Revance Therapeutics Inc. has never made a secret of its goal to build a better Botox. The Newark, Calif.-based company is making swift progress to reach that target as it prepares to file a BLA for lead program RT-002, an injectable formulation of daxibotulinumtoxinA, in moderate to severe glabellar lines after moving RT-002 into a pivotal phase III to treat cervical dystonia.

At the same time, Revance is stretching its global footprint with a potential $260.5 million license deal that gives Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd., wholly owned subsidiary of Shanghai Fosun Pharmaceutical (Group) Co. Ltd., exclusive rights to develop and commercialize daxibotulinumtoxinA for injection in mainland China, Hong Kong and Macau.

The deal enables Revance to focus on its core aesthetic and neuroscience therapeutic opportunities in North America while partnering elsewhere, both in terms of geography and indication, according to Dan Browne, president and CEO.

"What Mylan did early in the year and now Fosun late in the year validated that Revance is unique," Browne told BioWorld, referring to the company's February deal with Mylan NV, of Hertfordshire, U.K., to develop and commercialize a biosimilar to Botox (onabotulinumtoxinA, Allergan plc).

"We've been fortunate to raise capital, and we've been good stewards of the cash," Browne continued. "But you want to look at opportunities to minimize that capital need and develop these partnerships. There's not that many multibillion-dollar biologic molecules that have this type of differentiation and this kind of versatility, and that's good and bad. The good is that you have a lot of opportunities. The bad is that you can't work on everything."

RT-002 is a long-lasting neuromodulator that incorporates the company's stabilizing excipient peptide technology. The asset is in development to treat aesthetic conditions that include glabellar, or frown, and upper facial lines and therapeutic areas that include movement disorders, pain and related neuroscience indications. The agent is the first botulinum toxin product sourced, processed and manufactured in the U.S. and formulated without human blood-derived products or manufactured using animal-derived proteins, Browne said.

The open-label, long-term safety phase III SAKURA trial was the final effort in the SAKURA program testing RT-002 in moderate to severe frown lines. (See BioWorld, Dec. 6, 2017.)

The study enrolled nearly 2,700 patients who received more than 3,800 treatments – up to three per patient – and were followed for more than 18 months. Overall, safety findings were consistent with the known profiles for currently available neuromodulators in aesthetics. RT-002 was generally well-tolerated, and no new tolerability or safety concerns reported. Consistent with the pivotal SAKURA 1 and SAKURA 2 trials, adverse events (AEs) were mild, localized and transient, and the rate of treatment-related AEs decreased over successive treatments. The most common treatment-related AEs were headache (3.3 percent of treatments), injection site pain (2.7 percent) and injection site erythema (2.5 percent). No treatment-related serious AEs occurred.

In terms of efficacy, based on investigator assessment, more than 95 percent of patients achieved a score of none or mild glabellar lines at maximum frown at week four after each of three treatments. Measuring duration of effect, the median time to return to baseline glabellar line severity was 28 weeks. Median time to loss of none or mild wrinkle severity was 24 weeks. Those results also were consistent with findings from SAKURA 1 and 2, positioning Revance to submit a BLA to the FDA, expected in the first half of 2019.

'Strong attraction to aesthetics' in China

The aesthetics opportunity looms large; the global market for neuromodulator-based aesthetic treatments was estimated at about $1.6 billion in revenue in 2016, according to the market research firm Global Industry Analysts Inc. But Revance is looking for a much bigger piece of the neuromodulation pie, which accounted for $3.2 billion in 2017 sales of Botox.

Under terms of the Fosun agreement, Revance will receive $30 million up front and is eligible to receive development and sales milestone payments of up to $230.5 million, plus tiered low-double-digit to high-teen royalty payments on net sales. Fosun Pharma will be responsible for conducting clinical studies, marketing and sales in the licensed territory, while Revance will manufacture drug substance and finished drug product for both clinical and commercial activities in the territory. The deal excludes any transfer of intellectual property.

"Revance has always had an attraction out of the China territory," affording the company's executive team opportunities to meet with numerous Chinese biopharmas, Browne said. Despite its precommercial pipeline, "there was a resonance with the Revance technology" that prompted many of those biopharmas to track the company's trajectory.

Fosun came to know Revance first through equity investments, but "the more that Fosun looked at the opportunity in aesthetics and therapeutics, the more they got interested in a transaction that allowed them to take the U.S. clinical data and science and efficiently deploy that work into regulatory approvals in China," he added.

Fosun already has a presence in facial aesthetics, and Browne pointed to disclosures by Allergan on its third-quarter earnings call that sales for Botox increased 22 percent in the period over the prior year, with growth of 14 percent in the U.S. and 33 percent ex-U.S., driven largely by sales in China and the Middle East.

"Asia Pacific/Middle East/Africa continues to be our fastest-growing region, led by China, with growth of 64 percent this quarter compared to last year," William Meury, Allergan's executive vice president and chief commercial officer, said on the October earnings call, adding, "China is on pace to be our largest market internationally."

The Chinese market, though bifurcated, offers "a layer of the population that has significant purchasing power," affording "premium pricing for U.S.-like innovation," Browne pointed out. "There's a very strong attraction to aesthetics and the innovation on the aesthetics side inherent more in Western cultures."

But RT-002, like Botox, is more than a beauty product, and Revance intends to go far beyond its face value. In cervical dystonia, an indication with FDA orphan drug designation, the randomized, double-blind, placebo-controlled, parallel group phase III ASPEN program plans to evaluate the botulinum toxin A stimulator in approximately 300 participants, with a primary efficacy endpoint of change from baseline in the Toronto Western Spasmodic Torticollis Rating Scale total score, according to Cortellis Clinical Trials Intelligence. Secondary endpoints include duration of treatment effect as measured by Clinical and Patient Global Impression of Changes, Cervical Dystonia Impact Profile (CDIP)-58, patient-rated quality of life and safety.

Following an initial therapeutic approval, Revance will look to expand the label into potential indications such as plantar fasciitis and upper limb spasticity. The company also plans to conduct a phase II study of RT-002 in chronic migraine.

"Despite the enthusiasm with CGRPs, we see a lot of opportunity in pain and more broadly in the neurosciences, whether it be migraine, depression, mood or sleep disorders," Browne said.

"This neuromodulator, as an active drug substance, is arguably the most versatile drug substance in the world," he added. Although 12 indications are approved, "the number of potential indications is in the hundreds. We can't work on everything we want to work on. Allergan couldn't, either. You have to make choices of what you can develop and commercialize."

Shares of Revance (NASDAQ:RVNC) opened higher Tuesday and continued to strengthen, gaining $4.06, or 19.5 percent, to close at $24.91. Allergan shares (NYSE:AGN) were off 2.6 percent, closing at $154.00 for a loss of $4.09.