Principia Biopharma Inc.

This disclosure relates to the field of therapeutic tyrosine kinase inhibitors, in particular Bruton tyrosine kinase (“BTK”) inhibitors for treatment of subjects with relapsing multiple sclerosis.

The present disclosure relates to 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one variants or derivatives, and salts thereof, for use as agonists and antagonists. The disclosure further relates to compositions, methods of preparing, and methods of treatment.

This disclosure relates to the field of therapeutic tyrosine kinase inhibitors, in particular, Bruton tyrosine kinase (“BTK”) inhibitors, for treatment of patients with multiple sclerosis (MS).

This disclosure relates to the field of therapeutic tyrosine kinase inhibitors, in particular, Bruton tyrosine kinase (“BTK”) inhibitors, for treatment of subjects with myelin oligodendrocyte glycoprotein antibody disease (MOGAD).

Provided herein are BTK inhibitors containing piperidine modified at the 3-position. Further disclosed are methods of making and using said BTK inhibitors.

Modified release formulations, such as solid oral dosage forms comprising a core composition comprising Compound (I) and/or a pharmaceutically acceptable salt thereof; a sub-coating layer coating the core composition, said sub-coating layer comprising a polyvinyl alcohol and/or a hydroxypropyl methyl cellulose; and an enteric coating layer encapsulating the sub-coating layer and the core composition, said enteric coating layer comprising at least one polymer selected from an acrylic/methacrylic/ethacrylic acid homopolymer and copolymers thereof, a cellulose derivative, and a polyvinylpyrrolidone, and methods of administration of a Bruton's tyrosine kinase (BTK) inhibitor using said formulations.

Provided herein are substantially crystalline solid forms of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pen-t-2-enenitrile (identified herein as Compound (I), and also known as PRN 1008 or rilzabrutinib) as a pharmaceutically-acceptable salt selected from an HCI, oxalate, and/or a maleate salt or alternatively, as a pharmaceutically-acceptable methyl paraben co-crystal, and pharmaceutical compositions comprising the substantially crystalline forms.

Crystalline forms of Compound (I): are disclosed. Pharmaceutical compositions comprising the same, methods of treating disorders and conditions mediated by BTK activity using the same, and methods for making Compound (I) and crystalline forms thereof are also disclosed.

Provided herein are methods and immune biomarkers that identify progression and treatment options for multiple sclerosis (MS). Also provided are materials and methods for the prognosis, staging, and monitoring of MS in a sample and include methods of determining a subject as being at risk of developing MS. The methods include detecting at least one biomarker, such as CXCL13, CXCL10, CD27, NEFL, CCL4, and/or CCL3 in cerebrospinal fluid (CSF) in the subject; and administering a pharmaceutically effective amount of a treatment (e.g., tolebrutinib and potentially one or more additional therapies, such as an anti-CD20 therapy) to the subject.

Disclosed herein are improved synthetic routes for making (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (tolebrutinib). Also disclosed herein are novel compounds used in the synthesis of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.