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When urologists convene, they often discuss the newest technologies that can help them better serve their patients. In the case of upper tract urothelial carcinoma (UTUC), an exciting treatment paradigm shift is afoot that has urologists abuzz.

The upper urinary tract connects the bladder to kidney. UTUC is a rare malignancy in the lining of the ureter and kidney. Signs of UTUC include blood in the urine and flank pain. In the United States, approximately 7,500 new cases of UTUC are diagnosed each year, of which about 2,500 are low-grade. Today, approximately 14,500 people are living with low-grade UTUC.

Innovative non-surgical treatments needed for UTUC

Urologists most commonly treat UTUC with endoscopic surgery (tumor removal with a scope), or nephroureterectomy (removal of the entire kidney and ureter). The former approach isn’t ideal because it is associated with a very high recurrence rate. The latter is associated with worsening kidney function that, in some, can lead to dialysis, as well as an increased risk of heart disease.

In the past, urologists have attempted to use topical chemotherapy following endoscopic surgery to decrease recurrence rates after conservative surgical intervention; however, this approach is extremely challenging in the kidney and ureter because the upper urinary tract cannot retain medication suspended in water for more than a few minutes. Continuous urine production and flow through the system significantly limit the dwell time of the chemotherapy, washing it away before it can work, leading to poor efficacy.

“The treatment of UTUC represents a technical challenge for urologists,” said Dr. Mark P. Schoenberg, a urologic oncologist and Chief Medical Officer of UroGen, a clinical-stage biopharmaceutical company developing advanced non-surgical treatments to address unmet needs in the field of uro-oncology. “Because surgical therapy has limitations, low-grade UTUC remains a chronic relapsing problem among elderly patients who have relatively few effective treatment options.”

Shifting the treatment paradigm with new, non-invasive technologies

To address these issues, UroGen Pharma is working to develop innovative non-surgical treatments for UTUC. One promising treatment in Phase 3 clinical development is a new reverse-thermal gel platform called RTGel™, a hydrogel-based formulation that is liquid at lower temperatures and converts to semi-solid gel form at body temperature, that can deliver chemotherapy to the lining of the upper tract for up to eight hours. Known as UGN-101 (MitoGel®), this investigational gel-drug formulation delivers the chemotherapy mitomycin to the tumor. Mitomycin has been used successfully for decades to treat low-grade bladder cancer, but the physiology of the upper tract poses challenges in using the drug for UTUC. UroGen’s novel gel technology was designed to solve this problem by enabling longer exposure of mitomycin to the urinary tract tissue without clincially meaningful systemic absorption or toxicity. UGN-101, which is instilled into the upper tract with a standard catheter, utilizes the RTGel™ platform.

“UGN-101 was formulated to fill an unmet need,” said Dr. Karim Chamie, Associate Professor of Urology at UCLA. “It offers an opportunity to avoid major quality-of-life altering surgery and all the associated complications. This is a viable alternative to patients whose health may suffer as a result of major surgery or further renal functional loss.”

“Using chemotherapy to replace surgery is a real paradigm shift in the treatment of UTUC”, said Dr. Gary Steinberg, The Bruce and Beth White Family Professor, Vice Chairman, and Director of Urologic Oncology at the University of Chicago. “A non-surgical approach would make treatment much more palatable for patients. If you can manage UTUC medically, you can spare the kidneys. This is particularly important for elderly UTUC patients, for whom preserving as many nephrons as possible is critical.”

Promising clinical trial results with UGN-101

An interim analysis of data from the multi-center Phase 3 OLYMPUS trial of UGN-101 was presented at a recent medical meeting earlier this year by Dr. Seth Lerner, Professor of Urology at Baylor College of Medicine in Houston and primary investigator. Patients with low-grade UTUC received six weekly outpatient instillations of UGN-101. Fifty-nine percent (20 of 34) of patients in the intent-to-treat analysis achieved a complete response (CR; defined as a negative ureteroscopic evaluation and negative urinary cytology collected from the upper tract). In addition, five of 34 patients (15 percent) achieved a partial response. At the time of presentation, of the 20 patients who achieved a CR, 13 reached three-month follow-up and all remained in CR. Of those 13 patients, four reached six-month follow-up and one has reached nine-month follow-up. UGN-101 appears to be well tolerated, with most treatment-emergent adverse events (e.g., urinary infection, flank pain, ureteral narrowing) characterized as mild or moderate and transient.

The U.S. Food and Drug Administration has granted Orphan Drug and Fast Track designations to UGN-101 for the treatment of UTUC. Assuming that the OLYMPUS study, once completed, meets its primary endpoint, UroGen plans to submit a New Drug Application for UGN-101 for the treatment of low-grade UTUC in the first quarter of 2019.

“Treating patients with UTUC represents a true clinical challenge, but we believe that UGN-101 has the potential to be the first ever approved non-surgical therapy for this patient population,” said Dr. Schoenberg. “Based on the interim Phase 3 results, we believe UGN-101 could be a real treatment breakthrough not only in terms of how we think about this population and how we treat them, but also about the potential of this technology beyond UTUC.”

Is the urology community ready to change their approach to treating UTUC? According to Dr. Weizer, Professor of Urology at the University of Michigan, absolutely. “In general, urologists really like technology. We tend to be early adopters of new technologies and tend to embrace innovation,” he said. “I strongly suspect that urologists will very readily adopt this treatment option into their practices.”

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