Antidementia drugs: an update including the NICE review of drugs for AD

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Anti-dementia drugs an update including the NICE
review of drugs for AD

• Roy Jones
• The Research Institute for the Care of the
  Elderly, St Martins Hospital, Bath
• School for Health, University of Bath

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National Institute for Health and Clinical
Excellence (NICE)

• NICE is the independent organisation responsible
  for providing national guidance on the promotion
  of good health and the prevention and treatment
  of ill health.
• On 1 April 2005 NICE joined with the Health
  Development Agency to become the new National
  Institute for Health and Clinical Excellence
  (also to be known as NICE). Clinical
  Excellence                Public Health
  Excellence

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Centre for Health Technology Evaluation

• Technology Appraisals (TA) review clinical AND
  cost-effectiveness (for the NHS)
• Prepared by an Appraisals Committee (consisting
  of health professionals people familiar with
  issues affecting patients carers)
• but none with experience relevant to dementia!
• Commission a report from an independent academic
  centre obtain views of organisations
  representing health professionals, carers,
  manufacturers and government
• Advice is independent

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NICE Guidance (19 Jan 2001)

• Donepezil, rivastigmine and galantamine should
  be made available in the NHS as one component of
  the management of people with Alzheimers disease
• Mild and moderate AD with Mini Mental State above
  12
• Diagnosis in a specialist clinic according to
  standard diagnostic criteria
• Preferable to have a carer to ensure compliance

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NICE Guidance (19 Jan 2001)

• Only specialists (including Old Age
  Psychiatrists, Neurologists and Care of the
  Elderly Physicians) should initiate treatment
• Carers views of patient at baseline and
  follow-up should be sought
• GPs should only take over prescribing under an
  agreed shared-care protocol

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NICE Guidance (19 Jan 2001)

• Assess usually 2-4 months after reaching
  maintenance dose. Continue if improvement or no
  deterioration in MMSE score plus evidence of
  global improvement on the basis of behavioural
  and/or functional assessment.
• Normally only continue while MMSE remains above
  12 global, functional and behavioural
  condition remains at a level where drug thought
  to be having a worthwhile effect.
• Guidance accepted that no analysis available to
  identify those who benefit before treatment
  commences, and that cost effectiveness difficult
  to establish and quality of life not easily
  measured in people with dementia

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NICE HTA Process
Manufacturer or sponsors submission
Assessment team report
SHTAC
Appraisal committee meeting to produce Appraisal
Consultation Document(ACD)
Comments from consultees
Appraisal committee meeting to produce
Final Appraisal Determination(FAD)
Guidance issued
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NICE Timeline

• Manufacturers HTA Submission 03 June 2004
• SHTAC Report 20 September 2004
• 1st Appraisal Committee meeting 20 October 2004
• Further NICE analysis on cost effectiveness 20
  October 2004
• 2nd Appraisal Committee meeting 25 January 2005
• Appraisal Consultation Document (ACD) 01 March
  2005
• 3rd Appraisal Committee meeting 01 June 2005

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NICE Timeline (contd)

• Final Recommendations Final Appraisal
  Determination (FAD) not published by NICE
  Guidance Executive Committee 19 July 2005
• Request for further subgroup data 08 August 2005
• Subgroup data submission by manufacturers 21
  October 2005
• 4th Appraisal Committee meeting 20 December 2005
• Appraisal Consultation Document (ACD) 23 January
  2005
• 5th Appraisal Committee meeting 01 April 2006
• Final Appraisal Determination - planned
  publication July 2006

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March 2005 Not NICE!!Revised provisional
guidance (for discussion)

• Donepezil, rivastigmine and galantamine should
  not be made available for new patients with mild
  to moderate Alzheimers disease
• The drugs are clinically effective but not
  cost-effective
• Memantine should not be made available for
  moderate to severe Alzheimers disease, but only
  be used as part of clinical trials
• (even though the committee accepts that the drug
  saves on average 1.5h a day for caregivers)

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SHTAC (Southampton Health Technology Assessment
Centre) appraisal of ChEIs

• Delay cognitive impairment in mild to
  moderately-severe AD for at least 6m
• Improvements in many cases small ie mean
  ADAS-cog change of 3-4 may translate into a
  little difference in the lives of people with AD
• The 26 studies were generally judged to be of
  only moderate quality on the basis of information
  provided in the published papers
• Due to time restrictions, authors of references
  were not contacted for further details . where
  data was lacking
• The real impact is particularly difficult with
  the limited use of QOL measures

Takeda et al, IntJGerPsych 20062117-28
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How much is an ADAS-cog point worth in central
London?

• No new ground it is less complete and less
  informed than the various reviews and
  metaanalyses that preceded it
• Less transparent than the appraisers review and
  meta-analysis posted on the NICE website
• The authors dont understand instruments used in
  AD and astounding to say 3-4 points on ADAS-cog
  of little benefit when their own data shows a
  1-point change could knock about 25k of the
  cost/QALY
• Inadequate reporting of trials in publications
  does not mean the trials were inadequate (and
  other metaanalyses have obtained these data)

Schneider, IntJGerPsych 2006219-13
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Comments of NICE Dementia Guideline Development
Group

• Memantine is only drug available for severe
  dementia ( the committee has ignored caregiver
  time savings)
• All 4 drugs effective but NICE has evaluated cost
  effectiveness using inappropriate models for
  people with dementia and their families
• All 4 drugs may help with difficult behaviours
  (other drugs not recommended or poorly tolerated)
• AD2000 has been given unwarranted credibility
• The Guideline on dementia is being developed with
  SCIE to reflect the social aspects of dementia
  why has the Appraisal Committee failed to do this?

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The not NICE decision June 2005

• Appraisal Committee considered feedback from
  stakeholders and individual clinicians,
  families, friends and carers of those with AD.
  (Estimated to be several thousand responses)
• Agreed that, based on the evidence available
  and having taken full account of the response
  to consultation, they could not change their
  original conclusion!
• Agreed actually means that the committee voted
  12 for and 8 against the proposal

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The not NICE decision June 2005

• Appraisal Committees decision effectively
  overruled by the NICE Guidance Executive (the
  NICE senior management group)
• Why? Because the responses received suggested
  that the drugs might be particularly effective
  for certain groups of people
• Therefore asked the companies to look for
  evidence to support this in their clinical trial
  data (Despite the expert advisers and others
  saying that this is a waste of time like the
  search for the Holy Grail!!)
• Companies to respond by October for the NICE
  meeting on December 21 with a decision announced
  in January

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Appraisal Consultation Document Mark 2 January
2006

• ChEIs should be made available for moderate
  dementia (MMSE 20-10)
• ChEIs should not be made available for mild
  dementia
• Acquisition costs should be considered in
  therapeutic choices
• Memantine should only be used as part of ongoing
  clinical trials
• Dealt with by care of the elderly specialists

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Department of Health and Welsh Assembly Comments
on ACD (Feb 2006)

• Previously the Committee acknowledged concerns
  about the use of cost/QALY approach. Have the
  previous concerns now been addressed?
• Suggest reconsider potential cost-effectiveness
  of memantine in behavioural problems
• Is the Committee confident of the difference
  between mild and moderate AD since MMSE varies
  over short periods of time and scoring may not be
  applied consistently by clinicians especially if
  not convinced by the mild/moderate distinction
• Would NICE consider rewording their
  recommendation so that people with language
  deficits, learning disabilities and sensory
  impairments are not disadvantaged or consider
  more clinicall based measures

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Department of Health and Welsh Assembly Comments
on ACD (Feb 2006)

• Consider revising guidance to remove the
  requirement for diagnosis and assessment to be
  carried out in a particular setting (ie could
  operate in a community setting)
• Although acquisition costs of the ChEIs are
  important, there are differences in adherence to
  medication regimes, the health service
  requirements and side effect profile between the
  medications.
• Are you content that these factors have been
  adequately captured in the Committees
  deliberations!!!

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Other comments - ChEIs

• The methodology used is still flawed and
  inappropriate for people with AD and their
  families
• ChEIs are effective in both mild and moderate AD
  and on global improvement the changes are similar
• The apparently greater benefit in moderate
  dementia largely relates to non-linearity of the
  ADAS-cog and MMSE with both floor and ceiling
  effects
• It is inappropriate to restrict therapy to more
  severely impaired people and illogical to wait
  for people to deteriorate
• Inappropriate to restrict definition of moderate
  AD to those with a MMSE of 10-20

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Other comments - memantine

• There is no other treatment for severe dementia
  and it is a useful alternative in moderate
  dementia for people who cannot tolerate a ChEI or
  for whom it is contraindicated or who do not show
  benefit
• Why now ignore that memantine saves a most
  probable difference of 1 hour 30 minutes a day
  of a caregivers time

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Why is the committee continuing to ignore the
wider implications for people with dementia and
their families?

• BMJ 2004 239 224-6
• Professor Michael Rawlins (Chairman of NICE) and
  Professor Anthony Culyer (Vice Chairman from
  1999-2003)
• NICEs preferred measure for cost-effectiveness
  is the cost/QALY but there are a number of
  circumstances where this is not appropriate
  including where appropriate data on quality of
  life are not available.
• This applies to AD and was accepted by the
  Appraisal Committee in 2001 we still cannot
  effectively measure the quality of life of an
  individual with AD

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Galantamine safety concerns update

• 21 Jan 2005 Johnson Johnson press release
  health authorities are reviewing Reminyl safety
  data
• Galantamine 15 deaths/1026 (1.5) vs placebo
  5/1022 (0.5) in MCI studies ??significant or
  not
• GAL-COG-3002 (interim analysis) follow-up of
  pooled MCI subjects
• Original data RR (95CI) 4.86 (1.76, 13.4)
• Retrieved data RR 3.04 (1.26, 7.32)
• ITT at 24m from DB treatment start RR 1.73
  (1.00, 2.98)
• Separation of death rate within first 3m not
  true for non MCI studies
• Autumn 2005 Dear Doctor letter sent out in the
  UK advising of results but emphasising that MCI
  not a licensed indication. Large safety study
  will investigate this issue further.

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New once daily dosing information
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Galantamine OD formulation

• Prolonged-release capsule (PRC) marketed 2005
• Double-blind, 6-month placebo controlled
  multinational study of 971 patients
• Galantamine PRC 16 or 24mg/day has broadly
  similar tolerability, safety and efficacy
  profiles compared with twice-daily galantamine
• Brodaty et al Dement Geriatr Cogn Disord
  200520120-32

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Memantine once-daily versus twice-daily dosing

• Aim
• To evaluate the safety and tolerability of a 20
  mg once-daily dose of memantine in moderate to
  severe AD
• To evaluate a simplified titration scheme
• Patient population
• Moderate to severe AD (DSM-IV TR criteria and
  MMSE ?18), n78
• Outpatients, ?50 years
• 70 of the patients were on a stable dose of
  AChEI
• Endpoints
• AEs, vital signs weight, CGI

Jones et al. Poster presented at IPA, 2005
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Design
Jones et al. Poster presented at IPA, 2005
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Results Adverse Events (APTS)
APTSall patients treated set

• There were no clinically relevant differences
  between the treatment groups in terms of
  vital signs or weight changes

Jones et al. Poster presented at IPA, 2005
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Summary Once-daily versus twice-daily dosing

• In patients with moderate to severe AD
• Once-daily dosing with memantine 20 mg/day was as
  well-tolerated as the recommended twice-daily
  dosing
• The findings from this study provide further
  support for memantine as a well-tolerated
  treatment in Alzheimers disease

Jones et al. Poster presented at IPA, 2005
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New indications
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Memantine in moderate AD

• Recent EU approval for moderate AD (ie MMSElt20)
• Supported by post hoc meta-analysis of six Phase
  III, randomised, placebo-controlled, studies.
• Statistically significant effect in favour of
  memantine (vs placebo) for global status
  (plt0.001), cognition (plt0.001) and function (plt
  0.001).
• AEs generally mild to moderate in severity
  overall incidence rates comparable between
  memantine and placebo. The most frequent AEs in
  memantine compared with placebo were dizziness
  (6.3 vs 5.6), headache (5.2 vs 3.9),
  constipation (4.6 vs 2.6), and somnolence (3.4
  vs 2.2).

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Rivastigmine and Dementia associated with
Parkinsons disease

• 541 patients enrolled, 410 completed
• Mild to moderate dementia developing at least 2y
  post clinical PD diagnosis
• 3-12mg/day for 24weeks
• 1ry variables ADAS-cog, ADCS-CGIC
• 2ry variables ADCS-ADL, NPI (10 item), MMSE,
  CDR attention tasks, Verbal Fluency 10-point
  Clock-drawing test

Emre et al NEnglJMed 2004 351 2509-18
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Rivastigmine and Dementia associated with
Parkinsons disease

• Results
• Moderate improvement in dementia
• 410/541 completed study
• ADAScog 2.1pts better vs 0.7 worse
• (riva baseline 23.8/70 vs placebo 24.3)
• Global improvement 19.8 vs 14.5
• Global worsening 13.0 vs 23.1
• All secondary variables significantly better

Plt0.001
Emre et al NEnglJMed 2004 351 2509-18
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Rivastigmine and Dementia associated with
Parkinsons disease

• Results
• Adverse events
• Nausea 29.0 riva vs 11.2 placebo
• Vomiting 16.6 vs 1.7
• Tremor 10.2 vs 3.9

Plt0.001 p0.01
Emre et al NEnglJMed 2004 351 2509-18
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Rivastigmine and Dementia associated with
Parkinsons disease

• Conclusion
• In this 24-week placebo-controlled study
  rivastigmine was associated with moderate
  improvement in dementia associated with
  Parkinsons disease but also with higher rates of
  nausea, vomiting and tremor
• Update 2006 Novartis announce that rivastigmine
  is now licensed for use in dementia in
  Parkinsons disease

Emre et al NEnglJMed 2004 351 2509-18
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Medicines in development for dementia 2005 Phase
I (www.phrma.org)
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Medicines in development for dementia 2004 Phase
II (www.phrma.org)
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Medicines in development for dementia 2005 Phase
III (www.phrma.org)
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Amyloid treatment strategies

• To remove amyloid deposits already laid down
• To prevent the A? formed from acting as a toxin
• To prevent production of A?

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Amyloid treatment strategies

• To remove amyloid deposits already laid down
• Immunisation
• To prevent the A? formed from acting as a toxin
• To prevent production of A?

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Amyloid treatment strategies

• To remove amyloid deposits already laid down
• To prevent the A? formed from acting as a toxin
• To prevent production of A?

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A?-chelators

• Compounds that prevent A?-metal interactions may
  promote A? clearance from the brain, inhibit
  hydrogen peroxide and reduce A? toxicity
• Clioquinol (iodochlorhydroxyquin) prevents Cu
  binding and inhibits brain amyloid pathology in
  mice.
• In phase II trial, plasma A? levels were lowered
  and cognitive decline arrested
• Unfortunately development suspended (April 2005)
  because the manufacturing process contained
  mutagenic impurities that could not be removed
• Is a follow-on compound (PBT2) in phase 1

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Amyloid precursor protein metabolism
a
Secretase
b
g
b-secretase
a-secretase
g-secretase
Fibrillisation
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Alzhemed (Neurochem Inc)

• Small sulfonated molecule interfering with
  association between glycosaminoglycans (GAG) and
  A? peptides (GAG mimetic)
• Reduces amyloid fibrillogenesis and deposition
• Phase II clinical data positive (generally well
  tolerated and possible stabilisation of mild AD)
• Phase III study will look at cognition, global
  function and ADLs
• Start delayed in Europe, study underway in US

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Whats ahead for 2006

• Hopefully NICE will accept that the original 2001
  decision for ChEIs was correct and that memantine
  should also be made available
• We must keep up the pressure and publicity to
  ensure that the right decision is taken at their
  April meeting
• Newer medicines are undoubtedly needed but
  development isnt easy, there have been
  disappointments in 2005 but there are still a
  number of novel and interesting compounds in
  development (acting potentially on amyloid, tau
  and other areas of interest)