Project 4

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Project 4

• Human studies of neurokinin-1 receptor
  antagonists in HIV-1

PI Pablo Tebas, M.D. Co-PI Jeffrey Barrett,
Ph.D. Dwight Evans, M.D. David Dinges,
Ph.D. Jordan Orange, M.D., Ph.D. Ruben Gur,
Ph.D.
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Aim 1 Examine the safety and tolerability of the
SP antagonist aprepitant in HIV-infected patients
over 4-weeks of therapy. Assess the
exposure-response relationship to evaluate
aprepitants ability to suppress HIV-1 RNA.
Project 4
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Rationale for the selection of Aprepitant
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Substance P antagonists haveantiviral activity
in vitro
Effect of CP-96,345 on HIV infection of MDM
Lai, Jian-Ping et al. (2001) Proc. Natl. Acad.
Sci. USA 98, 3970-3975
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Aprepitant Blocks Brain NK1 Receptorsin Humans
Mean ( SD) Plasma Trough Concentrations of the
Aprepitant 3-Day Regimen
Binding of PET tracer to NK1 receptors prior to
aprepitant dosing
Brain NK1 Receptor Occupancy ()
Blockade of NK1 receptorsafter aprepitant dosing
Aprepitant Plasma Trough Concentration (ng/mL)
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Aprepitant has well-characterized PK that
permits once daily dosing in CINV
Aprepitant Plasma Concentration (ng/mL)
Time Postdose (hr)
N12
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Aprepitant works and it has been triedin large
populations.
Complete Response Acute and Delayed Phases
Protocol 052
Protocol 054
plt0.001
plt0.001
plt0.001
plt0.001
89
83
78
75
68
68
56
47
N
259
260
260
260
260
263
261
263
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Clinical Development Program
Number of Patients Receiving Aprepitant
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5. Aprepitant is safe, approved available.

• Clinical Adverse Experience Summary

• Aprepitant is approved by the FDA for emesis
• Readily available

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How do we want to test it?Phase 1b randomized
blinded study
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Main inclusion criteria

• HIV-1 infection
• CD4 cell count 350/mm3
• Plasma HIV-1 RNA of 2000 copies/mL
• Stable hepatic, renal, and hematological indices
• Not pregnant
• No current serious psychiatric disorder (by SCID)

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Endpoints

• Primary endpoints
• Safety and PK
• HIV-1 RNA compared with baseline.
• Secondary endpoints
• CD4 and CD8 T-cell counts, T-cell activation,
  and proliferation
• If we demonstrate antiviral activity check for
  amino acid substitutions
• CCR5 expression in peripheral PBMCs
• Fasting plasma glucose, insulin, HDL, FFA, and TG
  at 28 days.
• Fatigue and poor sleep, anxiety and depressed
  mood neuropsychiatric measures

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Schedule of events
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Sample size justification

• With a total of 13 subjects in a group, the width
  of a 95 confidence interval around the
• D log 10 viral load, with 90 coverage, will be
  1.5 s.d.s of the D log viral load distribution.
• (approximately 0.5 logs)
• The Table shows the probability of observing a
  toxicity at least once, based on true underlying
  levels of the toxicities
• Study large enough for viral dynamics analysis

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Aim 2 Determine aprepitant plasma concentrations
over the 4 weeks of clinical evaluation in order
to develop a population-based pharmacokinetic-phar
macodynamic (PK/PD) model for aprepitant in
HIV-infected patients.
Project 4
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Why PK is so important with this drug?The
problem of PK interactions

• Aprepitant is extensively metabolized primarily
  by CYP3A4 isozyme
• Inhibits CYP3A4 with aprepitant regimen (as early
  as 1 hr after Day 1 dosing)
• Induces CYP2C9 with aprepitant regimen
• Induces its own metabolism upon dosing for 2
  weeks (autoinduction)

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Effect of Aprepitant on CYP3A4 Drugs
Gastrointestinal Drugs Advisory Committee
Meeting March 6, 2003
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Effect of Other Drugs on Aprepitant
Gastrointestinal Drugs Advisory Committee
Meeting March 6, 2003
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Aprepitant Is a Moderate CYP3A4 Inhibitor
Inhibition of CYP3A4 Ranked According toFold
Increase in Oral Midazolam AUC
Ketoconazole
Itraconazole
Clarithromycin
Erythromycin
Diltiazem
Verapamil
Grapefruit juice
Strong
Moderate
Weak
Day 1 5
Aprepitant (125 mg Day 1 80 mg/d Days 2 to 5)
Aprepitant regimen for CINV produces CYP3A4
inhibition comparable to grapefruit juice and
widely used drugs (e.g., diltiazem, verapamil).
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Potential for interactions with other
antiretrovirals that are metabolized or inhibited
by CYP3A4

• Moderate CYPA4 inhibitor
• May increase the systemic exposure of
  antiretroviral drugs metabolized by CYP3A4 which
  can have a double effect
• Positive increase antiretroviral exposure
• Negative increased risk for toxicity
• Potential impact of antiretrovirals on aprepitant
  exposure (especially ritonavir)

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Aprepitant Pharmacology Summary

• Novel potential mechanism of action
• Blockade of (substance P) NK1 receptors
• Effective against both acute and delayed emesis
  in humans through the same mechanism/s that we
  are proposing it will work as an antiviral
• Favorable pharmacokinetics/pharmacodynamics
• Once daily oral dosing
• No dose adjustment in special populations
• Well characterized drug interaction potential
• Further characterization needed to evaluate
  interactions with other antiretrovirals (if
  antiviral activity is confirmed)

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How are we going to do this?

• Population PK Model
• (NLMEM)
• Structural Model
• Covariate Model
• Error Model
• Validation (data splitting or bootstrapping)

PD Exposure-response Psychologic
Disturbances (Categorical Analysis)
Clinical Trial Simulation Model for
Proof-of-Concept Phase IIA Trial
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How are we going to do this?

• Transfer aprepitant bioanalytical method to Core
  C.
• Summarize basic PK of aprepitant in HIV-infected
  patients via standard noncompartmental methods.
• Develop and validate population-based PK model to
  explain sources of variation in aprepitant
  exposure in HIV-infected patients.
• Construct exposure-response relationships via
  PK/PD modeling for both safety and activity
  (psychologic disturbances, viral dynamics and NK
  response) in HIV-infected patients.
• Develop clinical trial simulation model from
  which a Phase IIA proof-of-concept trial may be

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Exploratory Aim 3 To evaluate the potential
immunoregulatory role of NK-1R inhibition in HIV
infected individuals
Project 4

• CCR5 expression
• Natural Killer cell function

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CCR5 and substance P

• Substance P antagonists down- regulate CCR5
  expression
• CCR5 D32 heterozygosity is associated with slower
  disease progression

Lai, Jian-Ping et al. (2001) Proc. Natl. Acad.
Sci. USA 98, 3970-3975
de Roda Husman, A.-M. et. al. Ann Intern Med
1997127882-890
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How are we going to do this?
IN VIVO
IN VITRO

• Evaluate the effect of SP upon cytotoxicity
  (extend to fresh cells). Determine effect of SP
  on NK binding to target cells.
• Determine effect of SP upon the cytotoxic
  activity and Ca flux induced by ligation of
  specific activating receptors.
• Determine the effect of SP upon the expression of
  NK cell activating receptors including the NCRs.
• Determine the effect of SP upon NK cell cytokine
  production.

• Samples obtained from HIV-infected patients on 3
  separate occasions prior to the initiation of
  aprepitant.
• Absolute NK cell count.
• NK cell percentage of total lymphocytes.
• K562 lytic units per NK cell.
• Expression of NCRs on NK cells.

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Natural Killer cells and SP in HIV infection

• Natural killer cell number and function reduced
  in HIV (Ullum H et al. 1995 J. Exp. Med.
  182789-799)
• Natural killer number and function further
  diminished in HIV depressed subjects (Evans,
  Ten Have, Douglas et al. 2002 Am. J. Psychiatry
  1591752-59)
• 3. Reduced natural killer activity is correlated
  with
• elevated SP levels in HIV-infected men (Douglas,
  Ho, Evans, Cnaan 2001. AIDS 152043-45)

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Function of Aprepitant in natural killer cell in
vitro studies
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Function of Aprepitant in natural killer cell ex
vivo studies
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Exploratory Aim 4 Evaluation of the potential
link between immune cell function and indices of
neuropsychiatric disturbance Depression,
anxiety, fatigue, sleep quality, and
neurocognitive function (Phase 1B study in Aim 1)
Project 4
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Aprepitant as an antidepressant

• Major depression
• N117 (66A, 64P)
• 6 weeks
• 40 mg q day
• Aprepitant had a significant antidepressant
  effect

Kramer MS, Winokur A, Kelsey J, et al.
Demonstration of the efficacy and safety of a
novel Substance P (NK1) receptor antagonist in
major depression. Neuropsychopharmacology (2004)
29, 385-392
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Why and how to evaluate psychiatric symptoms in
Project 4?

• Aprepitant has been studied in depressed and
  anxious patients.
• This is the first time aprepitant will be studied
  in HIV patients.
• Pilot data will be needed on aprepitant effects
  on symptoms.
• We will evaluate the effects of aprepitant in all
  participants (before and after dosing) on
• Neuropsychological functions using tests
  sensitive to HIV infection
• Symptoms of depression
• Complaints of poor sleep and daytime fatigue

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Questions/future directions
Project 4

• Should we include a study that evaluates
  interactions (both ways) of aprepitant with
  approved ARVs in patients with fully suppressed
  virus?
• or
• Wait until we demonstrate antiviral activity?

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Questions/future directions
Project 4

• Obtain pilot data for estimating effect sizes
  now?
• or
• Should we leave neuropsychiatric evaluations for
  Phase III trials?