By David Bautz, PhD
On October 15, 2018, Soligenix, Inc. (SNGX) announced positive feedback from the independent Data Monitoring Committee (DMC) following an unblinded review of data from the first 100 patients enrolled in the Phase 3 study of SGX301 for the treatment of cutaneous T cell lymphoma (CTCL). The DMC recommended an additional approximate 40 patients be enrolled in the trial to maintain 90% statistical power. To clear up any confusion regarding the DMC’s recommendation and what it means for the study we spoke with Dr. Richard Straube, Soligenix’s Chief Medical Officer, and asked him a few questions regarding the outcome of the interim analysis.
David Bautz: Some investors may be surprised by the required addition of 40 patients to the study. Can you explain why it is necessary to add that many patients and why the original estimate of 120 patients is not sufficient?
Dr. Straube: First, we want to make it clear that nothing is wrong with the study and we weren’t far off with our estimated enrollment of approximately 120 patients. The sample size of a trial is a "best estimation" based on both statistical requirements and expected relative outcomes in the treated and control arms of the trial. Statistically, you must decide the degree of risk that you will accept that the trial will be "negative" despite the drug actually working (false negative result) referred to as the power of the trial (statistical jargon "1-β”) and the risk that the trial is "positive" despite the drug actually working (false positive result), referred to as the statistical threshold and usually set at a p<0.05 level. The expected success rates in the treated and control groups are estimated based on previous data with the drug. The "expected" rates of success in the hypericin and placebo arms were extrapolated from a smaller Phase 2 trial; therefore, the estimates for each group were very sensitive to the amount of variability in even a single patient.
The fact that we require an additional approximately 40 patients suggests that the difference between the two groups is very close to being statistically significant. We interpret the recommendation from the DMC as evidence that the drug is tracking in the right direction but the estimates of success rates in the two treatment groups were slightly off and this can be overcome with the addition of more patients.
David Bautz: Soligenix continually emphasizes the fact that its trials are “90% powered”, however many other biotech companies conduct trials that are not as highly powered (i.e., 80% powered). Why is the company so committed to having 90% power in its trials? Would it be more prudent to sacrifice a bit of statistical power in order to enroll fewer patients and be finished with the trial sooner?
Dr. Straube: The choice of 90% power is arbitrary and reflects our belief that it is in the trial's best interest to make sure that we only have a 10% risk of having a false negative result. We could choose to double that risk by calculating a sample size based on an 80% power that would yield a lower number of patients. However, given that we are pursuing approval based on a single pivotal trial in an orphan disease and have made a significant investment of time and money into the CTCL development program, we believe it would not be in the company's, shareholder’s, or trial's best interest to not give the drug the best chance of success.
David Bautz: What were the company’s assumptions in order to get the Phase 3 trial to 90% power?
Dr. Straube: We have not previously disclosed our trial assumptions or the assumed success rates for the SGX301 and placebo groups; however, I can say that while the need for about 40 additional patients (roughly 13 additional placebo and 27 hypericin patients) may sound large, it suggests that the actual rate of successes in each group appears to be off by only a few patients necessary to be statistically significant.
David Bautz: How confident are you that the trial will be successful with 160 total patients enrolled?
Dr. Straube: With no other information, the chance of a positive trial at 160 evaluable patients is 90%. It is important to note that review of the open-label portions of the trial suggest that the drug is having a biologic effect, making us more optimistic than the power calculation would suggest. In fact, after completing the mandatory Cycles 1 and 2 of the trial, a majority of patients are choosing to remain in the optional Cycle 3, which is another reason for optimism.
David Bautz: Can you elaborate on what type of results you’re seeing from the open label portion of the study (Cycle’s 2 and 3)?
Dr. Straube: The trial is designed with a double-blind, placebo controlled Cycle 1 that will be used in the primary endpoint analysis and, obviously, Soligenix is blinded as to the actual response rates seen in each of the treatment groups. The trial has an open-label Cycle 2 in which the index lesions in all patients are treated with SGX301 for 6 weeks and evaluated. This analysis includes two types of patients, those that have received 12 weeks of therapy (the 2/3 of patients randomized to receive SGX301 in Cycle 1) and those that have received 6 weeks of therapy (the 1/3 of patients that received placebo in Cycle 1). Given the overall success rate we are seeing at the end of Cycle 2, the data suggest that the drug is having a strong biologic effect. Cycle 3 was an optional portion of the trial that allowed patients that participated in the initial two cycles to use compassionate-use SGX301 on all of their lesions. Again, the majority of patients that have reached Cycle 3 have elected to continue therapy.
David Bautz: Why did you wait until 100 patients had been enrolled in the study before performing the interim analysis?
Dr. Straube: The FDA requires that the safety database on a new drug under review for marketing approval have sufficient numbers of patients to understand the risk-to-benefit ratio of its use. Given the size of the current Phase 3 study and the expectation that only a single study would support the NDA for synthetic hypericin in an orphan disease, which CTCL clearly is, it was unclear that stopping the trial early for efficacy would hasten the approval process. Therefore, the most critical information coming from the interim analysis was whether the assumptions concerning the relative success rates in the two treatment arms were 100% accurate. Assuming that they were not (which is what happened), the more precise measurement of the actual rates allowed for a more precise calculation on the total number of patients needed to conclusively prove that synthetic hypericin was working.
David Bautz: Did enrollment continue while the interim analysis was taking place and when do you anticipate the trial finishing now?
Dr. Straube: As prospectively defined, the trial continued to enroll patients while data for the interim analysis was being cleaned, locked, and analyzed. As we indicated in our press release, we are currently at approximately 120 subjects.
The primary endpoint is determined two months after enrollment and the necessary monitoring, review, and audit of the data necessary to lock the database typically requires an additional month or so. Thus, we expect that topline results could be available two to three months after the last patient is enrolled. Given the increased sample size of approximately 40 evaluable patients (a total of 160 evaluable), we conservatively estimate having topline results shift from the first half of 2019 (previous guidance) to completion of enrollment sometime in the second half of 2019 with topline results no later than the first quarter of 2020.
David Bautz: Do you anticipate there being any issues getting the additional 40 patients enrolled into the study?
Dr. Straube: Quite to the contrary! We expect that most investigators participating in the trial will view the data as positive since it strongly suggests that the drug is beneficial and requires only about 40 more patients to conclusively prove that SGX301 works. As I noted, we have provided very conservative timeline estimates to study completion and topline results; however, I suspect we have more than a reasonable likelihood of coming in ahead of this guidance.
David Bautz: Lastly, how will the additional 40 patients impact the trial’s budget and will this necessitate you raising additional capital to finish the trial?
Dr. Straube: We estimate that the approximate cost for enrolling the additional 40 patients or so will be in the general range of $1.5M dollars, plus or minus a couple hundred thousand. Given our currently available cash resources, we believe we have enough money to complete the trial.
David Bautz: Thank you Dr. Straube for providing this additional information!
Dr. Straube: Thank you for your interest in what we see as a positive milestone in this important clinical trial.
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By David Bautz, PhD