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BTK Inhibitors

Impetis has developed BTK inhibitors which are designed for selectivity and reversibility, making them highly differentiated from the competition in terms of their safety and sustained action over a long duration of treatment. Impetis’ BTK inhibitors are differentiated in the following ways:

Reversible and non-covalent inhibition

  • No risk of inhibition of other cysteine-containing kinases and other enzymes by covalent modification

  • No potential for drug resistance due to mutation of Cys-481 residue of BTK that forms covalent bonding with irreversible inhibitors

  • No potential for covalent protein conjugate adducts formation leading to immunogenicity or loss of selectivity

Intrinsic selectivity, with no/minimal inhibition of other kinases that may have potential safety risks

  • TEC-sparing: Decreased platelet dysfunction/bleeding risk

  • JAK-3-sparing: Decreased risk for profound immunosuppression

  • EGFR-sparing: Decreased potential for diarrhea/GI toxicity

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Small oral bid dose leading to full target coverage over 24 hrs, thus reducing the risk of Richter’s transformation or other mutations/clones, without compromising the safety and side-effect profile

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Key assets in Impetis' BTK Inhibitor platform include the following

PNQ-849: A reversible BTK inhibitor for Inflammation and
Auto-immune Indications

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Robust efficacy in standard models of Autoimmune disease -Robust efficacy at both BID and QD dosing in 2 RA models: Collagen Induced Arthritis (CIA) in mice and Adjuvant Induced Arthritis (AIA) in rats Clean preclinical safety profile -Excellent selectivity over other BTK and diverse non-BTK family kinases vs. irreversible inhibitors and other drugs -Selectivity vs. diverse 100 kinase and 121 DrugMatrix targets and hERG -Non-mutagenic in mini-Ames test -Well tolerated with dose-related TK profile in 28-day safety study in rat with a NOEL of 180 mg/kg/day IP Status -Composition of Matter Patent covering PNQ-849 and PNQ-617 has been granted in US (US9,233,983) IND ready profile, with clear development path -Process optimization completed -All IND directed safety studies have been completed

PNQ-154: an early stage reversible BTK inhibitor positioned for “Ibrutinib Resistant” Cancers

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Robust efficacy in standard models -Robust efficacy at both BID and QD dosing in 2 RA models: Collagen Induced Arthritis (CIA) in mice and Adjuvant Induced Arthritis (AIA) in rats -Diffuse large B-cell lymphoma (DLBCL) Xenograft model Clean preclinical safety -Excellent selectivity over other BTK and diverse non-BTK family kinases vs. irreversible inhibitors and other drugs -Selectivity vs. diverse 100 kinase and 121 DrugMatrix targets and hERG -14 day repeat oral dose toxicity in rats completed Clear IP -Patent granted- field in April 2013 under PCT and was published (WO2013157022) in October 2013 IND ready in under a year -Process optimization and final form selection ongoing -Material generation for IND-enabling studies initiated

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