AUPH: Are Investors Honestly Surprised With Results?
By: Mark Jukic (Boul)
The time has finally come for Aurinia, and they shocked investors with an extremely positive readout for their Phase IIb study of Voclosporin (Lupus Nephritis). After positive PIIa and (now) PIIb data released (24 week and 48 week trials), we now go into what’s next for Aurinia and Voclosporin for this indication.
Lupus Nephritis is the inflammation of the kidney that is caused by systemic Lupus Erythematous (SLE). According to the US National Library of Medicine; Lupus Nephritis: Current Update, 60% of Lupus patients will eventually develop clinically relevant Nephritis throughout the course of their illness. More specifically, LN is more likely to effect children more severely compared to the elderly. A Danish study showed that the death rate in Lupus still remains very high, with data pointing to people under the age of 30 more susceptible to severe LN. The mortality rate, however, has decreased from 1970 to 2000, which indicates that standard care and progress within the Lupus indication has improved. With that being said, there are still limited treatments available and a dire need of a product that can increase the remission response rates for all patients. Currently this debilitating disease (specifically Nephritis) affects roughly 1.5 million people.
BENLYSTA vs. VOCLOSPORIN
Benlysta, courtesy of Glaxo Smith Kline, is currently the only approved Lupus drug in the past 50 years. When investigating the long term safety of Benlysta in LN patients, a 52 week double-blind study was initiated, with a 24 week open-label period for patients that completed the 52 week study. The patients received intravenous Belimumab along with standard care throughout the study administered on days 0, 14, 28, and then every 28 days. Continuing on with the study, patients that completed the 24 week open-label study were able to continue with a long term open-label period in order to receive 10 mg/kg of Belimumab every 28 days (Lupus.org). Throughout the study, adverse events and safety/tolerance was thoroughly monitored. Adverse events noted were similar between the control and placebo population. It is worth noting that these adverse events were consistent between the initial study and the long term open-label study for the patients involved in the trial. The only limitation to the study itself was that there was no control group in the long term continuation study. The results showed that there were 5 deaths throughout the 4 year study on the safety/tolerability of Belimumab in patients. Two deaths occurred in the initial double blind study, and the other three deaths occurred in the long term open-label study. According to researchers, only one of the deaths was felt to be related to the injection of Belimumab. Other adverse events noted throughout the study included; infusion reactions, infections, opportunistic infections, and malignancies.
In 2016, the ACR/ARPH Annual Meeting provided a poster on Systemic Lupus Erthematosus. This investigated the long term safety and efficacy of LN with the use of Belimumab. This continuation study involved patients who completed BLISS-76 in the US. The patients were evaluated every 48 weeks. With the 268 total patients in the study, 140 patients completed the continuation study and 128 patients withdrew. It is worth noting that 24.2% of the withdrawals were due to patient requests and 19.5% due to adverse events. Through the long term study, the amount of adverse events have remained stable and/or declined throughout the 7 year time frame. The long term exposure noted in this study shows that it was consistent with the Phase II study provided by GSK for Belimumab in patients with SLE.
Phase II of Benlysta (the use of Belimumab) met primary endpoints, but failed to meet the co-primary endpoints assigned during the trial construction. GSK used a SELENA-SLEDAI scoring system to identify the activity of the disease in the patient population. In the trial, GSK only used scores of at least 4, as well as a history of autoantibodies in potential patients. Despite the failure, an analysis of the data showed that patients experienced significant improvements at the 52 week level with Belimumab throughout a variety of secondary endpoints. The implementation of the SRI study allowed a more focused view on measuring the SLE activity for the new patient population. With evaluating the SRI, the response rate was 46% in the Belimumab treated group at the 52 week mark compared to the 29% of the placebo population. This result was then used as the basis for the pivotal PIII study for Belimumab.
Phase III was a double blind, placebo controlled clinical trial. Within this trial, the patient population had to meet the SELENA-SLEDAI score of at least 6. It is worth noting that patients with severe lupus disease and lupus neurological problems were excluded from the trial conducted. The study met primary endpoints by providing a response rate of 57.6% (SRI), and 43.6% for Belimumab. Overall, the drug was well tolerated and no safety differences have been noted.
Voclosporin, the Lupus Nephritis drug currently being tested by Aurinia, has shown similar promise and safety throughout pivotal PII studies thus far. Phase IIa of Voclosporin was a randomized controlled study that had a patient population of 265. The drug was able to rapidly garner an impressive 32.6% Complete Response rate compared to the 19.3% placebo group (standard treatment). Patients who received Voclosporin were given 23.7 mg twice daily. On the other hand, the Complete Response rate was 27.3% for the patients that received the higher dose. The difference between the control group and the treated group were not statistically significant at 24 weeks. While partial remission has increased significantly overtime, seeing a complete response rate through this initial PII study was promising. Partial remission was achieved in 69.7% of the patients treated with low doses, and 65.9% achieved partial remission with high doses. This number was also significantly higher than the 49.4% partial remission rate of the patients treated with the placebo (standard care). Adverse events were noted throughout the trial, with infection and gastrointestinal disorders being the most common and reoccurring. Serious adverse events were more common in the Voclosporin groups (25% vs. 15.8% of control group). The primary issue with this trial was the 13 deaths that were involved with this Phase IIa trial. 10 out of the 13 reported deaths came from the low-dose group. With most of the deaths being involved with the low dose group, investors were not pleased to a potential safety concern in that patient population. Through the investigation of the company, it was noted that Voclosporin was not directly related to the deaths of the patients in that trial. In fact, it was noted that the deaths that have occurred may have been to poor population selection (significantly severe levels of the disease prior to treatment). In response to the deaths recorded in the trial, shares plummeted despite the impressive efficacy and overall safety profile.
Aurinia, while pleased with the initial results, conducted an additional safety evaluation to ensure investors that Voclosporin has significant potential in treating this deadly disease. With the professional opinions provided based on the conducted study, it was confirmed that Voclosporin was not the cause of the deaths that have occurred during the Phase IIa study. Shares reacted positively, leading the stock to go on a multi-day run well over $4 a share.
While the stock has been trading violently until the release of the Phase IIb (48 week trial) study of Voclosporin, the wait paid off. The Phase IIb results boasted the highest complete remission rate of any Lupus Nephritis study conducted globally. The low dose population achieved a complete response rate of 49.4% after 48 weeks, with a p value of less than .001. The higher dose group achieved a complete response rate of 40% after 48 weeks with the p value of .026. This result was significantly higher than the CR rate of the placebo group (24%). Partial remissions also showed solid results with 68% and a p value ion .007, as well as 72% for the higher dose group with a p value of .002. The control group experienced a partial remission of 49% with standard care. Investors were concerned that the partial remission rates indicated that the lower doses were going to outperform the higher doses. In this case, the long term study showed that the higher doses did in fact increase the rates of the partial and complete remissions within the patient population. More importantly, no safety issues have been noted, with 0 additional deaths while this study was conducted.
While comparing the two drugs, Voclosporin has shown stronger complete and partial remission rates, as well as a safe profile. Considering that Benlysta (Belimumab) has not been able to achieve such high complete response rates, Voclosporin has the advantage if it were to continue on to approval. With the results just released, I believe that Phase III will only reiterate the true potential of this drug, and it can take a considerable market share of the LN population compared to Benlysta when it becomes marketable.
Assuming relatively moderate pricing, the market potential for this drug could reach into the range of 600-800m in potential sales (1.5 mill approximation in patients and assuming 35-45% of market share). More importantly, this result can garner the attention of potential suitors. Glaxo Smith Kline could very well be one of the potential companies to make a move realizing that this drug could very well outperform Benlysta down the road. Assuming PIII has a similar result, the market value of Aurinia can rise significantly as this year moves on. But, with a limited cash position, investors should be weary of any potential financing. Ideally, a partnership would be the best situation for Aurinia to get this product moved efficiently. After today’s trading session, Aurinia is trading at a discount, similar to September of last year. I’ve been pounding the table on Aurinia since the low $2 mark and my sentiment continued to rise. Once Aurinia scheduled the re-evaluation of data with investors, the stock surged, reaching as high as $5 with momentum in the next few trading days. But, with that surge, the stock still struggled to hold any gains. The stock has continued to bounce between $2 to $4 prior to this data release.
Now, we are finally here, and Aurinia did the unthinkable. Or did they? The 48 week data was impressive to say the least. The safety and tolerability was clear throughout the entire trial from beginning to end. The efficacy shown improved over the next 24 weeks under scope, and ensured that the response rates were well represented through the differences between the lower and higher doses. Overall expectations seemed to show that a solid safety profile was likely, but, one can only wonder what took investors so long to make their move. My current long term price target for Aurinia is $12 a share, with the assumption that the pivotal PIII low dose study of Voclosporin will further solidify the potential impact it could make for LN patients. With only a select few treatments available, I can see Voclosporin be approved to treat Lupus Nephritis rather quickly.