LOU064: A highly selective and potent covalent oral BTK inhibitor with promising pharmacodynamic effects in skinKaul M.1, Storim J.2, End P.1, Cabanski M.1, Jakab A.1, Schuhler C.3, Funhoff E.1, Schaefer F.2, Dimanova E.2, Kistowska M.1, Kinhikar A.4, Maiolica, A.1, Sinn A.5, FuhrR.5, Cenni B.1

1Novartis Institutes for Biomedical Research, Basel, Switzerland; 2Novartis Pharma AG, Basel, Switzerland;3GCE Solutions, Basel, Switzerland; 4Novartis Institutes for Biomedical Research, Cambridge/MA, USA;5Parexel International, Early Phase Clinical Unit, Berlin, Germany

Immunology, Hepatology & Dermatology LBPD1718

Poster presented at the European Academy of Allergy and Clinical Immunology in Lisbon, Portugal, June 1–5, 2019

Zinc Number: GLDEIM/LOU/0001

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Background

§ LOU064 is a novel, oral, highly selective, potent, covalent inhibitor of Bruton’s tyrosine kinase (BTK)1

§ BTK is a cytoplasmatic tyrosine kinase and member of the TEC kinase family and selectively expressed in cells of the adaptive and innate immune system including mast cells, B cells, macrophages, basophils and thrombocytes2

§ For mast cell-mediated diseases like chronic spontaneous urticaria, inhibition of Bruton’s Tyrosine Kinase (BTK) is a novel promising therapeutic approach3

§ The objectives of this first-in-human study were to establish safety, human pharmacokinetics as well as pharmacodynamics in blood cells and in the skin

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1. Pares S, Navarro E. EFMC-ISMC, Ljubljana, Slovenia - September 2-6, 2018. Drugs of the Future 2018; 43:783; 2. Brunner C, et al. Histol Histopathol. 2005;20:945-955; 3. Min TK and Saini SS. Allergy Asthma Immunol Res. 2019;11:470–481Kaul M, et al. EAACI June 1–5, 2019, Lisbon, Portugal

Study design and population (1/2)

§ This first-in-human study consisted of 4 parts:− Part 1: 10 cohorts with single ascending doses (SAD) between 0.5 and 600 mg per cohort (n=80)− Part 2: 6 cohorts with multiple ascending doses every day (MAD qd) for 12 days between 10 and 600 mg (n=48)− Part 3: Cross-over food effect cohort (fed/fasted) with single dose of 60 mg (n=12)− Part 4: 2 cohorts with multiple ascending doses twice daily (MAD bid) for 12 days with 100 and 200 mg (n=16)

§ Each cohort of Part 1, 2 and 4 had 8 subjects randomized to receive either LOU064 or matching placebo in a 6:2 (active: placebo) ratio

§ Treatment duration for the MAD cohorts 2 and 4 was 12 days. Subjects were domiciled up to the morning of Day 16

§ Part 3 was an open-label, randomized, two-way cross-over, single dose study (60 mg) to assess food effects

§ Study population were healthy volunteers (18 – 65 years). For the MAD Parts 2 and 4, study subjects also had to have asymptomatic atopic diathesis as determined by a positive skin prick test to a known allergen at screening

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SAD, single ascending doses; MAD, multiple ascending doses; MAD qd, multiple ascending doses every day; MAD bid, multiple ascending doses twice daily Kaul M, et al. EAACI June 1–5, 2019, Lisbon, Portugal

Cohort 10.5 mg

Cohort 110 mg QD

Food Effect60 mg

Cohort 225 mg QD

Cohort 350 mg QD

Cohort 4100 mg QD

Cohort 1100 mg BID

Cohort 2200 mg BID

Cohort 21.5 mg

Cohort 35 mg

Cohort 415 mg

Cohort 530 mg

Cohort 660 mg

Cohort 7100 mg

Cohort 8200 mg

Cohort 9400 mg

Cohort 10600 mg

Cohort 6600 mg QD

Cohort 5400 mg QD8

88

88

12

88

88

88

88

88

8

8

8

8 Number of subjects8 Number of atopic subjects

Safety reviewPart 1, SAD cohortsPart 2, MAD QD cohortsPart 3, Food-effect cohortPart 4, MAD BID cohorts

Study design and population (2/2)

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BID, twice daily, MAD QD, multiple ascending doses every day; MAD BID, multiple ascending doses twice daily; QD, once daily; SAD, single ascending dosesKaul M, et al. EAACI June 1–5, 2019, Lisbon, Portugal

Aim of the study was to access safety and tolerability and dose, based on blood PK§ The primary and secondary objective of the study were

− to assess safety and tolerability of single and multiple ascending oral doses of LOU064− to assess blood PK as well as blood and tissue PD of single and multiple doses of LOU064 in healthy volunteers

and atopic subjects− to assess blood PK under fed and fasted conditions in healthy volunteers

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PK, pharmacokinetics; PD, pharmacodynamicsKaul M, et al. EAACI June 1–5, 2019, Lisbon, Portugal

Absorption of LOU064 was fast and blood concentration declined quicklySAD PK-PD Results• Absorption of LOU064 was fast with a

median Tmax value between 0.5 and1.25 hours for all doses between 0.5 and 600 mg

• Blood concentration declined quickly thereafter with a median T1/2 between 0.6 and 1.0 hour for the initial elimination phase

• A terminal elimination phase became only apparent in doses of >100 mg

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PD, pharmacodynamics; PK, pharmacokinetics; SAD, single ascending doses; T1/2, the time taken for the plasma concentration to fall by half its original value; Tmax, time of maximum plasma concentration observedKaul M, et al. EAACI June 1–5, 2019, Lisbon, Portugal

a) PK after single dose, linear view b) PK after single dose, semi-logarithmic view

0246812 24 36Hours post dose

Con

cent

ratio

n (n

g/m

L)48 72

0

100

200

300400

500

600

700

800

0246812 24 36Hours post dose

Con

cent

ratio

n (n

g/m

L)

48 720.1

1

10

100

1000

LOU064 0.5 mg LOU064 1.5 mg LOU064 5 mg LOU064 15 mg LOU064 30 mg LOU064 60 mgLOU064 600 mgLOU064 400 mgLOU064 200 mgLOU064 100 mg

PK of LOU064 after single oral administration 0.5–400 mg

No BTK occupancy in blood was observed at the lowest dose of 0.5 mgSAD PK-PD Results

a) BTK-occupancy in blood (%) b) % inhibition of basophil activation assessed by CD63 expression

LOU064 0.5 mg LOU064 1.5 mg LOU064 5 mg LOU064 15 mg LOU064 30 mg LOU064 60 mgLOU064 600 mgLOU064 400 mgLOU064 200 mgLOU064 100 mg

LOU

064

BTK

occ

upan

cy (%

)

Inhi

bitio

n of

CD

63 a

ctiv

atio

n (%

)

D1,

pD

D1,

0.5H

D1,

1H

D1,

2H

D1,

4H

D1,

8H

D2,

24H

Base

line

D1,

8H

D2,

24H

-80

0-20-40-60

4020

1201008060

140

Visit Visit

-80-60-40-20

20406080100120

0

BTK, Bruton’s tyrosine kinase; D, day; H, hour; pD, pre-dose; PD, pharmacodynamics; PK, pharmacokinetics; SAD, single ascending dosesKaul M, et al. EAACI, Lisbon Portugal. June 1–5, 2019.

PD of LOU064 after single oral administration 0.5–400 mg

• No BTK occupancy in blood was observed at the lowest dose of 0.5 mg. With 1.5 mg, a short peak was observed at 30 minutes. At doses of 5 mg and higher, BTK occupancy peaked at the first measurement (30’ after dose). Starting with a dose of 30 mg, BTK occupancy was complete (100%) for at least 24 hours post-dose

• Strong and long lasting blood basophil inhibition was measured by CD63. Increasing inhibition was observed starting from a dose of 5 mg. 24 hours post-dose, 60 mg LOU064 reached close to 90% inhibition and doses ≥100 mg yielded almost complete inhibition

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LOU064 absorption and elimination was fast and blood concentrations declined rapidlyMAD PK-PD Results

a) BTK-occupancy in blood (%) over initial 24 hoursb) BTK-occupancy in blood (%) after the last dose (Day 12)

LOU

064

BTK

occ

upan

cy (%

)

D1,

pD

D1,

0.5

H

D1,

1H

D1,

2H

Visit

D1,

4H

D1,

8H

D2,

pD

-60-40-20

020406080

100120

-60-40-20

020406080

100120

Visit

LOU

064

BTK

occ

upan

cy (%

)

D12

, pD

D12

, 0.5

HD

12, 1

H

D12

, 2H

D12

, 4H

D12

, 8H

D13

, 24H

D14

, 48H

D16

, 96H

D19

, 168

HD

23, 2

64H

EOS,

504

H

Placebo (MAD)LOU064 400 mg qd

LOU064 10 mg qd LOU064 25 mg qd LOU064 50 mg qd LOU064 100 mg qd

BTK, Bruton’s tyrosine kinase; D, day; EOS, end of study; H, hour; MAD, multiple ascending doses; pD, pre-dose; PD, pharmacodynamics; qd, once daily; Tmax, time of maximum blood concentration observedKaul M, et al. EAACI, Lisbon Portugal. June 1–5, 2019.

PD of LOU064 after multiple oral administration for doses 10–400 mg qd and bid over 12 days• LOU064 absorption and elimination was fast with a median Tmax between 0.5 and 0.875 hours. Blood concentrations declined rapidly thereafter, resulting in a mean residence time <3 hours (data not shown). Therefore, there is no relevant accumulation and a short time to steady state, both for once and twice daily dose intervals

• The SAD cohorts, first dose of 50 mg already reaches full BTK occupancy 30 min after administration that is maintained for 24 hours. At the time of the last dose at Day 12, all doses had already reached full BTK-occupancy at the pre-dose time point and maintained this level for at least 24 hours after the last dose with a dose-dependent gradual decline over several days thereafter

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Full blood basophil inhibition measured by CD63 expression was reached with 50 mg qd LOU064MAD PK-PD Results

BL, baseline; BTK, Bruton’s tyrosine kinase; CFB, change from baseline; D, day; H, hour; MAD, multiple ascending doses; PD, pharmacodynamics; qd, once dailyKaul M, et al. EAACI, Lisbon Portugal. June 1–5, 2019.

PD of LOU064 after multiple oral administration for doses 10–400 mg qd and bid over 12 days§ Full blood basophil inhibition measured by CD63 expression was reached with daily doses of 50 mg LOU064 or above over the entire treatment period (Day 1–12) and several days beyond

§ In subjects with atopic diathesis, a decrease in the average wheal size of about 3 mm was reached in doses of 100 mg daily and above

a) %-inhibition of basophil activation assessed by CD63 expression over the entire treatment period (Day 1 – 12) and beyond

b) Change from baseline (CFB) in average wheal size between pre- and post-treatment skin prick test in atopic subjects

CFB

in a

vera

ge w

heal

dia

met

er (m

m)

Total daily dose of LOU064 (mg)

-6-5-4-3-2-1012

0 100 200 300 400 500 600In

hibi

tion

of C

D63

activ

atio

n (%

)

Visit

BL D1,8H

D2,0H

D12,0H

D12,8H

D13,24H

D14,48H

D16,96H

D23,264H

-80-60-40-20020

6040

80100120

Emax model with 95% confidence band (qd doses only)

qd bid Placebo (MAD)Placebo (MAD)LOU064 400 mg qdLOU064 100 mg qd

LOU064 10 mg qd LOU064 25 mg qd LOU064 50 mg qd

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LOU064 was safe and well-tolerated in all tested strengths

§ LOU064 was safe and well-tolerated up to the 600 mg qd

§ No SAEs, deaths or AEs leading to study treatment discontinuation

§ Most frequently observed AEs were headache and nasopharyngitis with similar frequencies in the active and placebo group and with no apparent increase by dose of LOU064

§ No clinically significant changes in the hematology, biochemistry, or urinalysis parameters

§ No clinically significant changes in vital signs and ECG parameters

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AEs, adverse events; ECG, Electrocardiogram; qd, once daily; SAEs, serious adverse eventsKaul M, et al. EAACI June 1–5, 2019, Lisbon, Portugal

Conclusion

§ LOU064 is a novel, highly selective, and potent covalent BTK inhibitor that was safe and well tolerated up to the 600 mg qd over 12 days in healthy volunteers and subjects with asymptomatic atopic diathesis. No deaths or SAEs or any AE that led to treatment interruption were reported

§ No clinically significant changes were observed in vital signs, laboratory parameters or ECG parameters

§ LOU064 had a rapid absorption and elimination at all doses tested with a mean residence time of approximately 3 hours

§ The food effect part of the study demonstrated that administration of LOU064 on a fed state led to a small decrease in Cmax and an increase in Tmax and AUC which are considered clinically not relevant (data not shown)

§ Short systemic exposure of LOU064 was sufficient for > 24 hours lasting pharmacodynamic effects in blood, including complete BTK occupancy and basophil inhibition measured by CD63 expression

§ Effects on skin PD was demonstrated by a reduction of wheal size in SPT making LOU064 a strong candidate for basophil- and mast-cell driven skin diseases like chronic spontaneous urticaria

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AEs, adverse events; AUC, area under curve; BTK, Bruton’s tyrosine kinase; Cmax, maximum concentration; ECG, Electrocardiogram; PD, pharmacodynamics; qd, once a day; SAEs, serious adverse events; SPT, skin prick test; Tmax, time taken to reach the maximum concentrationKaul M, et al. EAACI June 1–5, 2019, Lisbon, Portugal