This year’s EFMC-ISMC conference in Nice, France, had a fantastic collection of talks. Among the highlights were the two First Disclosure sections, where companies shared the structures of their latest clinical candidates for the first time. Many thanks to Dr. Julien Lefranc, one of our featured reviewers, for sharing his notes on these sessions. We’ll go more in-depth into the science behind these compounds as it emerges, but for now, here’s a high-level overview.
Here are more details on all seven:
AstraZeneca’s Oral RXFP1 Agonist
AZD5462 is an oral RXFP1 agonist from AstraZeneca, bearing an interesting norbornane ring system, for the treatment of cardiorenal disease. It is entering a Ph. I trial to assess its safety, tolerability, and pharmacokinetics in healthy volunteers of Japanese descent, using single and multiple ascending dose administration. Preclinical studies in cyno monkeys with heart failure with reduced ejection fraction (HFrEF) showed an improved systolic heart function after 8 weeks of dosing, without significant increases in mean arterial blood pressure or heart rate. AZD5462 is highly selective for RXFP1, has no activity in the seven closest GPCRs (up to 10 µM), and shows no interaction with targets in the CEREP safety panel.
Boehringer Ingelheim’s mPGES1 Inhibitor
GS-248 is a membrane-associated prostaglandin E synthase-1 (mPGES1) inhibitor from Boehringer Ingelheim and Gesynta Pharma, for the treatment of pain and inflammation. It has been granted orphan status by the FDA for systemic sclerosis (SSc), and is entering a Ph. I trial to assess its efficacy vs. placebo on Raynaud’s Phenomenon in patients with SSc. Early assay conditions for PGH2 stabilization allowed for an HTS campaign, which led to a focus on 2-phenylamino-azoles and 3-acylaminomethyl-benzamides. A non-conventional MedChem optimization was necessary due to the high lipophilicity requirements of the target. Preclinical studies, in humanized ki mice, showed GS-248 had activity comparable to celecoxib and indomethacin.
Merck’s A2a/A2b Inhibitor
M1069 is a highly selective, oral dual inhibitor of the Adenosine A2a and A2a receptors from Merck, for use in the treatment of advanced solid malignancies. It is currently in Ph. I trials to assess safety, tolerability, PK, PD, and early signs of efficacy in patients with advanced solid tumors. M1069 was shown to have superior anti-tumor efficacy in a 4T1 tumor model, enhancing the activity of cisplatin and paclitaxel, in vivo. Interestingly, the drug will be given as a fumaric acid co-crystal, as this formulation improves its solubility and absorption. It is expected that M1069 will be combined with an immune checkpoint inhibitor, as A2a/A2b antagonists are known to be synergistic with immunotherapeutic agents in models.
RAPT’s oral CCR4 Antagonist
RPT193 is an oral CCR4 antagonist from RAPT Therapeutics for use in the treatment of atopic dermatitis. It is currently in Ph. IIb trials to evaluate its efficacy and safety as monotherapy in adults with moderate-to-severe atopic dermatitis. RPT193 specifically inhibits Th2 cell migration to the site of inflammation, where they secrete pro-inflammatory cytokines, which further induce the inflammatory response. Preclinical studies showed a >200-fold selectivity for CCR4 vs. other chemokine receptors and demonstrated significant improvement in atopic dermatitis-associated gene signatures in the skin. Perhaps most exciting is that oral dosing showed similar efficacy to biologics in an atopic dermatitis model. A Ph Ia trial supported once-daily dosing of 400 mg.
Roche’s Oral CB₂R Agonist
RG7774 is an oral CB2R agonist from Roche for the treatment of diabetic retinopathy, with a fascinating “nitrogen-loaded” polycyclic ring system. It is currently in Ph. II trials to assess its efficacy and safety in patients with diabetes mellitus (type 1 or 2) with treatment naïve diabetic retinopathy. In what has been described as a “multiparameter tour-de-force,” an initial HTS screen followed by extensive multiparameter optimization led to RG7774, which effectively combined several privileged structures. A clever, safe, and scalable synthesis was also described, which had 8 linear steps, 4 crystallizations, and removal of the proper regioisomer by extractive work-up, following the final step, giving a 35% overall yield.
GSK’s Inhaled PI4KB Inhibitor
“Compound 30” is an inhaled PIK4B inhibitor from GSK for the treatment of chronic obstructive pulmonary disease (COPD). It is currently in a Ph. I trial, with a dose of 3 mg. Although it did not carry this designation, it may be that “compound 30” is actually GSK3923868, which is currently planned for a Ph. Ib trial to evaluate its safety, tolerability, PK, and PD in mild asthmatics during an experimental human rhinovirus infection, after an initial Ph. I trial in both healthy and asthmatic adults. One of the most interesting aspects of the “compound 30” presentation is that the strategy to optimize its structure involved the analysis of structure-kinetic relationships. Specifically, groups that might affect a slow-off rate were employed such that the final compound would have a prolonged residence time, allowing for a smaller effective dose, and minimization of toxic tissue accumulation.
Boehringer Ingelheim’s Dual GCGR/GLP-1R Agonist
BI-456906 is a glucagon-derived dual GCGR/GLP-1R agonist from Boehringer Ingelheim for the treatment of people living with obesity. Specifically, it stimulates energy expenditure while reducing energy intake. BI-456906 is currently in a Ph. II trial to evaluate its efficacy, safety, and tolerability of subcutaneous dosing in patients with non-alcoholic steatohepatitis (NASH) and fibrosis. Furthermore, there are two additional Ph. I trials to evaluate BI-456906 in patients with cirrhosis and to investigate its occupancy in glucagon receptors (GCGR) in the liver and glucagon-like peptide 1 (GLP-1) receptors in the pancreas. BI-456906 is a derivative of glucagon and GLP-1, optimized to improve solubility and long-term chemical stability in solution. Lipidation of the peptide improved its half-life by targeting human serum albumin (HAS) as a carrier. Preclinical studies in diet-induced obese mice showed a strong, dose-dependent reduction in body weight after daily treatment, after 4 weeks. In overweight or obese patients, there was up to 13.7% body weight reduction after 16 weeks.
We hope this is helpful to you. Stay tuned to Drug Hunter for deeper dives on these molecules when more information is available.