First Big Test Approaches for Urovant

March 12, 2019 First big test approaches for Urovant

Amy Brown

Six months after floating, Urovant is gearing up to release pivotal data on its most advanced overactive bladder project.

Investors who backed Urovant’s $140m flotation last September will soon find out whether the money was well spent. Before the end of March the company will release topline pivotal data on the overactive bladder project vibegron, a β3-adrenergic receptor agonist licensed from Merck & Co, and a positive result should allow regulatory filings to follow.

It seems likely that the trial will hit: Merck successfully conducted a large phase IIb study of vibegron a few years ago, and a similar compound is already on the market in the shape of Myrbetriq, which has been sold by Astellas since 2011. This well-established product has only four years of US patent life left, so if Urovant has any chance of building vibegron into a similarly large product it needs to prove that its contender is both safer and more effective.

Astellas is expected to clock sales of $864m for Myrbetriq in the US this year; the product has become a commercial success despite a hypertension warning, an issue that logically should be a major stumbling block in a condition like overactive bladder. Both high blood pressure and incontinence issues are common in the elderly, and lack of options for patients suffering with the latter has driven demand for Myrbetriq.

First-line drug treatment for overactive bladder is an antimuscarinic, for example Toviaz or Vesicare, but this class is associated with cognitive decline, meaning that these drugs are also considered unsuitable for the elderly. Those patients that do try a pharmacological treatment for overactive bladder – either Myrbetriq or an antimuscarinic – frequently discontinue within six months, because of tolerability issues or lack of effectiveness. Overactive bladder: a shifting market

Sales ($m)

First global Product Company Mechanism 2015 2018 2021e 2024e launch

Beta-3 adrenoceptor Myrbetriq Astellas Pharma 2011 681 1,318 1,750 639 agonist

Botox* Allergan Injected botulin toxin 2013 (for OAB) 155 254 296 336

Toviaz Pfizer Antimuscarinic 2008 267 271 247 110

Vesicare Astellas Pharma Antimuscarinic 2004 1,130 849 239 67

Enablex Novartis/Allergan Antimuscarinic 2004 219 76 30 15

*Sales in OAB only. Source: EvaluatePharma.

It is this lack of satisfaction with existing options that presents an opportunity for Urovant. The company says that because vibegron is highly selective for the beta-3 adrenergic receptor it should prove more effective and safer than Myrbetriq, which as well as carrying a hypertension risk inhibits the CYP2D6 enzyme, which means that it cannot be taken with numerous other medications.

Urovant therefore needs to establish clear blue water between vibegron and the competition and, first and foremost, any hypertension risk with the newer project must be ruled out.

This issue did not arise in the original Merck trial, so hopes are high here; having randomised 1,395 people the study should have been large enough to detect a signal. Urovant’s Empowur study is slightly larger at 1,530 subjects, and to put the issue to bed completely the company is also running a 200-patient ambulatory blood pressure trial; data are due in the second half of the year.

A US regulatory filing for vibegron in early 2020 is the current target.

A hypertension signal would pretty much torpedo this project, but if that does not arise, Urovant must then go on to show improved efficacy. The bar that vibegron must beat is pretty clear: data published on Myrbetriq’s label are summarised below. The Empowur trial, which tests 75mg of vibegron, uses the same endpoints as co- primaries, measured over 12 weeks: change in average daily micturations, or urinations, and change in average daily urge urinary incontinence episodes.

Merck also used these endpoints in its earlier study, although it tested different doses, 50mg and 100mg. Urovant has pitched its attempt in the middle in an attempt to avoid the insistence from regulators for dose titration, a regimen that Myrbetriq users are obliged to follow. The bar to beat: data so far from the β3-adrenergic receptor agonist class

Myrbetriq: Placebo-adjusted results from phase III trials

Study 1 Study 2 Study 3

50mg 50mg 25mg 50mg

Avg daily micturations (wk 12) -0.60 -0.61 -0.47 -0.42

Avg daily incontinence episodes (wk -0.41 -0.34 -0.40 -0.42 12)

Note: All met statistical significance. Source: US drug label.

Vibegron: Placebo-adjusted results from Merck phase IIb study

50mg 100mg

Avg daily micturations (wk 8) -0.64 -0.91

Avg daily incontinence episodes (wk -0.72 -0.71 8)

Note: All met statistical siginficance. Source: European Urology.

On a recent conference call Urovant told analysts that replicating the results generated by Merck “would be an upside case”, saying the trial produced some of the best effects observed by a β3-adrenergic receptor agonist. They played down expectations of such an outcome, but said such data would make vibegron a blockbuster opportunity.

Such hyperbole comes with the territory in biotech, of course, but Urovant looks to be in with a chance of finding itself with a best-in-class asset. Should this come to pass, investors will no doubt hope that interested parties emerge; given Astellas’s strong position here, the Japanese company will be keeping a close eye on the data.

A wildcard here is another β3-adrenergic receptor agonist called solabegron, a Glaxosmithkline cast-off currently in the hands of Velicept. This private company started a 1,413-patient phase IIb study last year and, going by Urovant’s timelines, data could emerge in the summer.

Entering an increasingly generic market, even with an asset that claims to be better and different, will be no easy task for Urovant. Should a viable competitor emerge from Velicept, Urovant will have another challenge to think about.

OAB trials on the horizon

Project Company Study Trial ID

Vibegron Urovant Empowur NCT03492281

Velicept Solabegron VEL-2001 NCT03594058 Therapeutics