ARETE-ZOE: First-In-Man ... Risk Assessment
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Transcript of ARETE-ZOE: First-In-Man ... Risk Assessment
TeGenero TGN1412
FIRST-IN-MAN TRIAL …RISK ASSESSMENT
STAMP MEETING 16 MAY 2015 LEATHERHEAD, UK
<2 years 1 year 1.5-2.5 years
1-2 years
Target Identification & Validation
Lead Generation
Lead Optimization
Pre-clinical Development
Clinical Development
NDA IND * Compartmentalized data sets/intellectual property
1-3 years 4-8 years
Approval
Thorough understanding of the disease mechanisms and the role of enzymes, receptors or proteins within the disease pathology. simple experiments carried out to confirm regulation of the target and development of assay
Identification of chemical start points for drug discovery projects. Identification of related compounds with improved potency, reduced off-target activities (undesirable activities at other biological targets), and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics.
Optimise potency against the enzyme target, cellular and toxicity assays as well as those that govern good oral absorption, slow metabolic clearance in vivo and display activity in an animal model of the disease.
Toxicology in vitro and in vivo ADME studies pharmacokinetics Pharmacodynamics Chronic toxicity, Acute toxicity, Safety pharmacology
Phase 0: Very limited human exposure to the drug, with no therapeutic or diagnostic goals Phase 1: Healthy volunteers , emphasize safety. What the drug's most frequent and serious adverse events are and, often, how the drug is metabolized and excreted. Phase 2: Data on effectiveness (whether the drug works in people who have a certain disease or condition). The drug may be compared with placebo or a different drug. Safety continues to be evaluated. Phase 3: Data on safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
Phase 4: Studies occurring after launch. Additional information about a drug's safety, efficacy, or optimal use.
PARTICIPANTS’ OBJECTIVES
MILESTONE I: IND REVIEW
CORRECT APPROVAL | CORRECT REJECTION | INCORRECT APPROVAL | INCORRECT REJECTION
Existing safety hazard detected?
Limiting safety hazard?
Mitigated safety hazard?
IND Approved?
IND REVIEW COMPANY DATA
Approved Rejected Approved Rejected Approved Rejected Approved Rejected
PUBLICATIONS
MILESTONE I: IND REVIEW
Hazard not identified despite thorough investigation Hazard not identified because some investigations were not conducted Results of investigations misinterpreted or erroneously assessed as non-limiting Hazard identified but not mitigated Hazard actively concealed and not communicated to regulators.
Drug dossier does not accurately reflect safety and efficacy of drug in development • Inadequate/insufficient/misleading information provided • Critical safety information withheld
COMMUNICATED TO: • Study investigators • Study subjects • Regulators
• Study physicians cannot properly assess risk for their patients • Patients enrolled in study cannot properly assess risk for themselves • Regulators cannot properly assess benefit:risk profile of drug in development
PATIENTS ARE SUBJECTED TO UNACCEPTABLE RISK DURING CLINICAL TRIALS
Incorrect Rejection: Potentially useful drug
not available
Incorrect Approval: Harmful drug available
to consumers w/o appropriate warnings
Correct Rejection: Risks outweigh benefits
Correct Approval: Benefits outweigh risks
RESPONSIBILITIES
Target Validation
Lead Generation
Lead Optimization
Pre-clinical Development
IND
NDA/BLA MARKET CLINICAL DEVELOPMENT
1 year 1.5-2.5 years
1-2 years
1-3 years
Until withdrawn
<2 years 4-8 years
DRUG DISCOVERY | PRE-CLINICAL DEVELOPMENT
REGULATORY RESPONSE
WORLDWIDE IS ANYTHING BUT
CONSISTENT
SPONSOR (TeGenero) INVESTIGATOR
Academia Industry - TeGenero
Confidential information Publication bias Limited outside review (major flaw)
PUBLICATION
SPONSOR (TeGenero) INVESTIGATOR
Academia Industry - TeGenero
REGULATOR
Depends on jurisdiction where in vitro tests take place - GLP
SPONSOR (TeGenero) INVESTIGATOR (PAREXEL)
See Protocol
IRB/EC Brent Medical Ethics Committee
See Working Party Report
REGULATOR (MHRA)
See Working Party Report
CIRCARE | RAPS analysis
UNCLEAR ROLES AND RESPONSIBILITIES FOR PROTOCOL REVIEW
<2 years 1 year 1.5-2.5 years
1-2 years
GLOBAL PHARMA ASSESSMENT
Target Identification & Validation
Lead Generation
Lead Optimization
Pre-clinical Development
Clinical Development
NDA IND
1-3 years 4-8 years
Approval
Phase 4: Studies occurring after launch. Additional information about a drug's safety, efficacy, or optimal use.
WERE THESE PREVENTABLE?
PO
ST
Mar
ket
1 TNG1412 Assumption that monkey and human target is essentially the same proved wrong. Dosing intervals between subjects did not account for unexpected effects (cytokine storm). Preparation for possible serious adverse effects inadequate.
TGN1412 was administered to six healthy volunteers in a Phase I trial. All of them suffered multiorgan failure as a result of cytokine storm.
Interpretation of preclinical (primate) studies: human and primate cellular targets are different
Starting dose extrapolated from monkeys; dose based on fraction of predicted “no adverse effect level” proved wrong. Cross-species barrier proved to have unpredictable effect.
In vitro studies on human material as close as possible to the target tissue
Dosing intervals between subjects did not account for unexpected effects (cytokine storm).
Preparation for possible serious adverse effects inadequate
J Young Pharm. 2010 Jul-Sep; 2(3): 332–336.
TGN1412 PRE-CLINICAL STUDIES
Target Validation
Lead Generation
Lead Optimization
Pre-clinical Development
IND NDA/BLA MARKET CLINICAL DEVELOPMENT
1 year 1.5-2.5 years
1-2 years
Clinical Development
1-3 years
Approval
Until withdrawn
<2 years 4-8 years
DRUG DISCOVERY | PRE-CLINICAL DEVELOPMENT
In vitro evaluations of TGN1412 in human and non-human cells SPECIFICITY of TGN1412 to CD28 was evaluated by flow cytometry and Biacore analysis.
• The assays showed specificity of TGN1412 for CD28 receptor • TGN1412 did not cross react with other closely related molecular targets such as Cytotoxic T-
lymphocyte-antigen-4 and inducible co-stimulator. • T cells of rodents and non-human primates • TGN1412 had low-binding affinity for rodent CD 28 • High-binding affinity in case of T cells derived from cynomolgus monkey and rhesus monkey. • Determination of sequence homology of C′′D loop of CD28 of
• humans and rhesus revealed difference of one amino acid • marmoset monkey revealed difference of two out of six amino acids • rodents, the C′′D loop sequence homology with humans was very low • T cells obtained from healthy donors: only TGN1412 but not conventional CD28 antibody
was able to cause rapid proliferation of T cells in the absence of stimuli from T-cell receptor. • TGN1412 had superagonistic activity for T cells obtained from healthy donors and that they could
specifically react with CD28 receptor having sequence homology with human CD28 receptor.
J Young Pharm. 2010 Jul-Sep; 2(3): 332–336.
SYSTEMIC HAZARDS IN PRE-CLINICAL DEVELOPMENT
Target Validation
Lead Generation
Lead Optimization
Pre-clinical Development
IND NDA/BLA
MARKET CLINICAL DEVELOPMENT
1 year 1.5-2.5 years
1-2 years
Clinical Development
1-3 years
Approval
Until withdrawn
<2 years 4-8 years
DRUG DISCOVERY | PRE-CLINICAL DEVELOPMENT
Profile of drug pre-clinical testing in published literature misleading (alternative interpretations, incomplete data) Pipeline value of the compound affected, stakeholders’ expectations inaccurate Heavy reliance on IP protected data
Target validation incorrect: cross-species barrier not accounted for, insufficient data from in-vitro human tissues Unpredictable effects in first-in-man trials Any errors, omissions, misinterpretations, or flaws only manifest when the drug is first given to human subjects.
TeGenero: TGN1412. After very first infusion of a dose 500 times smaller than that found safe in animal studies, all six human volunteers faced life-threatening conditions involving multiorgan failure for which they were moved to intensive care unit. The side effects were consistent with cytokine release syndrome known from other antibody-based therapies. The target in monkeys on which the drug was tested differs from human targets. This cross-species difference was not taken into account.
PRESSURE TO CAPITALIZE ON INVESTMENT MAY CAUSE RISKS TO BE OVERLOOKED
• The participants’ objectives are to develop a drug, obtain approval, and make return on investment.
• Goals of an ideally balanced system are to accommodate interests of all parties and balance their objectives against each other.
• Design requirements of a safe system account for hazard identification, evaluation and elimination, as well as self-actualization of the system as whole.
• System operates within safety constraints: Time – Performance – Cost.
• Safety hazards mirror inadequacies of the checks and balances within the system.
• Series of historical examples of unidentified safety hazard adjudicated to each stage shows that no part of the process is inherently fail-safe.
• Regulatory response to known safety incidents in major markets is anything but consistent.
SUMMARY