Formulation
Formulated as a spray dry dispersion (SDD) to improve solubility.
What is BMS-986533 (RIPK1i)?
BMS-986533 has poor aqueous solubility. The SDD formulation improves solubility. The SDD process involves spray drying the API and converting it from the crystalline form (less soluble) to an amorphous solid dispersion with higher solubility which leads to higher oral exposures.
Next key trial milestone is ~ mid 2026
What is BMS-986446?
[NEED ADDITIONAL CONTEXT]
BALANCE is the name given to ongoing PoC trials
What is BMS-986368 (FAAH/MAGLi)?
BALANCE was chosen as it represents the MOA. FAAH/MAGL inhibition raises endocannabinoid levels which act to reduce neuronal signaling
Muscarinic acetylcholine receptor modulator not expected to be associated with SLUDGE (salivation, lacrimation, urination, defacation, GI upset, emisis)
What is BMS-986521 (M4 PAM)?
Cholinergic side effects such as SLUDGE, can result from pan-muscarinic ACh receptor activiation. BMS-986533 binds selectively to the M4 ACh receptor that is expressed in the brain (and heart). It is thus devoid of pan-muscarinic activation and corresponding cholinergic side effects such as SLUDGE.
Currently an IV infusion with ambitions to go from clinic to couch with a wearable pump.
What is BMS-986446?
BMS-986446 was initially developed for intravenous (IV) administration, including in its Phase 2 study. However, the program has since expanded to include a subcutaneous (SC) formulation with on-body delivery system (OBDS) development underway. This shift supports at-home administration, aligning with patient-centric care models for Alzheimer’s disease.
One of the major metabolites is known as Azoniaspironortropanol
What is trospium chloride?
Out of the major metabolites, this is the primary metabolite for the anticholinergic component of Cobenfy
Binds and activates mucarinic receptors, preferentially M1 and M4 in the brain.
What is KarXT (BMS-986510) or XT or Xanomeline/Trospium or Cobenfy?
Acetylcholine is a neurotransmitter that binds to two different types of receptors: muscarinic and nicotinic. Cobenfy binds to muscarinic subtypes M1 to M4.
Evifacotrep’s path to ID3 is currently pending results from this nonclinical safety evaluation
What is a rabbit embryo-fetal development (EFD) study.?
Rare skeletal and cardiovascular malformations findings were initially dismissed due to non-dose-dependent patterns, but BMS’s Nonclinical Safety team flagged them as potentially significant. A repeat EFD study is underway, with topline results expected in November 2025. A confirmed signal will result in a program No-Go at ID3.
This compound can be mixed with vanilla pudding for easier oral dosing.
What is BMS-986368 (FAAH/MAGLi)
This approach is used to support patient-friendly dosing in only the AAD trial. An ODT formulation is under development for Ph3.
This investigational agent was originally developed for protinuric kidney disease before switching to a CNS indication.
What is Evifacotrep (TRPC4/5)?
Evifacotrep (BMS-986511), a brain-penetrant TRPC4/5 inhibitor, was initially studied by Goldfinch Bio in proteinuric kidney disease. After acquisition by Karuna and later BMS, its development pivoted to neuropsychiatric indications, particularly Major Depressive Disorder with anxious distress.
Targets cellular stress pathways activated by misfolded proteins in neurodegenerative conditions.
What is BMS-986419 (eIf2b)?
[NEEDS CONTEXT]
Moderate to severe bile duct hyperplasia was observed in the 90 day and 2 year carcinogenicity studies which was significantly reversed after the recovery phase.
What is KarXT (BMS-986510) or XT or Xanomeline/Trospium or Cobenfy?
A warning exists in the USPI for Cobenfy which outlines this risk to the bile ducts and liver.
As a quaternary ammonium salt, it does not appreciably cross the blood-brain barrier
What is trospium chloride?
Trospium (brand name Sanctura) does not cross the blood brain barrier, and peripherally blocks muscarinic receptors
Its receptor occupancy will be assessed using the PET tracer [11C] Merck MK-6884.
What is BMS-986521 (M4 PAM)?
BMS-986521 is a substrate for PGP & BCRP which transports substances out of the brain. The PET tracer study using the [11C] Merck MK-6884 will confirm receptor occupancy in the brain and support progression to Ph2.
Correct disease-associated microglia (DAM) phenotype, protecting the beneficial phagocytosis of Aß by microglia
What is BMS-986533 (RIPK1i)?
RIPK1 is upregulated and activated in neurodegeneration and lies downstream of pathologic pathways where it mediates inflammation and cell death. RIPK1 inhibition has the potential to attenuate neuroinflammation and protect the microglia from impaired phagocytosis of Aβ.
If this exceeds 10 milliseconds, it could short-circuit a first-in-class Alzheimer’s hopeful.
What is the QTc interval?
The QTc interval is a corrected measure of cardiac repolarization. For BMS-986419, a selective eIF2B activator a Thorough QT (TQT) study is underway to assess whether the 200 mg QD dose causes QTc prolongation. A failure could halt development or require dose adjustments.
Approved in 1994, this anticonvulsant developed by BMS became widely used for both epilepsy and bipolar disorder before being divested to Novartis in 2007.
What is Lamictal (lamotrigine)?
BMS divested Lamictal as part of a business strategy to focus on becoming a “Biopharma” and much of primary care and neurology at the end of it’s lifecycle went out the door.