Aurinia’s Voclosporin Misses Superior Tolerability Vs. Restasis, But Pushes On In Dry Eye

Aurinia's voclosporin missed the primary endpoint of superior tolerability compared to Restasis, but hit objective secondary efficacy endpoints that that may better position it for approval in dry eye.

Aurinia Pharmaceuticals Inc.’s voclosporin ophthalmic solution (VOS) failed to show better tolerability than the standard of care for dry eye, Allergan PLC’s Restasis (cyclosporine ophthalmic solution 0.05%), in a Phase II head-to-head study, but it did show superiority versus Restasis on a pair of objective efficacy endpoints that are accepted by the US FDA for approval in dry eye.

That was the surprise mixed outcome for the 100-patient, double-masked, head-to-head study Aurinia revealed Jan. 22, and the British-Columbia-based firm said it now intends to advance VOS aggressively in dry eye while continuing to focus on its lead program, a different formulation of voclosporin for lupus nephritis. (Also see "New AURA Lupus Data Bode Well For Aurinia's Voclosporin In Future Phase III" - Scrip, 2 Mar, 2017.)

On a same-day investor call, Aurinia Chairman and CEO Richard Glickman said the head-to-head trial was intended mainly as an exploratory study to determine if it was worth developing VOS – a calcineurin inhibitor it claims is four-times more potent than Restasis, which is also of that drug class – in dry eye. It hoped to produce “interesting data” but on the expectation that VOS could show a clinically significant difference in drug installation discomfort at one minute.

Instead, there was little difference in discomfort between the two arms, as Restasis showed a lower-than-expected drop discomfort score. Aurinia designed the trial with several secondary endpoints for efficacy but did not think a 100-patient study would be sufficiently powered to show statistical significance compared to Restasis over four weeks of dosing, although it did. There were no serious adverse events or unexpected safety signals in the study.

In selecting the primary endpoint, “clearly we were wrong,” Glickman admitted. “In our study, both VOS and Restasis generated surprisingly low discomfort scores and both were very well tolerated. So, [tolerability] is definitely not the right choice as our primary endpoint in this exploratory study. However, we never imagined that the more challenging objective and subjective endpoints that encompass both signs and symptoms would yield such statistically significant and clinically relevant results.”

Statistical Significance On Tear-Production, Corneal Scarring

VOS showed statistically significant improvements compared to Restasis at four weeks for Schirmer Tear Test (STT, an objective measure of tear production) and fluorescein corneal staining, which measures scarring of the cornea – both validated endpoints for evaluating signs of dry eye disease. In addition, both arms of the study met statistical significance for a symptom of dry eye, the symptom assessment in dry eye (SANDE) questionnaire.

 

The FDA requires an investigational drug for dry eye syndrome to demonstrate benefit in at least one sign and one symptom of the disease to obtain approval. (Also see "In Dry Eye, A Variety Of Mechanisms Pursue Established Therapies" - Scrip, 15 Jan, 2018.) In addition to Restasis, FDA to date has also approved Shire PLC’s Xiidra (lifitegrast) and Sun Pharmaceutical Industries Ltd.’s Cequa (cyclosporine ophthalmic solution 0.09%). (Also see "Sun Hopes Cequa’s Nano Formulation Makes Big Impact" - Scrip, 17 Aug, 2018.) Cequa, Restasis and VOS all are calcineurin inhibitors, while Xiidra – the first drug approved with an indication to treat signs and symptoms of dry eye – is an anti-inflammatory agent that inhibits lymphocyte function-associated antigen 1 (LFA-1).

In the head-to-head study, 42.9% of patients receiving VOS showed a 10mm or greater improvement in Schirmer score after four weeks, compared to 18.4% of patients receiving Restasis (p=0.0055). “When the Schirmer score was assessed, we found that VOS was statistically superior against the active comparator Restasis at nearly all time points,” Aurinia Chief Medical Officer Neil Solomons told the call.

Trial investigator Joseph Tauber, head of the Tauber Eye Institute in Kansas City, Mo., said the rapid onset of benefit seen in the study with VOS might be the most meaningful benefit considering that both Restasis and Cequa take months to show a clinical benefit – and he noted that he’s served as an investigator on clinical trials for Restasis, Cequa and other investigational dry eye therapies. He called the results on the STT and FCS endpoints “extraordinary,” particularly compared to clinical data for currently approved dry eye treatments.

Analysts Like The Data More Than Investors Right Now

Glickman spoke enthusiastically about taking VOS forward in dry eye, saying he already had approval from his board to take on that expense. While his strategy is to continue working to increase VOS’ value proposition in dry eye before seeking a potential partner, it seems the biotech’s investors are less sure what to think. Aurinia’s stock finished the trading day Jan. 22 down nearly 9% to $6.89 per share.

Leerink Partners analyst Joseph Schwartz, however, echoed Glickman’s optimism, calling the efficacy data “highly encouraging.” He predicted a “positive impact” for the stock, maintaining an “outperform” rating, while cautioning that the Street in general “may superficially view today’s results as ‘mixed.’”

“We do not believe [missing the tolerability endpoint] is a detrimental blow to development,” Schwartz wrote. “Instead, we think the on-par tolerability of VOS despite a roughly 16 times higher concentration of drug delivered illustrates that there could be room for improvement via evaluating lower doses in future trials, a concept management disclosed as a potential strategy in their next study.”

While VOS is approximately four-times as potent as Restasis, Glickman explained that Aurinia also tested a larger dose of study drug that would mean delivering roughly 16 times more drug to the eye than with Restasis, because so much drug is lost with eye drops when a patient rubs his or her eyes after administration. VOS was given twice-daily in the study, but the exec said Aurinia now has seen data indicating that it can investigate a once-daily dose as well as smaller dose levels of the drug.

Mackie Research analyst Andre Uddin took a more measured stance on the trial results, but said VOS’ apparent ability to yield a clinical benefit after four weeks could be a substantial differentiating factor compared to Restasis. He added in a Jan. 22 note that STT and FCS are among “the most clinically meaningful measures of efficacy” in dry eye.

“More importantly, these results indicated that VOS should have a much faster onset of action than Restasis, that usually takes 3-6 months to take effect,” Uddin said. “Fast onset of action is a more important factor than eye tolerability for patient perception in treating [dry eye syndrome] in real world settings.”

Glickman said that while the Phase III program for voclosporin in lupus nephritis remains Aurinia’s lead program, the company sees good reason to keep the dry eye program in house and try to generate value-enhancing data in larger studies of longer duration.

“We intend to take this further down the pipeline because we really do believe we can create significant value with this asset and it's probably better for us to take it another step than it would be, for instance, to partner it out immediately,” he said. “We think that the development pathway is really clear. We know the regulatory pathway for the [calcineurin inhibitors]. It's actually fairly low-risk for us."

“Compared to doing a lupus nephritis trial, the access to patients, the speed with which we can do these trials, it's actually kind of enjoyable relative to the drudge work and the tough work we faced in our LN program,” Glickman continued. “So, we're not letting this asset go too quickly.”