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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 (CRBN), an E3 ligase active in hematopoietic cells. Cereblon itself is the target for a class of drugs with immunomodulatory activity, including lenalidomide and pomalidomide that induce cereblon to degrade so-called neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3). We have designed two BTK degraders with and without the ability to induce neosubstrate degradation, creating two functionally different drug candidates.

BTK
Drug CandidateTarget (Delivery)Therapeutic AreaDiscoveryIND enablingPhase 1Phase 2Phase 3
Clinical Pipeline
NX-2127 Degrader BTK + IKZF B-cell malignancies

 

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

 

NX-1607 Inhibitor CBL-B (Oral) Immuno-oncology

 

DeTIL-0255 Cell Therapy Adoptive cell therapy with ex vivo CBL-B inhibition Gynecologic malignancies

 

Drug CandidateTarget (Delivery)Therapeutic AreaDiscoveryIND enablingPhase 1Phase 2Phase 3
Discovery Pipeline
Wholly Owned Multiple targets* Undisclosed

 

Gilead Sciences 5 targets Undisclosed

 

Sanofi 5 targets Undisclosed

 

Candidate / TargetPhase
Clinical Pipeline
NX-2127 Degrader
BTK + IKZF
Phase 1
NX-5948 Degrader
BTK (Oral)
Phase 1
NX-1607 Inhibitor
CBL-B (Oral)
Phase 1
DeTIL-0255 Cell Therapy
Adoptive cell therapy with ex vivo CBL-B inhibition
Phase 1
Discovery Pipeline
Wholly Owned
Multiple targets*
Discovery
Gilead Sciences
5 targets
Discovery
Sanofi
5 targets
Discovery

NX-2127 (BTK + IKZF for B-cell malignancies)

NX-2127 is an oral small molecule that combines the activity of a targeted BTK degrader with cereblon immunomodulatory activity of an IKZF degrader. Cereblon immunomodulatory drugs that induce degradation IKZF1 and IKZF3 such as lenalidomide and 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 cereblon immunomodulatory 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 cereblon immunomodulatory 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.

Our initial Phase 1 trial of NX-5948 is for patients with B-cell malignancies who have failed prior treatments.