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