Patient-Centered Reverse Translation. John A. Wagner, MD, PhD

Transcription

1 Patient-Centered Reverse Translation John A. Wagner, MD, PhD

2 Key Take Home Message 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

3 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

4 E D Patient A Therapy & Tools Mechanism C B Wagner CPT 2018;103: Target

5 E D Patient A Forward Translation Therapy & Tools Application or translation of laboratory research to clinical experiments or patients Bench-to-bedside Mechanism C B Target

6 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

7 E D Patient A Reverse Translation Therapy & Tools Application or translation of clinical, patient-centered data to laboratory research Bedside-to-bench Mechanism C B Target

8 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

9 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)

10 4. IMPLEMENTATION: A NEW APPROACH Monoclonal antibodies, alirocumab and evolocumab, were approved 12 years after the initial bedside observations, E and have been shown to dramatically reduce LDL cholesterol in patients with D hypercholesterolemia Patient 1. Experiment of Nature PCSK 9 mutations associated with remarkably low cholesterol and reduced incidence of coronary A artery disease Therapy & Tools Mechanism 3. Inhibition of PCSK9 C Discovery of antibody inhibitors of PCSK9 resulted in forward translation of therapeutics that reduced degradation of LDL receptors and lowering cholesterol levels Target B 2. Understanding LDL Mechanism PCSK9 null mice confirmed low cholesterol and PCSK9 binding LDL receptors linked with control of LDL cholesterol levels

11 PLEMENTATION: A NEW APPROACH oclonal antibodies, alirocumab and locumab, were approved 12 years r the initial bedside observations, E and e been shown to dramatically reduce cholesterol in patients with D rcholesterolemia Patient 1. Experiment of Nature PCSK 9 mutations associated with remarkably low cholesterol and reduced incidence of coronary A artery disease Therapy & Tools Mechanism 3. Inhibition of PCSK9 C Discovery of antibody inhibitors of PCSK9 resulted in forward translation of therapeutics that reduced degradation of LDL receptors and lowering cholesterol levels Cohen JC et al. N Engl J Med 2006;354: Target B 2. Understanding LDL Mechanism PCSK9 null mice confirmed low cholesterol and PCSK9 binding LDL receptors linked with control of LDL cholesterol levels

12 4. IMPLEMENTATION: A NEW APPROACH Monoclonal antibodies, alirocumab and evolocumab, were approved 12 years after the initial bedside observations, E and have been shown to dramatically reduce LDL cholesterol in patients with D hypercholesterolemia Patient 1. Experiment of Nature PCSK 9 mutations associated with remarkably low cholesterol and reduced incidence of coronary A artery disease Therapy & Tools Mechanism 3. Inhibition of PCSK9 C Discovery of antibody inhibitors of PCSK9 resulted in forward translation of therapeutics that reduced degradation of LDL receptors and lowering cholesterol levels Stein EA et al. N Engl J Med 2012;366: Target B 2. Understanding LDL Mechanism PCSK9 null mice confirmed low cholesterol and PCSK9 binding LD receptors linked with control of LDL cholesterol levels

13 E D Patient A Therapy & Tools Mechanism C B Target

14 MC4R Mechanism of Action MC4R Agonism of MC4R proposed to food intake and weight Leptin Fat mass Food intake energy use Lipolysis? RQ Insulin sensitivity ( ) Glucose uptake ( ) Glucose production ( ) Insulin release ( )

15 Strong target validation, particularly genetic evidence 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

16 Single 500-mg MK-0493 Dose Had Marginal Effects on 24-hr Food Intake 24-hr intake: Sibutramine: ~18% 500 mg MK-493: ~ 7% p=0.065 p<0.001 p<0.001 p=0.009 p=0.020 p=0.004 Krishna R et al CPT 2009 Dec;86(6): N=28 4 hr 10 hr 14 hr 24 hr Total

17 Hint of Efficacy in POC Study in Obese Patients Suggested Higher Exposures May Be Necessary Mean Change in Body Weight (kg) Placebo (N=64) L mg (N=65) L 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) 400 mg AUC ~ 8.9 µm.hr C 24hr ~108 nm 25-3 Cumulative Incidence Rate (%) Rashes appear in 400 mg group 7-21 days on treatment Days After First Dose Placebo 200 mg 400 mg -2 Baseline Week 12 Week 12 LS Means (LOCF) LS Means (RMA) Week Krishna R et al CPT 2009;86:659-66

18 Repeat POC Study with MK-0493, Done at MTD, Indicated Weight Loss was Not Statistically Significant Change in Body Weight (kg) Placebo (n=53) MK-0493 (n=111) -1.2 (-2.6, 0.2) 800 mg AUC ~ 22.4 µm.hr C 24hr ~371 nm p= BL Week 18 Week RMA (84% CI) Probability >2.1 kg is ~11%

19 Targeting Upstream MC4 Pathway Defects Rare Diseases MC4 Pathway Rhythm Focus Upstream Downstream PCSK Setmelanotide MC4R LEPTIN SIGNAL LepR POMC Neurons MSH MC4R MC4 Neurons Decreased Appetite Decreased Weight Leptin Receptor Deficiency POMC Deficiency POMC Hetz / POMC Epigenetic Deficiency Bardet-Biedl & Alström Syndromes emers et al. Diabetes 2012; 61:383. llis et al. Human Molecular Genetics 2002; 11: no et al. Clinical Chemistry 2005; 51: 1358.

20 POMC Deficiency Obesity Phase 2 Study nal Article opiomelanocortin Deficiency ated with a Melanocortin-4 eptor Agonist Kühnen, M.D., Karine Clément, M.D., Susanna Wiegand, M.D., Oliver nstein, 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, nen P et al. N Engl J Med 2016;375:

21 E D Patient A Vision for translational medicine Research starts with and returns to the patient Therapy & Tools Powerful trend in research and medicine focusing on patientcentricity Mechanism C B Target

22 Key Take Home Message 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