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PRN1008, a Reversible Covalent BTK Inhibitor in Clinical Development for Immune Thrombocytopenic Purpura

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PRN1008, a Reversible Covalent BTK Inhibitor in Clinical Development for Immune Thrombocytopenic Purpura PRN1008, a Reversible Covalent BTK Inhibitor in Clinical Development for Immune Thrombocytopenic Purpura Langrish CL, Bradshaw JM, Owens TD, Campbell RL, Francesco MR, Karr DE, Murray SK, Quesenberry R, Smith PF, Taylor MJ, Zhu J, Nunn PA and Gourlay SG Principia Biopharma, South San Francisco, CA Abstract Mouse Immune Thrombocytopenia BTK and Platelets Clinical Platelet Counts PRN1008 is an oral, reversible covalent inhibitor of Bruton’s PRN1008 demonstrates significant dose-dependent Platelets express BTK, which is involved in collagen-GPVI PRN1008, at a dose that achieved maximal BTK tyrosine kinase (BTK) in clinical development for the prevention of platelet loss in the mouse anti-CD41 and vWF signaling pathways. occupancy, showed no clinically significant effects on treatment of multiple autoimmune diseases. Treatment with U46619 antibody immune thrombocytopenia model. ADP platelet counts in the 12 week Pemphigus Vulgaris TRAP PRN1008 in vitro profoundly inhibited B cell activation and phase 2 study. blocked antibody mediated activation of immune cells via PRN1008 is currently being used to treat Pemphigus Vulgaris Fc-receptor signaling. Preclinically, PRN1008 demonstrated a patients in an open-label 12 week study (NCT02704429). significant dose-dependent reduction of platelet-loss in the BTK anti-CD41 induced mouse model of immune PRN1008 % BTK BTK PV patients dosed with 400mg bid PRN1008 achieved >95% dose occupancy thrombocytopenia. In addition, PRN1008 showed rapid and BTK occupancy. Platelet counts were measured during mg/kg at 1hr significant anti-inflammatory effects in an antibody driven Figure 4. Signaling treatment and compared to baseline (interim study 10 51 ± 19 Collagen rat Arthus model and in spontaneous autoantibody- 6 Ristocetin analysis). 20 84 ± 3 pathways in platelets mediated canine pemphigus foliaceus. Platelets express high 40 91 ± 4 Screen Predose Day 15 Day 29 Day 57 Day 85 levels of BTK, however alternative signaling pathways exist Parameter (n=10) (n=9) (n=9) (n=8) (n=6) (n=5) which bypass BTK signaling to retain normal platelet Platelet Aggregation 9 Platelets x10 254 272 260 240 247 266 functions. The effect of PRN1008 on platelet function was Clinically relevant concentrations of PRN1008 do not (mean, range) (123,413) (187,373) (168,340) (189,352) (181,325) (186,363) assessed in vitro in both normal healthy volunteer and ITP interfere with normal platelet aggregation functions in % Change NA NA -3% -13% -8% +1% patient platelets using a standard panel of platelet agonists. from baseline healthy volunteer or ITP patient platelets. In contrast to ibrutinib, treatment with PRN1008 at clinically relevant concentrations did not impact collagen-induced Table 1. Median platelet counts in Pemphigus Vulgaris patients treated with 400mg bid PRN1008 in open label, 12 week study. platelet aggregation in either normal or ITP patient platelet Figure 2. Effect of PRN1008 on platelet counts at 6 hours in the mouse anti-CD41 induced immune thrombocytopenia model. samples, or interfere with responses to other platelet Balb/c mice were dosed with PRN1008 (10-40 mg/kg, po qd) or IVIG prior to agonists tested. In the clinic, PRN1008 has been well challenge with anti-CD41. Platelet counts were measured at 6 hours post Summary tolerated. An analysis of platelet counts from the ongoing challenge and compared to vehicle control, *p<0.05. Spleen % BTK occupancy clinical 12 week pemphigus vulgaris study (NCT02704429) was measured by binding of an irreversible fluorescent probe to unbound BTK, in Preclinical data suggests that PRN1008 could diminish prepared splenic cell samples collected from satellite animals at the time of platelet loss in ITP by two key mechanisms: showed no evidence of effects of PRN1008 on platelets. challenge (1 hr post dose). 1. Reduce platelet destruction via inhibition of γ autoantibody/Fc R signaling in splenic macrophages. ITP and BTK Rat Antibody Mediated Arthus 2. Reduce autoantibody generation through inhibition of B cell activation and maturation. ITP is an autoimmune disorder, driven by induction of auto- PRN1008 achieves significant dose-dependent inhibition antibodies targeting platelet glycoproteins, to drive splenic of the antibody mediated Arthus reaction in rats. BTK is expressed in platelets, however alternative macrophage mediated platelet destruction1,2. signaling pathways exist to bypass BTK and retain BTK is an essential signaling element of the B cell receptor, normal function: critical for B cell activation and antibody induction. BTK also 1. 12 week treatment with PRN1008 in PV patients regulates antibody-mediated activation of macrophages, PRN1008 % BTK showed no evidence of effects on platelet counts. and other immune cells via Fc-receptor signaling3. dose occupancy 2. PRN1008 treatment did not interfere with platelet mg/kg at 1hr Platelets express BTK, involved in collagen/GPVI signaling4,5, aggregation in ITP patient or healthy volunteer blood. 10 71 ± 11 however alternative signaling pathways exist. 20 94 ± 2 PRN1008 40 99 ± 1 Clinical Development Principia Biopharma is developing PRN1008 for the treatment of autoimmune diseases including ITP, pemphigus and other immunologic disorders where B cell autoantibodies and/or B-cell signaling are pathogenic. PRN1008 A phase 1/2 study investigating the safety, PK, PD, and Figure 5. Effect of PRN1008 or ibrutinib on agonist-induced clinical activity of PRN1008 in patients with relapsed ITP T cell Figure 3. Effect of PRN1008 on rat Arthus reaction. platelet aggregation in ITP patient and healthy volunteer platelets. Sprague-dawley female rats were dosed with PRN1008 (10-40 mg/kg, po qd) or Platelets from 5 ITP patients or 5 healthy volunteers (HV) were prepared and is underway. 1 prednisolone (10 mg/kg). Rats were administered with anti-OVA/OVA challenge in treated with 0.3µM , 1µM PRN1008 or ibrutinib (HV only), and tested for effect on Figure 1. ITP cellular mechanisms skin, and Arthus reaction was quantified by the level of dye extravasation. Ave ± Saline-, ADP-, TRAP- U46619-, Ristocetin- and Collagen-induced platelet 1. Cines DB, Blanchette VS. N Engl J Med. 2002. 346(13): 995-1008. SD, t-test vs vehicle *p<0.01. Spleen % BTK occupancy was measured by binding aggregation, measured by lumi-aggregator. Data shows % maximal aggregation References 2. McKenzie et al, Br J Haematol. 2013. 163:10-23. Contact: Claire L Langrish, PhD of an irreversible fluorescent probe to unbound BTK, in prepared splenic cell (MA), obtained by normalizing MA of all agonist-induced platelet aggregations to 3. López-Herrera G et al, J Leukoc Biol. 2014. 95(2): 243-50. samples collected from satellite animals at the time of challenge (1 hr post dose). the corresponding 1% DMSO-treated agonist-induced condition. 4. Futatani T et al, Br J Haematol. 2001. 114(1):141-9. 5. Kamel S et al, Leukemia. 2014. 29(4): 783-787. [email protected] 6. Varga-Szabo D et al, Arterioscler Thromb Vasc Biol. 2008. 28:403-412. American Society of Hematology 2017, #1052 Principia Biopharma (www.principiabio.com) .
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