July 11, 2016

Clash of Clans

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Every drug or drug compound, and drug category or class has a clan.

Clan members comprise all manner of biopharmaceutical industry constituency or stakeholder; from physicians, clinicians and medical researchers to global regulatory agency staff to Big Pharma/Biotech executives and employees to pharma and biotech investors and traders to media, journalists and commentators to medical conferences to...

Whether one's "schtick" are immune checkpoint inhibitors, targeted therapies, radiation or radiotherapy, intralesional therapies, etc., we've all got our clan or tribe.

I believe, by virtue of this blog and talking our book, that our clan(s) is(are):
  • First, PV-10, and Rose Bengal, which fall into the category of small [chemical] molecules that rely on their physical (and not biological) chemistry properties, and
  • Second, intralesional (IL) or intratumoral (IL) therapies (aka local, loco-regional or local-regional, and regional therapies), because route of delivery matters.
But there is good reason for the biopharmaceutical industry ecosystem to be skeptical of the class of IL therapies. First, until very recently (October 2015 for talimogene laherparepvec or T-Vec), there had been no history of clinical success and, thus, regulatory approval. Second, what promising, approved therapy there has been (T-Vec) has turned out to be a marginal product with an uncompelling clinical value proposition. Before Amgen's T-Vec was approved in 2015 as Imlygic for advanced melanoma, failure preceded it more than two year before in the form of Vical's IL agent velimogene aliplasmid (Allovectin-7) in August 2013 for the same indication. Before Vical, there was the failure of IL agent bacillus Calmette-Guérin (BCG) in 1978, also for advanced melanoma. Taken together, IL therapies would have a modest-to-no history of regulatory validation for nearly 40 years.

Now consider HemOnc Today's July 10, 2016 article entitled "Intralesional agents show promise in melanoma but may serve ‘narrow clientele.’" After reading it, I am struck by what seems to be physician clan members -- of the IL therapy clan -- endeavoring to frame the potentially notable clinical benefits and patient outcomes IL cancer therapies could generate or yield if only there was a better IL therapy to be their flagbearer. T-Vec was the first guy through the wall, opening the regulatory and commercial doors for IL therapies. The article made me think these clan members were waiting for PV-10 to bust through the door, breaking its frame in the process.
  • HemOnc Today's article's page links
  • Quoted physicians
    • Sanjiv S. Agarwala, MD (medical oncologist, aka Dr. Rose Bengal) —a T-Vec and PV-10 clinical trial investigator from St. Luke's University Health Network in Bethlehem, Pennsylvania,
    • Robert H.I. Andtbacka, MD (surgical oncologist) — a T-Vec and PV-10 clinical trial investigator from Huntsman Cancer Institute in Salt Lake City, Utah,
    • Dale Han, MD (surgical oncologist) — no affiliations were disclosed, and from Yale School of Medicine in New Haven, Connecticut,
    • Vernon K. Sondak, MD (surgical oncologist) — a consultant to Amgen and Provectus from Moffitt Cancer Center in Tampa, Florida, and
    • Jeffrey S. Weber, MD, PhD (medical oncologist) — an advisor to Amgen and a PV-10 clinical researcher from NYU Langone Medical Center.
Article paragraphs and quotes of interest to me:
  • "HemOnc Today spoke with medical and surgical melanoma specialists about the future of intralesional agents for melanoma, whether oncolytic agents likely will be used as single agents or in combination with immunotherapies, and the lingering questions surrounding T-VEC’s efficacy based on the OPTiM trial."
  • "“If you look specifically at patients with stage IIIB or stage IIIC disease on the OPTiM trial, their response rate was 52%,” Robert H.I. Andtbacka, MD, CM, FACS, FRCSC, associate professor of surgery at Huntsman Cancer Institute at University of Utah, as well as a HemOnc Today Editorial Board member, told HemOnc Today. “None of the other immunotherapies and checkpoint inhibitors have come close to having that response rate in that patient population.” 
Andtbacka, who served as an investigator on the OPTiM trial, said the positive outcome and FDA approval signal the utility of intralesional agents in the rapidly expanding melanoma landscape."
  • "The relatively mild toxicity profile of T-VEC may make it more appealing to some patients than immunotherapies, which can produce virulent adverse events, Sondak added.
“Adverse events can be quite modest when you are just injecting a [lesion], rather than trying to treat the entire patient,” Sondak said. “If we can get the immune system to pay attention to the melanoma and do something good because of it, then you are looking at a low-toxicity means of producing an important, clinically relevant immune response.”" 
  • "Although most oncologists agree T-VEC has a role in the melanoma treatment armamentarium, the design of the OPTiM trial has prompted a number of clinicians to question how large that role should be.
The primary reason for concern is the use of GM-CSF as the control. 
“T-VEC was approved on the basis of a clinical trial design that will certainly never be replicated,” Sondak said. “The control arm was basically a placebo, with no basis in why one would choose to use that particular regimen. I don’t know if that design would be approved today by the FDA.” 
OPTiM researchers enrolled patients between May 2009 and July 2011. The majority of new melanoma therapeutic options were approved after that period, leaving some oncologists to wonder how the results might differ if the trial were conducted now."
  • "“There are many patients who have tumors that do not have tumor-infiltrating lymphocytes, and checkpoint inhibitors cannot work unless those lymphocytes are there,” Andtbacka said. “Using an oncolytic therapy can actually change the tumor microenvironment, and essentially make a ‘cold’ tumor become a ‘hot’ tumor. When we do that, it appears that we can make a nonresponder into a responder.”"
  • "“The preliminary data for T-VEC combinations look promising,” Han said. “The whole idea of treating systemic melanoma has really blossomed into the idea of combination therapy. Combining T-VEC with other effective systemic treatments was the natural next step to see if we could further improve outcomes.”"
  • "“The beauty of combinations is that you can take a patient who has an in situ tumor reachable by a needle and inject it with something that makes the tumor more immunogenic,” Agarwala said. “If you throw in a confirmed immunotherapy that works well, you have the potential for synergy.”
    Because melanoma has been shown to respond to combinations, the use of these regimens should be considered when possible, Agarwala added. 
    “I like to say, ‘Make the tumor your friend, and make it your ally,’” he said. “If you can’t remove the tumor — if you’ve tried everything and it keeps coming back — instead of just trying to remove it again or giving systemic therapy, why not add an intralesional agent that gets into the microenvironment and releases antigens? That is a concept that highly appeals to me.”"
    • "The labor involved in preparing a T-VEC injection may drive cost-related considerations.
    “The biggest cost factor with an intralesional therapy, aside from the drug, is time,” Agarwala said. “It’s not just a nurse hanging a bag. You have to have a doctor or a provider actually do a procedure, and that procedure is billable. It taxes the provider’s time. I am not sure if anyone has studied the total cost yet, but the short answer is that it’s an issue.” 
    Weber agreed. 
    “An injection like this can take up a room for 20 minutes and might be viewed as a hassle by a doctor with a busy practice,” Weber said. “If a nurse practitioner is doing the injection, that’s time she or he is not seeing other patients. I do not think it is unreasonable to say that some busy oncologists view it as more work than it is worth.”"
    • "T-VEC is the first intralesional agent to be approved as monotherapy for the treatment of advanced melanoma. However, it is far from the only oncolytic agent under investigation.
    “These agents are safe and produce good response rates,” Agarwala said. “Some of the ongoing trials of new oncolytic agents can address the concerns left over from the OPTiM trial.” 
    Agarwala serves as an investigator on a phase 3 study investigating PV-10 (Provectus Biopharmaceuticals), an injectable form of rose bengal disodium that received FDA orphan drug designation for melanoma and hepatocellular carcinoma."
    • "“The current PV-10 randomized trial only includes patients who have failed immunotherapy or are not candidates,” Agarwala said. “In that sense, it is much more of a real-world trial [than OPTiM]. The control arm of the trial is chemotherapy, which is reasonable, because if you have tried everything else, it is a fair comparator.”"
    • "“These agents may have theoretical or practical advantages compared with T-VEC,” Sondak said. “They are all worthy of investigation, without question, and some could be real advances. There is value to having T-VEC available, but it will also be important for these other agents to have their chance to show what they can do.”"
    For the first time that I can recall, an article discussing by therapies addressed treatment administration by non-physician providers (e.g., nurse practitioners, physician's assistants, nurses). See page 6 of the article here.

    The article's author should have discussed this topic with Dr. Agarwala's NPs, PAs and/or RNs, and solicited their opinions of PV-10.

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