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.

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