After decades of lagging nearly many other disease areas, neurology is finally seeing signs of significant innovation. One of the biggest reasons has been the difficulty in teasing out the complex neurobiology necessary to design novel medicines. Rapport Therapeutics is playing a significant role in turning the tide. The company creates precision neuromedicines that act only in the brain regions where disease originates. This avoids the side effects that affect many of today’s treatments.
Rapport Therapeutics accomplishes precision by leveraging receptor-associated proteins, a novel target class discovered by the company’s co-founder and CSO David Bredt.
Neurology received the second-most new drug approvals from the FDA in 2023 among all disease areas. The year ended with two multi-billion M&A events: BMS’s $14 billion acquisition of Karuna and AbbVie’s $8.7 billion deal for Cerevel.
This week, we have a conversation with Rapport Therapeutics CEO Abe Ceesay. We cover the company’s transformational approach, and about what’s new in neuromedicine.
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About Rapport Therapeutics’ precision neuromedicines
Rapport Therapeutics is developing a new class of precision neuromedicines that could give patients better alternatives to current treatments for neurological and psychiatric diseases. Current treatments often come with reduced efficacy and side effects that lead to suboptimal dosing, noncompliance and discontinuation.
By more precisely targeting the neural circuits and cell types where diseases originate, Rapport’s approach has the potential to reduce the unwanted drug-target interactions that lead to these issues.
The company’s platform achieves precision through the discovery and targeting of receptor-associated proteins (RAPs). RAPs display regional or neural circuit-specific expression. Rapport Therapeutics has ongoing clinical trials and discovery-stage programs in epilepsy, hearing, pain, and psychiatric disorders.
“We think we’re about to embark on some real transformational change for patients,” Ceesay said.
“Now we know that word precision is used somewhat loosely in our industry, especially in neuroscience, but we believe our platform can really bring precision to life in neuroscience across a broad base of disorders as well as diseases.
“I think we are really at the cusp of transformational innovation for patients in neuroscience.”
TARPs: Targeting AMPA receptor modulation for brain-specific treatment
Bredt made the discovery of receptor-associated proteins during his academic career at the University of California San Francisco (UCSF).
AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors are a specific set of excitatory receptors in the brain. They are important for glutamate trafficking.
Bredt discovered that AMPA receptors had a family of proteins associated with them. Those proteins controlled both trafficking as well as conductance.
Ceesay said: “In the case of these transmembrane AMPA regulatory receptor proteins, which are called TARPs, what David was able to discover is that these specific TARPs had subfamilies that were located in certain areas of the brain.
“Given their neuroanatomical specificity, if you are able to drug that accessory protein receptor pocket, what you would be able to do is just modulate AMPA receptors in certain areas of the brain. And that opens a whole new world of opportunity.
“In the case of the limbic system, AMPA receptors are known to play critical roles in excitatory response as well as seizure control. So what this opened up was a whole new opportunity, as an example, to just modulate AMPA receptors in the limbic system that really could provide the opportunity for unprecedented specificity, but also the ability to provide efficacy with minimizing tolerability issues in the treatment of seizures.”
Challenges designing novel medicines for neurology
Ceesay noted that there are several issues in neuroscience when developing novel compounds, novel approaches, and innovative and transformational treatments for patients.
“One of the big challenges is the translational medicine or lack thereof, in neuroscience. The other issue that has really been a challenge in neuroscience is many of these conditions have very heterogeneous patient populations. The genetics just aren’t there in neuroscience as they are in some other therapeutic categories such as oncology,” Ceesay said.
However, Ceesay sees these challenges as opportunities.
“We think we’re about to embark on some real transformational change for patients.”
“Some of the science that we’re working on here at Rapport, we really think we can overcome some of those issues. So, as an example, in some of our programs, we know that there is a genetic association with certain receptors in certain conditions. But the challenge historically has been, can you modulate those receptors in a way that provides efficacy without having significant tolerability issues?” he noted.
“And that’s really the challenge in neuroscience, because oftentimes you’re modulating receptors that are ubiquitous throughout your brain and body. And although you might be driving efficacy, given the fact that you’re interacting with receptors throughout the brain and the body, you’re also usually having very narrow treatment margins and tolerability issues that really don’t make these targets druggable.
“What we’re doing at Rapport is through, one, the known genetics of receptors in certain diseases as well as being able to target receptor-associated proteins.
“We believe we can interact with receptors in only the sensory neurons or as well as the neuroanatomic region that really matters. So in that regard, we know the genetic drivers of certain receptors in diseases, but if we can drug those receptors in a way that are highly, highly precise and specific, we can really mitigate some of those issues that are associated with the development of neuromedicines historically.”
Rapport Therapeutics’ focus on epilepsy
While there are many challenging conditions within the neurological disorders and diseases space, Rapport Therapeutics is first tackling epilepsy. While there have been drugs developed for the condition, Ceesay said medicines often interact with receptors that are ubiquitous throughout the brain and the body.
“What you see in a disease like epilepsy is that in focal onset seizures, anywhere from 30 to 50% of patients are not fully managed, meaning those patients are still having breakthrough seizures. And the challenge for these patients is often the efficacy of drugs comes with significant tolerability issues.”
Ceesay said the precision neuromedicine Rapport Therapeutics is developing acts on a specific target, leading to effective seizure reduction, and significant tolerability.
Current clinical trials for Rapport Therapeutics’ precision neuromedicines
The company has finished its phase 1 study for its RAP-219 candidate.
Ceesay said the study helped the company understand the pharmacokinetics of the drug as well as the safety profile.
“We are very pleased by the results. We are getting to therapeutic concentrations and we are not seeing any of the traditional tolerability issues that are seen with anti-seizure medications,” he explained.
Traditionally, epilepsy has been treated with more than one drug. Ceesay said their drug needs to work and have no side effects, and it needs to not interact with other drugs that may be prescribed to patients.
In the next three to five months, a phase 2a proof of concept trial will start. Results are expected in 2025.
The company also has plans to develop drugs for other neurological conditions.
To learn more about precision medicine and neuromedicines
Here are some links to more articles on the subject of neurological disorders and neuroscience.