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.
POC will read in Feb 2027 and be based on this endpoint.
What is PET imaging for Tau reduction?
The Ph2 PoC study for for '446, the anti-MTBR ta mAb, is ongoing. Of note - while there are many anti-tau assets are in development, multiple lines of evidence indicate that the MTBR of the tau protein (as targeted by '446 and tau shuttle) is critical to the spread of tau in the brain of AD patients. Primary endpoint of Ph2 PoC trial is therefore change in tau brain deposition as meautred by tau PET at 18 months, with secondary endpoints that include different COAs of AD. Enrollment to the trial completed Jun2025 (360 participants), with topline PoC data targeted Feb 2027
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)?
In Alzheimer's Disease, upstream misfolded proteins incl. amyloid-beta and Tau are believed to trigger the Integrated Stress Response (ISR) in neurons. BMS-986419 has been shown to reduce expression of ISR-related genes and restore protein translation by activating eukaryotic initiation factor 2B (eIF2B) complex to provide neuroprotection in both in vitro and in vivo preclinical models of neurodegenerative disorders. By restoring normal protein homeostasis in AD, '419 could potentially enhance synaptic function and preserve neuronal structure to improve cognitive function.
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.
This IV-administered biologic may require a switch to subcutaneous delivery and is considering these two approaches.
What is 1) OBDS of the naked Tau mAb and 2) TfrxTau shuttle?
Biologic treatment landscape increasingly favors SC administration of mAbs via IV (reduced healthcare burden, improved patient/caregiver expereince, reduced cost and resource demand on infusion centers), including the AD treatment landscape. '446 acquired from Prothena as IV asset - Ph1 studies conducted via IV; same for Ph2 PoC trial (1400 mg and 4200 mg vs. pbo). '446 administered SC deemed a commercial imperative. there are 2 potential approaches: administer '446 via large volume OBDS (requiring complex bridging within clinical program from IV formulation); advance TfR1tau shuttle into development based solely on SC administration. Efforts initiated with commercial to assess and coordinate different development scenarios of the 2 tau assets ('446 and tau shuttle)
This asset is being explored for use in Lewy Body Dementia, expanding its potential beyond its original indication.
What is Cobenfy?
This is one of the ideas to expand the potential indications along with Bipolar, Autism, and AD.
This receptor subtype, when selectively modulated allosterically, avoids pan-muscarinic-mediated cholinergic side effects while still indirectly regulating dopamine in brain regions tied to antipsychotic activity.
What is the muscarinic M4 receptor?
Selective binding to the allosteric site of the M4 receptor enables modulation of the M4 receptor which indirectly modulate dopamine levels in areas of the brain associated with antipsychotic activity and cognitive improvement. Pan-muscarinic modulation is spared with selective M4 allosteric bindingin and is thus devoid of cholinergic side effects.
This regulatory designation, while not expected to impact commercial strategy, would trigger a shift to third-party CMC manufacturing for FAAH/MAGL
What is scheduling?
Controlled substance designation won’t alter the commercial strategy—but it would require shifting manufacturing to a third-party facility certified for scheduled compounds. Abuse liability data is being collected in Phase 2, and nonclinical toxicology studies are planned after RP2D to support regulatory discussions and mitigate scheduling risk.
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.