Bench to Bedside: Oncology Drug Product Development and Target Commercialization

1
Bench to Bedside Oncology Drug Product
Development and Target Commercialization

• April 2005
• Eric Malek
• Vice President, Corporate Development
• Allos Therapeutics, Inc
• 11080 CirclePoint Road, Suite 200
• Westminster, CO 80020
• 303-426-6262
• malek_at_allos.com

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Academic Collaborations- Biotech Perspective

• Allos Company Background
• Allos and Industry Approach to Licensing /
  Acquiring Products
• Allos Portfolio History of Academic
  Collaborations
• EFAPROXYN Overview of discovery to market
• Pralatrexate
• RH1
• Corporate Perspectives on Drug Development
• Formulation
• In-vitro
• In-vivo
• Clinical

3
Allos Therapeutics is a biopharmaceutical company
focused on developing and commercializing
innovative drugs for improving cancer therapy
4
Allos Background

• Founded in 1994
• 55 employees headquartered in Westminster, CO
• March 2000 IPO (NASDAQ ALTH)
• Three novel products targeting large medical
  markets in clinical development
• Focus in oncology clinical development and
  commercialization in US

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Allos Product Portfolio
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Academic Collaborations- Biotech Perspective

• Allos Company Background
• Allos and Industry Approach to Licensing /
  Acquiring Products
• Allos Portfolio History of Academic
  Collaborations
• EFAPROXYN Overview of discovery to market
• Pralatrexate
• RH1
• Corporate Perspectives on Drug Development
• Formulation
• In-vitro
• In-vivo
• Clinical

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Allos In-Licensing as a Strategy

• No in-house drug discovery programs financial,
  facilities and human resource challenge
• Permits operation in semi-virtual mode
• Leverages expertise in drug development IND to
  NDA
• Valuation driven by clinical development
  milestones
• Ad-hoc reviews and evaluations hold commercial
  strategic value
• Foster relationships with experts
• Remain opportunistic and aware of competitive
  environment
• Positioned to execute quickly as corporate
  objectives evolve
• Most top tier biotechs and pharmas proactively
  balance internal discovery with in-licensing
• Many fall back on licensing in response to
  pipeline gaps and product setbacks

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Allos In-Licensing Focus

• Leverage expertise in oncology clinical
  development
• Focus on clinical and IND-stage opportunities
• Preference for synergistic opportunities
• Small molecules manufacturing
• Similar target indications clinical development
• Radiosensitizers target physician audience
• Cytotoxics differentiation approach
• Supportive Care XRT and chemo side effects
• Opportunistic MAbs, novel targeted approaches,
  novel MOAs
• No vaccines, cell therapies, uncharacterized
  plant / animal extracts

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Allos In-Licensing Process
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Large Pharma In-Licensing Process
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Recommendations to Academia for Approaching
Industry

• Many functions and levels of mgmt. involved in
  decision making
• Many pathways to a no decision
• Many opportunities competing for attention, time
  and resources to evaluate
• --------------------------------------------------
  -----------------------------------------
• Understand the decision process in companies you
  target
• Build relationships with the scientists /
  clinicians
• Present data on differentiation and
  product/research or commercial synergies - less
  info and targeted
• Understand the data points that sell to
  reviewers
• Understand the downstream regulatory impacts of
  research decisions
• Address IP opportunities early on

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Academic Collaborations- Biotech Perspective

• Allos Company Background
• Allos and Industry Approach to Licensing /
  Acquiring Products
• Allos Portfolio History of Academic
  Collaborations
• EFAPROXYN Overview of discovery to market
• Pralatrexate
• RH1
• Corporate Perspectives on Drug Development
• Formulation
• In-vitro
• In-vivo
• Clinical

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In-Licensing History- EFAPROXYN

• Company founded in 1994 on technology licensed
  from Virginia Commonwealth University (VCU)
• VCU research in allosteric modifiers of
  hemoglobin underlies Allos lead clinical
  compound, EFAPROXYN
• Result of collaboration between Donald Abraham at
  VCU and Nobel Laureate Max Perutz

Efaproxiral (RSR13)

• Attractive platform for emerging biotech ? broad
  clinical applicability
• Hypoxia relevant to indications in oncology,
  cardiovascular, surgery and critical care
  specialties
• Favorable terms for pre-IND compound
• Fundable opportunity

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EFAPROXYN Development Timeline
ENRICH confirmatory study initiated
Fast Track granted for brain metastases
Phase 2 in brain metastases
Expand Development 1. primary
(extra-cranial) indications 2. emerging
regimens (Erbitux, Temodar, SRS)
Original license agreement
Phase 3 in brain metastases initiated
Phase 2 in CABG
Phase 1 in NSCLC (concurrent) initiated
Phase 1b in solid tumors
Phase 1/2 in cervical cancer initiated
Phase 2 in GBM
Market launch
1996
2004
2000
2007
NDA filed
MAA filed
1994
PK study
2006
1998
2002
Phase 2 in NSCLC
Phase 1b in GBM
Phase 1/2 in recurrent GBM initiated
ENRICH enrollment complete
INDs filed
ODAC
Phase 1b in surgery
Approvable letter and orphan drug designation
ALLOS IPO
Phase 1b in angina
TOTAL 207M
2M 94
3M 95
8M 96
18M 98
10M 99
15M 02
11M 03
50M 05
90M 00
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In-Licensing History- Pralatrexate (PDX)

• A novel antifolate (DHFR inhibitor) licensed from
  MSKCC, SRI, SoRI in January 2003
• Background and Rationale for License
• Differentiated among 100 compounds evaluated in
  2002
• Phase 2 single agent proof of activity in 2nd
  line NSCLC
• Broad development program underway at MSKCC
• Leverages internal expertise
• Unexpected Challenges
• Manufacturing process improvements
• Repeat Phase 1 dose escalation
• Validate benefit of vitamin supplementation
• Significant advances to NSCLC standard of care
  has complicated pathway to approval in lead
  indication

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In-Licensing History - RH1

• Targeted cytotoxic prodrug licensed from CRUK,
  University of Colorado and Salford University in
  2005
• Background and Rationale for License
• Interest in program dating from early 2002
• Resumption of Allos in-licensing activities (post
  ODAC) and CU commitment made 2005 execution
  possible
• Near-term milestone - Phase 1 data available in
  2005
• NCI sponsored pharm / tox and CMC work complete
• Potential Challenges
• Reformulation might be necessary to avoid IP
  issues
• FDA identifies IND gaps
• Both situations involve development delay
  additional expense

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Academic Collaborations- Biotech Perspective

• Allos Company Background
• Allos and Industry Approach to Licensing /
  Acquiring Products
• Allos Portfolio History of Academic
  Collaborations
• EFAPROXYN Overview of discovery to market
• Pralatrexate
• RH1
• Corporate Perspectives on Drug Development
• Formulation
• In-vitro
• In-vivo
• Clinical

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Preclinical Drug Development PitfallsA Corporate
Perspective- Formulation

• Purity of agent being tested should be reasonable
• At least 95 pure
• Need a reproducible source of agent which can be
  scaled up in sufficient quantity for clinical
  trials
• Solubility is a key issue and needs to be
  addressed early
• Many agents are soluble in DMSO, but nothing else
• Evaluate protein binding early
• Consider oral formulation if
• Frequent dosing will be needed
• Poor solubility in clinically relevant solvents

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Preclinical Drug Development PitfallsA Corporate
Perspective- In vitro studies

• Advantages
• Useful for early screening of analogs
• Helpful in screening for synergy or sequence
  dependency
• Inexpensive and quick
• Disadvantages
• Extremely poor correlation with clinical activity
• Suggestion
• Use only as a screening tool
• Use cell lines that are well characterized and
  accepted
• Avoid performing studies in solvents with no
  clinical counterpart (i.e., DMSO)
• Should not be only data related to antitumor
  activity

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Preclinical Drug Development PitfallsA Corporate
Perspective- In vivo studies

• Advantages
• Useful for early screening of analogs
• Helpful in screening for synergy or sequence
  dependency
• Better correlation than in vitro studies with
  clinical activity
• Disadvantages
• Costly and time consuming
• Suggestion
• A necessity for proving activity!!
• Use cell lines that are well characterized and
  accepted (PC3, HT29, MiaPaCa, MDA-231)
• Design studies based on industry standards
• Well characterized growth curves with small
  growth variation
• Appropriate sample sizes (10 animals / group)
  that allows for statistical analysis
• Avoid intratumor injection to deliver drug
• Use relevant controls and include pharmacokinetics

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Clinical Drug Development PitfallsA Corporate
Perspective - Clinical Studies

• Consider multiple Phase 1 studies using different
  schedules
• Quality of data is key
• Most Phase 1 and 2 studies conducted solely by
  academic centers result in data that cannot be
  used by companies for NDA purposes
• Data should stand up to outside auditing
• Strongly consider the use of an IRRP to review
  and confirm all responses
• Avoid the single center syndrome