RE:Seeking AlphaThis is a great article Beech, the most thorough I've seen.
Here's more but not all for your reading pleasure,
In Radiology, a colloquial term some used to describe an unexpected, interesting finding is fascinoma. This term applies quite well to the plucky, Montreal-based pharmaceutical company Telesta Therapeutics (OTCPK:BNHLF), as I believe that despite their recent setback, BNHLF has coyly approached a niche market, and has much to contribute to the well being of a select group of cancer patients.
The lead product in their pipeline, Mycobacterium phlei Cell Wall-Nucleic Acid Complex (MCNA), stands as a possible therapeutic alternative to cystectomy in the event of failure of the current biologic standard of care for superficial bladder cancer, intravesical administration of bacillus Calmette-Guerin (bCG). However, before launching into bCG and MCNA, let's first discuss bladder cancer.
Primary bladder cancer comes in three different types, including transitional cell carcinoma, adenocarcinoma, and squamous cell carcinoma, though mesenchymal, lymphogenic, and other neurogenic neoplasms may also arise in the tissues comprising the urinary bladder. Transitional cell carcinoma, also known as urothelial carcinoma, is the most common primary bladder neoplasm, accounting for up to 90% of all bladder tumors. It is further characterized by pathologic appearance - whether the cells appear flat or papillary (finger like) - and by its local behavior: muscle invasive or superficial.
Superficial bladder cancer, also known as non-muscle-invasive bladder cancer (NMIBC), involves the most superficial internal lining (mucosa) of the bladder, and/or the lamina propria, but spares the detrusor muscle. It can be high grade or low grade, depending on certain characteristics of the tumor cells, but needless to say, high-grade tumors impart a greater chance of recurrence and progression, while the opposite is true for low-grade tumors [1]. Fortunately, up to three quarters of all bladder cancers are categorized as NMIBC with most of those being low grade [2]. The standard of care for the treatment of low grade NMIBC is surgery and a single dose of intravesical chemotherapy.
Intermediate and high grade NMIBC undergo transurethral resection of bladder tumor (TURBT), followed later by intravesical administration of bCG, which has been shown in at least one meta-analysis to be superior to surgery alone or surgery + other chemotherapeutic agents [3]. bCG is the tuberculosis vaccine, which is cultured from live, attenuated Mycobacterium bovis. It was first utilized in an anticancer capacity in the 1930s, but became more commonplace as such in the 1970s [4]. Indeed, bCG can be thought of as one of the first biologics in that it engenders an immune response to the bacterium, which will also result in anti-tumor activity.
The logic of this regimen is to debulk the tumor, destroy microscopic disease, and spare the patient from cystectomy. However, 40-50% of patients with NMIBC will fail bCG therapy, putting them at risk for recurrence and progression of disease, especially in the case of high risk tumors (high grade T1/Ta tumors and/or carcinoma in situ, which is high-grade by definition) [5, 6]. As a result, bCG failure creates a major treatment dilemma: modify the intravesical treatment regimen or attempt additional bCG instillations and hope for success with the possibility of disease progression, or default to radical cystectomy - a major surgery with substantial quality of life considerations.
Here we begin our discussion of MCNA. Unlike bCG, MCNA does not contain live organisms, but is rather a suspension of the constituents of the bacterium; however, their mechanisms of action are thought to overlap. When placed in the human body, the immune system will recognize these constituents as foreign, and initiate an innate immune response. Similar to bCG, the immunologic mechanism is very complex and not fully understood, but it is thought that a cascading cellular and cytokine response mediated by toll-like receptors on cells of monocytic lineage results in tumor cell death. It is at this point that I would like to point out that, although the mechanisms of action of these two drugs are similar, MCNA was still able to illicit a beneficial therapeutic response in patients who failed bCG therapy as demonstrated in its Phase 3 clinical trial [7]. The implications of this are substantial, and raise the following important questions:
1. Does MCNA have the capacity to replace BCG as a standard of care? (We must remember that this drug was only tested in those who first failed BCG).
2. Can MCNA be administered concomitantly with BCG for a possible synergistic effect?
3. Will MCNA be tested in other neoplasms?
Now let's turn our attention to the FDA advisory committee's (ADCOM) recent "no" decision regarding the risk-benefit profile of MCNA. Indeed, a number of their concerns are significant in this imperfect trial, but not insurmountable. I'd like to highlight and discuss a few.
First, the ADCOM notes that the primary endpoint of at least 40% disease-free survival (DFS) was not reached. Instead, after accounting for some confounding factors, the FDA's analysis demonstrated a 20.9% DFS. Contrast this to Valrubicin, the only FDA-approved drug for patients with BCG-refractory carcinoma in situ, that demonstrates a 6-month remission of 18%, a two-year disease-free probability of 4% [8], and is thought comparable to MCNA [9]. All right, by the FDA's own admission, at least comparable to the current alternative therapy. Not too shabby.
Second, there is the concern of trial bias in that the analysis was conducted utilizing Kaplan-Meier technique, but whose results included patients that initiated the trial with carcinoma in situ (CIS), which would spuriously increase disease-free duration. This is certainly a big problem, especially considering how intimately the carcinoma in situ group is woven into the high-risk population upon which the indication is based, with 79 of the 129 patients in the study (61%) having a CIS component, according to the baseline demographics data.
Furthermore, informative data censoring in patients who undertook new or radical therapies may have omitted important event information, adding an additional degree of bias to the data. Subsequent studies could certainly address these issues, utilizing more stringent time-to-event analyses and/or population controls. Perhaps only CIS in a single arm in another study or maybe go a step further and include randomization?
Interestingly, the FDA was able to dig a valuable nugget out of the data, with caveats of course, indicating durable responses based on 6-month data in the CIS groups. This makes me think that subsequent studies could include time-to-cystectomy (TTS) or cystectomy-free-survival endpoints (CFS), which would, in my opinion, add a very valuable dynamic, especially considering the target patient demographic.
PS: If you ignore the idiots this board is much more useful, they will not go away