TRPA1

A multidisciplinary research group specializing in pediatrics, genetics, and psychophysics has identified wide variation in the sensory perception of a pediatric formulation of ibuprofen -- some that were tied to genetic ancestry, and some that were not. These findings indicate that a range of factors come into play in determining how a medicine tastes to an individual. Although there are some cultural exceptions to the rule, medicines for children are often given in liquid form that is sweetened to make it taste good. But not every child experiences the same medicine in the same way. A multidisciplinary research group specializing in pediatrics, genetics, and psychophysics, co-led by Julie A. Mennella, PhD, Principal Investigator at the Monell Chemical Senses Center, has identified wide variation in the sensory perception of a pediatric formulation of ibuprofen -- some that were tied to genetic ancestry, and some that were not. These findings indicate that a range of factors come into play in determining how a medicine tastes to an individual. Their work, recently published in the International Journal of Molecular Sciences, is the first in a series of studies funded by the National Institutes of Health to look at variation in the taste of medicines. "Taste is personal and determining how individuals differ and why is critical to understanding medication adherence and personal risks," said Mennella. Bitter taste and irritating sensations in the throat are the top reasons for non-compliance, as a child (or adult) is less likely to ingest a medicine that is unpleasant (or tastes bad). However, if a child finds the medicine bottle uncapped and finds it tastes sweet like candy, they may ingest too much. Discovering how individuals differ in sensory perception is especially key when it comes to liquid ibuprofen, which accounts for many unintentional poison exposures among children under the age of six years in the US, according to the U.S. Poison Centers. "Sweetening medicines like ibuprofen is a delicate balance between having it taste good enough that kids take it, but bitter enough that, should they get unguarded access to it, it's irritating enough that they stop drinking it and don't poison themselves" said Mennella. "We found genetic markers, both ancestry-related and independent of it, that could predict if someone would find a medication irritating or pleasantly sweet. If we get to the point of tailor-making medications in the future, knowing these associations could help us design taste specifically for each child in the not-so-distant future." The study included 154 adult panelists from Philadelphia, who represented the diversity of their city. According to a genome-wide association study, 63 had African ancestry, 51 European, 13 South Asian, seven East Asian, and seven American. They underwent training in sensory methods and then rated the sweetness, irritation, bitterness, and palatability of a pediatric formulation of a berry-flavored ibuprofen after swallowing, and also after just tasting it without swallowing. Researchers found that panelists of African genetic ancestry had fewer chemesthetic sensations such as tingling or an urge to cough, rated the medicine as tasting sweeter and more palatable than those of European genetic ancestry. Researchers also found a novel association between the TRPA1rs1198875 genetic variation and tingling sensations, independent of ancestry. This is significant as TRPA1 is a family of neuron receptors that are involved in sensory neural response to a variety of chemical irritants found in foodstuff and other medicines. Discovering both an ancestry-related link and non-ancestry-related genetic variation to taste and irritation perception shows that who perceives a medicine as palatable or not is a complicated picture and must consider a variety of factors. This first study was conducted with adults because the sensory measures were complex and included several hour-long test sessions. That does not mean future tests should not include children, Mennella said, adding that this is just the first in a line of studies on the taste of pediatric medicines and methods need to be developed to measure sensory irritation in children. "This is a small study, but it is the first step in showing how research on diverse populations is needed to be able to unravel the genetic, cultural, dietary, and developmental paths that underlie medicine adherence and also risk for poisoning," said Mennella. "It's looking at both sides of the same, very important coin." Findings from this research will affect how sensory tests can be designed in the future. Since participants did both swallow and sip-and-spit tests, the team was able to determine that just tasting medicine allowed predictions and perceptions after swallowing, which could simplify future studies in different age groups. Other studies as part of this National Institutes of Health grant are ongoing, including determining the variation and acceptance of medicines in children. This work was funded by the National Institutes of Health (R01 DC011287). Co-authors are co-first author Mengyuan Kan, University of Pennsylvania (Penn); Joel D. Mainland, Monell Chemical Sense Center; Luis R. Saraiva, Sidra Medicine, Qatar and Monell Chemical Senses Center; Elizabeth D. Lowenthal, Penn (co-PI of grant); Blanca E. Himes, Penn; and M. Yanina Pepino, University of Illinois at Urbana-Champaign.

Relay Therapeutics might not have been doing well recently, with the latest US stock market price being $11 and a market capitalization of around $1.3 billion, a reduction of three-quarters from its peak. As of the end of the first quarter in 2023, Relay Therapeutics held cash and cash equivalents of $937.8 million, lower than the $1 billion at the end of 2022. The company anticipates that these funds will support operations until 2025. Relay Company PipelineIn April of this year, Relay Therapeutics announced the early-stage clinical data of RLY-2608, which led to a 40% plummet in its stock price. RLY-2608 is an isoform-selective PI3K inhibitor, a type of drug that faces challenges in safety and effectiveness, and the FDA has previously issued a black box warning for it. In the phase 1 trial of RLY-2608, only one patient's partial response was observed, and the optimal dose of RLY-2608 has yet to be determined, introducing uncertainty to the drug's safety and efficacy. Although no reports of dose-limiting toxicity (DLT) have emerged so far, unexpected adverse reactions may occur as the drug is still in the early stages of clinical trials, and as the research continues. RLY4008 Clinical DataRelay company has two other promising assets. Firstly, RLY-4008 (see above image), a small molecule inhibitor, targets FGFR2 in patients with advanced or metastatic solid tumors with FGFR2 alterations. Preliminary data from its first human trial shows marked inhibition of FGFR2 without the limitation of off-target toxicity (such as hyperphosphatemia). Following discussions with the FDA in 2022, Relay chose to continue the single-arm trial design for FGFR2 fusion CCA treatment-naïve patients to expedite approval. RLY-4008 has received CCA orphan drug designation from both the FDA and EMA. Information collected from the synapse database up until May 26, 2023, shows a recommended Phase 2 dose of 70 mg QD. For the FGFRi-naïve CCA f/r group, the ORR is as high as 55%. For the Prior-FGFRi CCA f/r group, the ORR is just 14%, indicating a significant decline in ORR among patients who have previously undergone FGFRi treatment. The most common TRAEs at different dosages are low-grade PPE (57%), stomatitis (56%), dry mouth (38%), hair loss (28%), and dry eyes (22%). Secondly, GDC-1971 (previously RLY-1971) is another main asset of Relay. This drug targets SHP2 in patients with advanced or metastatic solid tumors. The phase Ia trial was completed with its enrollment in 2022. Relay reached a collaboration with Genentech on the development and commercialization of GDC-1971. Combination use of GDC-1971 with Osimertinib or CetuximabAs Novartis’ standalone SHP2 clinical trial fails due to insufficient effectiveness, many companies have been actively pursuing combinatory therapies. As shown in the above figure, an Ib phase study released in July 2023 found in the intelligence database aims to evaluate the safety, pharmacokinetics, and effectiveness of GDC-1971 and Osimertinib in the treatment of inoperable locally advanced or metastatic non-small cell lung cancer, or in combination with cetuximab in the treatment of metastatic colorectal cancer. The clinical trial recruited 172 patients and is expected to conclude by the end of December 2026. The primary endpoints are the percentage of participants experiencing adverse events and the number of patients exhibiting dose-limiting toxicity. All the three inhibitors mentioned above from Relay come from D.E. Shaw (Chief Scientist at DESRES), with each drug having a clear differentiation direction, targeting a specific subtype of a particular protein with high selectivity. The three drugs are FGFR2 inhibitor RLY-4008, PI3Kα structuring inhibitor RLY-2608, and SHP2 inhibitor RLY-1971. In addition, D.E. Shaw has developed the small molecule inhibitor DES-7114 for autoimmune and inflammatory diseases. On June 13, 2022, D.E. Shaw Research announced a global exclusive licensing agreement with Eli Lilly for the clinical development and commercialization of Kv1.3 inhibitor DES-7114. Eli Lilly will pay an upfront fee of $60 million, potential development and commercial milestones up to $475 million, and a royalty on global sales. Challenges in the Development of Kv1.3 Blockers: Strong Selectivity Required for Multiple SubtypesKV1.3 voltage-gated potassium channels participate in many physiological processes in the plasma membrane and mitochondria, primarily in the immune and nervous systems. Therapies targeting KV1.3 channels using specific peptides and small molecule inhibitors have shown enormous potential in treating cancer and autoimmune diseases (such as multiple sclerosis, type I diabetes, psoriasis, contact dermatitis, rheumatoid arthritis, and myasthenia gravis). However, so far, no compounds targeting KV1.3 have been approved for marketing. Some small molecule inhibitors with a clear SAR (Structure-Activity Relationship) have been optimized as selective inhibitors delivered to mitochondria, providing therapeutic potential for treating cancer and autoimmune diseases. T-cell activation associated with Kv1.3 ChannelIn 1999, small molecules WIN17317-3 and CP-339818 were discovered to target the Kv1.3 channel. However, these molecules lack the selectivity and specificity for the channel, apart from the Kv1.3 channel they have blocking effects on sodium ion channels and Kv1.4 channels, thus leading to potential side effects. Subsequently, various small molecules were discovered, but all failed to adequately address the issue of selectivity. Apart from inhibiting sodium ion channels and Kv1.4, they also produce a block on Kv1.1 and Kv1.2. Professor D.E. Shaw has stated that DES-7114 can inhibit the ion channel protein Kv1.3 in a highly selective manner. Preclinical studies have confirmed its effectiveness in various models of chronic inflammation and autoimmune diseases (including ulcerative colitis, Crohn's disease, and atopic dermatitis), and it has successfully completed Phase I clinical trials in healthy volunteers in early 2022. However, a year and a half later, no results of DES-7114 clinical trials have been reported. Clinical stage Kv1.3 blockersAnalyzing the indications, as shown in Figure below, the current clinical indications under study are all in the direction of autoimmunity, specifically psoriasis, psoriatic arthritis, and atopic dermatitis. Therapeutic Indication Heat MapRelated Patents of DES-7114A total of 82 applications were found in the synapse database associated with D. E. Shaw Research and Kv1.3, with 11 INPADOC family applications, predominantly applied in 2022 (two applications in March and May), 2020 (five applications), 2021 (one application) and 2023 (two applications). Moreover, the DES-7114 entered phase I clinical trials in January 2022. As early as September 2013, D.E. Shaw Research had disclosed a method for screening voltage-gated proteins. The structure of the clinical molecule DES-7114 is not yet disclosed. Clues could be extracted from six INPADOC family applications in 2021 and 2020. The six patents are: WO2022076285, WO2021071832, WO2021071812, WO2021071802, WO2021071803, and WO2021071821. The synthetic complexity of the structures in these patents is relatively low, although most of the compounds bear several chiral centers. Some fragments and core structures are relatively novel and worth attention. However, most compounds disclosed in these patents only display IC50 data and hERG data regarding the inhibition of the Kv1.3 channel, and are only in ranges. Additionally, there is no selectivity data for other channels, such as Kv1.1 and Kv1.2, thus the inference of specific structures remains challenging. Schematic Diagram of Synapse Database Patent SearchConclusionRelay Therapeutics is a well-known drug discovery company in recent years, characterized by computational chemistry, with three drugs in its pipeline all from D.E. Shaw. Although two of Relay's current three clinical compounds have had some hiccups in clinical trials, its drug discovery platform characterized by molecular dynamics has greatly promoted drug development. In the structural type exploration of the Kv1.3 channel blocker, it has been difficult for small molecules to achieve selectivity for Kv1.1 and Kv1.2 for more than 20 years. D.E. Shaw Research has extensive experience in differentiated targeting of ion channel protein subtypes. In addition to the Kv1.3 channel protein, there are also multiple published patents related to the TRPA1 cationic channel protein. According to intelligence gathered from the Synapse database, Kv1.3 blockers are mainly used clinically for the treatment of autoimmune diseases. In order to develop safer therapeutic drugs, it is necessary to pay close attention to the compound's selectivity for Kv1X channel subtypes (such as the Kv1.1 channel and Kv1.2 channel). Reference 1.https://seekingalpha.com/article/4620984-relay-therapeutics-stock-market-may-be-prematurely-dismissing-rly-2608. 2.Špela Gubič et.al, Discovery of KV1.3 ion channel inhibitors:Medicinal chemistry approaches and challenges.Med Res Rev. 2021;41:2423–2473. 3.Antonio Felipe et.al; Fighting rheumatoid arthritis: Kv1.3 as a therapeutic target.Biochemical Pharmacology 165 (2019) 214-220.

The pain drug market has many products, but there’s still a need for pills with better properties, such as avoiding addiction. Eli Lilly sees potential in the non-opioid pain drug research from Confo Therapeutics and it’s paying $40 million for rights to the biotech’s most advanced program. The sum is an upfront payment. According to terms of the deal announced Thursday, Indianapolis-based Lilly gets global rights to the Confo drug, CFTX-1554, as well as back-up compounds. As the research progresses, Confo could earn up to $590 million in milestone payments per program, plus royalties if any of these drug candidates reach the market. Belgium-based Confo develops drugs that target G-protein coupled receptors (GPCRs), receptors found throughout the body that are involved in a wide range of physiological functions. While there are many GPCR-targeting drugs on the market, drug hunters have been searching for ways to hit GPCRs thought to be undruggable. Confo, which spun out of Vrije Universiteit Brussel in 2015, says its technology stabilizes GPCRs to address receptors that were previously inaccessible as drug targets. The lead Confo program, CFTX-1554, targets the angiotensin II type 2 receptor (AT2R), a GPCR that has been studied for its role in pain. In particular, this receptor is thought to be a promising target for neuropathic pain, which stems from damage to nerves outside of the brain and spinal cord. Cancer patients can experience neuropathic pain. It’s also associated with diabetic nephropathy and shingles, among other conditions. The Confo drug is small molecule designed to block AT2R. The Phase 1 clinical trial is currently enrolling healthy volunteers and will evaluate multiple doses of CFTX-1554. Lilly won’t pick up development of the program until after Phase 1. The deal gives Confo the option to participate in the funding of future development programs after they show clinical proof of concept. With CFTX-1554, Lilly adds a fourth pain drug to its pipeline. The pharma giant has reached mid-stage clinical development with small molecules that address the targets P2X7, SSTR4, and TRPA1. “CFTX-1554’s progression through the clinic will benefit from Lilly’s experience and global organization, while we will continue to develop and expand our growing, innovative pipeline of GPCR-targeted assets, both small molecules and biologics,” Confo CEO Cedric Ververken said in a prepared statement. Advances in GPCR research have led to several investments and deals in the past year. In early 2022, GPCR startup Septerna launched with $100 million to develop drugs for endocrinology, the central nervous system, metabolic disease, and inflammation. Last fall, AbbVie paid $255 million to acquire DJS Antibodies, a biotech whose technology discovers antibodies that can hit GPCRs. And in January, Structure Therapeutics raised $161 million from its IPO to finance clinical development of its GPCR-targeting drugs for metabolic disorders and cardiopulmonary indications. Photo by Flickr user Jernej Furman via a Creative Commons license