Rapport Therapeutics, Inc. Common Stock Status update

Welcome to the Rapport Therapeutics KOL call on bipolar mania and Rapport's RAP-219 clinical program. Following prepared remarks, we will take questions. Please limit yourselves to one question and one follow-up. During this call, management will make forward-looking statements, including related to its phase II trial of RAP-219 and bipolar mania, as well as the timing of data, the company's development plans, and the potential commercial opportunity for RAP-219. Actual results and timing of events could differ materially from those anticipated in such forward-looking statements as a result of risks and uncertainties caused by factors described in the company's securities filings. Rapport undertakes no duty or obligation to update any forward-looking statements. Rapport sponsors this presentation. Any opinions identified as those of the key opinion leaders reflect their independent clinical and scientific judgment and do not necessarily represent the views of their employer or affiliated institutions.

Information is current as of September 22nd, 2026. Do not record, reproduce, or distribute this presentation without prior written permission. I will now turn the call over to Abe Ceesay, Chief Executive Officer of Rapport Therapeutics. Please go ahead, Abe. Good afternoon, everyone, and thanks for joining us today.

My name is Abe Ceesay, Chief Executive Officer of Rapport Therapeutics. To help provide context for the bipolar mania phase II trial top-line data expected next month, we've invited two leading bipolar disorder experts, Dr. Mauricio Tohen and Dr. Gary Sachs, to share their perspectives. Dr. Tohen is University Distinguished Professor and Chairman of the Department of Psychiatry and Behavioral Science at the University of New Mexico Health Sciences Center. He trained in psychiatry at the University of Toronto and completed a psychopharmacology fellowship at McLean Hospital, Harvard Medical School, later earning a doctorate in epidemiology from Harvard and an MBA from Indiana University. He is currently President of the American Association of Chairs of Departments of Psychiatry.

Dr. Sachs is the Founding Director of the Bipolar Clinic and Research Program at Massachusetts General Hospital and an Associate Clinical Professor of Psychiatry at Harvard Medical School. He trained at the University of Pennsylvania and the University of Maryland School of Medicine, completing his residency at MGH and later led the NIMH's STEP-BD program, the largest treatment study ever conducted for bipolar disorder. He is also past president of the International Society for CNS Clinical Trial Methodology. Thank you both for being here. I'll begin today with a brief overview. Dr. Tohen will then provide background on bipolar mania and the current treatment landscape, and Dr. Sachs will review the RAP-219 results. Following our prepared remarks, we'll open the call for questions, where we'll be joined by Rapport's Chief Medical Officer, Jeff Sevigny, and our Chief Financial Officer, Troy Ignelzi. Rapport's vision is to create the leading precision neuroscience company.

Our technology platform is based on receptor-associated proteins or RAPs, biology discovered by our Chief Scientific Officer, David Bredt. RAPs have distinct neuroanatomical and cell-type expression. Targeting receptors through their receptor-associated proteins provides a more precise way to modulate receptors that are otherwise broadly distributed throughout the brain, allowing us to potentially address long-standing challenges in neuroscience. RAP-219 is an investigational potential first-in-class TARPγ8 AMPA modulator. TARPγ8 is expressed in brain regions that are directly implicated in focal seizures and, we believe, bipolar mania. Last September, we announced positive phase II results with RAP-219 in patients with focal onset seizures. Treatment with RAP-219 resulted in a 71% reduction in long episodes, which is an objective biomarker of abnormal epileptiform activity, a 78% median reduction in clinical seizures, with 24% of patients achieving seizure freedom during the entire 8-week treatment period and a generally well-tolerated profile.

The majority of those patients have enrolled in the open-label long-term safety trial. Our phase III FOS program is underway, with two global placebo-controlled trials currently recruiting patients. Additionally, we're evaluating RAP-219 in patients with primary generalized tonic-clonic seizures or PGTCs. We believe that RAP-219 could also be a transformational treatment for bipolar mania, the focus of today's call. We're also developing a long-acting injectable formulation. This would potentially be the first LAI approved in epilepsy and also an important option for the treatment of bipolar mania, if approved. RAP-219 was designed to inhibit AMPA receptors associated with TARPγ8, a transmembrane regulatory protein that amplifies the effects of glutamate on the receptor. The structure on the left shows the TARPγ8 AMPA receptor complex. Our drug binds at the interface between TARPγ8 and the AMPA receptor to inhibit its amplifying effects.

Whereas AMPA receptors are distributed widely in the central nervous system, TARPγ8 is selectively expressed in forebrain structures and largely absent from the hindbrain, as shown in these PET images. This gives RAP-219 the potential to act in the areas of the brain where it matters for treatment and avoid tolerability issues associated with broad AMPA receptor inhibition. The scientific rationale to test RAP-219 as a potential therapy for bipolar mania is based on three points. First, while the exact cause of bipolar mania is not yet fully elucidated, there is a growing body of evidence characterizing it as a condition of excess glutamate activity. As you know, glutamate is the brain's main excitatory neurotransmitter, and AMPA receptors mediate most of these excitatory transmissions. By inhibiting the TARPγ8 AMPA receptor complex, RAP-219 may inhibit an underlying mechanistic pathway of bipolar mania.

Second, the areas of the brain that appear to be hyperactive in bipolar mania are the mesial temporal and frontal lobes, and in particular, the corticolimbic network that connects them. This is relevant for RAP-219 because these are the regions where TARPγ8 is expressed. Lastly, three commonly used treatments for bipolar disorder, lithium, valproic acid, and lamotrigine, mediate their effects through multiple mechanisms, including modulating glutamate signaling or suppressing AMPA activity, which is the mechanism central to our hypothesis with RAP-219. If successful, bipolar mania represents a significant potential expansion opportunity for RAP-219. Approximately 8 million U.S. adults have bipolar disorder. Roughly 3.5 million are diagnosed, and half of these have bipolar mania. Current standard of care is limited by side effects of dopaminergic atypical antipsychotics and anti-seizure medications, including weight gain, metabolic changes, extrapyramidal symptoms, and sedation or somnolence, which drive low adherence.

We'll hear more on this from Dr. Tohen and Dr. Sachs. With that, I'll turn it over to Dr. Tohen. Dr. Tohen? Great to be here.

As Nav mentioned, I'm at the University of New Mexico, and I call myself a student. Always things to learn about bipolar disorder for all my career. Actually, my doctoral thesis was an outcome in bipolar disorder. I should mention that in terms of conflicts of interest, I've worked for a number of pharmaceutical companies advising on research design, and at some point I was an industry scientist. I worked at Eli Lilly and Company during a number of years. Let's talk now about bipolar disorder. First, let's talk about the epidemiology, and the epidemiology is what gives us the numbers. It's not that we have an epidemic. Sometimes we have what we think is epidemic, but it's because more cases are being identified. It affects approximately 1% of the population, regardless of gender, race, or socioeconomic status. It actually can be a lethal condition.

It is the most lethal of all psychiatric conditions, and that is by suicide. Up to a third, to 20% is completed. In terms of the attempts, there's usually a family history, more common in females of young age when they're in a depressive polarity and frequently suffering from comorbid, that's other conditions, other psychiatric conditions or substance use disorders. In terms of completed suicide, more common in males. Again, attempts more common in females, but completed suicides more common in males. I mentioned comorbidities. Having another condition is not the exception. The majority of individuals with bipolar disorder have another psychiatric condition, like anxiety disorder, substance use disorder. After a number of years, more than 60% of them suffer from substance use disorder, and medical conditions. As we will mention, bipolar disorder does not only affect the brain, it is systemic.

That's why there's more conditions with inflammation in patients with bipolar disorder. Diagnosis is challenging, because we don't have a valid biomarker. We cannot do a blood test and diagnose. For that matter, even doing a brain scan will not tell us that the patient suffers from bipolar disorder. It's really what we call observation. What are the symptoms that we observe or that the patient reports? In the clinical assessment, there's different phases. We have to identify mania, hypomania, which is less severe mania. I'll talk a little bit about it, the depressive phase, and then the combination of both. We can have patients who have both symptoms of mania and symptoms of depression at the same time. Something that is quite challenging in bipolar disorder is that there's disability. Actually, some individuals have no disability.

I am sure that among us there are some who suffer from bipolar disorder. In other words, high-functioning individuals. But in the majority of individuals, there is poor functioning and cognitive impairment. That is in the majority. The challenge is that sometimes the condition starts, and we don't diagnose it right away. It usually starts with depression or anxiety, and studies have shown that sometimes it takes up to 5 to 10 years from the beginning of the first symptoms until the patient is appropriately diagnosed and therefore treated. Course of the illness. The condition of bipolar disorder, as we mentioned, it has many different phases. So there is fluctuations of mood, and then, as mentioned, there is impairment. So this graph illustrates bipolar disorder. So you can have what we call the prodrome, that is mild symptoms early on. This would be the first episode.

So we have mild symptoms early on, and then you can have episodes of hypomania, less severe mania, and you have episodes of mania and episodes of depression. Something that I don't think it's emphasized enough is that it's not that you have periods of wellness and then you have the episodes. In most cases, you have patients who have mild depressions or mild manias, and sometimes that does not lead to good functioning. So it's not only the episode of mania. Also, when you have hypomania, there's impairment, and as mentioned, you also have the mixed states where you can have both symptoms of mania and symptoms of depression. Unfortunately, the condition doesn't burn out. It unfortunately is with the individual until the end of life. So let's talk about the diagnosis. As mentioned, we have no biomarkers.