Patient-Centered Reverse Translation

John A. Wagner, MD, PhD

• Research starts with and returns to the patient

• Powerful trend in research and medicine focusing on patient-centricity

• Precision medicine approaches driven by reverse translation drives companion diagnostics

Key Take Home Message

• Reverse. [adjective] Going in or turned towards the direction opposite to that previously stated.

• Translation. [noun] The process of translating words or text from one language into another.

oxforddictionaries.com

Therapy & Tools

Patient

Target

A

BC

DE

Mechanism

Wagner CPT 2018;103:168-170

Therapy & Tools

Patient

Target

A

BC

DE

Mechanism

Forward Translation• Application or translation of

laboratory research to clinical experiments or patients

• Bench-to-bedside

Bench-to-bedside approach is limiting

• The most obvious limitations are in target discovery and the frequent route reversals necessary for drug discovery and development

• Targets do not emerge from a vacuum, and that is where a patient-centered reverse translation approach is particularly critical

Therapy & Tools

Patient

Target

A

BC

DE

Mechanism

Reverse Translation• Application or translation of

clinical, patient-centered data to laboratory research

• Bedside-to-bench

Reverse translation (A & B)

• Reverse translation activities aim to explain disease and patient biology through an integrative, cross-functional approach linking “omic” data derived from a deep characterization of patients with their health phenotype data

• The goal is to generate actionable hypotheses about disease mechanisms and drug response supporting validation of existing targets, identifying new targets and disease mechanisms/indications and driving precision medicine strategies

• Data for reverse translation can be derived from exploratory characterization of patients in clinical trials, non-interventional human studies or through access to well characterized patient databases/tissue repositories, including public-profit consortia efforts

• Precision medicine strategies may ultimately become companion diagnostics

Reverse translation (E)

• Forward translation does not formally account for the critical reverse steps

• Learnings from patients that are reflected back to drug discovery and development tools (e.g., biomarkers, animals models, or modeling and simulation approaches, including quantitative disease models)

• Refinements of a therapeutic (e.g., pharmacokinetically unacceptable profiles leading to different desired molecular or metabolic properties)

Therapy & Tools

Patient

Target

A

BC

DE

Mechanism

1. Experiment of Nature

PCSK 9 mutations associated with remarkably low cholesterol and reduced incidence of coronary artery disease

2. Understanding LDL MechanismPCSK9 null mice confirmed low cholesterol and PCSK9 binding LDL receptors linked with control of LDL cholesterol levels

3. Inhibition of PCSK9Discovery of antibody inhibitors of PCSK9 resulted in forward translation of therapeutics that reduced degradation of LDL receptors and lowering cholesterol levels

4. IMPLEMENTATION: A NEW APPROACH

Monoclonal antibodies, alirocumab and evolocumab, were approved 12 years after the initial bedside observations, and have been shown to dramatically reduce LDL cholesterol in patients with hypercholesterolemia

Therapy & Tools

Patient

Target

A

BC

DE

Mechanism

1. Experiment of Nature

PCSK 9 mutations associated with remarkably low cholesterol and reduced incidence of coronary artery disease

2. Understanding LDL MechanismPCSK9 null mice confirmed low cholesterol and PCSK9 binding LDL receptors linked with control of LDL cholesterol levels

3. Inhibition of PCSK9Discovery of antibody inhibitors of PCSK9 resulted in forward translation of therapeutics that reduced degradation of LDL receptors and lowering cholesterol levels

MPLEMENTATION: A NEW APPROACH

noclonal antibodies, alirocumab and locumab, were approved 12 years

er the initial bedside observations, and ve been shown to dramatically reduce L cholesterol in patients with ercholesterolemia

Cohen JC et al. N Engl J Med 2006;354:1264-1272.

Therapy & Tools

Patient

Target

A

BC

DE

Mechanism

1. Experiment of Nature

PCSK 9 mutations associated with remarkably low cholesterol and reduced incidence of coronary artery disease

2. Understanding LDL MechanismPCSK9 null mice confirmed low cholesterol and PCSK9 binding LD receptors linked with control of LDL cholesterol levels

3. Inhibition of PCSK9Discovery of antibody inhibitors of PCSK9 resulted in forward translation of therapeutics that reduced degradation of LDL receptors and lowering cholesterol levels

4. IMPLEMENTATION: A NEW APPROACH

Monoclonal antibodies, alirocumab and evolocumab, were approved 12 years after the initial bedside observations, and have been shown to dramatically reduce LDL cholesterol in patients with hypercholesterolemia

Stein EA et al. N Engl J Med 2012;366:1108-1118.

Therapy & Tools

Patient

Target

A

BC

DE

Mechanism

Leptin

energy use ↑

Food intake ↓

RQ ↓Insulin sensitivity (↑)Glucose uptake (↑)

Fat mass ↓

MC4R ↑

Lipolysis ? Insulin release (↓)Glucoseproduction (↓)

Agonism of MC4R proposedto ↓ food intake and weight

MC4R Mechanism of Action

• Humans with mutations in MC4R– have obesity, hyperphagia (binge-eating), hyperinsulinemia– homozygotes worse than heterozygotes– similar syndrome in POMC-deficient humans

• MC4R knockout mice– similar phenotype as humans

• Animal pharmacology in rodents– MC4R antagonists increase food intake and body weight– MC4R agonists decrease food intake and body weight– effects in wild-type but not MC4R-knockout mice

Strong target validation, particularly genetic evidence

4 hr 10 hrN=28 14 hr 24 hr Total

p<0.001

↓p=0.009↓

p=0.020↓

p=0.065↓

p<0.001↓

p=0.004

24-hr intake:Sibutramine: ~18% ↓500 mg MK-493: ~ 7% ↓

Krishna R et al CPT 2009 Dec;86(6):659-66

Single 500-mg MK-0493 Dose Had Marginal Effects on 24-hr Food Intake

Hint of Efficacy in POC Study in Obese Patients Suggested Higher Exposures May Be Necessary

-2 Baseline 2 4 8 12 Week 12 Week 12 LS Means (LOCF) † LS Means (RMA) ‡

Week

-4

-3

-2

-1

0

1

2

3

4

Mea

n C

hang

e in

Bod

y W

eigh

t (kg

)

Placebo (N=64)L-000222628 200 mg (N=65)L-000222628 400 mg (N=61)

Significance from placebo established at Week 2 with N=80 per group

Efficacy of 200 mg diminishes after 4 weeks; 400 mg diminishes after 8 weeks (p=0.154 at week 12)

Rashes appear in 400 mg group 7-21 days on treatment

Placebo 200 mg 400 mg

Cumulat

ive Inci

dence R

ate (%)

0

5

10

15

20

25

Days After First Dose0 7 14 21 28 35 42 49 56 63 70 77 84

-2 Baseline 2 4 8 12 Week 12 Week 12 LS Means (LOCF) † LS Means (RMA) ‡

Week

-4

-3

-2

-1

0

1

2

3

4

Mea

n C

hang

e in

Bod

y W

eigh

t (kg

)

Placebo (N=64)L-000222628 200 mg (N=65)L-000222628 400 mg (N=61)

Significance from placebo established at Week 2 with N=80 per group

Efficacy of 200 mg diminishes after 4 weeks; 400 mg diminishes after 8 weeks (p=0.154 at week 12)

Rashes appear in 400 mg group 7-21 days on treatment

Placebo 200 mg 400 mg

Cumulat

ive Inci

dence R

ate (%)

0

5

10

15

20

25

Days After First Dose0 7 14 21 28 35 42 49 56 63 70 77 84

400 mgAUC ~ 8.9 µM.hrC24hr ~108 nM

Krishna R et al CPT 2009;86:659-66

-2 BL 2 4 6 10 14 18 Week 18RMA‡

(84% CI)

Placebo (n=53)MK-0493 (n=111) -1.2 (-2.6, 0.2) †

Chan

ge in

Bod

y W

eigh

t (kg

)

-5

-4

-3

-2

-1

0

1

2

Week

p=0.099

Probability >2.1 kg is ~11%

800 mgAUC ~ 22.4 µM.hrC24hr ~371 nM

Repeat POC Study with MK-0493, Done at MTD, Indicated Weight Loss was Not Statistically Significant

Targeting Upstream MC4 Pathway DefectsRare Diseases

eemers et al. Diabetes 2012; 61:383.allis et al. Human Molecular Genetics 2002; 11: 1997. ono et al. Clinical Chemistry 2005; 51: 1358.

Rhythm FocusMC4 Pathway

Decreased AppetiteDecreased Weight

MC4 NeuronsPOMC NeuronsMC4R

Setmelanotide

LepR

DownstreamUpstream

MC4R

MSH

PCSK

POMC DeficiencyPOMC Hetz / POMC Epigenetic Deficiency

Leptin Receptor Deficiency

LEPTIN SIGNAL

Bardet-Biedl & Alström Syndromes

hnen P et al. N Engl J Med 2016;375:240-246

inal Article

oopiomelanocortin Deficiency eated with a Melanocortin-4 ceptor Agonist

Kühnen, M.D., Karine Clément, M.D., Susanna Wiegand, M.D., Oliver enstein, M.D., Keith Gottesdiener, M.D., Lea L. Martini, M.D., Knut Mai, Ulrike Blume-Peytavi, M.D., Annette Grüters, M.D., and Heiko Krude,

POMC Deficiency Obesity Phase 2 Study

Therapy & Tools

Patient

Target

A

BC

DE

Mechanism

Vision for translational medicine• Research starts with and returns

to the patient• Powerful trend in research and

medicine focusing on patient-centricity

• Research starts with and returns to the patient

• Powerful trend in research and medicine focusing on patient-centricity

• Precision medicine approaches driven by reverse translation drives companion diagnostics

Key Take Home Message