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BTK Degraders

Innovative Drugs Designed to Improve Patients’ Lives

Our pipeline includes internally discovered and wholly owned drug-candidates designed to treat patients with hematologic malignancies, solid tumors, autoimmune diseases, and viral diseases. It comprises both Chimeric Targeting Molecules (CTMs) for targeted protein degradation to eliminate disease causing proteins and Ligase Inhibitors that target key control elements in immune regulation. Drug discovery alliances with Gilead Sciences and Sanofi further enhance our pipeline, each focusing on the discovery and development of CTMs against a set of unique targets.

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BTK Degraders

Bruton’s tyrosine kinase (BTK) is a validated clinical target for the treatment of hematologic malignancies and autoimmune diseases. BTK is a master regulator of B-cell activity, and inhibition of BTK results in improved clinical outcomes for patients with a variety of B-cell mediated cancers such as non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and B-cell mediated autoimmune diseases such as graft versus host disease (GVHD).

The FDA and global regulatory agencies have approved several inhibitors of BTK, which are now the standard of care across multiple tumor types. We believe that removal of the BTK protein through Targeted Protein Degradation could generate superior outcomes for patients who no longer respond to or do not tolerate current therapies.

We have developed two unique and functionally distinct BTK degraders that harness cereblon, an E3 ligase active in hematopoietic cells. Cereblon itself is the target for a class of drugs known as immunomodulatory imide drugs (IMiDs), including Revlimid (lenalidomide) and Pomalyst (pomalidomide). We have designed two BTK degraders with and without IMiD activity, creating two functionally different drug candidates.

BTK
Drug CandidateTarget (Delivery)Therapeutic AreaDiscoveryLead OptimizationPreclinicalPhase 1Phase 2Phase 3
Protein Degradation Chimeric Targeting Molecule (CTM) Portfolio
NX-2127 BTK + IMiD Activity (Oral) B-cell malignancies

 

NX-5948 BTK (Oral) B-cell malignancies and autoimmune disease

 

KINASE-CTM3 Undisclosed T-cell malignancies and autoimmune disease

 

COVID-CTMs 3 targets Anti-viral

 

Drug CandidateTarget (Delivery)Therapeutic AreaDiscoveryLead OptimizationPreclinicalPhase 1Phase 2Phase 3
Ligase Inhibitor Portfolio
NX-1607 CBL-B (Oral) Immuno-oncology

 

DeTIL-0255 CBL-B (ex vivo) Tumor infiltrating lymphocytes

 

LIGASE-INH2 Undisclosed Immuno-oncology

 

Drug CandidateTarget (Delivery)Therapeutic AreaDiscoveryLead OptimizationPreclinicalPhase 1Phase 2Phase 3
Partners and Subsidiaries
DeCART CBL-B and others (ex vivo) Chimeric antigen receptor T‑cells (CAR-T)

 

Gilead Sciences 5 targets Undisclosed

Undisclosed Progress

 

Sanofi 5 targets Undisclosed

Undisclosed Progress

 

Candidate / TargetPhase
Protein Degradation Chimeric Targeting Molecule (CTM) Portfolio
NX-2127
BTK + IMiD Activity (Oral)
Phase 1
NX-5948
BTK (Oral)
Preclinical
KINASE-CTM3
Undisclosed
Lead Optimization
COVID-CTMs
3 targets
Discovery
Ligase Inhibitor Portfolio
NX-1607
CBL-B (Oral)
Phase 1
DeTIL-0255
CBL-B (ex vivo)
Preclinical
LIGASE-INH2
Undisclosed
Lead Optimization
Partners and Subsidiaries
DeCART
CBL-B and others (ex vivo)
Lead Optimization
Gilead Sciences
5 targets
Undisclosed Progress
Sanofi
5 targets
Undisclosed Progress

NX-2127 (BTK degrader + IMiD activity for B-cell malignancies)

NX-2127 is an oral small molecule that combines the activity of a targeted BTK degrader with the therapeutic activity of the immunomodulatory imide drug (IMiD) class. IMiDs such as Revlimid (lenalidomide) and Pomalyst (pomalidomide) are FDA approved for a variety of hematologic malignancies including multiple myeloma, follicular lymphoma, and mantle cell lymphoma. We hypothesize that the combination of BTK degradation and IMiD activity will have enhanced therapeutic benefit in patients suffering from a variety of B-cell malignancies.

Preclinical data support the activity of NX-2127 in tumor models harboring either wild-type BTK or BTK with mutations conferring clinical resistance to FDA approved agents. Studies in non-human primates confirm potent BTK degradation with once daily oral dosing. NX-2127 is being tested in an ongoing Phase 1 trial for patients with B-cell malignancies who have failed prior treatments.

NX-5948 (BTK degrader for B-cell malignancies and autoimmune disease)

NX-5948 is an oral small molecule degrader of BTK. Preclinical data support the activity of NX-5948 in tumor models harboring either wild-type BTK or BTK with mutations conferring clinical resistance to leading FDA approved agents. Unlike NX-2127, our other BTK degrader, NX-5948 lacks IMiD activity and has demonstrated the ability to cross the blood brain barrier in animal models. NX-5948 has also demonstrated activity in animal models of autoimmune disease.

We anticipate starting clinical development of NX-5948 in 2021. Our initial Phase 1 trial will be in hematologic malignancies, with potential future studies in autoimmune diseases.