Carna Biosciences, Inc.

Carna Biosciences, Inc.

Pipeline

Carna has leveraged its expertise in kinase biology to establish an innovative product pipeline focused on cancer and immune disorders. We achieve success by coupling our deep understanding of cell signaling with our extensive drug discovery expertise to generate therapeutics that inhibit kinases and provide new treatment options for patients with high unmet medical needs.

  • COMPOUND
  • TARGET
    • Discovery
    • Preclinical
    • Early Clinical
    • Late Clinical
  • PARTNER
  • REGION
  • monzosertib
    (AS-0141)
  • TARGET: CDC7/ASK
  • Discovery Preclinical Early Clinical Late Clinical
  • PARTNER:
  • REGION:
monzosertib (AS-0141)
Monzosertib is a potent, selective, orally bioavailable small molecule inhibitor of CDC7 kinase, originally discovered by Carna. Monzosertib exhibited a potent anti-proliferative activity against various cancer cell lines including solid and blood cancers with minimal effects against normal cells. In several human tumor xenograft models, oral administration of monzosertib demonstrated strong anti-tumor efficacy. Monzosertib is currently being evaluated in an open-label Phase 1 study in patients with advanced, metastatic, relapsed or refractory malignancies. This study consists of two parts: the dose escalation part that aims to identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of monzosertib and the expansion cohort that aims to ensure the appropriateness of PR2D and to evaluate the preliminary anti-tumor effect.
CDC7
CDC7 (cell division cycle 7) is a serine-threonine kinase that plays a critical role in DNA synthesis and is required for the activation of DNA replication origins throughout the S phase of the cell cycle. Inhibition of CDC7 in cancer cells causes lethal S phase or M phase progression, whereas normal cells survive, most likely through induction of cell cycle arrest at the DNA replication checkpoint. It has been reported in the literature that CDC7 is overexpressed in many cancers including colon cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer and leukemia.
  • Small
    Molecule
  • TARGET: DGKα
  • Out-licensed to Gilead Sciences
  • PARTNER: Gilead Sciences
  • REGION: Worldwide
  • Small
    Molecule
  • TARGET: Kinase
  • Joint Research with Sumitomo Pharma
  • PARTNER: Sumitomo Pharma
  • REGION: Worldwide
  • sofnobrutinib
    (AS-0871)
  • TARGET: BTK
  • Discovery Preclinical Early Clinical Late Clinical
sofnobrutinib (AS-0871)
Sofnobrutinib is an investigational small molecule drug designed to bind non-covalently to Bruton's tyrosine kinase (BTK) with high selectivity, currently in development for inflammatory and immune disorders. In in vitro experiments, sofnobrutinib strongly inhibited B cell and basophil activation and suppressed production of inflammatory cytokines such as TNF-α, IL-17, MCP-1 and IL-6 in human blood. Oral administration of sofnobrutinib demonstrated the excellent therapeutic effects in a mouse model of collagen-induced arthritis. In addition, sofnobrutinib prevented IgE-mediated skin inflammation in mice and rats.
The Phase 1 clinical study of sofnobrutinib in heathy volunteers, consists of single ascending dose (SAD) study and multiple ascending dose (MAD) study, was conducted in the Netherlands. In the SAD study, sofnobrutinib was safe and well-tolerated at all dose levels and showed favorable pharmacokinetic (PK) profile. Sofnobrutinib achieved plasma level to demonstrate pharmacodynamic (PD) effects with strong inhibition of anti-IgD-induced CD69 expression in naïve B cells and anti-IgE-induced CD63 expression in basophils at doses of 100 mg and above. In the MAD study with a new formulation, sofnobrutinib was safe and well tolerated at all dose levels and the exposure levels increased dose-dependently. Also, sofnobrutinib showed robust pharmacodynamics effect, achieved ≥90% inhibition of basophil activation at 150 mg and 300 mg twice daily. The data from the Phase 1 study support further investigation of sofnobrutinib in Phase 2 study.
BTK inhibitors in inflammatory and immune disorders
BTK is a Tec family tyrosine kinase expressed in B cells and myeloid cell populations including monocytes, macrophages, neutrophils, basophils and mast cells. BTK has a crucial role in B cell antigen receptor (BCR) signaling during B cell development and activation. In autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, aberrant BCR signaling is considered to promote diseases through production of autoantibodies. In addition to BCR signaling, BTK mediates downstream signaling of the Fcγ receptors in myeloid cells to produce inflammatory cytokines such as IL-6 and TNF-α, which would aggravate RA symptoms. In allergic diseases, BTK is a critical enzyme for Fcɛ receptor (FcɛR) signaling in mast cells and basophils to regulate release of chemical mediators such as histamine and leukotrienes. Therefore, BTK is being paid attention as an attractive therapeutic target for the treatment of autoimmune diseases and allergic diseases.
  • AS-1763
  • TARGET: BTK
  • Discovery Preclinical Early Clinical Late Clinical
AS-1763
AS-1763 is a highly selective, orally bioavailable, non-covalent inhibitor of both the wild type and mutant Bruton’s tyrosine kinases (BTK) for the treatment of chronic lymphocytic leukemia(CLL) and other B cell malignancies. Covalent BTK inhibitors including ibrutinib are key therapeutic options for patients with B cell malignancies. However, patients are reported to develop resistance during the treatment due to substitution of cysteine residue at 481 position with serine (C481S mutation) in BTK, which reduces the efficacy of the covalent BTK inhibitors. In addition, the emergence of other types of resistance mutations to non-covalent BTK inhibitors in development, including recently approved pirtobrutinib, have been reported. AS-1763 potently inhibited both wild type and those mutant BTKs, strongly suggesting that AS-1763 will be a new therapeutic option for treating patients with B cell malignancies both having wild type and resistance mutations in BTK.
The Phase 1 single ascending dose study in healthy volunteers was conducted in the Netherlands in 2021, in which AS-1763 was well-tolerated and demonstrated a favorable safety, pharmacokinetic and pharmacodynamic profile at all dose levels.
The Phase 1b study of AS-1763 was initiated in 2023 in the U.S. for patients with previously treated CLL, B-cell small lymphocytic lymphoma(SLL), and B-cell non-Hodgkin lymphoma(B-cell NHL). The study consists of dose escalation part and dose expansion part. The primary objective of the ongoing dose escalation part is to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of AS-1763. Safety profile, tolerability, PK, and preliminary efficacy will be also evaluated as secondary objectives. The dose expansion part will further recruit patients with previously treated CLL/SLL or B-cell NHL to evaluate safety, efficacy, and PK of AS-1763 at multiple doses selected in the dose escalation part and to determine the recommended phase 2 dose (RP2D).
BTK inhibitors in CLL and B cell malignancies
BTK plays a crucial role in B cell antigen receptor (BCR) signaling which is essential for B cell development, and BTK has been recognized as a validated therapeutic target for B cell malignancies including CLL. Covalent BTK inhibitors have been appreciated as a promising targeted therapy for patients with B cell malignancies. However, the emergence of clinical resistance to these covalent BTK inhibitors is becoming serious concerns. BTK C481S mutation predominantly confers this drug resistance by preventing covalent binding of the existing BTK inhibitors. Therefore, there is a high unmet medical need for new therapeutic approaches to overcome the BTK C481S-mediated resistance. The next generation non-covalent BTK inhibitor is expected to be a promising option to treat patients with BTK C481S mutation.
  • Small
    Molecule
  • TARGET: ALK5
  • Discovery Preclinical Early Clinical Late Clinical
  • Small
    Molecule
  • TARGET: malaria
  • Discovery Preclinical Early Clinical Late Clinical
  • Small
    Molecule
  • TARGET: CDK1
  • Discovery Preclinical Early Clinical Late Clinical
  • Small
    Molecule
  • TARGET: STING
    (antagonist)
  • Discovery Preclinical Early Clinical Late Clinical
STING antagonist
The cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) signaling pathway plays a central role in innate immunity. The cGAS-STING signaling is activated in response to the presence of cytosolic DNAs produced by microbial infection or cellular stress. The activated cGAS-STING signaling induces type I interferons (IFNs) production to trigger immune responses for host defense. It has been reported that aberrant cGAS-STING signaling is implicated in the pathogenesis of several diseases. Mutations in several genes have been identified that cause the constitutive activation of the cGAS-STING pathway, resulting in severe autoinflammation in lung, kidney, joint, etc. These include rare genetic diseases such as Coatomer-associated protein subunit alpha (COPA) syndrome, STING-associated vasculopathy with onset in infancy (SAVI), Aicardi–Goutières syndrome (AGS), and familial chilblain lupus (FCL). Moreover, numbers of non-genetic diseases are also suggested to be associated with the aberrant cGAS-STING signaling. These include a subset of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and several cancers.