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Samuel J. Klempner, MD: The indications for Vistogard on the FDA-approved label—Vistogard is uridine triacetate—are overdose from oral 5-FU, or overdose after intravenous administration in both adults and pediatric patients. This is regardless of symptoms, as well as severe or life-threatening toxicity in adults or pediatric patients within 96 hours after administration of 5-FU or capecitabine. Both these populations are on the label, and they’re somewhat nonoverlapping. If you think about the overdose patients, it is largely an accidental phenomenon that the patients are recognized to have an overdose in the office, although they may be largely asymptomatic from the event at that time. However, uridine triacetate is indicated in this situation because of the risk of going on to develop severe or life-threatening toxicities, and the mortality from them is quite high. So, those patients are included regardless of symptoms.
The severe toxicity population are patients who are largely given appropriate dosing but develop severe or life-threatening toxicity, which is unanticipated, and these are largely related to patient factors such as altered clearance and underappreciated enzymatic deficiencies that were unknown. These 2 populations, both the overdose and the severe toxicity, are non-overlapping, but both get to the same endpoint of severe toxicity. So, they are considered to be warranted for antidote.
Uridine triacetate is essentially a uridine prodrug. It’s rapidly absorbed from the GI tract after oral administration either by mouth or via NG tube. It undergoes rapid deacetylation to yield free uridine. And the free uridine undergoes phosphorylation to uridine triphosphate, where it competes with the fluorouridine triphosphate (FUTP), which is the metabolite of 5-FU or capecitabine, and it competes for incorporation into RNA. So, incorporation of normal uridine in the form of uridine triphosphate results in normal RNA function, whereas incorporation of the FUTP inhibits RNA function. You’re essentially outcompeting the toxic metabolite. The reason that uridine triacetate is given over a 5-day course is to maximize the ability to outcompete the metabolite, and certainly this has to do with preclinical data supporting that timeline, as well as the clinical trial data supporting the uridine triacetate label.
Vistogard is given as an oral drug. The FDA-approved label is 10 g, or 6.2 g/m2, and that’s largely for pediatric patients, given over 20 doses. This is an every-6-hour regimen—4 times a day for 5 days—and it’s important to recognize that completion of the prescribed course is important even if symptoms are improving early during the treatment course. So, 10 g every 6 hours for 20 doses is a 5-day course of uridine triacetate.
Similar to the toxicities, severity and timing are equally important for the use of uridine triacetate. In preclinical mouse data, administration with 24 hours following lethal 5-FU exposure prolonged survival, and later administration had declining efficacy. And this is, unfortunately, recapitulated in some human data, where 2 of the 4 patients who were treated outside of the 96-hour window died. So, the efficacy is considered unknown in patients treated outside the 96-hour window, whereas patients treated within the 96-hour window, their overall survival is 96%. That’s a dramatic difference between early and later administration, and earlier is certainly better. If you recognize the toxicity, you should treat the patients as soon as it’s recognized and you can obtain the uridine triphosphate.
The safety and efficacy data for Vistogard comes from a pooled analysis of essentially 2 studies, and this is a really interesting approval pathway that I think the FDA deserves a lot of credit for. You can imagine the design of a prospective clinical trial is really not possible when you have a very rare and unpredictable toxicity or overdose. So, you can’t randomize patients, and it’s arguably unethical to make a placebo arm in a toxicity that has such a high mortality.
Essentially, the first 75 patients with a pooled analysis from a bunch of single-patient INDs were part of an emergency use protocol for uridine triacetate. The FDA then requested additional expanded protocol for another 60 patients to get better safety and efficacy data. The overall data set that led to the approval is [a] pooled analysis from 135 patients. And these are patients who had a known overdose or a severe or life-threatening toxicity within 96 hours of completion of 5-FU or oral capecitabine. So, capecitabine events were allowed. The primary endpoints of the study were survival at 30 days and/or resumption of chemotherapy if it occurred within the 30-day period.
Within that population, the majority of patients—I think roughly 112 of the 135—were treated for overdose, and roughly 18 or so were included after severe or life-threatening toxicity was recognized. The majority of patients included in the analysis were overdosed patients. The efficacy for the pooled analysis or for the primary endpoint was a 96% survival at 30 days, or resumption of chemotherapy at 30 days. Within the overdose cohort, the survival is better than within the early-toxicity cohort. So, it’s roughly 89% in the early-toxicity group. And this is, of course, not unexpected. These patients are already much sicker when they’re recognized as having experienced a life-threatening toxicity.
The historical control, just as a way of reference, because there was not a control arm to this—from the published literature of cases of 5-FU overdose or toxicity, the mortalities range from 84% to 100%, depending on the series—up to 100% in people who are not recognized until they’ve experienced a life-threatening toxicity. So, the 96% survival in the Vistogard series is a dramatic improvement, compared with the historical controls that were accepted by the FDA for review.
The clinical efficacy data are quite convincing. The safety data are a little bit difficult to tease out. If you think about the patient population, these are patients who have significant toxicities from chemotherapy, so they may be neutropenic; they may have refractory nausea, vomiting, or diarrhea. That confounds your ability to assess the side effects from the uridine triacetate a little bit. But among the study population, I believe only 2 patients were discontinued for side effects—and this was nausea, vomiting, or diarrhea, which are the most common side effects for uridine triacetate. But these are generally considered mild, and certainly the clinical efficacy strongly outweighs the mild side effect profile, in my opinion. But generally, GI side effects were the most common—specifically, nausea, vomiting, and diarrhea—although it’s a little bit difficult to tease those out from the 5-FU effects themselves.
So, the ability to resume chemotherapy following Vistogard administration was studied in the clinical data, but you have to remember that this is also a little bit tricky. Patients who were treated for an overdose…this is something where you might postulate it would be easier to resume therapy because it was an overdose issue, not a toxicity issue. Patients who were treated because of severe or life-threatening toxicities may require a longer time to recover.
But if you look at the data, I think 38% of the patient population was able to resume chemotherapy within 30 days following uridine triacetate. And this is actually pretty remarkable when you consider the toxicities that some of these patients experienced, including ICU admissions, prolonged cytopenias, and recovery. So, the recovery, once the toxicity has passed, was quick in this data set. Roughly 40% of the patients were able to resume.