Acadia Pharmaceuticals Inc. Study result

Good morning and thank you for joining us on today's call to discuss the top-line results from the phase II portion of our ongoing RADIANT clinical trial program evaluating remlifanserin for the treatment of hallucinations and delusions associated with Alzheimer's disease psychosis or ADP. On today's call, Catherine Owen Adams, our Chief Executive Officer, will provide opening remarks. Following Catherine, Liz Thompson, PhD, Executive Vice President and the Head of Research and Development, will review the study design and discuss the phase II top-line efficacy, safety, and tolerability results from RADIANT. Catherine will then provide closing remarks before we open the call for your questions. I would also like to point out that we are using supplementary slides, which are available in the events and presentations section of our website.

Before we proceed, I would like to remind you that during today's call, we will be making a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, including goals, expectations, plans, prospects, growth potential, development timelines, regulatory activities, future study outcomes, commercialization opportunities, and future results are based on current information, assumptions and expectations that are inherently subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially. These factors and other risks associated with our business can be found in our filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of today's date. I'll now turn the call over to Catherine Owen Adams.

Thank you, Al, and good morning, everybody. Thank you very much for joining us today. We're very pleased to share the top-line results from our phase II portion of the RADIANT clinical trial program evaluating remlifanserin for the treatment of Alzheimer's disease psychosis are phase III enabling. Importantly, these phase II results demonstrated meaningful and consistent efficacy trends across endpoints. The 60 milligram dose narrowly missed statistical significance on the primary endpoint of change from baseline in SAPS-H+D total score at week 6 and demonstrated nominal statistical significance on the key secondary endpoint of change from baseline in CGI-S-ADP. Remlifanserin across both doses also demonstrated a favorable safety and tolerability profile with no new safety signals identified. Taken together, we are excited that the efficacy and safety results support the further development of remlifanserin in the two phase III ADP trials currently underway.

I'll now turn the call over to Liz to review the phase II study design and results in greater detail, after which I will return with some closing remarks.

Liz. Thank you, Kathryn. I'd like to begin by thanking the patients, caregivers, investigators, study coordinators, and of course, the dedicated internal ACADIA team whose dedication made this study possible.

RADIANT is a global randomized, double-blind, placebo-controlled, operationally seamless phase II and phase III program evaluating remlifanserin in Alzheimer's disease psychosis. The phase II portion of the study was designed to evaluate the efficacy and safety of two doses, 30 milligrams and 60 milligrams given once daily, and to inform the dose and patient population for the phase III program. The results provide clear and important information to support the continued development of remlifanserin, including the selection of dose and considerations on how we could refine the patient population for phase III. In RADIANT, patients were randomized in a one-to-one-to-one ratio to receive 60 milligrams of remlifanserin, 30 milligrams of remlifanserin or placebo once daily for six weeks.

The primary endpoint was change from baseline in the SAPS-H+D total score at week six, and the key secondary endpoint was the change from baseline in a clinician global assessment of severity, called the CGI-S-ADP at week six. Our pre-specified population for our efficacy analyses was the modified full analysis set, which is referred to in these slides as the MFAS. This comprised 326 patients who received at least one dose of study drug, had a baseline SAPS-H+D total score of at least 10, and had at least one post-baseline SAPS-H+D assessment. In the MFAS population, 109 patients were assigned to the 60 milligram dose, 110 to the 30 milligram dose and 107 to placebo. Demographic and baseline characteristics were generally well-balanced across treatment groups. The mean age was about 75 years old and approximately two-thirds of patients were female.

Baseline SAPS-H+D and CGI-S-ADP scores were also generally similar across the treatment groups, supporting the interpretability of the results. Going to the next slide. Turning to the efficacy results, the 60 milligram dose of remlifanserin narrowly exceeded the pre-specified thresholds for statistical significance on the primary endpoint. At week six, the 60 milligram dose demonstrated an effect size of 0.26 on the SAPS-H+D total score with a p-value of 0.0603. For the key secondary endpoint, the effect size was 0.37 with a nominal p-value of 0.0077. This corresponded to reductions from baseline of 12.4 versus 10.4 for SAPS-H+D and 1.3 versus 0.9 for CGI-S. A dose effect was observed as the 30 milligram dose showed minimal improvement relative to placebo with effect sizes of 0.05 and 0.11 across the primary and key secondary endpoints.

Now, as we have discussed this topic previously, I want to make a quick note about the NPI-C. As you will recall, we added this as an exploratory endpoint and collected it only in patients who were enrolled later in the study. We are early in our analyses of this endpoint, but to date it appears that a small numerical improvement in NPI-C was also seen in the 60 milligram arm. Now returning to SAPS-H+D in this study. On this slide, we show the performance over time where the data suggests increasing separation through week 6. In totality, the efficacy data combined with safety data that support either dose, which I will review later in the presentation, gave us confidence in selecting the 60 milligram once daily dose of remlifanserin for further development.

The next question we turned our minds to was whether there were any modifications to the inclusion criteria that hold the potential to improve phase III outcomes. We used pre-specified subgroups to guide us regarding the potential impact on both efficacy and patient eligibility of several criteria modifications. One promising area with the potential to further improve efficacy in phase III while maintaining the significant majority of the trial population is further refining the enrollment criteria for modestly higher baseline psychosis. On this slide, you can see the impact of one potential version of this refinement when applied to the phase II trial. First, 80% of patients in the trial would still have qualified for participation. Second, the effect sizes in the resulting population increase for both the primary and key secondary endpoint.

For the primary endpoint, the resulting effect size was 0.33, and for the key secondary it was 0.43. Interestingly, on the later enrolled patients where we collected NPI-C D+H data, there was a similar suggestion of improved effect in this population, though again, I must emphasize that the data are limited based on the timing of adding the endpoint to the study. We are considering whether this refinement to modestly higher baseline psychosis or similar refinements would be beneficial to the overall profile of remlifanserin. Turning now to safety and tolerability. The overall safety profile observed in this study was favorable and supported continued development of remlifanserin. Now recall that one of our main goals with remlifanserin was to avoid the QT prolongation signal that had prevented our evaluating higher doses of pimavanserin.

Preclinical and phase I data had supported our desired profile for remlifanserin, and we were pleased to see that in this data set there was no signal of QT prolongation compared with the placebo group. Expanding to the safety profile more broadly, rates of adverse events, serious adverse events, and discontinuations due to adverse events were all seen at similar rates to placebo. There were no deaths in either remlifanserin treatment group compared with 2 deaths in the placebo arm. Rates of individual adverse events were also low. In fact, no individual adverse event was reported in more than 5% of patients receiving 60 milligrams once daily remlifanserin. Somnolence at 3.2% and nausea at 2.4% were the only adverse events reported in more than 2% of patients receiving 60 milligrams that occurred at a numerically higher rate than placebo.

Finally, I've talked previously about our target profile for remlifanserin and what aspects could yield an important treatment option for patients. I was pleased to see that this data set suggested no negative impact on motor symptoms or cognition. Taken together, the safety and tolerability findings were consistent with our hopes for the molecule and support continued evaluation of remlifanserin in the ongoing phase III studies. Looking ahead, we plan to present additional efficacy and safety results from the phase II study at the Clinical Trials on Alzheimer's Disease, or CTAD conference, which takes place November 16th through 19th in Boston. The phase III program continues while we implement protocol amendments, including removing the 30 milligram dosage arm. With that, I turn the call back to Catherine.