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Retrophin presentation03 13 Retrophin presentation03 13 Presentation Transcript

  • Confidential - Not for Duplication or Distribution Retrophin March 19, 2013
  • 2Confidential: Not for Duplication or Distribution Forward-Looking Statements This presentation contains forward-looking statements, including statements about our prospects, competitive position, regulatory filings and agency actions, and the anticipated development, timing, data readouts and therapeutic scope of programs in our clinical pipeline. These forward- looking statements may be accompanied by such words as “anticipate,” “believe,” “estimate,” “expect,” “forecast,” “intend,” “may,” “plan,” “project,” “target,” “will” and other words and terms of similar meaning. You should not place undue reliance on these statements. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including the safety and efficacy of our product candidates, product competition, the occurrence of adverse safety events with our products, adverse market and economic conditions, our dependence on collaborations and other third parties over which we may not always have full control, failure to comply with government regulation, our ability to protect our intellectual property rights, and have sufficient rights to market our products and services together with the cost of doing so, problems with our manufacturing processes and our reliance on third parties, our ability to attract and retain qualified personnel, our level of indebtedness, environmental risks, change of control provisions in our collaborations and the other risks and uncertainties that are described in the Risk Factors section of our most recent annual or quarterly report and in other reports we have filed with the SEC. These statements are based on our current beliefs and expectations and speak only as of the date of this presentation. We do not undertake any obligation to publicly update any forward-looking statements.
  • 3Confidential: Not for Duplication or Distribution About Retrophin • Retrophin is a biopharmaceutical company dedicated to discovering, developing and marketing therapies for rare and life-threatening diseases. • We work to better the lives of the patients and families we serve. We are dedicated to working on medical problems where the biopharmaceutical industry has limited interest or effectiveness.
  • 4Confidential: Not for Duplication or Distribution Pipeline RE-021 RE-024 Focal Segmental Glomerulosclerosis Pantothenate Kinase Associated Neurodegeneration Duchenne Muscular Dystrophy Spinal Muscular Atrophy RE-001 RE-003 Phase IPre- clinical Phase II Phase III Market
  • 5Confidential: Not for Duplication or Distribution Our R&D Approach Catastrophic Properties • Not always rare • Lethal • Pediatric • High cost to system and patient • Low QOL, inability to have a productive life • Phase I/II approval possible Retrophin Understood Properties • Often monogenic • Traditional treatment modality (no gene therapy, stem cells) • Scientific consensus • IND within 24 months • Defined target engaged Catastrophic Disease & Phenotype Understood Biology & Pathogenesis
  • 6Confidential: Not for Duplication or Distribution RE-021 • Endothelin Receptor Antagonist (ERA) – Best-in-class selectivity – One of only two ERAs (zibotentan) ever advanced into the clinic that does not bind the ET-B receptor – High affinity for angiotensin receptor • Discovered by Bristol-Myers Squibb and developed by Pharmacopeia (7 Phase I studies, 2 Phase II studies) for hypertension – Phase II data reveals a very potent and well-tolerated drug • 2024 Composition of Matter Patent • Licensed from Ligand and Bristol-Myers
  • 7Confidential: Not for Duplication or Distribution ERA Properties and Choosing the RE-021 Indication Anti-hypertensive (~20mm sBP reduction) PAH: Well served by Tracleer, macitentan & Letairis Essential Hypertension: therapeutic index too narrow Refractory Hypertension: clinical and commercial path questionable Anti-proteinuric (~50% reduction in uACR) Diabetic Nephropathy: therapeutic index requirement too narrow; lowering minor amounts of proteinuria is of unclear consequence FSGS, MN, LN, IgAN (rare and severe nephropathies): ideal diseases to harness the anti-proteinuric property of ERAs Anti-inflammatory (unproven) Pro-wound healing (weak effect?) Tracleer approved for digital ulcers in system sclerosis
  • 8Confidential: Not for Duplication or Distribution Focal Segmental Glomerulosclerosis (FSGS) • Disease where the glomeruli become progressively scarred and the kidney is dysfunctional • This dysfunction is manifested by marked proteinuria (2-10g/day), dyslipidemia, hypoalbuminemia and severe edema including anasarca and ascites • Reduction in proteinuria is the main treatment goal – "The goal of therapy [for FSGS] is to induce a complete or partial remission of proteinuria". D'Agati et al. NEJM 2011;365:2398-2411. • Only 20-30% of patients respond to steroids, and the majority of non-responders will develop kidney failure in 5-10 years • Most patients are pediatric • We think there are more than 50,000 patients with FSGS in the U.S. alone and they cost at least $25,000 per annum to the system – Dialysis >$50,000 PPPY – Transplant >$100,000 PPPY – Estimated sales potential $1 billion+
  • 9Confidential: Not for Duplication or Distribution FSGS is a Growing Problem • 2,421 biopsy-confirmed FSGS patients progressed to ESRD in 2010 (2% of all new ESRD patients), according to the US RDS • If non-biopsied patients are included, there may be as many as 3,800 (4% of all ESRD) FSGS patients progressing to ESRD annually Kitiyakara et al, 2004. NIH ESRD RDS database.
  • 10Confidential: Not for Duplication or Distribution FSGS is Driven By Proteinuria 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Healthy Diabetic Nephropathy FSGS 0.002- 0.200 5.000 • Proteinuria is not just a surrogate marker, but damages glomerular filtration integrity by overloading renal tubules causing an inflammatory and fibrotic cascade (Abbate et al., 2006) Proteinuria:g/day FSGS DN Symptomatic? YES NO Likelihood of ESRD 70% 3% Time to ESRD 5-15y 20-40y Age of Onset 5-15yo 50-70yo # of patients 50,000 2M Disease-dependent mechanisms of albuminuria. Cooper et al. Am J Physiol Renal Physiol 295:F1589-1600, 2008.
  • 11Confidential: Not for Duplication or Distribution Mechanism of Action Afferent arteriole Blood enters the glomerulus here at rapid speed. Too much vasoconstriction (narrowing of the vessel) will result in less filtration. To compensate, flow rate is increased by endothelin in a vicious cycle. Blocking ET-A stops ET-1 from constricting the vessel. ET-B, when activated by ET-1, is vasodilatory. Podocyte Forms the barrier to stop proteins from entering the urinary space. Damaging the integrity of the podocyte results in proteinuria. Efferent arteriole all the protein in blood exits here – none should enter the urinary space. ET-B ET-A ET-B naturally blocks the re-absorption of Sodium and Water from the collecting duct. Natriuresis and diuresis are vital processes to keeping fluid accumulation down. If a drug blocks ET-B, it blocks natriuresis and diuresis, resulting in profound edema. vasopressin aquaporin
  • 12Confidential: Not for Duplication or Distribution FSGS Standard of Care • Current Standard of Care and treatment goal is to lower proteinuria – 1L: Steroids (prednisone) to induce remission  20%-30% of patients are responsive – 2L: ARB (almost all patients on ARB/ACEi)  Demonstrated to lower proteinuria and assumed to be renoprotective (Kangovi et al) – 3L: cyclosporine, MMF, rituximab  Experimental  Benefits are usually short-term with high toxicity – 4L: Transplant, Dialysis, Plasmapheresis  Transplant in FSGS recurs in 20-40% of allograft •No FDA approved medicine for FSGS
  • 13Confidential: Not for Duplication or Distribution ERAs ARBs FSGS ? Diabetic Nephropathy ERAs lower proteinuria by 40%-60% in DN atrasentan (Kohan et al, avosentan: Mann et al.) ARBs lower proteinuria 40-60% in DN and events by 16% (losartan in RENAAL, Brenner et al.) ARBs lower proteinuria by ~45% in FSGS (Kangovi et al, 2011) Retrophin is conducting this trial. Dhaun et al. showed ~35% reduction with sitaxsentan High fidelity between and across diseases Will ERAs Lower Proteinuria in FSGS?
  • 14Confidential: Not for Duplication or Distribution ERAs Reduce Proteinuria as a Class-Effect • Atrasentan (Abbott Labs) – Phase II demonstrated -35% to -42% reduction in proteinuria in diabetic nephropathy patients as primary endpoint (p=0.073 and p=0.023) Kohan et al. JASN 2011 • Darusentan (Gilead / Myogen) – Phase III demonstrated -60% reduction in proteinuria in rHTN patients with albuminuria at baseline as a secondary endpoint (p=0.0087) Weber et al. Lancet 2009 • Avosentan (Novartis / Speedel) – Phase III demonstrated -44% (25mg) and -49% (50mg) reduction in proteinuria in diabetic nephropathy patients as a secondary endpoint (p<0.0001) Mann et al. JASN 2010 – Phase II demonstrated -45% reduction in proteinuria in diabetic nephropathy patients as a primary endpoint (p<0.0001) Wenzel et al. JASN 2009 • Sitaxsentan (Pfizer / Encysive) – Phase II demonstrated -35% reduction in proteinuria as a primary endpoint (p=0.0069) in all nephropathies, including FSGS Dhaun et al. Hypertension 2011 • RE-021 (Retrophin) – Hypothesize it will reduce proteinuria in-line with the ERA class
  • 15Confidential: Not for Duplication or Distribution ERA Landscape Name Company Phase Indications ETa Affinity ETB Affinity ETa/ETb Proteinuria ambrisentan Gilead Marketed PAH 1.0 nM 195 nM 200 N/A bosentan Actelion Marketed PAH, IPF, SS 4.7 nM 95 nM 20 N/A macitentan Actelion Filed PAH 0.5 nM IC50 391 nM IC50 600 N/A RE-021 Retrophin II pivotal FSGS, HTN 9.3nM Ki >10,000uM IC50 N/A N/A atrasentan Abbott III CRPC, DN 0.034nM 63.3nM 1,862 -42% avosentan Novartis discontinued (toxicity) DN 142nM ??? -44% zibosentan AstraZeneca discontinued (failure) CRPC 21 nM > 100 uM N/A N/A clazosentan Actelion discontinued (failure) HF 9.5 nM 6.4 nM 1,300 N/A tezosentan Actelion discontinued (failure) SH 18 nM 21 nM 1 N/A darusentan Gilead discontinued (failure) rHTN, HF 6 nM 1000 nM 170 -60% sitaxsentan Pfizer discontinued (toxicity) PAH, FSGS 0.430 nM Ki 9800 nM IC50 7,000 -35%
  • 16Confidential: Not for Duplication or Distribution FSGS: Why is Proteinuria Important? • Cattran, Gipson and Lewis have found patients with reductions in proteinuria have improved kidney survival in FSGS • Unlike DN, physicians and patients are intensely focused on proteinuria levels in FSGS
  • 17Confidential: Not for Duplication or Distribution Lowering Proteinuria has Multiple Positive Effects • Supavekin et al. showed ACE+ARB resulted in 63% reduction in proteinuria – Accompanying 28% reduction in cholesterol – 30% improvement in serum albumin – 21% reduction in steroid dose – Blood pressure improvement • FDA letter shows the agency understands multiple improvements in symptoms are crucial for these patients and would support accelerated approval in absence of outcomes data
  • 18Confidential: Not for Duplication or Distribution RE-021 in Hypertension In a Phase IIB trial, RE-021 showed potent blood pressure reductions above and beyond the ARB irbesartan.
  • 19Confidential: Not for Duplication or Distribution ERAs and Edema • RE-021 Phase IIB peripheral edema – 3% in n=58 200mg cohort – all mild/moderate – 7% in n=58 400mg cohort – all mild/moderate – 11% in n=28 800mg cohort – all mild/moderate two discontinuations – 2% in n=59 placebo cohort – 3% in n=58 irebsartan 300mg cohort • Avosentan Phase III “ASCEND” fluid overload data – 45% in n=455 avosentan 25mg – 46% in n=478 avosentan 50mg – 31% in n=459 placebo • Darusentan Phase III edema/fluid retention data in rHTN – 25% in 50mg darusentan cohort – 32% in 100mg darusentan cohort – 25% in 300mg darusentan cohort – 14% in placebo cohort
  • 20Confidential: Not for Duplication or Distribution RE-021 Phase II “FONT-3” Study • n=72 study beginning in 1H13 • Initiation activities are underway – All patients have baseline ARBs on board at screening and wash-out at week 0 • Potential pivotal study • identifier: NCT01613118 • Proteinuria at 12 weeks is primary endpoint – Secondary endpoints  LDL reduction  Serum albumin  Weight change • Randomized, double-blind vs. irbesartan – RE-021 200mg + placebo – RE-021 400mg + placebo – RE-021 800mg + placebo – Irbesartan + placebo
  • 21Confidential: Not for Duplication or Distribution RE-021 Regulatory Status • Retrophin received letter from Dr. Stockbridge, head of CardioRenal Division at FDA – Noted FDA “would consider proteinuria primary endpoint under Subpart H approval” – Is sympathetic to FSGS patients, noting that there are no approved therapies – Allows for FONT-3 to proceed, but FDA guidance on registration path was unsolicited and welcomed by Retrophin • FDA has told patient advocacy group they will accept proteinuria as a pivotal trial primary endpoint
  • 22Confidential: Not for Duplication or Distribution RE-021: Potential for Multiple Indications DIgAN FSGS MN SR- MCD MPGN LN DIABETIC NEPHROPATHY • Focal Segmental Glomerulosclerosis • Lupus Nephritis • Steroid-Resistant Minimal Change Disease • Membranous Nephropathy • Membranoproliferative Glomerulonephritis • IgA Nephropathy • Diabetic Nephropathy • Obesity-related Glomerulopathy • … 20 more X-Linked Alport Syndrome
  • Confidential - Not for Duplication or Distribution Earlier Stage Pipeline
  • 24Confidential: Not for Duplication or Distribution Pantothenate Kinase Associated Neurodegeneration (PKAN) • Lethal autosomal recessive inborn error resulting in pantothenate kinase 2 defectiveness – Patients with PANK2 deficiency cannot phosphorylate pantothenate (vitamin B5) into phosphopantothenate • Typical onset of disease is 3 years of age • Patients die within 10 years • 5,000-10,000 estimated global commercial patients • March 11, 2013 – RE-024 rescued the phenotype of pantothenate kinase associated neurodegeneration (PKAN) in vitro and in vivo, demonstrating successful replacement therapy proof-of-concept. Pantothenate Phosphopantothenate PANK2
  • 25Confidential: Not for Duplication or Distribution RE-024 • Retrophin has developed a library of phosphopantothenate molecules which will serve as replacement therapy • NCEs with no prior art or similar disclosure of structure in literature • IP filed, 100% Retrophin owned • Research collaboration with St. Jude Children’s Research Hospital • IND filing within 12-24 months
  • 26Confidential: Not for Duplication or Distribution RE-001 for Duchenne Muscular Dystrophy • In preclinical development for Duchenne Muscular Dystrophy (DMD) – Plan to move into a Phase I clinical trial in 2014 pending successful IND-enabling studies • Designed to replace dystrophin, the missing protein that causes DMD,by providing a recombinant supply of a very similar protein (utrophin) linked to a cell- penetrating moiety which allows for delivery of protein into the cell where it is needed for structural support and integrity – Because missing dystrophin is the only physiological cause of Duchenne, we believe a dystrophin replacement therapy has a very good chance of being a disease-modifying agent for DMD – Treatment with RE-001 resulted in a survival benefit versus placebo in the “double-knockout” (utrophin and dystrophin-knockout) mouse model.
  • 27Confidential: Not for Duplication or Distribution Financials • 8.6 million shares outstanding as of 1/2013 • $3.50 per share price (2/8/2013) • $30 million market capitalization • $0.5 million cash balance as of 1/2013 • RTRX stock symbol on OTC Bulletin Board – Up-listing planned
  • 28Confidential: Not for Duplication or Distribution 2013 Milestones RE-021 Initiate “Font 3” study H1 Report results Y/E Initiate second RE-021 study Q4 PKAN Preclinical data H1 Lead selection/IND-enabling toxicology Q3
  • Confidential - Not for Duplication or Distribution THANK YOU
  • Confidential - Not for Duplication or Distribution Retrophin March 19, 2013