-stage disease. As result, companies established various combination study relationships, and continue to do so.

Checkpoint inhibitor companies do this because PD-1s and PD-L1s should work more effectively in combination depending on the setting (e.g., co-inhibitory/co-stimulatory). Companies with no checkpoint inhibitors (and no robust immune system primers) do this because a combination should provide them an advantage for their treatments that would be surpassed if they did not do these partnerships at all, and potentially permit much earlier market access for their non-checkpoint inhibitor agent.

For example:

• Pfizer (#11): Merck's PD-1 + targeted therapy (crizotinib/Xalkori),  + targeted therapy  axitinib/Inlyta), and + 4-1BB co-stimulatory agent (PF-05082566), 

• Amgen (#2): Bristol-Myers's CTLA-4 + intralesional (tamilogene laherparapvec or T-Vec), and Merck's PD-1 + intralesional (T-Vec),

• Celgene (#4): Bristol-Myers' PD-1 + targeted therapy (paclitaxel/Abraxane), and

• Novartis (#3): In addition to PD-1s and CAR (chimeric antigen receptor)-T cell therapy, Bristol-Myers' PD-1 + [separately] three targeted therapies (ceritinib/Zykadia, INC280, and EGF816).

SugarCone Biotech's Paul Rennert, in his September 2014 blog post Rational Immunotherapy Combinations: How’s That Work Again?, wrote about "...the question of how to parse the potential immunotherapy combinations that may soon become available, noting that different combinations may prove differentially useful across a wide range of oncology indications." His post is very informative. It is a not-so-simple process to understand and develop the appropriate rationale for why, what and how one combines different agents and therapies, as he clearly illustrates in a cursorily-populated table:

Click to enlarge.

Rennert goes on to write (where I look past his use of vaccines to the broader issue of how to generate many more antigens in order for PD-1s and PD-L1s to be more successful in their individual efforts towards the combination):

"There are other consequences in this new landscape. Nearly every oncology vaccine company claims that as soon as they run a combo trial with an anti-PD-1 or anti-CTLA4 antibody their particular vaccine approach will perform beautifully. There are a few problems with this, notably, very few of these companies have a chance in hell of getting an anti-PD-1 antibody via collaboration, and the rest will pay heavily for the privilege. Second we have no idea of how to rationally pair vaccines with immune checkpoint exposure in order to induce optimal responses. Third, there are not enough patients to go around, a simple fact in many indications."

As recent as the company's ESMO 2014 poster Provectus highlighted the combination study aspect of its business/corporate development strategy.

Click to enlarge.

The value proposition/rationale (but not necessarily the specific medical and scientific rationale and sequencing) for combining PV-10 with a checkpoint inhibitor seems straightforward:

• Immune checkpoint inhibitors have been and will be combined with intralesional agents. Thus far, Bristol-Myers & CTLA-4/ipilimumab/Yervoy and Amgen's T-Vec, Merck & PD-1/pembrolizumab/Keytruda and T-Vec. As expected, the combination of ipilimumab and T-Vec produced responses rates higher than the individual treatments themselves (ASCO 2014). That is, Response_A+B > Response_B > Response_A (A = ipilimumab, B = T-Vec).

• The combination produced notable immunologic signaling. This also was reported from the CTLA-4/ipilimumab and T-Vec combination study at ASCO 2014. The greater the immunologic signaling, the greater [one would imagine] the response and interaction of the immune system to fight and hopefully beat cancer. That is, perhaps, Signaling_A+B > Signaling_B > Signaling_A. The poster presented at ASCO of this work only conveyed the immunologic signaling of the combination.

• PV-10 kills tumors far better than T-Vec. PV-10 produce higher complete responses than T-Vec. The medical community has understood for a while the more antigens produced and presented as a result of tumor destruction (antigenization) the more likely the potential of a greater immune response by the body.

If T-Vec works, PV-10 should work better. But, how much better?

Dr. Agarwala noted in his October 12th presentation at the III Eurasian Melanoma and Skin Cancers Forum that intralesional therapies (PV-10 and T-Vec, since Allovectin-7 failed its metastatic melanoma Phase 3 trial) would form the backbone of combination therapies.

Click to enlarge.

The challenge for Big Pharma, perhaps for some of them more than others, is the lack of "hard data" about PV-10's strong immunologic properties. Presumably Moffitt Cancer Center's presentation on November 8th -- Coinhibition and Costimulation: Targets and Strategies session, Efficacy of Intralesional Injection with PV-10 in Combination with Co-Inhibitory Blockade in a Murine Model of Melanoma poster -- will provide it.

What makes Provectus think they can overcome Rennert's obstacles above?

First, does Provectus have a chance of collaborating with a PD-1 and/or PD-L1 owner? I think the company has a good chance, but the cost or benefit of doing so has yet to be determined (i.e., the details, considerations and concessions of a contractual relationship, and not so much the trial design itself). Obviously, the more a checkpoint inhibitor owner wants to combine with PV-10, the better for Provectus.

I think it's reasonable to believe the Global 5 are aware of PV-10's potential, and its possibilities in combination with immune checkpoint inhibitors. Due diligence begins with getting to know the compound, the available data and practitioners knowledgeable in its use, and then learning more about its combination potential. In regards to the former (i.e., getting to know PV-10), a Merck researcher purportedly attended Moffitt's Dr. Vernon Sondak's June 27th PV-10 presentation at the 4th European Post-Chicago Melanoma/Skin Cancer Meeting specifically to hear/learn more about the drug (a European-based Provectus shareholder routinely attends PV-10 data presentations at European medical conferences). Roche seems to be aware of PV-10, but questions the lack of "hard data" about the compound's immunologic signaling.

Second, how would Big Pharma and Provectus rationally pair immune checkpoint blockade with PV-10? Moffitt's upcoming SITC work presumably should begin to describe how to rationally pair, and dose and sequence PV-10 and a checkpoint inhibitor. It seems the immune system primer & activator/cancer antigen releaser should be given first, followed by the checkpoint inhibitor. In the ipilimumab + T-Vec trial noted above, the investigators sequenced the drugs in that way:

T-VEC was given intralesionally at week 1, week 4, and then every other week. Ipilimumab was given every third week starting at week 6. Treatment continued until dose limiting toxicity, intolerance, all injectable tumors disappeared or disease progression.

I think Rennert's larger question is the whys of rationally pairing drugs, before getting around to the hows. I liken it to understanding what step or steps of the cancer immunity cycle each drug partner in a combination promotes.

Third, are there enough patients to go around? According to Provectus there are sufficient patients available because investigators have asked to use PV-10 in combination with other agents in studies when they are established. This too remains to be seen.

Speaking of Dr. Agarwala, he probably will make a similar presentation to the one he made in Suzdal, Russia at the 2014 Society for Melanoma Research Congress in Zurich, Switzerland (a satellite symposium sponsored by Amgen and entitled Oncolytic immunotherapy – engaging the immune system to target melanoma).

The company PV-10 keeps

There is a saying "you are the company you keep," or perhaps "you're only as good as the company you keep." PV-10's company? MPDL3280A (Roche),  Yervoy and nivolumab (Bristol Myers), MK-3475 (Merck), T-Vec (Amgen), Abraxane (Celgene), etc.

Over the next three months, April to June, PV-10 data will be presented and/or discussed in at least 6 presentations at five medical conferences. Never in Provectus' history has data been presented at so many venues in such a short period of time.

Click on the figure to enlarge it.

First, on April 6th, Moffitt Cancer Center presents a poster at the 2014 annual meeting of the American Academy of Cancer Research ("AACR") entitled Induction of anti-melanoma immunity after intralesional ablative therapy. The focus likely should be on the second step of PV-10's two-step mechanism of action ("MOA"), and perhaps further explanation of the drug's viability for multiple indications like breast cancer, on which I think Moffitt and Provectus may further collaborate.

Second, on April 11th, "PV-10 will be an integral part of..." the HemOnc Today - Melanoma and Cutaneous Malignancies Conference's Session 4: Local and Regional Therapy. The session will include Amgen's T-Vec, Vical's failed Allovectin-7, other intralesional therapies, and a debate about the role of systemic intralesional therapy.

Third, on May 7th, St. Luke's University Health Network's and Provectus principal investigator Dr. Sanjiv Agarwala will participate in a plenary session at the 10th European Association of Dermato-Oncology ("EADO") congress entitled New Drugs and new trials. Other drugs on the agenda include:

• Amgen's T-Vec,
• Bristol-Myer's Yervoy (ipilimumab, an anti-CTLA4 agent),
• Roche's MPDL3280A (an anti-PD-L1 agent),
• BMS' nivolumab (an anti-PD-1 agent),
• BMS' combination of Yervoy and nivolumab,
• Merck's MK-3475 (an anti-PD-1 agent), and
• OncoSec's ImmunoPulse.

Click on the figure to enlarge it.

Amgen, Bristol-Myers, Roche, Merck and...Provectus.

Fourth, on June 2nd, Dr. Agarwala will present a poster at the 2014 annual meeting of the American Society of Clinical Oncology ("ASCO") during the day's Poster Highlight Session (in addition to the regular poster presentation day and time) entitled Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions. The focus likely should be on the 28-patient data subset of Provectus' metastatic melanoma Phase 2 trial that formed the basis of the company's breakthrough therapy designation ("BTD") application.

You know, the BTD submission stated or commented on publicly by management [at least] 11 times thus far --five press releases, three Provectus News items (to be fair, BTD submission was picked up by third parties),  two 8-Ks, one 10-K, and a partridge in a pear tree -- and on the website.

I'm obviously poking fun at management. For a company with a history of being somewhat opaque or obtuse in communications regarding clinical data, regulatory interaction, and other matters, it's not unreasonable for the casual observer to think Provectus currently is promotional in regards to their BTD submission. The change in stride certainly is notable. Once or twice, in an SEC filing, I get. But, more than ten times? The same casual observer might think it strange; however, long-time investors who have done their due diligence on Eric's historical interactions with the FDA along the company's regulatory approval journey understand, and I think the company has said as much in its PRs: the Agency appears to have (has) agreed tumor-based endpoints (i.e., complete response: "...if you inject PV-10 into melanoma tumors, the tumors go away...") and not survival-based endpoints (e.g., overall survival, progression free survival, etc.) are appropriate for approving this drug. If you assume this Agency embracing of PV-10 and hurdle-clearing of endpoints, and I cannot fault folks if they don't, one could understand management's confidence in securing BTD, and then (and only then) these many BTD submission mentions.

BTD, in some respects, marks the beginning of a potentially speedy pathway to approval. The decision tree might be one of the FDA either (a) requiring the company to conduct a bridging study in order to file a new drug application ("NDA") for PV-10 -- "...before...we have approval to sell PV-10..." -- or (b) permitting the study to be a post-marketing requirement/commitment -- "...after we have approval to sell PV-10..."

Click on the figure to enlarge it.

Managing our investment in Provectus of course requires me to manage risk. Even as a presumably well-informed investor, it's still very hard for me to assume a BTD award is in the bag. Probable, yes. Certain, no. The FDA may say no, and the company (like others turned down before them) very likely would have been told by the Agency to obtain more clinical data. But, as I wrote in my post Provectus Submits Application to FDA for Breakthrough Therapy Designation, the FDA doesn't want nor does it encourage companies to submit BTD applications that are more likely to be turned down than accepted. One would imagine the boldness with which management speaks of BTD suggests they very strongly believe they'll attain it (because of interactions with the Agency that suggest so) on, before or well before May 23rd.

Fifth, also on June 2nd, Moffitt will present a poster at ASCO, also during the day's Poster Highlight Session (again, in addition to the regular poster presentation day and time) entitled Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions. This presentation should elaborate on both the clinical (MOA step #1, ablation/destruction of injected lesions) and immune (MOA step #2, immune response/destruction of non-injected lesions) efficacy observed in patients enrolled in the cancer center's feasibility study, where Moffitt essentially experimented on them.

Sixth, on June 27th, Moffitt's Dr. Vernon Sondak will participate in a symposium session at the 4th European Post-Chicago Melanoma/Skin Cancer Meeting entitled New drugs and trials: An update on immunotherapy and chemotherapy. Other drugs on the agenda include:

• Bristol-Myer's Yervoy (ipilimumab),
• BMS' nivolumab,
• Merck's MK-3475,
• GlaxoSmithKline's failed MAGE-A3 (a cancer vaccine),
• Amgen's T-Vec,
• OncoSec's ImmunoPulse, and
• Celgene's Abraxane (chemotherapy nab-paclitaxel).

Click on the figure to enlarge it.

Bristol-Myers, Merck, GlaxoSmithKline, Amgen, Celgene and...Provectus.

This month and over the next two, we can expect a lot of pre-clinical and clinical PV-10 data, and potentially a positive BTD decision. More data and MOA elucidation is good (and I am very much looking forward to reading them). Regulatory clarity and steps (i.e., BTD and what comes with it) is better, and very, very necessary for this company.

But how now China? And/or other regional transactions? And/or the endgame?

If management believes it will get BTD for PV-10 for locally advanced melanoma, thinks they might have to conduct a bridging study prior to filing the NDA (i.e., in this case de facto approval) "at worst," has about $16 million of cash on the balance sheet (see the company's March 24th PR), and possibly estimates the cost of a bridging study at $5-$10 million or thereabouts (comparable or less if the trial is terminated early, and some patient number overlap is acceptable to the various geographical regulatory agencies), why consummate a deal with a Chinese partner or any partner for that matter until after a BTD decision and clarity is achieved as to the step(s) toward and after approval?

I'm particularly interested in Dr. Agarwala's ASCO presentation, which will focus on the 28-patient subset that formed the basis for Provectus' BTD application and in all likelihood its awarding. This data was first broken out at the 2013 European Cancer Congress in September: Exploratory Data Analyses of Intralesional PV-10 Clinical Phase 2 Study Results Presented at ECC 2013 Demonstrate Effective Locoregional Disease Control and Support Systemic Immunologic Activity in Refractory Metastatic Melanoma:

Click the table to enlarge it. Poster source is here.

If one were to not consider the non-evaluable subjects (NEV above), loco-regional control of the disease -- the value proposition underscoring approval of PV-10 for locally advanced melanoma: the drug forestalls or defeats the spread of the disease to a metastatic stage, or alternatively "...if you inject PV-10 into melanoma tumors, the tumors go away..." -- increases to 88%.

Craig would tell you the residual percentage, 12% w/o NEV (or 18% as presented at ECC 2013 for the full subset), is more than likely due to physicians not injecting the lesions properly and thus not getting the expected result. The results PV-10 and PH-10 generate appear to be startlingly consistent from properly injected lesion (volume of drug per unit volume of tumor, proper administration) to properly injected lesion.

88% loco-regional control, and you want to do a deal now? Wouldn't it make sense to wait or seriously contemplate waiting until after a decision (unless a counter party aggressively bids for a deal, which doesn't appear to be the case at the moment)? There is of course risk in doing so; however, if you're supremely confident based on clinical data and regulatory interaction heretofore, you wait. Wait for the bigger regional check as milestone payments turn into upfront payments based on what transpires regulatory-wise. Wait to submit a BTD application or two for your liver program (e.g., in combination with maintenance sorafenib, cancers metastatic to the liver). Wait until impatient Big Pharma with drugs and compounds that are not sufficiently efficacious or safe, and very expensive, see their respective Kodak moment coming and decide to deal. By Kodak moment, I specifically mean technology disruption that could end in a near-zero sum game in the case of PV-10. If you own it you survive, and flourish. If you don't...

As folks line up to associate themselves with Provectus, and/or deal with the company, Pfizer might lose first mover advantage. Provectus has three executives from two Top 15 ranked (by pharmaceutical sales) companies on its strategic advisory board. It may add executives from up to three more Top 15 firms.

Click on the figure to enlarge it. The table source is here.

There is much for the company to accomplish before thoughts of the end-game can and should percolate. And although I've written often on this blog that I think Pfizer will be the end-game acquirer, and a topic for another post, it's not a given the company with the biggest checkbook (and the nose under the tent for the longest time) wins. Vision, strategic rationale, ambitiousness and, ultimately, verve, together with a not inconsequential balance sheet should win the M&A day.

PVCT on SeekingAlpha: Yervoy Vs. Zelboraf: Melanoma Drugs Battle For Market Share

An article on SeekingAlpha by Peter Geschek on July 24 contrasted and compared metastic melanoma drugs Yervoy (Bristol Meyers) and Zelboraf (Roche). Towards the end, the author briefly mentions Provectus.