May 25, 2016

Checkpoint Inhibition Differentiation or Death: Proprietary Combinations with Protectable Agents

Updated below.

From this project's Twitter feed: Dr. Sally Church, PhD, ‏@MaverickNY
Click to enlarge. Tweet image source
How would Big Pharma distinguish each of its immune checkpoint inhibitors (CIs) from another? Efficacy? Tolerability? Cancer indication? Cost? Within groups (e.g., PD-1s, PD-L1s, etc.), efficacy and safety should equivalent. Different antibodies — for example, with the PD-1s, like nivolumab/Opdivo and pembrolizumab/Keytruda — function in almost identical fashion and differ only by means of manufacture and corporate decisions made with regards to clinical development (e.g., dose schedule, target indication). Magically, there is parity in pricing.

Based on drug sales to date and sales projections thus far, captured in part by @grhyasen's tweet graphic above, Bristol-Myers (nivolumab/Opdivo) and Merck & Co. (pembrolizumab/Keytruda) may be in no serious rush to differentiate their CIs beyond their current, respective corporate strategies. But Roche (atezolizumab/Tecentriq), AstraZeneca (durvalumab) and Merck KGaA/Pfizer (avelumab), all with "late to market" CIs, surely must be thinking about ways to differentiate their respective compounds.

Does meaningful, sustainable and profitable differentiation come in the form of combination, and thus in the form of a partner compound for a CI? In other words, could combination create branded differentiation — ultimately based on efficacy, tolerability, indication and cost of the combination. Proprietary combinations with protectable agents.

Novartis, one Big Pharma without a "lead CI" but having PD-1, TIM-3, LAG-3 and PD-L1 CIs within its pipeline, seems to have begun its brand differentiation by expanding its strategic thinking to include or focus on first-in-class combinations. See Pharmaceuticals and Oncology Business Units, Meet Novartis Management, May 24-25, 2016:
Click to enlarge. Fuzzy orange rectangle is mine
Click to enlarge. Fuzzy orange rectangle is mine
PV-10's, and thus Provectus', value proposition to the likes of Roche, AstraZeneca, Merck KGaA, Novartis, etc. might be to (a) combine their CI with PV-10 and (b) use Provectus' combo patent* to defend the unique combination thus formed — a proprietary combination with a protected agent.

* United States Patent No. 9,107,887, Eagle et al., August 18, 2015, Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer

Updated (6/11/16): Deena Beasley, Reuters, June 11th, Regulator says too many drugmakers chasing same cancer strategy:
"A new type of cancer drug that takes the brakes off the body's immune system has given drugmakers some remarkable wins against the deadly disease, but a top U.S. regulator says too many companies are focused on the same approach. 
Dr. Richard Pazdur, head of the Food and Drug Administration's office of oncology products, was referring to therapies designed to disable the PD-1 protein that tumors use to evade the immune system...  
"People should ask themselves ... would we be better off spending those resources into looking at more novel drugs?" Pazdur told Reuters during the annual American Society of Clinical Oncology (ASCO) meeting in Chicago this week.... 
"As with everything in drug development, it is about reduction of risk," he said. But the number of similar drugs in development at the same time is a first in the oncology field, and latecomers to the PD-1 market will likely be relegated to "niche" indications, he added. 
Drug company executives disputed Pazdur's critique. In interviews with Reuters, they argued that the science around cancer is advancing rapidly, with a focus on how to best combine therapies to attack multiple mechanisms of the disease, determine which patients are most likely to respond to them and how long patients will need to be treated."
Blumenthal and Pazdur, Response Rate as an Approval End Point in OncologyJAMA Oncol. 2016;2(6):780-781.
"Overall response rate (ORR) as a surrogate end point in oncology drug approval has a long history. In the 1970s, the US Food and Drug Administration (FDA) usually approved drugs on the basis of ORR. In the 1980s, after discussions with the Oncologic Drug Advisory Committee, the FDA determined that cancer drug approval should be based on more direct evidence of clinical benefit, such as improvements in overall survival (OS), tumor-related symptoms, or physical function.1 In the past decade, due to an improved understanding of the genomic underpinnings of cancer, better molecular characterization of tumors, and more precisely targeted agents, unprecedented rates of response have radically altered the therapeutic landscape in a number of malignant neoplasms. Therefore, ORR and duration of response as assessed in single-arm trials has served as the basis of accelerated approval and at times regular approval in a number of refractory malignant neoplasms, including non–small-cell lung cancer (NSCLC), lymphoma, melanoma, and myeloma."
This presumably works [very well] only for systemic drugs using standard RECIST. Provectus' pivotal melanoma Phase 3 is employing [standard] RECIST 1.1.

Road tripping:
My proxy vote should be posted by June 14th.

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