Rapport Therapeutics, Inc. Common Stock TD Cowen 6th Annual Novel Mechanisms in Neuropsychiatry Summit

Sure. Thanks, Joe, for the opportunity, and good afternoon, everybody. Rapport Therapeutics is a company that we started through a collaboration between Third Rock and J&J, really to create what we hope to be the leading precision neuroscience company. We have a real scientific foundation that drives not only our lead program, RAP-219, but also our entire discovery focus, and that is the realization and the utilization of receptor-associated proteins. This allows us to have specificity with small molecules in neuroscience that we think is unprecedented. We think we've seen that play out with RAP-219. We're making significant effort across our discovery portfolio as well. We hope to continue to build that pipeline. Specifically, RAP-219 targets a specific receptor-associated protein, TARPγ-8, that is associated with the AMPA receptor. We presented and released unprecedented results in focal onset seizures September of last year.

We've continued to update that data set with a presentation at AAN this year that further elucidated the clinical utility of the drug. As you mentioned, Joe, we're on our way to potentially having some bipolar data here in the coming month.

Sure. Our approach when we started the company thinking about RAP-219 and the opportunity was always thinking about it as a pipeline and a target, a pipeline and a product potential. We really prioritized a set of indications where we felt the biology took us. First clearly was epilepsy, given what is known about the excitatory process driving seizures, but also the role of glutamate and the AMPA receptor. It was really kind of de-risk pass as we think about the opportunity and the path forward in epilepsy. Really next on the list was bipolar mania specifically. That was based on a few different points of evidence. One, the emerging literature was really supporting the role of glutamate in specific, the manic process.

Second was the region of the brain that functional MRI as well as other imaging was showing, which was that glutamate expression was focused in the corticolimbic network, which really overlapped with TARPγ-8 expression. Then the third was a long history of anti-seizure medications being effective therapies for bipolar disorder, both in terms of mania as well as mood stabilization. So it was always kind of a bet that we felt was the right experiment to run as we thought about the opportunity for RAP-219. We were buoyed as we saw the epilepsy results as well, because what we really understood from the epilepsy results is, one, we can confirm target engagement. Two, we felt that we had a tolerability profile that would be, along with efficacy, highly differentiated in bipolar disorder.

That really gets to your question around what is the unmet need in this patient population. The first I'll say is it's significant, and it's a large population. We're talking about roughly 1.6 million patients with bipolar I disorder. There has not been much innovation at all for these patients. As you think about the therapies that are available to them, they really are bucketed into three. One are atypical antipsychotics or the dopaminergic pathway. Two is lithium. Then three are a couple approved anti-seizure medications. When you think about this patient population, it's really a high-functioning patient population.

Although they do live with bipolar disorder, both in the manic side as well as the depressive side, the reality is they are looking to stay highly engaged in their lives, whether that is their family life, their social life, their work life, whatever it may be. The current available medications and the tolerability profile really takes them away from those things that they need to be engaged in. We really know what the tolerability limitations are of atypical antipsychotics. Those are the extrapyramidal symptoms, the weight gain, metabolic changes, et cetera. Then on the anti-seizure medication side, it is the sedation, somnolence, as well as gait impairment.

We saw a really nice opportunity that potentially bringing a novel MOA to bipolar disorder, and one that has a tolerability profile that would be much more appealing to patients and clinicians as they think about staying on a therapy long term.

Sure. Going into the bipolar study, we had the benefit of a lot of data as compared to going into our phase II study in epilepsy. Going into the phase II study with bipolar, we had the benefit of our human PET study. Clearly, all of our phase I studies, as you mentioned, Joe, which the PET study was one of them. We did not have the PET study when we went into our phase II study for epilepsy, the human PET study. We also had the phase II data from the epilepsy study as we considered dose selection going into the bipolar study. A couple of key aspects here and imperatives for us as we thought about dose selection going into the bipolar study. First was our understanding of receptor occupancy, and really informed by two things.

One, what was the maximal efficacy we saw in the corneal kindling model, which is a model of epilepsy, but also can be used as a model to inform bipolar mania, dose selection as well as efficacy. The second was thinking about how that receptor occupancy and PK lined up with a pharmacodynamic effect, and we really were able to glean that from our epilepsy study because we were able to leverage this novel biomarker, which is the long episode or that EEG electrographic data. What we really understood from all of this data is that with RAP-219, we are able to achieve a level of RO as well as a PD effect very early in dosing. In our epilepsy study, we saw that via the electrographic readings within 2 or 3 days of dosing.