This document summarizes the development of a tablet formulation for the drug Nelotanserin (APD125) that provides similar pharmacokinetic exposure to current soft gel capsules but with superior chemical stability. Key challenges addressed included APD125's low solubility, polymorphism, and stability issues. The optimal tablet formulation utilized the metastable polymorph, micronized drug, PVP for solubility enhancement, and methyl cellulose to inhibit polymorphic conversion. Monkey pharmacokinetic studies showed similar exposure to soft gels, and accelerated stability testing demonstrated improved chemical stability and maintained polymorphic form over 3 months.

1. Confidential
Nelotanserin (APD125) Tablet Formulation
Screening, Selection & Optimization
07 December, 2015

2. Nelotanserin (APD125)
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• A potent & selective inverse agonist for
5-HT2A receptors previously investigated as a
Treatment for insomnia and related sleep disorders.
• BCS class 2 drug exhibiting good permeability, but extremely low
aqueous solubility (< 0.007 mg/mL)
• Exhibits polymorphism (2 anhydrous forms, denoted as Forms I & II,
plus an acetonitrile solvate)
• Early clinical trials conducted using soft-gel capsules, containing
APD125 solubilized in a lipid matrix
– Formulation yielded excellent bioavailability, but exhibited greater degradation
than desired to form 2,4-difluoroaniline (DFA) after one month at 25°C/60%RH
and 40°C/75%RH, respectively.

3. Objective
• Develop a tablet demonstrating superior chemical stability and
similar pharmacokinetic exposure to the current soft gel capsule.
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4. Challenges Unique to APD125
• APD125 is a BCS class 2 drug exhibiting good permeability, but
extremely low aqueous solubility (< 0.007 mg/mL)
• APD125 exhibits polymorphism (2 anhydrous forms, denoted as
Forms I & II, plus an acetonitrile solvate)
• Acceptable monkey PK results were not achievable using the
thermodynamically stable Form II, necessitating the development
of the metastable Form I
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5. • Use of the metastable Form I, exhibiting 3 to 4 times the solubility
of the thermodynamically stable Form II
• Micronization of API to increase surface area, reduce particle size,
and thereby, maximize dissolution rate
• Addition of a surfactant, SLS, to improve API wettability
• Aid dispersion of APD125 particles in water by coating API on PVP
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Steps Taken to Enhance Solubility

6. Monkey PK Results— Polymorphic Form & Micronization
• Data below shows, in general, Form I performs better than Form II.
In addition, methyl cellulose (MC) & povidone (PVP) addition, as
well as API micronization enhance exposure in monkeys.
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7. Impact of SLS upon Aqueous Solubility of APD125
• Addition of SLS significantly improves the solubility of APD125 in
water
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Vehicle Solubility (mg/mL)
H2O <0.01
0.25% SLS <0.01
0.50% SLS 0.04
0.75% SLS 0.06
1.0% SLS 0.12

8. Optimal API/PVP Ratio— How much PVP is needed?
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• Assumptions
– Used Dv50 from LALLS data as representative particle diameters
for PVP and micronized Form I
– Assumed spherical particle shape for both PVP and Form I
– Modeled Form I packing on a particle of PVP in both square and
hexagonal arrangements
– Assumed the true density of Form I to be the same as the
acetonitrile solvate
• Results
– Square packing model – 1:3.8
– Hexagonal packing model – 1:3.3
Estimation of Minimum Form I:PVP Ratio required for 100% Loading of Form I
on Surface of PVP
Theoretical Minimum Ratio = 1:4

9. Optimal API/PVP Ratio— SEM Confirmation
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Micronized Form I PVP
1:1 API:PVP 1:3 API:PVP 1:5 API:PVP 1:8 API:PVP
All images @ 500x, except
for micronized Form I
(3000x)
Visually Determined
Minimum Ratio = 1:5
3D Images

10. Monkey PK Results—Optimal API/PVP Ratio in Tablets
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Formulation Dose (mg) N
Cmax
(µg/mL)
AUCinf (hr•µg/mL)
Tmax
(hr)
Mean SD Mean SD Mean SD
APD125 FI:PVP 1:1 dry 10 6 0.077 0.057 0.548 0.321 4.7 2.1
APD125 FI:PVP 1:4 dry 10 6 0.085 0.071 0.575 0.379 4.7 4.3
APD125 FI:PVP 1:6 dry 10 6 0.125 0.174 0.572 0.556 4.3 2.3
APD125 FI:PVP 1:8 dry 10 3 0.335 0.138 1.262 0.660 2.7 0.8
APD125 FI:PVP 1:8 wet 10 6 0.227 0.153 1.507 1.218 2.2 1.0
SGC 10 6 0.942 0.303 3.192 1.291 2.2 1.0
1:8 API/PVP appears to provide best exposure in monkeys

11. Tablet vs SGC—How do they compare?
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Test Article Dose (mg) Cmax (ug/mL)
AUCinf
(hr.ug/mL)
Softgel #1 40 1.007 5.804
Softgel #2 40 0.971 6.283
Softgel #3 40 1.270 6.054
Softgel 10 0.942 3.192
Wet Granulation Tablet
(1:8)
30 0.504 4.988
Wet Granulation Tablet
(1:8)
10 0.227 1.507
Direct Compression
Tablet (1:8)
10 0.335 1.262
Although tablet shows ca. ½ exposure of SGCs at a 10 mg dose, it
appears to become more similar to the SGC at a 30 mg dose.

12. Steps Taken to Control Solid-State Form
• Good News—Conversion of the metastable Form I to the
thermodynamically stable Form II is solvent mediated, meaning if
Form I is kept away from direct solvent contact, it appears to
remain Form I indefinitely
• More Good News—Methyl cellulose was found to inhibit the
conversion of Form I to II in the presence of water
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13. Effect of Compression/Milling Upon Form I
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Good News—Mortar & pestle milling of
micronized APD125 Form I for 1, 5 & 10
minutes didn’t result in a conversion to
Form II
More Good News—Compression of
micronized APD125 Form I at 2, 5 & 10K
PSI didn’t result in a conversion to Form II

14. Effect of Methyl Cellulose Concentration
• Sample preparation:
– Form I/PVP (1:8) direct compression tablets were prepared at 0, 2, 5 & 8% w/w
MC loading. In addition, Form I/coPVP (1:8), direct compression tablets were
prepared at a 5% w/w MC loading.
– PXRD was obtained for 1 tablet of each blend to confirm initial presence of
Form I.
– Remaining tablets were ground into a composite, weighed, and spiked with an
equivalent mass of water to obtain an approximate 50:50 tablet blend/water
paste. Samples were stored in 40°C chamber.
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15. Effect of Methyl Cellulose Concentration
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All tablets initially contain Form I

16. Effect of Methyl Cellulose Concentration
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Tablet without methyl cellulose shows conversion to Form II in less than 24 hrs

17. Effect of Methyl Cellulose Concentration
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Tablet with 2% w/w methyl cellulose shows conversion to Form II @ 1 wk

18. Effect of Methyl Cellulose Concentration
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Most samples showing partial or complete conversion to Form II @ 1 month

19. Effect of Methyl Cellulose Concentration
• Overall, 5% w/w MC or higher yielded best solid-state form stabilization.
However, it also resulted in 2 to 3 times the DFA formation rate of 2% w/w MC or
lower. Therefore, 2% w/w MC was chosen as the best compromise between best
Form I stabilization and minimization of DFA formation.
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Formulation Primary Form
(1 day)
Primary Form
( 1 week)
Primary Form
(1 month)
APD 125 FI / PVP
(1:8) No methyl
cellulose
Form II n/a n/a
APD 125 FI / PVP
(1:8) 2% methyl
cellulose
Form I Form II n/a
APD 125 FI / PVP
(1:8) 5% methyl
cellulose
Form I Form I Form I
APD 125 FI / CoPVP
(1:8) 5% methyl
cellulose
Form I Form I Form II
APD 125 FI / PVP
(1:8) 8% methyl
cellulose
Form I Form I Form I/II Mixture

20. Prototype Tablet Accelerated Stability Testing
• “Wet granulation” tablet 3 month stability PXRD results @
40°C/75%RH show the tablets to still contain Form I
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Form1
Form1
Form1

21. Prototype Tablet Accelerated Stability Testing
• “Wet granulation” tablet 3 month stability DFA results show a
significant improvement over the current SGC, reducing DFA levels
by an overall factor of 8:1
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22. TAM Excipient Compatibility Screening
• Most stable formulations by TAM, defined as exhibiting zero heat
transfer as a function of time, were found to be PVP based. In
addition, the use of MC was not found to adversely affect chemical
stability.
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23. Steps Taken to Improve Chemical Stability, while Maintaining
Exposure
• Utilize tablet rather than liquid formulation, since APIs can be
expected to exhibit superior chemical stability in the solid-state,
relative to dissolved state
• Dry granulate to minimize potential of both chemical degradation
and polymorphic form change
• Micronize the API to maximize surface area
• Utilize PVP as a dispersing agent and solubility enhancer
• Add a surfactant to improve wettability
• Utilize metastable APD125 Form I to improve API dissolution
• Add methyl cellulose to inhibit Form I to II conversion upon contact
with water
• Protect final tablets from moisture uptake via application of a
OPADRY II PVA BLUE coating
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24. Conclusions
• Through the collaborative efforts of Arena scientists in multiple
groups/departments, APD125 prototype tablets have been
successfully developed, with preliminary data indicating good PK
exposure in monkeys, superior chemical stability and effective
solid-state form control.
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40 mg tablets

25. Acknowledgements
• Justin Bach
• William Betts
• Deam Given
• Natalie Jamgochian
• Nada Mitic
• Mike Morgan
• Maiko Nagura
• Yun Shan
• Jesse Shao
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26. Divider Page
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27. Abstract
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Tablets provide a number of key advantages over liquid formulations—better
chemical stability, lower manufacturing cost & typically higher manufacturing
volume & speed. In the case of APD125, a tablet formulation offers the potential
of a significant improvement in chemical stability over the soft gel
capsule. However, a number of important challenges exist, with respect to
bioavailability and polymorphic form stabilization. In the case of bioavailability,
proper polymorphic form selection and particle size control was found to be
essential, along with the novel use of PVP and methyl cellulose to enhance
solubility and solid-state form stabilization, respectively. This presentation details
the research efforts supporting the successful development of the APD125
prototype tablets.
Nelotanserin (APD125) Tablet Formulation Screening, Selection &
Optimization
Alani Selvey , Justin Bach, Deam Given, Jesse Shao, Maiko Nagura, Mike Morgan,
Nada Mitic, Natalie Jamgochian, William Betts, Yun Shan