Positive phase III data from the Advocate trial by Chemocentryx Inc. and Vifor Fresenius Medical Care Renal Pharma caused Chemocentryx’s stock (NASDAQ:CCXI) to dramatically rise 281% on Tuesday, clearing the way to an NDA filing for the star small-molecule attraction, avacopan, an oral, selective complement 5a receptor inhibitor.

The worldwide study in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA-associated vasculitis, or ANCA vasculitis) hit both of its primary endpoints: disease remission at 26 weeks and sustained remission at 52 weeks as assessed by the Birmingham Vasculitis Activity Score (BVAS). Remission was defined as a BVAS score of zero and being off glucocorticoid treatment for ANCA vasculitis for at least the preceding four weeks. BVAS remission at week 26 was achieved in 72.3% of the avacopan-treated subjects vs. 70.1% of subjects in the glucocorticoid standard-of-care (SOC) control group  (p<0.0001 for noninferiority). Sustained remission at 52 weeks was observed in 65.7% of the avacopan-treated patients vs. 54.9% in the glucocorticoid SOC control group, achieving both noninferiority and superiority to glucocorticoid SOC (p=0.0066 for superiority of avacopan).  

“The superiority finding was a positive surprise,” HC Wainwright & Co. analysts wrote Tuesday. SVB Leerink analysts said the results may call for the C5a receptor inhibition’s mechanism to be reevaluated as a therapeutic approach. “As a start, we think eGFR and proteinuria benefits seen with avacopan lends credence to potential utility in other kidney indications and we remind investors that C3 glomerulopathy (C3G; ACCOLADE trial) is ongoing with data expected in 2020. In addition, the anti-inflammatory effect seen with avacopan may also speak to potential efficacy in hidradenitis suppurativa (HS; AURORA trial) with its data also expected in 2020,” they wrote Monday.

Thomas J. Schall, Chemocentryx’s president and CEO, said the outcomes exceeded his expectations.

“Until now, ANCA vasculitis patients have had to endure regimens that contain chronic high doses of steroids and all their noxious effects, but with today’s data it is clear that the time of making patients sick with steroid therapy in an attempt to make their acute vasculitis better may at last be over,” Schall said.

“Based on these results, we believe avacopan could replace steroids in SOC treatment of [antibody-associated vasculitis] and potentially more broadly,” Piper Jaffray analysts wrote Monday.

This past summer, Schall said the drug "smartly targets the C5a receptor, avoiding collateral damage to C5L2, which is a second C5a-binding pathway and one which is known to have protective effects. Leaving C5L2 alone is important. Published literature has shown that destruction of C5L2 has, for example, been linked to worsened acute lung injury, worsening of inflammation in contact dermatitis and indeed to an exacerbated signal and deficiencies in an [AAV-vasculitis] disease model," he said, noting that taking aim at the C5a receptor is preferable to targeting C5a itself and that "the amount of C5a in the local environment is unknown, and there are many different ways to produce C5a" by way of enzymatic processes.”

Mountain View, Calif.-based Chemocentryx and Vifor Fresenius plan to submit marketing proposals to the FDA first and then to the EMA in 2020.

ANCA-associated vasculitides are three separate conditions – granulomatosis with polyangiitis (once called Wegener's granulomatosis), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (previously known as Churg-Strauss syndrome). While in the past 15 years, life expectancy for those patients increased from 99.4 months to 126.6 months, the rare diseases associated with that type of vasculitis inflame blood vessels and lead to ischemic or hemorrhagic events.

Vifor Fresenius has the exclusive license to commercialize avacopan outside the U.S. and it granted Kissei Pharmaceutical Co. Ltd. the exclusive sublicense to develop and commercialize the drug in Japan.  The company was founded in 2010 and is owned 55% by Vifor Pharma Group and 45% by Fresenius Medical Care.

“Importantly, though, what we get in the sales milestones, I think, is quite interesting and structured in a way that's, I think, very good in terms of – we have teens to mid-20s royalties that come off the top line,” Schall said to investors in Monday’s conference call. “Those are based on sales tiers. And I think those steps to these tiers are fairly shallow, so we can get to new tiers, I think, fairly quickly.”

Shares of Chemocentryx closed Tuesday at $30.73, up $22.67.

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