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NEKTAR Marion REUMAUX, Camille SAUVAGE, Cécile TARNUS Faculty of Pharmacy, Lille2, March 2010 Biopharmaceutical company developing a robust pipeline of novel therapeutics based on its advanced polymer conjugate chemistry technology platform. Objective: create value by advancing our lead drug candidates through early to mid-stage clinical development. Corporate statut : Founded in 1990 in California under the name of Inhale therapeutic system Chief Executive Officer : Howard W. Robin Publicly-traded (NASDQ: NKTR) since 1994 350 employees Localisation: strategy reduce risks and time associated with drug development – Drugs approved – Pharmacologic target known and approved =the known safety and efficacy. =approval in indications for which the parent drugs have not been studied or approved Partners Strategy of development : Partnerships and co-development agreements with pharmaceutical companies partnering strategy • to fund further clinical development • manage the global regulatory filing process • manage the marketing • sell the approved drugs • depend on factors: • the cost • complexity of development, • marketing • commercialization needs Advantages of these partnering for Nektar • few needs of cash to fund the end of developpment and others part of drug life. • Royalties function of sales in the different countries. • payment for licence exploitation. Conditions of partnering Obligation of partner: Obligation of Nektar: Responsible for: - future clinical development - commercialization costs - worldwide regulatory filings Possible Responsibility for: - raw material manufacturing - medical device manufacturing Termination of Agreements • 10 years after first commercialization in a country • upon the expiration of their last relevant patent containing a valid claim • if marketing authorization is withdrawn • If marketing is no longer feasible due to certain circumstances 9 approved products for partners Different therapeutic area of R&D MAP0004 NKTR-102 NKTR-118 NKTR-125 Cipro Factor inhale VIII -Préclinical -Phase II III modified CNS/ Pain Immunology / Oncology Inflammation Therapeutics areas Antiinfectives Others Hemophilia --MAP -AstraZeneca -No -Bayer 4 different partner -Preclinical indications NKTR-119 Cimzia NKTR-061 Hematide -Baxter --Phase No --Preclinical newpartner indication II III -AstraZeneca -UCB -Bayer -Affymax NKTR-105 NKTR-181,NKTRNKTR-063 CDP791 -Phase -Phase 194 IIII -No partner -UCB NKTR-171 NKTR-140 -Preclinical -Preclinical -No partner -No partner From inhale therapeutics system to nektar therapeutics 1990 The begining of the story… Creation of INHALE THERAPEUTICS SYSTEMS advantages of pulmonary delivery • greater patient compliance (vs injection) • rapid onset of action • more efficient and targeted treatment of lung disorders • for systemic and local drug administration Inhale therapeutic products products Indication Phase Partners Cipro inhal Cystic Fibrosis Infection Phase II Bayer NKTR-061 (inahled amikacin) Gram-negative pneumonia Phase II Bayer NKTR-063 (inhaled vancomycin) MAP004 Gram-positive pneumonia Phase I Migraine Phase III MAP Exubera diabetes AMM 2006 Pfizer 1990 1995 Neulasta ® : - stimulates the production of neutrophils - neutropenia treatment Exubera ® :inhaled insulin diabetic treatment Nektar and Pfizer : inhaled insulin An important market (2007) • 2.5 millions in France • 246 millions in the world Almost 8 % of the European and north American population • In 2025 : estimate to 300 millions by OMS Medical need • Discovery of insulin 90 years ago converted insulin-dependent diabetes from a fatal to a treatable disease • At that time, scientists were already looking for a more pleasant and less damaging way to administer the hormone. • Admittedly, today's throwaway syringes with ultra-thin are a huge improvement. And the insulin itself produces far fewer side effects than the impure animal insulins available then. But many diabetics still yearn for an alternative to injection Challenges to Alternate of Insulin Delivery • Oral administration: limited bioavailability • Transdermal: delivery and efficacy insufficient so far • Intranasal: limited bioavailability, enhancers needed • Pulmonary: provides alternative route Liability of Inhale : -supplying the delivery devices -And insulin powder Achievement receive a share of the royalties on sales June 1998 January 1995 Inhale and Pfizer announced their collaboration Trials (IIb) indicate their inhaledinsulin product is as effective as insulin shots November 1998 Pfizer and Hoechst Marion Roussel (Sanofi aventis) go into partnership to help foot the bill -for the clinical development programme - building the Frankfurt production plant -Aggreement : jointy manufacture, codevelop and co-promote Novembre 2007 janvier 2006 Pfizer buys exubera part to Sanofi Aventis (for 1.3 milliard $) AMM payment of $135 million from Pfizer in satisfaction of all remaining obligations Marketing janvier 2006 Novembre 2007 pfizer rachete les parts d’exubéra a sanofi aventis (pour 1.3 milliard de dollars) payment of $135 million from Pfizer in satisfaction of all remaining obligations AMM on October Pfizer made a jolting turnabout, announcing it was pulling the plug on Exubera, returning all rights to Nektar. Failure of Exubera • higher prices for a product that offered no medical advantage over injected drugs Some insurance companies are refusing to pay • unwieldy and not very discreet • Exubera caused a slight decline in lung function. • Problematic delivery • the need for spirometry (before and periodically) Scott Joy, associate professor of medicine at Duke University Medical •Center Lack of“I long-term safety data. said, have not prescribed Exubera to a single patient yet, with the reason being that I don’t have a spirometer here in the office.” Coup de grace in 2007 occurrence of lung cancer Impact to nektar - total revenue from Pfizer: in % of nektar total revenue 2006 2007 2008 64% 67% 0% - For the termination agreement they received$135.0 million from Pfizer. - For manufacturing termination agreement with Bespak and Tech Group they paid $39.9 million. • Until april 2008, nektar search a new partner to fund exubera commercial program. • They kept maintenance agreement with both Pfizer and Tech Group to preserve key personnel and manufacturing capacity. • But lung cancer increased and they decide to stop all collaboration with potentiel partner for exubera 1990 1997 1995 Pegasys ® : treatment of Hepatitis C 1990 1995 1997 2001 2000 Somavert ®: Micera®: Cimzia®: - -human growtherythropoietin hormon a-continuous at the moment 2 indications receptor antagonist receptor activator -crohn desease - treatment ofofacromegaly - treatment anemia associated with rheumatoid arthritis PEG-Intron®:Acquisition chronic kidney disease of -a pegylated recombinan human interferon-alpha -treatment of Hepatitis C PEGylation technology • Significant business: in 2005, sales for Pegyleted proteins amounted to more than $5 billion • PEGylation create blockbusters products, such as PEG-Intron® and Pegasys® • Improve the pharmacological property of a drug, but it has also has to be considered as a life cycle extention PEGylation interests • Non-toxic, non-antigenic, non-immunogenic • Improve safety • Different PD and PK properties but the same target INCREASE STABILITY / HALF-TIME Reduced dosing frequency PEGylation interests Creat new drugs with optimized properties Reposition approves products for new indications Rescue non-viable drug candidates Multiple therapeutics areas PEGylation limitations Reactions are not hightly specific, Pegylation can be incomplete Traditional PEG systems are polydisperse => problem for Quality Control Now => monodisperse Pegylation Can accumulated in the liver Loss of biological activity but it is compensated by the prolonged body half time Small Molecule Polymer Conjugates • Can pass trough intestinal gate to act on a cell surface target receptor • Or, reduced transport across specific membrane barriers in the body, such as the blood-brain barrier ( => depend on the type of polymer used) The drug can also be engineered to cross cell membranes to reach an intracellular target Increase oral bioavailability NKTR-118, NKTR-140 and NKTR-171 Pro-Drug Conjugates Several drug molecules attached to a large molecular weight polymer in a multi-arm architecture Programmable releasable linkers Above all for oncolytics drugs NKTR-102 and NKTR-105 The active parent molecule is cleaved from the prodrug through pH or enzymatic hydrolysis Large Molecule Polymer Conjugates The linkage allows for a programmed and complete release of the therapeutic to optimize its bioactivity and allow it to bind to this receptor in its natural state. • Peptides => smaller in size than biologics •Nektar has designed a novel hydrolyzable linker •Half life extended •Also for proteins and larger molecules •No drug candidate yet in there pipeline Antibody Fragment Conjugates • Branched PEG conjugated to antibody fragment => become the Fc fragment • Stable or degradable linkage AVANTAGES Improve toxicity profile Extend half-life Reduce glomerular filtration rate Reduce antigenicity 1990 1995 1997 2001 2000 2002 Acquisition of Macugen ®: in treating age-related macular degeneration 1990 1995 1997 2001 2000 2005 2002 2003 Acquisition of Inhale Therapeutics Systems change to NEKTAR THERAPEUTIC Acquisition of AEROGEN • Aerogen is a specialty medical device company • Nektar Therapeutics buy drug delivery specialist Aerogen for $32 million boost its position in respiratory technologies. 1990 1995 1997 2001 2000 2005 2002 Acquisitio n of 2007 2007 Collaboration with Bayer HealthCare • NKTR-061 ( inhaled amikacin) • Indication: Gram-negative pneumonias, result of complications of other patient conditions or surgeries • used: with conventional mechanical ventilators or as a hand-held ‘off-vent’. 1990 1995 1997 2001 2000 2005 2002 Acquisition of 2008 2007 2008 sale and transfer part of research to Novartis Pharma AG On December 31, 2008 Pulmonary area acquisition • To 115 millions $ • Assignment concerned: – – – – – Research Development Formulation and manufacturing technology Equipement,140 personnel Intellectuel propreties • retained all rights to BAY41-6551, partnered with Bayer Healthcare + royalty rights for the Cipro Inhale 1990 1995 1997 2001 2000 2005 2002 Acquisition of 2008 2007 2009 NKTR-118 and NKTR-119 as study case Deal between Nektar and AstraZenaca for NKTR-118 andNKTR-119 development Initial payment: $125 million Total payement: $1.4 billion ? 2007 2009 2010 NKTR-118: a novel PEGylated naloxol conjugate for the treatement of opioid-bowel dysfunction (OBD) naloxol OBD 40% of patients taking opioid Traditional constipation treatment PEGylated naloxol • not so effective • Direct action on opiod-receptor Commercial opportunity for prevention and treatment > $1 billion NKTR-118: a novel PEGylated naloxol conjugate for the treatement of opioid-bowel dysfunction (OBD) Central μ-opioid receptors => analgesia peripheral μopioid receptors => inibits bowel fonction Opioid agonists still No reversal activating analgesia receptors No crossing of the bloodbrain barrier No adverse GI effects Peripheral antagonists disloge opiod Study design Results Conclusion • Oral NKTR-118 restores GI function by increasing the frequency of SBMs • No reversal or no reduction of opioid-mediated analgesia • Well tolerated, side effects being dose dependent NKTR-118 => NKTR-119 NKTR-118 • Indication: Opiod bowel dysfunction • Phase 2 complete NKTR-119 • Co-formulation: NKTR-118 and opioid • Indication: Analgesic for pain • Clinical programme to demonstrate proo-ofprinciple in humans initiated in 2009 Total revenue (millions) 300 $273,027 250 $217,718 collaboration and other product sales and royalties 200 150 $90,185 100 $71,931 50 0 2006 2007 2008 2009 Revenue Different collaboration deals (2008) Others 31% Roche 14% Revenue by geographic area Bayer 24% Novartis 15% 100% 90% UCB 16% 80% 70% 60% other countries 50% US 40% EU 30% 20% 10% 0% 2006 2007 2008 R&D expenses (millions) 180 160 $149,381 $153,575 $154,417 140 120 $95,109 100 80 60 40 20 0 2006 2007 2008 2009 Futur for Nektar • Possibility of repurchase ? • many partnering with big pharma • Desire to lead their product from research to commercialization. SWOT analysis STRENGTH WEAKNESSES •Strong and strategic alliance • Financially dependant on its partnerships •Innovating technological platform • R&D budget too high •Blockbusters • few products on the market •diverse sectors of applications •Since the pulmonary sector sale => only one technological platform •Various pipeline OPPORTUNITIES • Short term: to strengthen the partners network • Long term: develop its own molecule to commercialization THREATS • Competitors •Fail of NKTR-118 and 119 Thanks for your attention