What changed in this filing

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Item 1. Business

2023-03-24 compared with 2022-03-21 · 129 added, 124 removed, 625 unchanged (29% of the section changed)

We are a biotechnology company dedicated to developing and commercializing innovative solutions that treat urothelial and specialty cancers.

We have developed RTGel ™

We have developed RTGel ®

reverse-thermal hydrogel, a proprietary sustained release, hydrogel-based technology that has the potential to improve therapeutic profiles of existing drugs.

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Our Reverse Thermal Hydrogel Technology

RTGel is a novel proprietary polymeric biocompatible, reverse thermal gelation hydrogel, which, unlike the general characteristics of most forms of matter, is liquid at lower temperatures and converts into gel form when warmed to body temperature.

We believe that these characteristics promote ease of delivery into and retention of drugs in body cavities, including the bladder and the upper urinary tract, forming a transient reservoir of drug that disintegrates over time while preventing rapid excretion, providing for increased dwell time.

RTGel is a novel proprietary polymeric biocompatible, reverse thermal gelation hydrogel technology, which, unlike the general characteristics of most forms of matter, is liquid at lower temperatures and converts into gel form when warmed to body temperature.

We believe that these characteristics promote ease of delivery into and retention of drugs in body cavities, including the bladder and the upper urinary tract, forming a transient reservoir of drug that dissolves over time while preventing rapid excretion, providing for increased dwell time.

RTGel leverages the physiologic flow of urine to provide a natural exit from the body.

RTGel ’s components are polymer-based and are inactive ingredients that have been approved by the FDA for use in Jelmyto  and other products such as Oraqix, a periodontal gel, Namenda, an oral solution for Alzheimer’s disease, and Xeloda, an oral chemotherapy.

RTGel ’s components are polymer-based and are inactive ingredients that are used in FDA-approved 

We formulate RTGel with an active drug:

mitomycin in the case of Jelmyto and UGN-102.

The resulting formulations are instilled intravesically in liquid form directly into the bladder or upper urinary tract using standard instillation methodologies via catheters or nephrostomy tube, and thereafter convert into gel form at body temperature.

The resulting formulations are instilled intravesically in liquid form directly into the upper urinary tract or bladder using standard instillation methodologies via catheters or nephrostomy tube, and thereafter convert into gel form at body temperature.

Subsequently, upon contact with urine, RTGel gradually dissolves and releases the active drug over a period of several hours and is less affected by urine creation and voiding cycles as compared to water formulations.

We believe that RTGel , when formulated with an active drug, may allow for the improved efficacy of treatment of various types of urothelial and specialty cancers without compromising the safety of the patient or interfering with the natural flow of fluids in the urinary tract.

We believe that RTGel , when formulated with an active drug, may allow for the improved efficacy of treatment of various types of urothelial and specialty cancers and urologic disease without compromising the safety of the patient or interfering with the natural flow of fluids in the urinary tract.

RTGel achieves this by:

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RTGel is liquid at lower temperatures and converts into gel form at body temperature.

This temperature-dependent viscosity characteristic allows for simple and convenient instillation of the cooled Jelmyto in its liquid form to the upper urinary tract via nephrostomy tubes, or via 

standard urinary procedures utilizing a catheter .

This temperature-dependent viscosity characteristic allows for instillation of the chilled Jelmyto in its liquid form to the upper urinary tract via 

standard urinary procedures utilizing a catheter or nephrostomy tube .

Once instilled, Jelmyto converts into gel form at body temperature.

Subsequently, upon contact with urine, Jelmyto gradually disintegrates and releases the active drug, mitomycin, over a period of four to six hours versus several minutes for mitomycin in its water-based formulation.

Subsequently, upon contact with urine, Jelmyto gradually dissolves and releases the active drug, mitomycin, over a period of four to six hours versus several minutes for mitomycin in its water-based formulation.

We believe that this substantial increase in dwell time of mitomycin positions Jelmyto as a chemoablation treatment for low-grade UTUC, potentially sparing patients from repeated tumor resection procedures and potentially reducing the need for upper urinary tract surgeries, including kidney removal.

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Approximately 40% of the patients diagnosed annually with UTUC in the United States have low-grade UTUC.

 Upfill-Brown 2018, 2.

Cutress 2012, 3.

Grasso et al.

(2012) BJU International, 4.

(2014) Pharmacoeconomics

RNU = radical nephroureterectomy

Limitations of Other Treatments for Low-Grade Upper Tract Urothelial Carcinoma

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It has been designed to prolong exposure of urinary tract tissue to mitomycin, thereby enabling the treatment of tumors by non-surgical means.

New product exclusivity for Jelmyto exists through April 15, 2023, Orphan Drug exclusivity through April 15, 2027 as well as a composition of matter patent through 2031.

The main patents that protect Jelmyto in the United States are set to expire on January 20, 2031.

New product exclusivity for Jelmyto exists through April 15, 2023, Orphan Drug exclusivity through April 15, 2027 as well as a composition of matter patents.

The main patents that protect Jelmyto in the United States are set to expire in January 2031.

These patents were listed in the FDA's Orange Book (Approved Drug Products with Therapeutic Equivalence Evaluations).

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Jelmyto was also granted Breakthrough Therapy Designation by the FDA, which was created to expedite the development and review of drugs developed for serious or life-threatening conditions with high unmet need.

The FDA approval is based on results from our Phase 3 OLYMPUS trial showing Jelmyto achieved clinically significant disease eradication in adults with low-grade UTUC.

The FDA approval was based on results from our Phase 3 OLYMPUS trial showing Jelmyto achieved clinically significant disease eradication in adults with low-grade UTUC.

Findings from the final study results include:

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The most commonly reported adverse events (≥ 20%) were ureteric obstruction, flank pain, urinary tract infection, hematuria, abdominal pain, fatigue, renal dysfunction, nausea, dysuria and vomiting.

Most adverse events were mild to moderate and manageable using well established treatments.

Most adverse events were mild to moderate and manageable.

No treatment-related deaths occurred.

In June 2020, we initiated our commercial launch of Jelmyto in the United States.

In December 2022, we presented new data from the OLYMPUS trial designed to obtain long-term follow-up data on Jelmyto .

Based on data available for 16 of the 23 patients who had remained in CR at the end of the OLYMPUS study, the median duration of response was 28.9 months.

Thirteen patients remained in CR, two patients had recurrence of low grade-UTUC on the same side as treated in OLYMPUS, and one patient underwent RNU due to ureteral stricture without evidence of UTUC at the time of surgery.

No patient had progressed to high-grade disease.

We initiated our commercial launch of Jelmyto in the United States in June 2020.

We have staffed, trained and prepared a customer-facing team comprising territory business managers with deep experience in both urology and oncology.

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Uro-Oncological Indications Targeted by Our Product Candidates

UGN-102 (mitomycin) for intravesical solution

UGN-102 is our sustained-release formulation of mitomycin that we are developing for the treatment of low-grade intermediate risk NMIBC.

It is administered locally using standard urinary procedures utilizing a catheter inserted into the bladder, and is designed to conform to the bladder’s anatomy and persist in the bladder despite urine flow and bladder movement.

It is administered locally using standard urinary procedures utilizing a catheter inserted into the bladder, and is designed to persist in the bladder despite urine flow and bladder movement.

Once instilled, UGN-102 converts into gel form at body temperature.

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We estimate based upon a review of peer-reviewed and publicly available data that approximately 20% of the prevalent low-grade NMIBC population in the United States (80,000) may be described as intermediate risk in any given year.

SEER, AUA/SUO joint guideline 

Babjuk et al.

European Urology (2019), Simon (2019), 3.

Tobert et al Urology (2019), Rhijn et al Nature Urology (2016), 4.

Bryan et al Ann R Coll Surg Engl (2010)

*Adjuvant chemotherapy only used in 0-30% of U.S.

eligible population 

TURBT = trans urethral resection of bladder tumor

Limitations of Current Therapies for Low-Grade Non-Muscle Invasive Bladder Cancer

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Our Solution:

UGN-102 (mitomycin gel) for intravesical solution

UGN-102 (mitomycin) for intravesical solution

We are evaluating the safety and efficacy of UGN-102, our novel sustained-release formulation of mitomycin for the treatment of low-grade intermediate risk NMIBC.

In October 2021, we reported final data from the Phase 2b OPTIMA II trial. The single-arm, open label trial completed enrollment of 63 patients at clinical sites across the United States and Israel in September 2019.

Patients were treated with six weekly instillations of UGN-102 and underwent assessment of CR (the primary endpoint) four to six weeks following the last instillation.

Consistent with our previous reports, 65%, or 41 out of 63 patients, treated with UGN-102 achieved a complete response three months after the start of therapy.

Patients were treated with six weekly instillations of UGN-102 and underwent assessment of CR (the primary endpoint) four to six weeks following the last instillation; 65%, or 41 out of 63 patients, treated with UGN-102 achieved a complete response three months after the start of therapy.

In this subset of patients, 39 (95%), 30 (73%), and 25 (61%) remained disease-free at six, nine, and 12 months after treatment initiation, respectively.

The probability of durable response nine months after CR (12 months after treatment initiation) was estimated to be 72.5% by Kaplan-Meier analysis. Thirteen patients had documented recurrences.

Fifty-seven of 63 (90%) patients completed all six instillations of UGN-102 according to study protocol.

Fifty-seven of 63 (90%) patients completed all six instillations of UGN-102 according to the study protocol.

Median duration of response was not reached.

The most common adverse events, greater than 10%, were most often reported as mild to moderate in severity and include dysuria, hematuria, urinary frequency, fatigue, urgency and urinary tract infection. The final data was published online in The Journal of Urology in October 2021 and was included in the January 2022 print edition.

Urothelial cancer, which is comprised of bladder cancer and UTUC, affects a large, and what we believe to be, an underserved patient population.

Annual expenditures for Medicare alone in the United States for the treatment of urothelial cancer were estimated to be at least $5.0 billion in 2020.

The majority of the expenditures are spent on tumor resection surgeries such as TURBT.

The prevalence of bladder cancer in the United States based on most recently published data was approximately 724,000 and estimated 2021 annual incidence of bladder cancer was approximately 85,000.

We estimate based upon a review of peer-reviewed literature and publicly available data that there are approximately 80,000 low-grade intermediate risk NMIBC patients in the U.S.

We believe that UGN-102 has the potential to be a new therapeutic option for the treatment of low-grade intermediate risk NMIBC patients.

In December 2022 we presented new data from the OPTIMA II study designed to obtain long-term follow-up data on UGN-102 that shows median duration of response of 24.4 months based on available data for 15 out of 25 patients. Seven patients remained in CR, six patients had recurrence of low-grade disease, one patient had progression to high-grade disease and one patient withdrew consent but remained in CR at the last evaluation prior to discontinuation.

All patients were alive at the last contact, and five patients were known to have had post-study treatment with transurethral resection of the bladder tumors or fulguration.

UGN-102 is administered locally using the standard practice of intravesical instillation directly into the bladder via a catheter.

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In parallel, we continued to engage in discussions with the FDA and, based on this dialogue, we designed a trial in order to demonstrate the efficacy and safety of UGN-102.

This new Phase 3 ENVISION trial is a single-arm, multinational, multicenter study evaluating the efficacy and safety of UGN-102 as primary chemoablative therapy in patients with low-grade intermediate risk NMIBC.

The design for the Phase 3 ENVISION trial is similar to our Phase 2 OPTIMA II trial in that the patient population will have similar clinical characteristics, receive the same treatment regimen and undergo the same efficacy and safety assessments and qualitative follow-up.

Study participants will receive six once-weekly intravesical instillations of UGN-102.

The planned primary endpoint will evaluate the complete response rate at three months after the first instillation, and the key secondary endpoint will evaluate durability over time in patients who achieve complete response at the three-month assessment.

In February 2022, we announced the initiation of the Phase 3 ENVISION trial, which is expected to enroll approximately 220 patients across 90 sites, with completion of enrollment expected by the end of 2022. Assuming positive findings, we anticipate submitting a NDA for UGN-102 in 2024.

This Phase 3 ENVISION trial is a single-arm, multinational, multicenter study evaluating the efficacy and safety of UGN-102 as primary chemoablative therapy in patients with low-grade intermediate risk NMIBC.

The design of the Phase 3 ENVISION trial is similar to our Phase 2 OPTIMA II trial in that the patient population has similar clinical characteristics, receives the same investigational treatment regimen and undergoes similar efficacy and safety assessments and qualitative follow-up.

Study participants receive six once-weekly intravesical instillations of UGN-102.

The primary endpoint will evaluate the complete response rate at three months after the first instillation, and the key secondary endpoint will evaluate durability of response in patients who achieve complete response at the three-month assessment.

In February 2022, we announced the initiation of the Phase 3 ENVISION trial, targeting enrollment of 220 patients across 90 sites.

In December 2022 we completed our target enrollment of the Phase 3 ENVISION trial.

Assuming positive findings, we anticipate submitting an NDA for UGN-102 in 2024.

As a result of the FDA's acceptance of a single arm approach, we have stopped enrollment of the Phase 3 ATLAS study. However, at the time enrollment was stopped, any patients who had signed an informed consent were able to complete screening, and if eligible were randomized into the trial.

Patients continue to be followed in the Phase 3 ATLAS study, and clinical results from these patients are expected to generate additional safety data and other insights in our evaluation of UGN-102 as a primary therapy in the treatment of low-grade intermediate risk NMIBC.

We have also initiated a Phase 3b study with the objective of demonstrating whether UGN-102 can be administered at home by a qualified home health professional, avoiding the need for repeated visits to a healthcare setting for instillation. Patients in the ongoing Phase 3b study will receive six once-weekly intravesical instillations of UGN-102.

The Phase 3b study aims to enroll up to 10 patients across four centers.

The initial treatment visit will occur at the investigative site and instillation will be performed by a qualified physician.

Treatment visits two to six will take place at the patient's home and instillation will be performed by a properly trained and qualified home health professional.

The primary endpoint of the study is the incidence of treatment-emergent adverse events ("TEAEs"), serious TEAEs, TEAEs of special interest, discontinuations from at home study treatment, and clinically significant abnormalities in laboratory tests (hematology, serum chemistry, and urinalysis).

We believe the ease and convenience of home instillation has the potential to transform care and facilitate alternative access to treatment.

Our immuno-uro-oncology pipeline includes UGN-301 (zalifrelimab), an anti-CTLA-4 antibody, which we intend to study as a combination therapy with multiple potential agents.

Our initial approach, currently in nonclinical development, involves the sequential use of UGN-201 (imiquimod), a toll-like receptor-7 ("TLR 7") agonist, and UGN-301, as an investigational treatment for high-grade non-muscle invasive bladder cancer ("high-grade NMIBC"). UGN-301 is delivered using our proprietary RTGel technology, which has been designed to significantly improve the effectiveness of certain intravesical therapies.

Clinical results from these patients are expected to generate additional safety and efficacy data and other insights in our evaluation of UGN-102 as a primary therapy in the treatment of low-grade intermediate risk NMIBC.

We also initiated a Phase 3b study with the objective of demonstrating whether UGN-102 can be administered at home by a qualified home health professional, avoiding the need for repeated visits to a healthcare setting for instillation.

As per the study design, patients in this study received six once-weekly intravesical instillations of UGN-102 with the initial treatment visit occurring at the investigative site and instillation performed by a qualified physician.

Treatment visits two to six took place at the patient's home and instillation was performed by a properly trained and qualified home health professional.

The primary endpoints of the study include safety and tolerability, discontinuations from at home study treatment and feedback from patients, home health professionals and investigators via standardized questionnaires.

The study completed enrollment with a total of eight patients across four centers and all study visits for these enrolled patients have been completed.

We reported preliminary results in February 2023.

The results found that UGN-102 was suitable to administer at home by a visiting nurse under the supervision of a treating physician and resulted in 75% of patients achieving a complete response, defined as no detectable disease three months after starting treatment.

Patients, nurses and investigators also completed home instillation feasibility questionnaires.

These standardized feasibility questionnaires highlighted that all eight patients preferred at-home to in-office treatment, and five of six patients recommended UGN-102 home instillation instead of TURBT.

Home instillation was reported as feasible for visiting nurses, and three of four investigators considered at-home treatment “not different”

than in-office treatment.

We believe establishing the precedent for a convenient at home solution may facilitate access to care and address quality of life issues that certain patients may face with the current standard of care.

UGN-301 (zalifrelimab) intravesical solution

Our immuno-uro-oncology pipeline includes UGN-301 (zalifrelimab), an anti-CTLA-4 antibody, which we intend to study as a standalone agent and as a combination therapy with multiple potential agents.

The first combination we are seeking to investigate clinically involves the sequential use of UGN-201 (imiquimod), a toll-like receptor-7 ("TLR 7") agonist, and UGN-301 in high-grade non-muscle invasive bladder cancer ("high-grade NMIBC").

UGN-301 is delivered using our proprietary RTGel technology, which has been designed to significantly improve the effectiveness of certain intravesical therapies.

High-Grade 

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TURBT followed by adjuvant intravesical immunotherapy with Bacillus of Calmette and Guerin ("BCG") is the current standard of care therapy for high-grade NMIBC. However, the high rates of recurrence and significant risk of progression to muscle-invasive tumors are particularly dangerous.

Radical cystectomy, or bladder removal is strongly advocated in patients with BCG-unresponsive NMIBC (i.e.

patients with BCG-refractory and BCG-relapsing tumors in whom further BCG therapy is not recommended) or for patients who cannot tolerate BCG.

Radical cystectomy, or bladder removal is strongly advocated in patients with BCG-unresponsive NMIBC (i.e., patients with BCG-refractory and BCG-relapsing tumors in whom further BCG therapy is not recommended) or for patients who cannot tolerate BCG.

Drugs such as Keytruda have been recently approved for the BCG refractory population.

Nielsen, 2014 analysis of SEER data, 2.

UroGen market research

Limitations of Current Therapies for High-Grade NMIBC

O nly four drugs have been approve d for high-grade NMIBC, all used as adjuvant treatment:

Thiotepa, which was approved in 1959, and is no longer used in practice, BCG, which was approved in 1989;

O nly five drugs have been approve d for high-grade NMIBC, all used as adjuvant treatment:

Thiotepa, which was approved in 1959, and is no longer used in practice; BCG, which was approved in 1989;

Valstar®

(valrubicin), which was approved in 1998;

and Keytruda, approved by the FDA in 2020.

Keytruda, which was approved by the FDA in 2020; and Adstiladrin, which was approved by the FDA in 2022 for BCG unresponsive CIS.

BCG, an immunotherapy-based drug, is used as an adjuvant treatment for patients with high-grade NMIBC.

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UGN-301 (zalifrelimab) intravesical solution

We are exploring the use of immunotherapy for the treatment of high-grade NMIBC, and have pursued a series of pre-clinical studies to determine whether our proprietary RTGel technology might provide a method for delivering highly potent immunomodulators directly to the bladder surface thereby avoiding toxicity associated with systemic administration.

Our immuno-uro-oncology pipeline includes UGN-301, an anti-CTLA-4 antibody, which we intend to study as a combination therapy with multiple potential agents.

The completion of non-human primate toxicity studies support the initiation of a multi-arm Phase 1 study of UGN-301 in combination with other agents planned to begin in the first half of 2022.

We are exploring the use of immunotherapy for the treatment of high-grade NMIBC, and have pursued a series of nonclinical studies to determine whether our proprietary RTGel technology might provide a method for delivering highly potent immunomodulators directly to the bladder surface thereby avoiding toxicity associated with systemic administration.

Our immuno-uro-oncology pipeline includes UGN-301, an anti-CTLA-4 antibody, which we intend to study as a single agent and as a combination therapy with multiple potential agents.

The completion of non-human primate toxicity studies supported the initiation of a multi-arm Phase 1 study of UGN-301 in combination with other agents.

We believe that this approach leverages our unique drug delivery technology and provides an opportunity to evaluate intravesical delivery of UGN-301 in combination with other immuno-modulators, chemotherapies, gene therapy and innate immune stimulators.

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Telormedix conducted all of the previous studies related to UGN-201, including the Phase 1 and Phase 1b studies.

We have have obtained Orphan Drug Designation for UGN-201 for the treatment of CIS in the bladder.

We have obtained Orphan Drug Designation for UGN-201 for the treatment of CIS in the bladder.

We have an active Investigational New Drug Application ("IND") for UGN-201, which has been effective since 2013.

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In November 2019, we entered into a worldwide license agreement with Agenus Inc.

to develop and commercialize zalifrelimab via intravesical delivery in combination with UGN-201 for the treatment of urinary tract cancers, initially in high-grade NMIBC.

("Agenus") to develop and commercialize zalifrelimab via intravesical delivery in combination with UGN-201 for the treatment of urinary tract cancers, initially in high-grade NMIBC.

We believe that the combination treatment makes local therapy a potentially more effective treatment option while minimizing systemic exposure and potential side effects.

In March 2022, we announced FDA clearance of our IND to begin a novel Phase 1 clinical study of UGN-301 in patients with recurrent NMIBC. The novel study design utilizes a Master Protocol that we believe is a more efficient and streamlined approach to development.

It will provide more flexibility to add study arms as the trial progresses and is expected to increase efficiency and potentially reduce costs.

We expect the Master Protocol will allow us to more quickly evaluate safety, tolerability and dosing of UGN-301 in combination with additional immunomodulators and chemotherapies, with the goal of developing optimized treatment regimens for patients. The multi-arm Phase 1 study, which is expected to support the development of UGN-301 in high-grade NMIBC, was initiated in April 2022 and is actively enrolling. 

Research and Development and License Agreements

Allergan/AbbVie Agreement

In October 2016, we entered into an exclusive license agreement (the "Allergan/AbbVie Agreement") with Allergan Pharmaceuticals International Limited ("Allergan"), a wholly owned subsidiary of Allergan plc, which is now a part of AbbVie Inc.

("AbbVie") and granted Allergan an exclusive worldwide license to research, develop, manufacture and commercialize pharmaceutical products that contain 

RTGel  and clostridial toxins including BOTOX.

The license granted the exclusivity for the 

RTGel  and clostridial toxins including BOTOX alone or in combination with certain other active ingredients, referred to as the Licensed Products, which are approved for the treatment of adults with overactive bladder ("OAB") who cannot use or do not adequately respond to anticholinergics.

In October 2017, Allergan commenced a Phase 2 clinical trial of BOTOX/RTGel for the treatment of OAB, with the potential to evolve from multiple injections of BOTOX into the bladder to a single instillation of the novel formulation.

In August 2020, we announced that the Phase 2 APOLLO trial did not meet the primary endpoint. The data suggested that this result may have been due to BOTOX not effectively permeating the urothelium.

Over the past year, we have been in discussions with AbbVie to determine whether other products in their portfolio would be complementary with RTGel. Based on this review, there was limited interest to pursue combinatorial products, and therefore, in November 2021 the Allergan/AbbVie Agreement was terminated.

Agenus Agreement

In November 2019, we entered into a license agreement with Agenus Inc.

(“Agenus”).

Pursuant to the agreement, Agenus granted us an exclusive, worldwide license (not including Argentina, Brazil, Chile, Colombia, Peru, Venezuela and their respective territories and possessions), royalty-bearing, sublicensable license under Agenus’s intellectual property rights to develop, make, use, sell, import and otherwise commercialize products incorporating a proprietary antibody of Agenus known as AGEN1884 for the treatment of cancers of the urinary tract via intravesical delivery.

AGEN1884 is an anti-CTLA-4 antagonist that is currently being evaluated by Agenus as a monotherapy in PD-1 refractory patients and in combination with Agenus’

anti-PD-1 antibody (AGEN2034) in solid tumors.

UGN-301 is a formulation of 

RTGel  and zalifrelimab (AGEN1884) that is in early-stage development for high-grade NMIBC.

Pursuant to the terms of the agreement, we paid Agenus an upfront fee of $10.0 million and have agreed to pay Agenus up to $115.0 million upon achieving certain clinical development and regulatory milestones, up to $85.0 million upon achieving certain commercial milestones, and royalties on net sales of licensed products in the 14% to 20% range.

We will be responsible for all development and commercialization activities.

Under the terms of the license agreement, Agenus has agreed to use commercially reasonable efforts to supply AGEN1884 to us for use in development and commercialization.

Unless earlier terminated in accordance with the terms of the license agreement, the license agreement will expire on a product-by-product and country-by-country basis at the later of (a) the expiration of the last to expire valid claim of a licensed patent right that covers the licensed product in such country or (b) 15 years after the first commercial sale of the licensed product in such country.

We may terminate the license agreement for convenience upon 180 days’

written notice to Agenus.

Either party may terminate the license agreement upon 60 days’

notice to the other party if, prior to the first commercial sale of a licensed product, we substantially cease to conduct development activities of the licensed products for nine consecutive months (and during such period, Agenus has complied with its obligations under the license agreement) other than in response to a requirement of an applicable regulatory authority or an event outside of our control.

In addition, either party may terminate the license agreement in the event of an uncured material breach of the other party.

In November 2019, we entered into a license agreement with Agenus, pursuant to which Agenus granted us an exclusive, worldwide (not including Argentina, Brazil, Chile, Colombia, Peru, Venezuela and their respective territories and possessions), royalty-bearing, sublicensable license under Agenus’s intellectual property rights to develop, make, use, sell, import, and otherwise commercialize products incorporating a proprietary monoclonal antibody of Agenus known as AGEN1884 (zalifrelimab), an anti-CTLA-4 antagonist, for the treatment of cancers of the urinary tract via intravesical delivery.

UGN-301 is a formulation of zalifrelimab administered using RTGel  technology that is in Phase 1 clinical development for high-grade NMIBC.

MD Anderson Agreement

Based on nonclinical studies conducted by us, UGN-201 in combination with anti-CTLA-4 antagonists have shown encouraging results for the potential treatment of high-grade NMIBC.

In January 2021, we announced that we entered into a three-year strategic research collaboration agreement with MD Anderson focusing on the sequential use of UGN-201 and UGN-301 as an investigational treatment for high-grade NMIBC.

Under the agreement, we and MD Anderson will collaborate on the design and conduct of nonclinical and clinical studies with oversight from a joint steering committee.

We will provide funding, developmental candidates, and other support.

In January 2021, we announced that we had entered into a three-year strategic research collaboration agreement with MD Anderson focusing on the sequential use of UGN-201 and UGN-301 as an investigational treatment for high-grade NMIBC. Pursuant to the agreement, as of December 31, 2022 we have made bi-annual payments totaling $2.0 million to MD Anderson to fund the collaboration, recognized evenly over the associated period through research and development expenses. In July 2022, we determined that we had achieved the objectives that we established when the agreement was initiated, and notified MD Anderson that we were exercising our right to conclude the collaboration in 2022 as we did not foresee initiating further development activities as part of the collaboration, although we will continue to collaborate on existing joint projects.

As a result of this notification, we are not responsible for any further fixed bi-annual funding payments, although we will be responsible for costs related to existing joint projects that exceed the payments already made to MD Anderson.

Our Competitive Strengths

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Strong intellectual property position.

We have a robust intellectual property portfolio that includes 40 granted patents worldwide and more than 45 pending patent applications filed in the US, Europe, Israel, Japan, Canada, China, Mexico and Australia.

We have a robust intellectual property portfolio that includes 42 granted patents worldwide and more than 45 pending patent applications filed in the US, Europe, Israel, Japan, Canada, China, Mexico and Australia.

In the United States, we currently have 19 granted patents that are directed to protect our approved product, 

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We submitted an IND for UGN-102 in June 2018.

In November 2020 we reported final topline data from an open-label, single-arm Phase 2b clinical trial to evaluate the efficacy and safety of UGN-102 for the treatment of patients with low-grade intermediate risk NMIBC and are currently enrolling patients in a Phase 3 trial.

We believe that this local drug treatment has the potential to become the standard of care in this patient population.

UGN-102 is currently in a Phase 3 trial.

We believe that UGN-102 has the potential to be a new therapeutic option for the treatment of low-grade intermediate risk NMIBC patients, if approved.

Expand our uro-oncology product pipeline.

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In November 2019, we entered into a worldwide license agreement with Agenus to develop and commercialize zalifrelimab, an anti-CTLA-4 antibody, via intravesical delivery. We believe that the combination treatment makes local therapy a potentially more effective treatment option while minimizing systemic exposure and potential side effects.

In January 2021, we entered into a strategic research collaboration with MD Anderson, a world-renowned cancer research institution, to advance the development program for UGN-301 for the treatment of high-grade NMIBC.

Utilize our proprietary technology to expand our pipeline to other body cavities and indications.

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These issued patents are set to expire between 2024 and 2037.

In total, our IP portfolio includes 40 granted patents worldwide, and more than 45 pending patent applications filed in the US, Europe, Israel, Japan, Canada, China, Mexico and Australia that are directed to cover various methods, systems and compositions for treating cancer locally, by intravesical means, utilize various active ingredients and the combinations thereof.

In total, our IP portfolio includes 42 granted patents worldwide, and more than 45 pending patent applications filed in the US, Europe, Israel, Japan, Canada, China, Mexico and Australia that are directed to cover various methods, systems and compositions for treating cancer locally, by intravesical means, utilize various active ingredients and the combinations thereof.

These patent applications, if issued, are set to expire between 2031 and 2041.

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Accordingly, we have listed two patents for Jelmyto in the FDA’s Orange Book upon approval of Jelmyto for commercial sale, as part of the NDA process.

Our worldwide intellectual property portfolio includes patents and patent applications filed in many jurisdictions such as the US, Europe, Israel, Japan, Canada, China, Mexico and Australia of which are expected to remain in effect until 2037:

Our worldwide intellectual property portfolio includes patents and patent applications filed in many jurisdictions such as the US, Europe, Israel, Japan, Canada, China and Australia of which are expected to remain in effect until 2037:

Hydrogel-based pharmaceutical compositions for optimal delivery of various therapeutic agents to internal cavities such as the bladder and/or urinary tract.

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Special catheters and in-dwelling ureter-catheter systems for optimal delivery of a drug into the renal cavity.

Pharmaceutical compositions comprising an imidazoquinolin-amine (specifically imiquimod) and lactic acid for treating bladder cancer diseases.

Pharmaceutical compositions comprising an imidazoquinolin-amine (specifically imiquimod) for treating bladder cancer diseases.

Composition comprising immunomodulators such as anti-PD1 and/or anti-CTLA4 for topical/intravesical administration as a monotherapy or a combo-therapy.

Novel phospholipid drug analogs (new chemical entities) for treating cancer or infections.

In addition to patents, we have filed applications for trademark registration with the United States Patent and Trademark Office ("the USPTO"), as well as certain other international jurisdictions for Jelmyto ®, RTGel ™, UroGen ®

Hydrogel for removal ureteral and renal stones. 

In addition to patents, we have filed applications for trademark registration with the United States Patent and Trademark Office (the "USPTO"), as well as certain other international jurisdictions for Jelmyto ®, RTGel 

®, UroGen ®

and Cystoject ™and for certain other tradenames and logos.

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We are aware of a company called Steba Biotech with an IND granted in December 2020 who has initiated a Phase 3 study of padeliporfin ImPACT for the treatment of adult patients with low-grade and unifocal high-grade UTUC in the first quarter of 2021.

We do not know whether other competitors in the NMIBC space are already developing, or plan to develop, UTUC treatments.

In January 2023, SURGE Therapeutics received FDA clearance on an IND to proceed with a Phase 1/2a study of its SURGERx platform with resiquimod for prevention of recurrence and/or progression after TURBT in NMIBC, previously diagnosed with high-grade disease and experience recurrence. We do not know whether other competitors in the NMIBC space are already developing, or plan to develop, UTUC treatments.

Competition may increase further as a result of advances in the commercial applicability of technologies and greater availability of capital for investment in this industry.

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In the case of high-grade disease without papillary tumor (CIS), BCG is used alone as primary therapy.

BCG was approved by the FDA in 1989, since its approval, only two other drugs were approved for high-grade NMIBC:

BCG was approved by the FDA in 1989, since its approval, only three other drugs were approved for high-grade NMIBC:

Valstar, approved by the FDA in 1998;

and Keytruda, approved by the FDA in 2020.

Keytruda, approved by the FDA in 2020;

and Adstiladrin, approved by the FDA in 2022 for BCG unresponsive CIS.

Valstar is indicated for patients with CIS that do not respond to BCG treatment and is rarely used.

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There are several products in the development pipeline, most of which are treatments targeted for high-grade NMIBC patients who have failed BCG treatment and are facing cystectomy. 

We are aware of several pharmaceutical companies that are developing drugs in the fields of urology and uro-oncology, such as Roche, Vyriad, GSK, Celgene, Samyang biopharma, Merck Sharp & Dohme Corp., Sesen Bio, Viralytics Limited, AADi, LLC, Biocancell Ltd., ImmunityBio, Seagen Inc., Steba Biotech Ltd., FKD Therapies Oy and Janssen.

We are aware of several pharmaceutical companies that are developing drugs in the fields of urology and uro-oncology, such as AADi, LLC, Biocancell Ltd., Bristol Myers Squibb, FKD Therapies Oy, GSK, ImmunityBio, Janssen, Merck Sharp & Dohme Corp., Roche, Samyang biopharma, Seagen Inc., Sesen Bio, Steba Biotech Ltd., SURGE Therapeutics, Viralytics Limited, and Vyriad.

Steba Biotech was granted an IND in December 2020, and has initiated a Phase 3 study of padeliporfin ImPACT for the treatment of adult patients with low-grade and unifocal high-grade UTUC in the first quarter of 2021.

SURGE Therapeutics received clearance for an IND application in January 2023 to proceed with a Phase 1/2a study of SURGERx with resiquimod, for prevention of recurrence and/or progression after TURBT in NMIBC, previously diagnosed with high-grade disease and experience recurrence.

We are also aware that other companies, such as Janssen and Lipac, are conducting, or have recently conducted clinical trials for product candidates for the treatment of low-grade intermediate risk NMIBC.

In addition, we face competition from existing standards of treatment, surgical tumor resection procedures.

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FDA approval of an NDA to permit commercial marketing for particular indications for use.

The testing and approval process require substantial time, effort and financial resources.

The testing and approval process requires substantial time, effort and financial resources.

Nonclinical studies include laboratory evaluation of drug substance chemistry, pharmacology, toxicity and drug product formulation, as well as animal studies to assess potential safety and efficacy.

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This regulatory pathway enables the applicant to rely, in part, on the FDA’s prior findings of safety and efficacy for an existing product, or published literature, in support of its application.

Section 505(j) establishes an abbreviated approval process for a generic version of approved drug products through the submission of an abbreviated new drug application, ("ANDA").

Section 505(j) establishes an abbreviated approval process for a generic version of approved drug products through the submission of an abbreviated new drug application ("ANDA").

An ANDA provides for marketing of a generic drug product that has the same active ingredients, dosage form, strength, route of administration, labeling, performance characteristics and intended use, among other things, to a previously approved product.

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O ther Healthcare Regulations

Our business activities, including but not limited to, research, sales, promotion, distribution, medical education and other activities following product approval will be subject to regulation by numerous regulatory and law enforcement authorities in the United States in addition to the FDA, including potentially the Department of Justice, the Department of Health and Human Services, ("HHS"), and its various divisions, including the Centers for Medicare & Medicaid Services ("CMS"), and the Health Resources and Services Administration, the Department of Veterans Affairs, the Department of Defense and state and local governments.

Our business activities, including but not limited to, research, sales, promotion, distribution, medical education and other activities following product approval will be subject to regulation by numerous regulatory and law enforcement authorities in the United States in addition to the FDA, including potentially the Department of Justice, the Department of Health and Human Services ("HHS"), and its various divisions, including the Centers for Medicare & Medicaid Services ("CMS"), and the Health Resources and Services Administration, the Department of Veterans Affairs, the Department of Defense and state and local governments.

Our business activities must comply with numerous federal, state, and foreign healthcare laws and regulations, including those described below.

The federal Anti-Kickback Statute prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward, or in return for, the referral of an individual for, or purchasing, leasing, ordering, or arranging for the purchase, lease or order of, any good, facility, item or service reimbursable, in whole or in part, by Medicare, Medicaid or other federal healthcare programs.

The federal Anti-Kickback Statute prohibits, among other things, any person or entity from knowingly and willfully offering, paying, soliciting or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward, or in return for, the referral of an individual for, or purchasing, leasing, ordering, or arranging for the purchase, lease or order of, any good, facility, item or service reimbursable, in whole or in part, by Medicare, Medicaid or other federal healthcare programs.

The term remuneration has been interpreted broadly to include anything of value, including unlawful financial inducements paid to prescribers and beneficiaries, as well as impermissible promotional practices.

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The ACA amended the federal health care fraud criminal statute implemented under HIPAA so that a person or entity no longer needs to have actual knowledge of the statute, or the specific intent to violate it, to have violated the statute.

Additionally, the federal Open Payments program pursuant to the Physician Payments Sunshine Act, created under Section 6002 of the ACA and its implementing regulations, require some manufacturers of drugs, devices, biologicals and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with specified exceptions) to report annually information related to specified payments or other transfers of value provided to physicians, (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of, physicians and teaching hospitals and to report annually specified ownership and investment interests held by physicians and their immediate family members.

Beginning in 2022, applicable manufacturers will also be required to report such information regarding its payments and other transfer of value to physician assistants, nurse practitioners, clinical nurse specialists, anesthesiologist assistants, certified registered nurse anesthetists and certified nurse midwives during the previous year.

Additionally, the federal Open Payments program pursuant to the Physician Payments Sunshine Act, created under Section 6002 of the ACA and its implementing regulations, require some manufacturers of drugs, devices, biologicals and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with specified exceptions) to report annually information related to specified payments or other transfers of value provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of, such professionals and teaching hospitals and to report annually specified ownership and investment interests held by physicians and their immediate family members. 

In addition, we may be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business.

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Our experience to date has demonstrated coverage with CMS and commercial payors for Jelmyto, and we have established written policies with certain commercial providers.

For example, in October 2020, a Medicare C-Code was issued for Jelmyto and we obtained pass-through status for two years, no more than three.

For example, in October 2020, a Medicare C-Code was issued for Jelmyto and we obtained pass-through status, which expires in 2023.

We continue to engage with CMS in relation to ongoing pass-through status. 

CMS has established a permanent and product-specific J-code for Jelmyto that took effect on January 1, 2021.

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Supreme Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the individual mandate was repealed by Congress.

Thus, the ACA will remain in effect in its current form.

Moreover, prior to the U.S.

Supreme Court ruling, on January 28, 2021, President Biden issued an executive order to initiate a special enrollment period for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

It is possible that the ACA will be subject to judicial or Congressional challenges

in the future.

On August 16, 2022, President Biden signed the Inflation Reduction Act of 2022 (“IRA”) into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

The IRA also eliminates the “donut hole”

under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and creating a newly established manufacturer discount program.

It is possible that the ACA will be subject to judicial or Congressional challenges in the future.

It is unclear how any such challenges and the healthcare reform measures of the Biden administration will impact the ACA.

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A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.

This includes aggregate reductions of Medicare payments to providers up to 2% per fiscal year, which went into effect in April 2013 and, due to subsequent legislative amendments to the statute will remain in effect through 2031 unless additional U.S.

Congressional action is taken.

However, COVID-19 relief support legislation suspended the 2% Medicare sequester from May 1, 2020 through March 31, 2022.

Under current legislation, the actual reduction in Medicare payments will vary from 1% in 2022 to up to 3% in the final fiscal year of this sequester. In addition, in January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several categories of healthcare providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. Congress is also considering additional health reform measures.

Under current legislation, the actual reduction in Medicare payments will vary from 1% in 2022 to up to 4% in the final fiscal year of this sequester. In addition, in January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several categories of healthcare providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Further, there has been increasing legislative and enforcement interest in the United States with respect to specialty drug pricing practices.

2 unchanged sentences

Congressional inquiries and proposed and enacted legislation at the federal and state levels designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the cost of drugs under Medicare, and reform government program reimbursement methodologies for drugs.

At the federal level, the Trump administration used several means to propose or implement drug pricing reform, including through federal budget proposals, executive orders and policy initiatives.

For example, on July 24, 2020 and September 13, 2020, the Trump administration announced several executive orders related to prescription drug pricing that attempt to implement several of the former administration’s proposals.

The FDA concurrently released a final rule and guidance in September 2020, implementing a portion of the importation executive order providing pathways for states to build and submit importation plans for drugs from Canada.

Further, on November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed by the Biden administration until January 1, 2023.

On November 20, 2020, CMS issued an interim final rule implementing President Trump’s Most Favored Nation executive order, which would tie Medicare Part B payments for certain physician-administered drugs to the lowest price paid in other economically advanced countries, effective January 1, 2021.

As a result of litigation challenging the Most Favored Nation model, on December 27, 2021, CMS published a final rule that rescinds the Most Favored Nation model interim final rule.

Additionally, in July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,”

At the federal level, in July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,”

with multiple provisions aimed at prescription drugs.

In response to Biden’s executive order, on September 9, 2021, HHS released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles.

No legislation or administrative actions have been finalized to implement these principles.

It is unclear whether these or similar policy initiatives will be implemented in the future.

Further, on November 15, 2021, President Biden signed into law the Infrastructure Investment and Jobs Act.

A provision within the act requires manufacturers of certain single-dose container or single-use package drugs payable under part B of the Medicare program to provide refunds with respect to discarded amounts of such drugs.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

Additional health reform measures may continue and affect our business in unknown ways.

Further, it is possible that additional governmental action is taken in response to the COVID-19 pandemic.

Beginning on January 1, 2023, manufacturers will be required to pay quarterly refunds to CMS for discarded amounts of certain single-dose container and single-use package drugs payable under part B of the Medicare program.

Refunds are based on the discarded volume above 10% of the total allowed amount.

However, in unique circumstances, CMS will increase the applicable threshold to 35%.

At this time, CMS has determined that Jelmyto fits within this unique circumstance classification. 

In addition, the IRA, among other things, (1) directs HHS to negotiate the price of certain single-source drugs and biologics covered under Medicare and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions will take effect progressively starting in fiscal year 2023, although they may be subject to legal challenges.

It is currently unclear how the IRA will be implemented but is likely to have a significant impact on the pharmaceutical industry.

On October 14, 2022, the Biden administration released an additional executive order directing HHS to report on how the Center for Medicare and Medicaid Innovation can be further leveraged to test new models for lowering drug costs for Medicare and Medicaid. At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

Additional health reform measures may continue and affect our business in unknown ways. 

The Foreign Corrupt Practices Act

23 unchanged sentences

Our commercial management team is comprised of experienced professionals in sales, sales operations, market access, marketing and medical affairs.

In addition, we have established a field-based organization comprised of approximately 70 individuals, including a sales team, reimbursement support team, clinical nurse educators, national account managers and medical liaisons.

In addition, we have established a customer-facing team that includes territory business managers with deep experience in both urology and oncology.

These territory business managers are led by seven regional business directors, who are in turn supported by three regional operations managers.

Each region is additionally supported by one to two clinical nurse educators to provide education and training around instillation, as well as a field reimbursement manager to help ensure access and reimbursement for appropriate patients.

In addition, our organization currently includes several medical science liaisons who appropriately engage with physicians interested in learning more about UroGen, Jelmyto and our technology, both in person and virtually.

In total, our customer-facing team comprises approximately 80 colleagues.

Our sales force is focused on promoting Jelmyto,  and educating potential prescribers to identify patients, activate accounts and gain formulary access, as applicable.

1 unchanged sentence

In addition, we may out-license some or all of our worldwide patent rights to more than one party to achieve the fullest development, marketing and distribution of any products we develop.

As of January 31, 2022, we had 195 employees worldwide, 153 in the United States and 42 in Israel, many of whom hold advanced degrees.

As of January 31, 2023, we had 200 employees worldwide, 158 in the United States and 42 in Israel, many of whom hold advanced degrees.

None of our employees are subject to a collective bargaining agreement.

25 unchanged sentences

and “UroGen”

refer to UroGen Pharma, Ltd.

refer to UroGen Pharma Ltd.

and its subsidiary.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business