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A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan,...

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Page 1: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

A new oral drug for

asthma treatment

1

Page 2: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

The leadership team is expert in asthma/lung physiology, medicinal

chemistry, drug development, & clinical medicine

Alexander (Leggy) Arnold, PhDAssoc. Professor

James Cook, PhDDistinguished Professor

Douglas Stafford, PhD, MSDirector, Milwaukee Inst. for Drug DiscoveryChemistry & BiochemistryUniversity of Wisconsin-Milwaukee

Charles Emala, MD, MSHenrik H. Bendixen Professor of AnesthesiologyVice Chair for ResearchColumbia University College of Physicians & Surgeons

Mitchell Grayson, MDDirector, Division of Allergy and ImmunologyProfessor of Pediatrics, Nationwide Children’sHospital and The Ohio State University

The program has received generous funding:

SM2

Page 3: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

A novel asthma strategy:target GABAA receptors

in the lung

Innovation:

• New molecular entities• Small molecule (positive

modulators)• Oral delivery• First line therapy• No steroids• Better compliance

GABAA receptor 3

Page 4: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Pending patents claiming novel drug compositions and uses

Columbia/UWM Research Foundation patents on novel asthma treatment

PCT [8/2017 submission] Inventors: Arnold, Alexander E.; Stafford, Douglas C.; Cook, James M.; Emala, Charles W.Title: Novel GABA(A) receptor modulators and methods to control airway hyperresponsiveness and inflammation in asthma.Claims: 35 claims pending on novel drug compositions and methods of use

PCT/US2013/060859 Filed: Sept. 20, 2013Inventors: Stafford, Douglas C.; Cook, James M.; Arnold, Alexander E.; Emala, Charles W.; Gallos, George, and; Stephen, Michael Rajesh. Title: Novel GABAA agonists and methods of using to control airway hyper-responsiveness and inflammation in asthma.Claims: 13 claims pending on novel drug compositions and methods of use

4

Page 5: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

• Chronic disease economics with large global prevalence

• Current first-line drugs have safety/efficacy liabilities

• Current inhaler medications have compliance liabilities

• Differentiated product – new drug composition, no inhaler

• Developing for first-line asthma indication

• Patents pending on compositions and therapeutic uses

A compelling opportunityfor improved asthma treatment

The Opportunity

5

Page 6: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

• Fundamentally novel asthma drug target identified

• Target has been safely drugged for other indications

• No use of steroids or β2-adrenergic agonists

• Drug design is a small molecule for oral dosing

• Development team is recognized as experts in target/compound class

• Several well-characterized leads

• Leads have good animal safety, pharmacokinetics, and lung exposure

• Efficacy has been demonstrated in established animal disease models

• Compound class has low cost of manufacturing

A ground-breaking approachin targeting and compound design

The innovation

6

Page 7: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

0

2

4

6

8

10

1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010

Pe

rce

nt

Year

Current asthma prevalence, 2001-2010

Asthma period prevalence, 1980-1996

Asthma is a growing healthcare challenge

Content source: National Center for Environmental Health

• 25 million Americans (~8% of population; 2015 data)

• Most common chronic disease in children

• Over 2 million emergency room visits

• More than $56 billion US disease burden

7

Page 8: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

NormalAsthmatic

Inflammation (excess mucus)

• corticosteroids

• leukotriene receptor antagonists

Airway smooth muscle constriction

• β2-adrenergic agonists

Asthma features targeted by treatment:

Lung inflammation and airway smooth muscle hyperresponsiveness are

hallmarks of asthma

8

Page 9: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Objectives of asthma treatment:

Numerous inhaler medicationsare used for first-line treatment

• Reduce impairment (frequency and intensity of symptoms)

• Reduce risk

(likelihood of future asthma attacks, progressive decline, and medication side effects

9

Page 10: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

According to the "Real-World Evaluation of Asthma Control and Treatment" (REACT) study, more than half

(55 percent) of Americans with moderate-to-severe asthma self reported they do not have their asthma

symptoms under control despite the fact that most had health insurance and regular doctor visits.

But, asthma is not well controlled

10

Page 11: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Limitations of current asthma therapies

Biologics- Can be very effective- High cost (>$30,000/yr)- Not first-line therapy

• Disease resistance (ICS)

• Imprecise use/poor compliance

(inhalers)

• Growth delay, osteoporosis,

cataract formation, adrenal

suppression, infection, dysphonia,

cough, throat irritation (ICS, oral CS)

• Poor efficacy (LTRA)

• Toxicity of lipox5 inhibitors (Zileuton)

• Plasma monitoring (theophylline)

• “Black Box” warning (LABAs)

54.9% of adult and 78.3% of

pediatric patients are non-

adherent to medication therapy

. . . Based on the available information, FDA concludes there is an increased risk for severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric and adult patients as well as death in some patients using LABAs for the treatment of asthma.

From FDA’s LABA black box warning

11

Page 12: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Innovation in asthma therapy:modulate GABAA receptor

function in the lung

• Airway smooth muscle • Immune/

inflammatory cells

GABAA receptors are present on lung cell types responsible for asthma

pathophysiology

• Chloride ion channel• Well characterized CNS activity • Positive modulators work at

allosteric sites and increasechannel efficacy

• Receptor is readily druggable; approved small molecule drugs in wide-spread clinical use

GABAA receptors are established drug targets

12

Page 13: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

RT-PCR analysis of airway smooth muscle RNA shows GABAA

receptors restricted to α4 and α5 containing subtypes

Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and Charles W. Emala, Sr. GABAA

receptors are expressed and facilitate relaxation in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2008 Jun; 294(6): L1206–L1216.

GABAA receptors on airwaysmooth muscle have restricted

subunit expression

Lane1 = MW standards2 = Buffer control3 = Cultured human ASM4 = Freshly dissected human ASM5 = Human brain

13

Page 14: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Mouse spleen cells (mixed immune cell population) express GABAA

receptor subunits (western blot). Positive control is mouse brain.

GABAA receptor subunits are also expressed on immune cells

14

Page 15: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Targeting GABAA receptors in the lung

• α4 and α5 GABAA receptors are expressed in both airway smooth muscleand immune/inflammatory cells.

• UWM researchers have >30 years experience designing GABAA receptorligands with α-subtype selectivity.

• Novel GABAA receptor ligands are derivatives of benzodiazepines; possessing desirable selective receptor efficacy, good oral availability, good PK, and general safety.

• These compounds are readily manufacturable at large scale and low cost.

• Asthma compounds retain target selectivity and therapeutic efficacy, butrestrict CNS exposure (to preclude any CNS effects).

Representative data on various α4 and α5 GABAA selective receptor ligands are shown in the following slides.

Key points to consider:

15

Page 16: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Yocum GT, Gallos G, Zhang Y, Jahan R, Stephen MR, Varagic Z, Puthenkalam R, Ernst M, Cook JM, Emala CW. Targeting the γ-AminobutyricAcid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction. Am J Respir Cell Mol Biol. 2016 Apr;54(4):546-53.

XHE-III-74 has GABAAR selectivity to α4 subtype

Patch clamp of αxβxγx expressing oocytes showing selectivity to α4–subunit containing GABAA receptors

Positive allosteric modulatorstarget discrete GABAA receptors

XHE-II-74; a representative α–subunit selective GABAA receptor ligand

16

Page 17: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Optimization of substituted imidazobenzodiazepines as novel asthma treatments.Jahan R, Stephen MR, Forkuo GS, Kodali R, Guthrie ML, Nieman AN, Yuan NY, Zahn NM, Poe MM, Li G, Yu OB, Yocum GT, Emala CW, Stafford DC, Cook JM, Arnold LA. Eur J Med Chem. 2017 Jan 27;126:550-560

Compound 1 does not cause CNS motor impairment

Notes:• Prior to animal testing, compounds must be non-

toxic and metabolically stable in vitro.• Because GABAA receptor modulators have well-

known CNS suppressive activity; to be suitable for asthma, compounds must be devoid of α1 efficacy and CNS exposure.

• The rotarod is an established assay for assessing any motor impairment due to CNS exposure.

Rotarod studies in mice showing no motor impairment (latency) up at 100 mg/Kg po(contrast diazepam control at 5 mg/kg ip).

Rotarod apparatus

17

Page 18: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Selective GABAA compoundsrelax airway smooth muscle

α4 (compound 1) and α5 (compound 2) selective GABAA receptor ligands relax guinea pig tracheal smooth muscle (A) and human tracheal smooth muscle (B) in vitro.

Muscle strips were precontracted with substance P or acetylcholine. 18

Page 19: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Human Jurkat T-cells were stimulated with PMA/PHA (phorbol myristate acetate/phytohemagglutinin). Change in [Ca2+] was measured with a cell-permeable fluorescence probe Fluo-4.

Mechanism of action: GABAA receptor modulation of lymphocyte Ca2+ signaling

19

Page 20: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

0 100 200 300 400 5000

2000

4000

6000

8000

10000

12000

14000

Blood

Lungs

Brain

Blood Lung Brain

tmax (min) 60 60 60

Cmax (µg/g) 12.51 10.23 0.33

Erate (min-1) 0.010 0.003 0.004

t1/2 (min) 70 238 159

Arate (min-1) 0.014 0.046 0.039

AUC0-t (µg*min/g) 2270.2 1640.4 56.3

Time (min)

concentr

ation 1

(ng/g

)

A B

0 100 200 300 400 5000

2000

4000

6000

8000

10000

12000

14000

Blood

Lungs

Brain

Blood Lung Brain

tmax (min) 60 60 60

Cmax (µg/g) 10.13 9.55 0.23

Erate (min-1) 0.0007 0.0034 0.0022

t1/2 (min) 905 203 313

Arate (min-1) 0.043 0.035 0.024

AUC0-t (µg*min/g) 2648.9 1687.7 66.7

Time (min)

con

ce

ntr

atio

n 2

(n

g/g

)

Selective GABAA compoundsare orally available with good PK,

and minimal brain exposure

Representative mouse pharmacokinetic study with α4 (compound 1) and α5 (compound 2) selective GABAA receptor ligands following oral dosing.

20

Page 21: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Selective GABAA compounds relax airway smooth muscle in asthmatic mice

0

1

2

3

4

5

CTL

Ova S/C

Ova S/C+ 1

1.56 3.13 6.25 12.5 14

Methacholine [mg/ml]

sR

aw

0

1

2

3

4

5

CTL

Ova S/C

Ova S/C+ 2

1.56 3.13 6.25 12.5 14

Methacholine [mg/ml]

sR

aw

0

1

2

3

4

5

CTL

Ova S/C

Ova S/C+ALB

1.56 3.13 6.25 12.5 14

Methacholine [mg/ml]

sR

aw

**

***

**

***

***

A B C

Mice are sensitized and challenged with ovalbumin (Ova S/C), leading to lung inflammation and airway hyperresponsiveness that models human asthma. Efficacy of compounds (sRAW) in conscious mice following airway challenge with methacholine is measured using a non-invasive airway monitoring device (Buxco). CTL = control (no treatment); ALB = albuterol; 1 = compound 1; 2 = compound 2.

21

Page 22: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Selective GABAA compoundsreduce lung inflammatory

cells in asthmatic mice

CTL

Ova

S/C

Ova

S/C

+Dex

Ova

S/C

+ 1

Ova

S/C

+ 2

0

1

2

3

4

CC

R3

+ c

ells

/ m

L (

10

^5)

CTL

Ova

S/C

Ova

S/C

+Dex

Ova

S/C

+ 1

Ova

S/C

+ 2

0

1

2

3

4

GR

1+

ce

lls/

mL

(1

0^5

)

CTL

Ova

S/C

Ova

S/C

+Dex

Ova

S/C

+ 1

Ova

S/C

+ 2

0.0

0.5

1.0

1.5

2.0

CD

4+

ce

lls/

mL

(1

0^4

)

CTL

Ova

S/C

Ova

S/C

+Dex

Ova

S/C

+ 1

Ova

S/C

+ 2

0

1

2

3

4

CD

11

b+

ce

lls/

mL

(1

0^5

)

** **

*** ***

** *

*****

* *

A B

C D

*

As described previously, mice are sensitized and challenged with ovalbumin (Ova S/C) leading to lung inflammation and airway hyperresponsiveness that models human asthma. Efficacy of compounds is measured by flow cytometric analysis of specific cell types from bronchoalveolar lavage fluid (BALF). CCR3+, GR1+, CD4+ and CD11b+ cell populations are quantified. Dex = dexamethasone; 1 = compound 1; 2 = compound 2; control = unsensitized mice; *, p≤0.05; **, p≤0.01; ***, p≤0.001.

22

Page 23: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Selective GABAA compoundsreduce lung inflammatory

cells in asthmatic mice

As described previously, mice are sensitized and challenged with ovalbumin (Ova S/C) leading to lung inflammation and airway hyperresponsiveness that models human asthma. Efficacy of compound is measured by flow cytometric analysis of specific cytokines in lung homogenate. IL-4, IL-17a and TNFα are down-regulated. *, p≤0.05; **, p≤0.01; ***, p≤0.001.

23

Page 24: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Summary of studies

• Targeting lung GABAA receptors is a compelling drug strategy to safelyreduce key asthma features of airway smooth muscle hyperreactivity andlung inflammation.

• A restricted set of GABAA receptors are found on target tissues, allowing for ligands (drugs) with narrowly tailored effects.

• Compounds have good oral availability, good PK, and no observabletoxicities.

• Compounds lack brain exposure and are devoid of CNS adverse effects.

Key scientific takeaways:

• Novel ligands with α4 and α5 selectivity have good drug-like properties andpharmacodynamic performance in relevant in vitro and in vivo models.

• Clinical leads identified

24

Page 25: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Forkuo, G., et al. 2017. Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAA Receptor Modulators. Mol Pharm. 14(6):2088-2098.

Yocum, G., et al., 2017. GABAA Receptor α4 Subunit Knockout Enhances Lung Inflammation and Airway Reactivity in a Murine Asthma Model. Am J Physiol Lung Cell Mol Physiol. May 4 [Epub ahead of print]

Jahan, R, et al. 2017. Optimization of substituted imidazobenzodiazepines as novel asthma treatments. Eur J Med Chem. 126:550-560.

Forkuo, G., et al. 2016. Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments. Mol Pharm. 13(6):2026-38.

Yocum, G., et al. 2016. Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction. Am J Respir Cell Mol Biol. 54(4):546-553.

Clayton, T., et al. 2015. A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model. Int J Med Chem. 2015:430248.

Mizuta, K, et al. 2008. GABAA receptors are expressed and facilitate relaxation in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2008 Jun;294(6):L1206-16

Research results published in several scientific journals

Selected publications:

25

Page 26: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Moving the program forward

Target validation

Initial compounds

Lead optimization

Oral PK/ADME/tox

Efficacy in PD models

2 Patent pending (US/EU/CA/JP)

NIH R01 grants (UWM, Columbia)

UWM-RF grant

Numerous publications

Partnering discussions

Research Proof Of Concept

IND Clinical Proof Of Concept

Lead lock

GLP/IND-enabling pkg.

Phase I

Formulation

API/DP manufacturing

Clinical plan

CM&C

Lead optimization

Phase IIa

Additional patents

Translational grants

Expanded immunoRx indications

26

Page 27: A new oral drug for asthma treatment · 2018-02-20 · Kentaro Mizuta, Dingbang Xu, Yaping Pan, George Comas, Joshua R. Sonett, Yi Zhang, Reynold A. Panettieri, Jr., Jay Yang, and

Contact

Sara Gusik(212) [email protected]

A new oral drug for

asthma treatment

27

Jessica Silvaggi, PhD, CLPSr. Licensing Manager(414) [email protected]


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