April 29, 2015

The first guy through the wall

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Today's joint meeting of the Cellular, Tissue and Gene Therapies Advisory Committee ("CTGTAC") and Oncologic Drugs Advisory Committee ("ODAC") voted by an overwhelming 22-to-1 margin in favor (i.e., yes to the question) of talimogene laherparepvec ("T-Vec") having an overall favorable benefit-risk profile for the treatment of injectable regionally or distantly metastatic melanoma, and thus supporting traditional approval of the drug.

The meeting's positive outcome for T-Vec and Amgen also is a positive for PV-10 and Provectus. Both T-Vec and PV-10 are investigational intralesional ("IL") therapies, often referenced together, and share existing and potential clinical trial investigators and/or paid consultants such as MD Anderson Cancer Center's Dr. Merrick Ross, MD, St. Luke's Cancer Center's Dr. Sanjiv Agarwala, MD, Hunstman Cancer Institute's Dr. Robert Andtbacka, MD, and Moffitt Cancer Center's Dr. Vernon Sondak, MD and Dr. Jonathan Zager, MD.

Two great sources of meeting coverage, with both insightful and observational tweet comments and commentary, were Jamie Singer (@JSwatercooler) and SAC Tracker (@FDAadcomm). Jamie is a consultant to Provectus. Tarius SAC Tracker provides global regulatory intelligence to the healthcare industry, and later wrote a summary of the meeting entitled US FDA Advisory Committee Supports Amgen’s T-Vec to Treat Metastatic Melanoma.

Amgen is seeking approval of T-Vec for the treatment of injectable regionally or distantly metastatic melanoma (side note: unresected or unresectable was not included in Big Biotech's proposed indication). FierceBiotech's John Carroll noted in his article about today's meeting: "The final decision is being left in the hands of the FDA, though today's vote would make T-Vec an odds-on favorite for approval." T-Vec's PDUFA date is October 27th (it previously was July 28th, and pushed back for Amgen to submit additional information.

My takeaways about the meeting's outcome as it relates to PV-10 include:

1. Today's decision was a very big win for IL agents for cancer.
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It bears repeating. The panel concluded that the reduction of injected tumors equates to/is clinical benefit.
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Hwu is MD Anderson Cancer Center's Dr. Patrick, MD (medical oncology), chair of Melanoma Medical Oncology and Sarcoma Medical Oncology, and recently named division head of Cancer Medicine.

Fierce further observed "[a] number of the experts noted that the more "arrows" they had in their therapeutic quiver, the better off patients would be," although Jamie tweeted:
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2. There is more work to do for IL agents to better clarify and demonstrate their role in treating late-stage cancer and patients with heavy disease burden and visceral disease — i.e., an IL agent like T-Vec or PV-10 (a stimulatory agent, co-stimulatory, start the engine, step on the gas pedal) plus an immune checkpoint inhibitor (an inhibitory agent, co-inhibitory, release the brakes).

Nevertheless, today's decision, assuming it is accompanied by FDA approval of T-Vec later this year, first opens the door for IL agents to metastatic or advanced melanoma. Approval would place T-Vec in the same group of approved agents for advanced melanoma that includes ipilimumab (approved in 2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), trametinib (2013), pembrolizumab (2014) and nivolumab (2014). All of the nibs and mabs are systemic agents. Peginterferon is systemically administered.

More than likely, use of IL agents for advanced melanoma as monotherapies will be limited to Stage IV M1a.
Click to enlarge. Amgen CTGTAC / ODAC Meeting Briefing Document, page 53. Purple emphasis is mine.
Click to enlarge. FDA CTGTAC / ODAC Meeting Briefing Document, page 14. Purple emphasis is mine.
Even more likely is the treatment of Stage IV M1a to M1c (especially) with the combination therapy of an IL agent and immune checkpoint blockade. Amgen currently has T-Vec in trials with ipilimumab and pembrolizumab for advanced melanoma (i.e., Stage IIIb to IVM1c Melanoma).

3. Today's decision reaffirmed the value of good IL agents for the treatment of earlier stages of disease (i.e., Stage 3), when all of the disease is accessible for injection, and for use first or second before other treatment options are considered, when the immune system is not overwhelmed by tumor burden and spread (as it is for most Stage 4 patients).
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PV-10's upcoming pivotal Phase 3 trial is for locally advanced cutaneous melanoma, and will be exclusively comprised of Stage IIIb-c patients (although it would appear 50% of the patients in the treatment arm must have failed at least one systemic immunotherapy or not be a candidate for them).

While members of the panel wanted to distinguish T-Vec's use between non-visceral (e.g., Stage IIIb-c and IVM1a) and visceral (IVM1b-c), rather than an overly broad distinction between Stage 3 and 4, one of hypotheses of PV-10's Phase 3 trial is that if the drug make lesions go away it will forestall progression of the patient's disease (which would be shown via the trial's progression free survival primary endpoint.)
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Amgen is pushing further to the left (i.e., earlier use) with T-Vec, comparing T-Vec and surgery to surgery alone in completely resectable Stage 3b-c and IVM1a melanoma: Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Melanoma.

4. PV-10 is of course a competitor to T-Vec.

From a 2012 presentation by Huntsman Cancer Center and lead T-Vec Phase 3 trial investigator Dr. Robert Andtbacka, MD (and now paid Provectus consultant and likely PV-10 Phase 3 trial investigator):
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Andtbacka recently said of T-Vec: “Our patients are living longer, and we’re able for the first time in melanoma to potentially talk about a cure, which is something we have not been able to talk about before,” said Dr. Robert Andtbacka, who is a surgical oncologist. Andtbacka said the new treatment teaches the body to heal itself. See Familiarity (April 7, 2015) on the blog's News Page.

Johns Hopkins University's Dr. Suzanne Topalian, MD referred to the drug as an autologous tumor vaccine (along with T-Vec and Allovectin-7). See Keep talking (and keep doing) (January 29, 2015) on the News Page.
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5. PV-10 is a much better IL agent than T-Vec.

Moffitt's Dr. Sondak (again, a paid consultant to both Amgen and Provectus) noted last year at the 4th European Post-Chicago Melanoma Meeting:
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Hunstman's Dr. Andtbacka historically has compared Phase 2 trial results of T-Vec and PV-10, the version below from 2012:
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My comparison (a sampling):
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Click to enlarge. Footnote 6 of above table.
T cells in the peripheral blood mononuclear cell ("PBMC") of melanoma patients

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