PL100, a Novel Protease Inhibitor with a High Genetic Barrier

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• PL-100, a Novel Protease Inhibitor with a High
  Genetic Barrier
• Clinical data indicate that PPL-100 could be an
  un-boosted QD drug for both PI-naïve and
  experienced patients
• Serge Dandache, Luc Daigneault, Brent Stranix,
  Michael Ge, Mark A. Wainberg, Chandra Panchal,
  and Jinzi J. Wu

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Introduction to PL-100 and Its Prodrug, PPL-100

• PL-100 is a potent, specific and non-cytotoxic
  HIV-1 protease inhibitor
• PL-100 has a very favorable cross-resistance
  profile
• Potential for good activity against Multi-PI
  resistant viruses in treatment experienced
  patients
• PPL-100, prodrug of PL-100, is an oral HIV drug
  in clinical trials
• PPL-100 is very safe in animal models
• No observed adverse effect levels (NOAEL) after
  repeated dosing determined in both rats and dogs
  equivalent to 10g per day in man
• Favorable cardiovascular safety pharmacology and
  genotoxicity results
• PPL-100 is inexpensive and easy to manufacture
• 5 synthesis steps
• PPL-100 has a favorable formulation
• Neat API filled capsules because of its highly
  water solubility and bioavailability
• Easy to be co-formulated with other anti-virals
• PPL-100 is IP protected through 2023
• Additional patents filed providing protection
  through 2025

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PPL-100 vs. PL-100

• PPL-100 a phosphorylated pro-drug of PL-100

PPL-100
PL-100
Phosphate moiety metabolically cleaved

• Ki 36 pM against HIV-1 protease
• EC50 5.3 1.75 nM against wild-type virus in
  PhenoSense assays

• PPL-100 (gt145 mg/ml) is 1800-fold more
  water-soluble than PL-100
• PPL-100 is 2 to 3-fold more orally bioavailable
  than PL-100
• Not active against HIV-1 protease

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PL-100 Selects a Novel Mutation Pattern
Drug concentration increments during in vitro
resistance selection and genotyping of the
HIV/IIIB variants isolated from CBMCs in the
presence of PL-100 or APV.

• A novel mutation pattern (K45R, M46I, T80I and
  P81S) selected after 25 weeks and maintained
  until 48 weeks.
• T80I and P81S novel mutations (active-site,
  substrate cleft residues)
• K45R and M46I known mutations (non-active site,
  flap tip residues)

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PL-100 Has a High Genetic Barrier
No cross-resistance to marketed PIs

• Site-directed mutagenesis

• Single and double mutations selected by PL-100 do
  not confer resistance to PL-100 in vitro
• A mild resistance to PL-100 is conferred only in
  the presence of all four mutations
• T80I induces hypersensitivity to SQV and NFV
  P81S is a lethal mutation
• Mutations selected by PL-100 do not confer
  cross-resistance to marketed PIs

Antiviral activity of PL-100 against HIV/NL-4.3
site-directed mutants (SDMs) was determined by
MTT assay in MT4, 6 days post-infection. Determ
ined by standard replication kinetics in MT4 for
7 days. ND not determined.
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First-in-Man, Single-Dose Escalation Studies

• Study Title
• A Phase I, Single-Dose Escalation Study
  Evaluating the Safety and Pharmacokinetics of
  PPL-100 in Healthy Male Volunteers
• Objectives
• To evaluate the safety and tolerability of
  PPL-100
• To evaluate the pharmacokinetics after a single
  oral dose of PPL-100 administered under fasting
  or fed conditions
• To determine the maximum tolerated dose (MTD) of
  PPL-100
• Design
• 8 subjects per cohort to receive once daily study
  drug or placebo (randomized and double-blinded)

Summary of safety assessment PPL-100 is safe
and well tolerated up to 2400mg with only mild
(grade 1 and 2s) adverse events reported for all
cohorts.
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PPL-100 Has a Favorable PK Profile in Man
Cmax
Drug exposure (AUC)
The drug exposure (AUC) increases linearly with
doses but less than dose-proportional.
Cmax increases linearly until 1200 mg and
increases less thereafter.
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Food Has a Minimum Impact on PK of PPL-100

• Pharmacokinetics of PPL-100 without and with a
  light meal

The light meal is two slices of white bread, one
pat of butter, one portion of mild cheddar cheese
(21g), two pats of strawberry jam and one carton
(200 ml) of 3.25 M.F. milk.
A light meal reduces Cmax, and extends Tmax from
1 to 2 hours without the significant effect on
AUC, suggesting that PPL-100 has no food
restrictions.
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PPL-100 Has a Long Elimination Half-Life
PPL-100
Marketed PIs
The long elimination half-life supports PPL-100
as a QD PI.
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• Pharmacokinetic Modeling Objectives
• Predict steady-state pharmacokinetic profile
  based on single-dose studies
• Help select doses for repeated-dose studies

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Population Pharmacokinetic Modeling

• The population pharmacokinetic model was
  developed by Dr. George Drusano, MD and his
  colleagues at Ordway Research Institute, Albany,
  NY. Such modeling strategies are becoming the
  standard for dose selection.
• The single dose data from the clinical trials
  were best fit by a 3 compartment model with a
  zero-order rate input, first-order linear and
  parallel Michaelis-Menten elimination.
• Using Monte-Carlo simulation, 5000 subjects were
  simulated to receive different dosing regimens of
  PPL-100 up to steady state under fasting
  conditions and trough concentrations and PK-PD
  target attainment were evaluated.

A similar model, developed and published by Dr.
George Drusano, well predicted viral load
reduction against different HIV isolates for
Atazanavir (BMS-232632) at steady state. G.L.
Drusano et al. The Journal of Infectious Diseases
2001 183 1126-9
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Steady-State PK Predicted by the Model
Population PK modeling
As part of the validation, the population PK
model was able to well predict plasma PL-100
concentrations at 18 and 24 hours. These
predicted values are consistent with the observed
values in the clinical trials.
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The Model Predicts PPL-100 Is an Un-boosted, QD PI
One of modeled regimens (600 mg, QD, un-boosted)
for plasma target ( Cmin24) attainment during
dosing interval (24hr) at steady state for 5000
simulated subjects
600 mg QD, un-boosted
Subjects with target attainment
EC50 11 nM EC50 5.3 nM
EC50 (nM) in PhenoSense assay

EC50 cutoff is derived from anti-viral
activities of PL-100 against wild-type virus
(NL-4.3) and 63 multi-PI resistant strains using
PhenoSense assay (Monogram Biosciences) Plasma
target (Cmin24) is defined as 4XEC50, then
adjusted for protein-binding.
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PPL-100 against Resistant Strains Failing Boosted
PIs
The boosted PI regimen against 22 multi-PI
resistant strains
Published references for PI selection
Monogram Biosciences, XV HIV drug resistance
workshop, Spain, 2006 Pending further
investigation
Based on the prediction from PK modeling
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The Model Indicates PPL-100 Has an Excellent
Forgiveness
The modeled regimen (600 mg, QD, un-boosted) for
plasma target (Cmin48) attainment during dosing
interval (48hr, missing a dose) at steady state
for 5000 simulated subjects
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PPL-100 is not only a next generation PI but also
a PK enhancer of other anti-virals
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PPL-100 as a PK Enhancer In Vitro Data
Human CYP450 inhibition
In vitro metabolism of ATV by human liver
microsomes in absence or presence of PL-100 (ATV
1.0 µM, PL-100 2.0 µM)
PPL-100 is also a PK enhancer for other
anti-virals.
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PPL-100 as a PK Enhancer In Vivo Data
Pharmacokinetics of ATV when co-administered with
either PPL-100 or RTV
PPL-100 appears to be long lasting but less
potent than RTV
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Conclusions

• PPL-100 has a high genetic barrier
• Key characteristic of the first-line HIV PI
• The first-in-man, single dose escalation studies
  indicate PPL-100 has a favorable safety and PK
  profile with a long plasma half life ( 30 hours)
• Key characteristic of the un-boosted, once daily
  PI.
• The population PK modeling and simulation predict
  that PPL-100 has a favorable steady-state PK
  profile
• Suggesting that PPL-100 is an un-boosted, once
  daily PI for both PI-naïve and experienced
  patients infected with highly resistant strains.
• Indicating that PPL-100 is an ideal PI to address
  non-adherence issues because of its excellent
  forgiveness.
• PPL-100 is a PK enhancer
• Safe and long lasting
• An excellent candidate for co-formulation.

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Acknowledgments
Ambrilia team Guy Milot, Ph.D Isabelle
Pelletier Joseph Musto Helen Paparis Valerie
Perron Guy Sevigny, Ph.D Jocelyn Yelle,
Ph.D Heimo Scheer Marco Petrella, Ph.D
Ordway Research Institute George L. Drusano , M.D
Ólanrewaju Okusanya, Pharm.D. Sujata M.
Bhavnani, Pharm.D., M.S. Paul G. Ambrose,
Pharm.D., FIDSA
Dr. Mark Wainbergs lab Maureen Oliveira
SFBC Anapharm team
Nucro-Technics team
Monogram Biosciences Team
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Thank you
www.ambrilia.com