NCI Development Resources for Cancer

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NCI Development Resources for Cancer

• Jill Johnson, DTP
• October 29, 2001

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http//dtp.nci.nih.gov
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Overview

• DTP provides resources for discovery (compounds,
  informatics, cell lines, screening), and
  development (formulation, in vivo testing,
  pharmacology, toxicology), to academic,
  non-profit, and corporate investigators.
• Main avenues of access Grants,
• Routine services, RAND, BEC,
• RAID, DDG

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For Information on various GrantsPrograms see

http//dtp.nci.nih.gov and click
on Grants/Contracts
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Features Benefits of Using NCIResources

• Almost all of our services are cost free.
• Only in rare instances is IP involved.
• The application processes are relatively simple.
• We are always open to suggestions for additional
  needed resources and methods of improving our
  service.

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Definition of NCI Terminology

• Routine Services -
• In vitro cell line testing of single pure
  compounds
• (on-line application)
• In vitro testing of libraries (by letter request
  sent
• to us)
• requests for research samples (on-line request
• form and requires simple letter agreement)
• requests for sets of plated compounds (letter
  
• sent to us and requires MTA)
• All decisions are made by DTP staff.

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Definition of NCI Terminology

• BEC - (Biological Evaluation Committee) - Cmpds
• with interesting results from 60 cell line
  testing are
• referred to BEC for possible action. One can
  also apply w/o
• 60 cell line testing for resources - in vivo
  testing, PK/PD,
• early formulation and tox work. (Requires
  application - all
• decisions are made by DTP staff.)
• DDG - (Drug Development Group) - Approves
• resources for mid to late stage development
  leading to
• NCI-filed IND and trials (Requires application -
  all
• decisions are made by NCI staff with non-voting
  peer
• review).

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Definition of NCI Terminology

• RAND - (Rapid Access to NCI Discovery
• Resources) - for academics and non-profits.
  Utilize for
• analog or library synthesis, assay development
  assistance,
• microarray technology, early formulation or PK/PD
  work
• in order to select best candidate from multiple
  early
• leads (Requires application and is peer-reviewed)
• RAID - (Rapid Access to Intervention
  Development)
• for academics and non-profits. Mid- to late-
• development resources formulation,
  range-finding
• and IND-directed toxicology, Bulk synthesis of
  drug.
• (Requires application and is peer-reviewed)

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Which resource do I need?
DDG
BEC
RAID
RAND
NCI IND-filing and Clinical Trials
Lead Selection
Candidate Development
Target Id
Assay Devel
Hit
Screen
PK/PD, tox, formulation, synth.
As a general rule
RAND/BEC - multiple hits, no in vivo data,
good target info. RAID/DDG - 1 lead candidate
with some in vivo data, activity relates to
novel target.
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Resource Utilization Examples - Development

• Early stage
• You have one or more lead compounds and you would
  like to confirm target and/or acquire initial
  indications of pharmaceutical tractability
• Apply to Biological Evaluation Committee (BEC)
• contact ncidtpddginfo_at_mail.nih.gov

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Resource Utilization Examples -Development

• Middle stage
• You have a lead candidate which requires
  additional formulation, PK/PD and range-finding
  toxicology
• Apply to DDG (Drug Development Group) contact
  ncidtpddginfo_at_mail.nih.gov
• Can lead to NCI-filed IND and Trial
• Or..

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Resource Utilization Examples -Development

• Middle-Late stage
• Apply to the RAID (Rapid Access to Intervention
  Development) program
• PI files IND as opposed to NCI
• Peer-reviewed
• Modular task approach
• Applications accepted twice yearly
• more info ncidtpraidinfo_at_mail.nih.gov

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RAID Example - Alan Solomon, U TennImmunotherapy
in Patients with Light-chain-Associated (AL)
Amyloidosis

• Finding
• administration of certain murine anti-human light
  chain MoAbs capable of recognizing an epitope
  present on fibrils results in complete
  degradation of human AL? or AL? amyloid deposits.
  
• RAID will
• support production of the chimeric anti-AL MoAb
  first. Additional in vivo data supporting
  production of the anti-MoAb are needed before
  proceeding to humanized Ab.

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RAID Example - Alan Solomon, U Tenn

• RAID tasks (cont)
• Non-GMP production of murine anti-Al? MoAb
• Non-GMP production of chimerized anti-Al? MoAb
• In vivo testing of murine and chimerized MoAbs in
  model system
• Good performance
• will support further applications to allow
  full-scale GMP production and/or humanization of
  the chimeric MoAb.

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RAID Example - Mathias Gromeier, Duke University
Medical Center - Oncolytic Poliovirus

• Raid Task
• Production of Non-Pathogenic Oncolytic Poliovirus
  Chimeras for the Treatment of Brain Tumors
• Rationale
• Polioviruses can be generated by exchanging the
  cognate internal ribosomal entry site of
  poliovirus with its counterpart from human
  rhinovirus type 2.
• This yields PV1(RIPO), a poliovirus strain which
  does not replicate in normal neuronal cells but
  which exhibits activity against malignant gliomas
  or medulloblastomas.

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RAID Example - Mathias GromeierDuke Univ Med
Center.

• Approved
• for production of cGMP-grade material and
  IND-directed toxicology studies in non-human
  primates.
• Progress
• based on safety recommendations, BDP will develop
  recombinant virus using the Sabin vaccine.
• Dr. Gromeier has demonstrated that inoculation
  with the new virus PVS-RIPO, completely
  eradicates growth of astrocytoma tumor cells in
  mouse xenografts.

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Resource Utilization Examples -Development

• Late stage
• Apply to the DDG for NCI-held IND
• IND-Directed Toxicology
• Clinical Lot Manufacturing
• IND-filing and NCI-Monitored Trials
• DDG utilizes same contract resources as
• RAID
• Meetings are held quarterly
• more info ncidtpddginfo_at_mail.nih.gov

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DDG Example - (NSC 639829)DimethylBenzoylphenylur
ea (Ishihara Sangyo Kaisha)

• Rationale
• Tubulin mechanism predicted by COMPARE and
  confirmed in lab studies
• Good in vivo activity (breast tumors) and other
  tumors resistant to standard agents
• Structurally unrelated to paclitaxel
• DDG tasks
• Non-GMP synthesis of agents
• detailed in vivo studies to select best analog

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DimethylBenzoylphenylurea

• Good Performance (selection of best analog) leads
  to
• pharma studies in rodents
• formulation studies
• range-finding toxicology
• IND-filing
• Current Status
• Orally active drug (BPU) now in phase I clinical
  trials

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Which program is best for you?

• DTP staff will be happy to assist you in
  determining which of these resources fits your
  needs, and, more importantly, which process will
  give you the best chance of success in the
  approval process.

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Thank you!

• Any questions?

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Our next speaker is Dr. Steve
Creekmore Biopharmaceuticals Resources
Branch Developmental Therapeutics Program