New Drugs

1
New Drugs New Hope

• Ronald D. Wilcox MD FAAP
• Project Director/PI, Delta AETC
• Asst. Professor Med/Peds, LSUHSC

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Speaker Disclosure

• Speakers Bureau Pfizer
• Research Support Tibotec, GlaxoSmithKline,
  Bristol-Myers-Squibb
• No other financial relationship

This slide set has been peer-reviewed to ensure
that there areno conflicts of interest
represented in the presentation.
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New ARV

• Fusion / Entry Inhibition
• Maraviroc
• Non-Nucleoside Reverse Transcriptase Inhibition
• Etravirine
• Integrase Inhibition
• Raltegravir
• Protease Inhibition
• Darunavir

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Chemical Structures
Darunavir
Etravirine
Maraviroc
Raltegravir
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Life Cycle
Borrowed from www.gladstone.ucsf.edu
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Maraviroc (Selzentry)

• August 6, 2007 FDA accelerated approval
• First CCR5 co-receptor inhibitor
• Approved for treatment-experienced patients over
  16 years of age with CCR5-tropic virus
• Has NOT shown efficacy in those with mixed or
  dual virus tropism

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Chemokines
Borrowed from article at hivandhepatitis.com
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Maraviroc - Pharmacokinetics

• Peak plasma concentration 0.5-4 hours
• Metabolized by CYP450 system
• Renal clearance of 25
• Terminal half-life at steady state 14-18 hours
• 76 protein bound
• Pregnancy category B

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Maraviroc

• No food restrictions
• Available forms 150 mg, 300 mg film-coated
  tablets
• Dosage 300 mg po BID usual dose
• 300 mg BID all NRTIs, nevirapine, tipranavir,
  enfuvirtide
• 150 mg BID CYP3A inhibitors (with or without with
  a strong CYP3A inducer) protease inhibitors
  (other than tipranavir), delavirdine
• 600 mg BID CYP3A inducer (if used without a
  strong CYP3A inhibitor see above) efavirenz,
  etravirine

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Motivate 1 2

• Trial design474 patients were randomized 122
  to placebo or maraviroc 150 mg once daily (qd) or
  maraviroc (mvc) twice daily (bid), all 3 groups
  along with OBT, optimized therapy background. 

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MOTIVATE 1 2

• Patient characteristics

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MOTIVATE 1 2Viral Load Results
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MOTIVATE 1 2CD4 Results
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MOTIVATE 1 2

• Adverse effects seen at week 24
• lt 5 stopped medication due to ADEs
• No increase in mortality, malignancy,
  hepatotoxicity
• Increased incidence of Candida, herpes, and
  influenza infections
• Most common cough, fever, URI, rash,
  musculoskeletal symptoms, abdominal pain,
  dizziness

• Serious adverse events in lt 2 angina, heart
  failure, MI, hepatic cirrhosis or failure,
  jaundice, viral meningitis, pneumonia, myositis,
  osteonecrosis, rhabdomyolysis
• Grade 3-4 lab abnormalities in at least 2
  increase in bilirubin, amylase, lipase, AST, ALT
• At week 48 diarrhea, nausea, fatigue, headache
  same as in OBT groups.

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Hepatotoxicity - Maraviroc

• One case in healthy volunteer of possible
  drug-induced hepatotoxicity with allergy
• Evidence of allergic reaction include pruritic
  rash, eosinophilia, increased IgE levels
• Immediate evaluation and possible discontinuation
  of agent suggested if signs or symptoms of
  systemic rash reactions of hepatotoxicity develop

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Life Cycle
Borrowed from www.gladstone.ucsf.edu
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Etravirine (Intelence)

• FDA approval on 1-18-2008
• First of the Second Generation NNRTIs
• Approved for treatment-experienced patients

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Etravirine - Pharmacokinetics

• Bioavailability in current formulation improved
  compared to early formulations with decreased
  pill burden
• Metabolism metabolized by CYP liver enzymes and
  primarily excreted in feces
• Pregnancy Category B but not studied in
  pregnancy
• Inducer of CYP3A4

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Etravirine - Efficacy

• TMC125-C207
• 10 HIV men with 10-500 fold resistance to
  Efavirenz
• 7 day treatment with TMC125
• Median decrease in viral load slightly less than
  10-fold with 44 over 10-fold
• No relationship between response and genotype or
  phenotype results

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Etravirine - Efficacy

• TMC125-C223 Trial
• 199 HIV patients with NNRTI and PI-resistance
  assigned to OBT either 400 mg or 800 mg TMC125
  BID or standard-of-care regimen
• Week 24 VL decreased gt90 in the two treatment
  arms compared to 50 in the SOC arm
• Week 48 mean VL drop 0.88 for 400 mg, 1.01 for
  800 mg, 0.14 for SOC arm

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DUET 1 2

• Study Design
• N 1203 total

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DUET 1 2
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DUET 1 2
VL lt 50 copies/ml
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DUET 1 2
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Etravirine Adverse Effects

• HCV and HBV co-infected patients had a worsening
  of hepatitis-related symptoms
• Nausea and rash (15) most commonly reported
  ADEs rash may require discontinuation
  reported cases of Stevens-Johnson Syndrome
• Others abdominal pain, fatigue, peripheral
  neuropathy, headache, hypertension

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Etravirine - Dosing

• Standard dose 2 100 mg po BID
• Take after a meal
• Intelence should not be combined with the
  following Norvir (ritonavir)-boosted Aptivus
  (tipranavir), Norvir-boosted Lexiva
  (fosamprenavir) or Norvir-boosted Reyataz
  (atazanavir) any protease inhibitors given
  without a boosting dose of Norvir or any of the
  other approved NNRTIs.

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Etravirine Resistance

• Mutations
• K103N no effect
• Worst responders had V179F, Y181V, Y106I, and
  V179O
• Also seen with EFV and NVP, always found
  together

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Life Cycle
Borrowed from www.gladstone.ucsf.edu
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Raltegravir (Isentress)

• FDA approval on 10-12-2007
• First of the Integrase Inhibitors
• Approved for treatment-experienced patients

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Raltegravir - Pharmacokinetics

• Inhibits catalytic activity of HIV-1 integrase
• Cmax in fasted state at 3 hours delayed after a
  high fat meal
• 83 protein bound
• Metabolism 51 excreted in feces, 32 in urine
• Pregnancy Category C

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Raltegravir - Efficacy

• 198 treatment-naïve patients
• (Raltegravir at varying doses ranging from
  100-600 mg po BID or Efavirenz 600 mg po qHS)
  tenofovir 3TC
• Changes in CD4 counts similar

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Raltegravir - Efficacy

• 179 treatment-experienced patients with VL gt 5000
  and resistance to at least one drug in each
  anti-HIV class
• Raltegravir 200, 400, or 600 BID or placebo with
  optimized background tx
• Week 24 mean viral load decreases from baseline
  of 99 for raltegravir groups versus 50 for
  placebo group

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BENCHMRK 2

• Methods Pts failing ART with triple-class
  resistant HIV were randomized 21 to oral BID RAL
  400 mg or placebo (PBO). All pts received OBT.
• Groups
• Baseline characteristics were similar in the RAL
  and PBO groups.
• At baseline, median CD4 counts were 102 and 132
  cells/mm3, and geometric mean viral loads were
  4.7 and 4.7 log10 copies/mL in the RAL and PBO
  groups, respectively.
• Genotyping demonstrated that OBT contained lt1
  active drug (sensitivity score 0) in 20 and
  27 of pts in the RAL and PBO groups,
  respectively.  

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BENCHMRK 2
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BENCHMRK 1 2
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Raltegravir - Dosing

• Recommended dose 400 mg tablet po BID
• No significant drug-drug interaction with other
  ARVs
• Use with caution when administered with strong
  inducers of UGT, such as rifampin, which may lead
  to low levels

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Raltegravir Adverse Drug Effects

• Most commonly reported adverse effects
• Diarrhea, nausea, headache, dizziness, itching
• Others constipation, flatulence, sweating
• All above similar to incidence in the placebo
  groups
• Grade 2 to 4 elevations in creatine kinase seen

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Life Cycle
Borrowed from www.gladstone.ucsf.edu
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Darunavir (Prezista)

• Approved by FDA 6-23-2006
• Approved for use by treatment-experienced
  patients may also be very effective in naïve
  patients
• Second generation PI

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Darunavir - Pharmacokinetics

• Inhibits cleavage of HIV-encoded Gag-Pol
  polyproteins
• Cmax approximately 30 higher when taken after a
  meal compared to fasting
• 95 protein bound
• Metabolism extensively by CYP enzymes,
  predominantly CYP3A
• Pregnancy Category B

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Darunavir - Efficacy

• TMC114-C202 TMC114-C213 Trials
• N319 318 all with baseline VL gt 1000 and
  previous treatment with 3 classes of meds and had
  at least one primary PI mutation
• Darunavir/r or investigator-selected PI with
  optimized background
• Results at 24 weeks
• 63 versus 19 had VL lt400 copies/ml
• CD4 increase 92 versus 17 cells/mm3.

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POWER 1 and 2

• Phase IIb trials in treatment-experienced
  patients
• Week 48
• 61 on darunavir/r had at least a 90 reduction
  in viral load compared to 15 in control PI arm
• Viral load lt 50 copies/ml 45 versus 10

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TITAN

• Tx-experienced patients naïve to lopinavir and
  darunavir N595
• Virologic failure
• 10.4 on darunavir compared 22 on lopinavir.
• Among people with virologic failure
• proportionately fewer in the darunavir arm with
  new mutations conferring PI resistance (21
  versus 36)
• fewer with darunavir failure had new
  nucleoside-related mutations (14 versus 27).

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ARTEMIS

• 689 tx-naïve patients
• Assigned to TDF/FTC plus either
• once daily darunavir/r 800/100 mg
• or lopinavir/r given once or twice daily

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Darunavir Dosing

• Usual dosing 600 mg 100 mg ritonavir po BID
• New formulation approved by FDA of 600 mg
• Darunavir may be given with atazanavir but not
  other protease inhibitors. Maraviroc must be
  decreased when given with darunavir.
• Should not be used with carbamazepine,
  phenobarbital, phenytoin, St. Johns wort, and
  rifampin
• Use cautiously with azoles preferably not more
  than 200 mg po daily

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Darunavir - Adverse Drug Effects

• Most common ADEs diarrhea, nausea, headache,
  nasopharyngitis
• Severe skin reactions, including erythema
  multiforme and Stevens-Johnson Syndrome, reported
• Also reported high lipids, decreased WBCs,
  fever, elevated transaminases (25 incidence of
  grade 3 or 4 lab abnormalities)
• Not well studied yet in patients with chronic
  hepatitis

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Darunavir - Resistance

• Cross-resistance with other PIs seen
• DRV-resistant viruses not susceptible to AMP,
  ATV, IND, LPV, NLF, RTV, SQV
• Limited cross-reactivity with tipranavir
• Decreased response
• 6-21 fold decrease if 3 of the following
  mutations present S37N/D, R41E/S/T, K55Q, K70E,
  A71T, T74S, V77I, I85V

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Summation

• Maraviroc
• Must have CCR5-tropic virus on Trofile testing
• Etravirine
• Still active with NNRTI-resistant strains with
  K103N
• Raltegravir
• Minimal drug-drug interactions, active against
  resistant organisms
• Darunavir
• Good activity in deeply experienced patients
  use cautiously in patients with chronic hepatitis.