Absent Minded Professor

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Yesterday was an important day for FDA to hear from physicians treating patients with bladder cancer and with papillary disease without CIS and listening to the real-world evidence of the struggle (and that is the word the clinicians in the panel discussion used) that faces clinicians addressing patients with bladder cancer. The BCG shortage has such incredible implications and even ethical implications in which the doctors reveal that while they feel an ethical dilemma in order for patients to receive access to BCG, they have to force the patient into a clinical trial. Today, I will address the issue of Panel 1 (Is CIS and Papillary the same disease and how do we treat it in the real-world?) and my takeaway and tomorrow of Panel 2 (BCG Shortage and how it affects America today after 14-years of shortage). The Key Takeaways from Panel 1 (I will also add further details in a future Article on my X): Here we go of what I learned from listening to the panel of thought leaders in the field and I sat in the audience quietly taking notes. The feedback and conclusions I understood that were made by these thought leaders and shared with the FDA are as follows that: 1. Papillary disease and CIS disease are the SAME DISEASE – this was the core of the discussion since it affects how patients are treated in the real-world. 2. This conclusion came from TWO relevant findings 1. The biological basis of the disease and 2. The real-world diagnosis of papillary disease alone and once such a diagnosis is made, the real-world treatment that urologists apply. These conclusions and statements made by the panelists were of great significance to educating the FDA and more importantly on behalf of a patient diagnosed with papillary disease since it affects the decision of how patients with papillary disease alone are treated today in the real-world and not some hypothetical approach to making therapies available. 3. One basis for the conclusion that the panelists made that papillary disease and CIS disease is the same was based on the BIOLOGY of the origin of CIS and papillary cancer in the bladder: that papillary and CIS cancer arise from the SAME CANCER GENERATING CLONE, and that CIS (flat) is just a different phenotypic evolution into papillary (the raised form and grape like). In fact, there was some statements that perhaps papillary is just a further growth which starts from CIS which has not been recognized or missed before. 4. The second and REAL WORLD BASIS OF HOW UROLOGISTS IN THE REAL-WORLD make a diagnosis that CIS is present was highly revealing to even to some of the panelists in the audience, as well as to the FDA: that in the real-world only ~6% percent of urologists use a type of light (blue) that helps identifying CIS even if CIS was present with the papillary disease and in most cases the presence of CIS is missed during the initial cystoscopy. 5. But, the most revealing statement made by the clinicians in the panel were when a diagnosis of papillary alone is made, CIS actually probably exists we just don’t see it (and in some cases, the panelists went on to say, once we have diagnosed high-grade papillary, we don’t bother to look for CIS since the decision of how to treat the patient with papillary disease alone IS THE SAME as if the patient had CIS and the presence of CIS was irrelevant to the panelist treatment decision)...  this is worthy repeating... that the treatment in the decision making of the clinicians that once they find high-grade papillary alone, they go on to TREAT NO DIFFERENTLY THAN WITH CIS AND PAPILLARY in high-grade BCG unresponsive non-muscle invasive bladder cancer! But here is the rub: THE FDA has not approved any therapy for papillary disease alone since they insist on doing a randomized trial (which some of the panelists state may take hundreds of patients and many years… and furthermore what would be the control to compare to since nothing in the treatment of papillary disease alone is approved??? The FDA wants to consider CHEMO as the control and even named a project during the panel discussion to advance more chemo! (yet we NOW KNOW based on the FDAs own recent approval for chemo on behalf of a large pharma, in BCG unresponsive non-muscle invasive bladder cancer in CIS and papillary that chemo (gemcitabine) results in a 1.2% percent fatality and a 24% percent lymphopenia in patients with bladder cancer receiving chemotherapy and worse we also now know in peer reviewed scientific articles that lymphopenia results in more rapid progression to muscle invasive disease (the whole point of what we are trying to prevent) and early mortality! We did not have this information years ago. But we do have the information today. In fact, in 2026 NCCN panelists consisting of ~30 thought leaders treating patients with bladder cancer from NCI comprehensive cancer centers voted that a chemo free, immunotherapy with BCG and an IL-15 superagonist is a viable treatment for BCG unresponsive non-muscle invasive bladder cancer of patients with papillary disease alone, based on the data published in peer review journal and sitting in the hands of FDA for review as a supplemental approval for the already approved indication of BCG unresponsive non-muscle invasive bladder cancer with CIS and papillary. This already approved indication is important to note when you hear what the panelists in the real-world do when faced with a patient with papillary disease alone. This treatment decision is made in the real-world by clinicians, and was revealed to the FDA at this workshop as follows: • This reveal by the clinicians in the real-world to the FDA is THE MOST TELLING. When asked by the FDA of the panel, what do these clinicians do when they find a patient with papillary disease alone they state: "WE USE AS ON OFF-LABEL TREATMENT THE THERAPIES THE FDA HAS ALRADY APPROVED FOR CIS AND PAPILLARY SINCE THE FDA HAS NEVER APPROVED ANYTHING FOR PAPILLARY ALONE!!" Boom!!! That is the real-world and I hope the reviewers heard this loud and clear. So what was not said on behalf of the patients and the doctors in that meeting to the FDA was “Why should both the doctor and patient have to go through the pain of arguing with their insurance companies to be allowed to use the non-FDA approved drug (but in essence already approved) in an off-label setting??” • This treatment decision by the panelists of trying everything to spare the patients from losing their bladder was consistent amongst them. Ironically the day before the panelist meeting, I had a podcast interview with one of the most respected bladder specialists, Dr. Ashish Kamat, who was instrumental in developing guidelines for FDA in 2016 as to how to manage and design clinical trials for patients with BCG unresponsive bladder cancer and the co-editor with Dr. Peter Black on the book entitled, “Bladder Cancer, A Practical Guide”, Dr. Kamat volunteered during our taped conversation together that he too treats high-grade PAPILLARY DISEASE THE SAME WHETHER IT IS PAPILLARY ALONE OR PAPILLARY WITH CIS!... especially since most miss the CIS component even if it is there! So that was my takeaway and the rationale  we have been  making with FDA for years now. Please listen to the workshop meeting that the FDA recorded and see what you think. Our sBLA is in the hands of the FDA now. I truly hope they listen to the real-world pleas of both the thought leader panelists they convened as well as the interests of the patients suffering from bladder cancer and looking for any way in which the patients could avoid the high morbidity and life changing event of having their bladder removed. Any treatment that could avoid a loss of an organ should be made available to Americans as rapidly as possible. Cancer is a war against time. The most encouraging statement I heard from the FDA was a question near the end of the session to the panelists that, “should high-grade non-muscle invasive bladder cancer be considered a single unit of identification for the indication?”. I took that to mean that finally the reviewers understood that currently approved treatment for NMIBC was the treatment of the biology (high-grade non-responsive to BCG, non-muscle invasive bladder cancer) and not the indication as currently limited to the treatment of a compartmentalized anatomy of whether the patient had CIS alone, or CIS with papillary, or papillary alone. In fact, this question posed by the FDA reviewers to the panelists was exactly the right question and my answer (even though I was not invited to participate) is absolutely yes – that the indication for the treatment of non-muscle invasive bladder cancer that is non-responsive to BCG should be “for the treatment of BCG exposed high-grade non-muscle invasive bladder cancer”. This is the real-world. By the way, I think the FDA may have been surprised by the statement of the panelists that in the real-world, there is no such thing as a clinical diagnosis of BCG unresponsive disease and in fact clinicians go through contortions of 5+2 BCG treatment just to accommodate this artificial non-clinical terminology. BCG exposed and non-responsiveness is the real-world. Next, I will present more details based on peer reviewed scientific evidence in the Articles section of X on panel 1 and will address panel 2 (BCG shortage on how it affects Americans).

It’s been quite a day. News coming soon re our sBLA response from FDA. Stay tuned.