Rapport Therapeutics, Inc. Common Stock Study result

Please go ahead. Thank you, operator, and good morning, everyone.

Thank you for joining us today. Earlier this morning, Rapport issued a press release reporting top-line results from the phase II trial evaluating RAP-219 in bipolar mania. The release is available on the company's website and through our SEC filings. During this call, management will make forward-looking statements, including related to its phase II trial of RAP-219 in bipolar mania, as well as the timing of data, our ongoing plans and future clinical trials, the company's development plans, and the potential commercial opportunity for RAP-219. These statements are subject to risks and uncertainties described in our filings with the Securities and Exchange Commission. Actual results may differ materially from those expressed or implied. Please refer to our SEC filings for a discussion of those risks. The company undertakes no obligation to update these statements except as required by law.

With me on today's call from Rapport are Abe Ceesay, Chief Executive Officer, Dr. Jeff Sevigny, Rapport's Chief Medical Officer, and Troy Ignelzi, Chief Financial Officer. We'll provide an overview of RAP-219 and the need and opportunity in bipolar mania. We'll then share top-line results of our phase II trial in bipolar mania and walk through our near-term catalysts and provide a financial overview. We are joined by Dr. Gary Sachs, Founding Director of the Bipolar Clinic and Research Program at Mass General Hospital and Associate Clinical Professor of Psychiatry at Harvard Medical School, who will share his perspective on the clinical trial results. At the end of the prepared remarks, we'll open the call up for questions. With that, I'll now turn the call over to Abe.

Thank you, Julie, and good morning to everyone, and thank you for joining us today on the call. This is a very exciting day for patients and for Rapport. We're pleased to share results from our phase II proof-of-concept trial of RAP-219 in bipolar mania. On our path to building the leading precision neuroscience company, our vision was always to establish a pipeline and a product with RAP-219. We took our first step towards that vision last year when we established proof of concept in focal onset seizures with our robust phase II data. Today, we take the next step, achieving proof of concept in bipolar mania. On an individual basis, focal onset seizures and bipolar mania each represent multibillion-dollar market opportunities. Our phase II trial achieved statistically significant results on both the primary and secondary endpoints, and the product candidate was well-tolerated.

In neuropsych trials, it is important to see a consistent pattern of benefit across measures. Importantly, the clinical benefit was seen consistently across measures. A key way to evaluate and understand efficacy data in clinical trials with this patient population is to look at the single items that make up the YMRS. As Jeff will share shortly, RAP-219 improved more than placebo on every YMRS single item score, achieving nominal significance on several key scores. From a tolerability standpoint, the drug was well-tolerated. All TEAEs were mild to moderate, and the incidence was similar to placebo. There was a low discontinuation rate due to adverse events, and we continue to see a favorable tolerability profile. Like in FOS, in bipolar mania, a differentiated tolerability profile achieved by its novel mechanism positions RAP-219 to be potentially transformational for this patient population.

The data clearly support us advancing to phase III, and the team is preparing for that as we speak. After walking through the data in more detail, Jeff will talk about our next steps for the program and some enhancements that we think we can bring to the phase III program to potentially build further on these results. I would like to briefly review the scientific rationale for advancing RAP-219 into bipolar mania. Unlike our work in focal onset seizures, this program did not have the same degree of direct preclinical translation. Instead, our decision to study RAP-219 in bipolar mania was grounded in the scientific literature and our understanding of the mechanism. That rationale rests on two key themes. First, a growing body of literature identifies excess glutamate as a key driver of bipolar mania.

Second, this excess glutamate is highly expressed in the corticolimbic network, which directly overlaps with the expression of TARPγ8 containing AMPA receptors, the target of RAP-219. Fundamentally, we believe that if we achieved proof of concept, RAP-219 could represent a novel precision-based approach to treating bipolar mania. One, to drive clinical activity while potentially mitigating the burdensome adverse events associated with current therapies. In terms of the market opportunity, bipolar mania could significantly expand the potential of RAP-219. About 8 million U.S. adults have bipolar disorder. Of those, roughly 3.6 million are diagnosed, and an estimated 1.6 million experience bipolar mania. We believe the immediate TAM is the more than 1 million adults receiving second-line or third-line treatment, where combination therapy and switching is common.

To help frame these data, it is useful to understand the current treatment landscape for patients living with bipolar mania and where RAP-219 could potentially fit in. This is a population with substantial unmet need. Patients present in both inpatient and outpatient settings and are treated acutely, primarily with atypical antipsychotics, anti-seizure medications approved for this condition, and lithium. These broadly acting agents are associated with well-known burdensome adverse events, including sedation, akathisia, extrapyramidal symptoms, weight gain, and metabolic changes. These tolerability challenges are unacceptable for patients and carry a significant burden, often driving them to stop taking their medication. Discontinuation and non-adherence rates are high, with roughly 40% of patients discontinuing treatment, and as a result, many patients relapse and continue to cycle through their illness. Before I turn it over to Jeff, I would like to put the patients who entered this trial into context.

Bipolar mania is a complex condition. At the top of this slide are the DSM-5 criteria that define a manic episode. Seven core symptoms, of which three or more characterize an episode. At the bottom are the symptoms these patients actually present with. At baseline, they are agitated and often display disruptive and aggressive behavior, psychotic features, anxiety, substance abuse, suicidal ideation, and impaired insight. As you review the data Jeff will share, I would encourage you to keep two considerations in mind. First, where is the drug having an impact from an efficacy standpoint? Second, how does it perform on tolerability? Behavioral adverse events such as aggression have been a consideration for this mechanism, and on our data, we did not observe those adverse events with RAP-219 to date. In fact, we saw improvements in the behavioral domain of the YMRS.

We believe these data support our path forward in bipolar mania and also inform the broader development of RAP-219, including in epilepsy. With that, I will turn it over to Jeff.

Okay, great. Thank you, Abe. Good morning, and thank you for joining us this morning. I am Jeff Sevigny, Chief Medical Officer of Rapport Therapeutics. The phase II proof of concept trial in bipolar mania met both the primary and the secondary endpoints and was well-tolerated. The placebo-adjusted change from baseline on the YMRS at week 3, that was the primary endpoint, was 3.1 points and statistically significant. The effect was driven by an absolute reduction of 15.4 points in the RAP-219 treatment arm. The secondary endpoint was the placebo-adjusted CGI bipolar severity mania score, which demonstrated a statistically significant improvement of 0.4 points at week 3. In a pre-specified exploratory analysis, all 11 items on the YMRS numerically favored the RAP-219 treatment arm, with four items, including irritability and aggressive behavior, achieving nominal significance.

In terms of safety, RAP-219 was well-tolerated, and there were no severe or serious AEs during the treatment period. Discontinuations due to AEs were below 5%. The incidence of TEAEs and of psychiatric TEAEs were balanced between the two groups. Lastly, adverse events commonly reported with atypical antipsychotics such as somnolence, dizziness, akathisia, and other extrapyramidal symptoms were not reported or occurred at very low rates in this study. The design of the study was a conventional one. It enrolled patients with acute bipolar mania in accordance with DSM-5 criteria and having a YMRS score of 25 or greater. Eligible patients were randomized to RAP-219 using a 2 or 4-day titration to the 0.75 milligrams or to placebo, and then followed in an inpatient setting for a 3-week treatment period. After completing the 3-week treatment period, patients entered an 8-week safety follow-up period.

I would point out that this was a monotherapy study, so patients were required to wash out of any treatments used for bipolar disorder and any anxiolytics or hypnotics prior to enrollment. A protocol-defined rescue lorazepam was permitted during the screening and treatment periods. The primary endpoint was placebo-adjusted change from baseline on the YMRS scale, and the secondary endpoint was placebo-adjusted change from baseline on the CGI bipolar mania severity scale, both at week 3. Today, we are presenting the results from the 3-week treatment period. Regarding patient disposition, of the 253 patients randomized, 127 received placebo and 126 received RAP-219, of which 112 and 95, respectively, completed the 3-week treatment period. The main reason for early discontinuation in both groups was withdrawal of consent. The reasons are listed on the right, and as you will notice, the most common reasons were for personal or for family reasons.