With a deep knowledge of the urology space, Urovant is developing a unique approach to treating overactive bladder - an injectable plasmid human cDNA encoding maxi-K channel gene therapy.
Courtesy of Urovant Sciences
Let’s play a word association game. Moderna? mRNA. Alnylam? RNAi. Amgen? Cancer. All of these companies are leaders in their respective fields. Urovant Sciences intends to ring the same tone when patients and physicians think of urology.
Riding the wave of a successful first drug launch, the Irvine, California-based company is seeking to establish a position of leadership in the field of urology, with a current specialization in overactive bladder (OAB). While not life-threatening, OAB, a bladder control disorder characterized by a sudden urge to urinate, can lead to much embarrassment and constant anxiety. From the need to always know where the closest bathroom is to the humiliation of suddenly losing the contents of one’s bladder and the resultant intimacy issues, a patient’s quality of life can be seriously disrupted. The condition is actually fairly common, impacting 30% of men and 40% of women across the United States.
“The most important component of overactive bladder is to improve patients’ quality of life by reducing the impact of daily symptoms of urgency, frequency and accidental leakage,” Urovant Chief Medical Officer Sef Kurstjens, M.D., Ph.D. told BioSpace in an interview. “I think one of the important things that specialty companies should do is find ways to include innovative approaches when looking for treatments for the diseases that they’re focused on.”
Urovant has set out to do just that with URO-902, an injectable plasmid human cDNA encoding maxi-K channel gene therapy currently being investigated in Phase IIa clinical trials.
A Pioneering Gene Therapy
When you hear the term “gene therapy,” you think of single gene deficiencies and gene replacement. URO-902, Kurstjens explained, has a different kind of impact.
“URO-902 represents the potential for disease modification,” he said. “It’s based on a deep understanding of the role of ion channels, the way in which smooth muscles, specifically the smooth muscles in the bladder, function. Based on that, it provides a therapy that can augment these ion channels and provide a sustainable alternative to pharmacology. To me, it’s really cool science.”
It is believed to work through the human BK channel, a calcium-activated potassium channel. Scientists have attempted to target this BK channel with small molecules. But, “one of the reasons those molecules didn’t work was largely because they were not specific enough,” Kurstjens explained. “That’s one of the interesting things about this approach in urology. The bladder is accessible, so it’s possible to have local therapy with URO-902. We can actually administer those plasmids directly into the muscle.”
It’s a unique potential opportunity, he said, because it “brings together the knowledge of the uniqueness of the anatomy of the disease area that we understand, and this new innovative approach to therapy.”
According to Dr. Kenneth Peters, M.D., chief of the department of urology at Beaumont Hospital and principal investigator on the Phase IIa trial of URO-902, “This is the first-ever report of using this type of gene therapy in a controlled clinical trial.”
Innovations like this are a key therapeutic benefit to building a specialty company. “It enables a company to get very knowledgeable and develop expertise about the disease and what the current therapies and current treatment paradigms are. But perhaps more than that, [it enables us] to understand what patients and also their physicians are looking for in a therapy,” Kurstjens shared. Ultimately, “It allows the company to get really good at that space.”
Patient-Focused Mentality
Pioneering approaches are particularly necessary in an era where patients (rightfully) demand more. While 20 years ago, the ethos of the pharmaceutical industry was “doctor knows best”, Kurstjens said that has now changed.
“It was always considered that physicians knew best, but I think we’ve passed that phase now. I think it’s at least equally important to speak to the patient. At the end of the day, they’re the person with the disease - especially for a quality-of-life condition,” he said.
Building and nurturing relationships with patients and healthcare providers in the urology space is also a crucial aspect for an industry leader.
“We’re in the process of cementing old relationships and establishing new relationships,” Kurstjens said. “As we have that interaction, we’re understanding more and more about what our next product might look like and how it may meet the needs that are currently not being met.”
The objective assessment of a drug in this space, Kurstjens noted, relies heavily on patient-reported outcomes. Quantitative measures like rates of urgency and incontinence are required, of course, but, “they underpin this overall qualitative sense that individuals have in terms of the impact on their quality of life. For us, that’s the most important objective.”
Therefore, minimizing off-target side effects that come with systemic therapies like anticholinergics, such as “incapacitating dry mouth and constipation” is of pivotal importance.
“Our hope [with URO-902] is that there won’t be any off-target effects because you’re putting it directly into the bladder,” Kurstjens said.
The other thing patients want to know is, how long will the therapy last?
“This is plasmid therapy. It’s not a gene that’s incorporated within the DNA, so it’s unlikely to be in perpetuity,” Kurstjens explained. “It’s dependent upon uptake in the nucleus and upon expression there, and the turnover rate of the cells is also an important variable.” However, “Based on what we’ve seen, our hope is that it will be a long-lasting therapy, and that’s what patients are looking for.”
Interim 12-week analysis from the ongoing Phase IIa trial, presented in May at the American Urological Association’s annual meeting, revealed that the therapy led to clinically relevant improvement in the common symptoms of overactive bladder (OAB) compared to placebo in adult women. The most commonly reported adverse event was urinary tract infection.
With proof of concept in hand, Urovant plans to launch a Phase IIb study that Kurstjens said would be more statistically pathed with an expanded study population scope. The targeted start date for this trial will be in mid-to-late 2023. Later this year, Urovant anticipates 48-week data from the Phase IIa trial. At that point, Kurstjens said, “We’ll have a greater sense of the durability of the therapy.”
A Sound Commercial Strategy
From a commercial perspective, specialization allows a company to avoid some of the challenges faced by many of the large pharmaceutical firms.
“They’re trying to spread themselves too thin to cover many therapeutic areas,” Kurstjens said “They’re not necessarily focused on one particular discipline. They are designed to make investment choices between therapeutic areas based on estimates of financial return. As a consequence, their attention can be diverted, and either they don’t develop focus or they lose focus.”
The company is also able to devote the necessary time and attention to building unmatched expertise in its area of focus. “If you have that understanding, then you’re able to identify where the current shortfalls are,” Kurstjens said.
The key to building such an organization is to populate it with leaders who bring that in-depth understanding to the table.
“We’ve got a bunch of folks who are very experienced in the pharma space, especially in the R&D and on the commercial side. Many worked in companies that have had urology products including products in the OAB space,” Kurstjens said. “So that has provided us really a huge advantage in achieving a successful trajectory and maintaining momentum.”
Chief Executive Officer James Robinson took the reins days after the COVID-19 pandemic struck North America. Robinson brought considerable launch experience along with him, having previously served as president of Astellas Pharma U.S., where he led the commercial organization.
Kurstjens also highlighted the invaluable experience the Urovant team has gained from shepherding a new program from development through commercialization.
On the Horizon
In addition to URO-902, Urovant also has clinical trial programs underway for men with OAB symptoms who are receiving pharmacological therapy for benign prostatic hyperplasia (BPH) and pediatric neurogenic bladder dysfunction. Without disclosing specifics, Kurstjens said the company is also considering adjacent bladder disease areas.
“As you would imagine, focusing on the potassium channel in the bladder has other potential. We think there’s actually a lot of potential in URO-902,” he shared.
Becoming a therapeutic leader is not an overnight achievement. Just ask Moderna and BioNTech, who were focused on mRNA long before an urgent global need provided its proving grounds. But innovative solutions to urinary diseases like OAB are already a pressing need, one Urovant intends to meet.
“It’s a marathon, not a sprint,” Kurstjens said. “Establishing leadership in a space is something that takes time and I think we’re on a really great trajectory to achieve that.”
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