NEKTAR

1. NEKTAR Faculty of Pharmacy, Lille2, March 2010 Marion REUMAUX, Camille SAUVAGE, Cécile TARNUS

2. 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.

3. Corporate statut : • Founded in 1990 in Californiaunder the name ofInhale therapeutic system • Chief ExecutiveOfficer : Howard W. Robin • Publicly-traded (NASDQ: NKTR) since 1994 • 350 employees • Localisation:

4. 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

5. Partners Strategy of development : Partnerships and co-developmentagreementswithpharmaceuticalcompanies

6. partnering strategy

7. Advantages of thesepartnering 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.

8. Conditions of partnering Responsible for: - future clinicaldevelopment - commercializationcosts - worldwideregulatoryfilings Possible Responsibility for: - rawmaterialmanufacturing - medicaldevicemanufacturing

9. Termination of Agreements

10. 9 approved products for partners

11. Different therapeutic area of R&D • NKTR-102 • Phase II • 4 different indications • No partner • NKTR-105 • Phase I • No partner • NKTR-118 • Phase II • AstraZeneca • NKTR-119 • Preclinical • AstraZeneca • NKTR-181,NKTR-194 • NKTR-171 • Preclinical • No partner • NKTR-125 • Préclinical • No partner • Cimzia • new indication • UCB • Cipro inhale • Phase II • Bayer • NKTR-061 • Phase II • Bayer • NKTR-063 • Phase I • No partner • NKTR-140 • Preclinical • No partner • Factor VIII modified • Preclinical • Baxter • MAP0004 • Phase III • MAP • Hematide • Phase III • Affymax • CDP791 • Phase II • UCB

12. From inhale therapeutics system to nektartherapeutics

13. The begining of the story… 1990 Creation of INHALE THERAPEUTICS SYSTEMS

14. advantages of pulmonarydelivery • greater patient compliance (vs injection) • rapid onset of action • more efficient and targeted treatment of lung disorders • for systemic and local drug administration

15. Inhale therapeutic products

16. 1990 1995 Neulasta ® : - stimulates the production of neutrophils - neutropeniatreatment Exubera ® :inhaledinsulin diabetictreatment

17. Nektar and Pfizer : inhaled insulin

18. 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

19. Medicalneed • Discovery of insulin 90 years ago converted insulin-dependent diabetes from a fatal to a treatable disease

20. 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. At that time, scientists were already looking for a more pleasant and less damaging way to administer the hormone.

21. But many diabetics still yearn for an alternative to injection Challenges to Alternate of InsulinDelivery • Oral administration: limitedbioavailability • Transdermal: delivery and efficacy insufficient so far • Intranasal: limited bioavailability, enhancers needed • Pulmonary: provides alternative route

24. Liability of Inhale : • supplying the delivery devices • And insulin powder • Achievement •  receive a share of the royalties on sales • to help foot the bill • for the clinical development programme • building the Frankfurt production plant • Aggreement : jointy manufacture, co-develop and co-promote

26. Marketing

28. on October Pfizer made a jolting turnabout, announcing it was pulling the plug on Exubera, returning all rights to Nektar.

29. Failure of Exubera • higher prices for a product that offered no medical advantage over injected drugs • unwieldy and not very discreet • Exubera caused a slight decline in lung function. • Problematic delivery • the need for spirometry(before and periodically) • Lack of long-termsafety data. Someinsurancecompanies are refusing to pay Scott Joy, associate professor of medicine at Duke University Medical Centersaid, “I have not prescribed Exubera to a single patient yet, with the reason being that I don’t have a spirometer here in the office.”

30. Coup de grace in 2007 occurrence of lung cancer

31. Impact to nektar • total revenue from Pfizer: in % of nektar total revenue - For the termination agreement they received$135.0 million from Pfizer. • For manufacturingtermination agreement withBespak and Tech Grouptheypaid $39.9 million.

32. Untilapril 2008, nektarsearch a new partner to fundexubera commercial program. Theykeptmaintenance agreement withboth Pfizer and Tech Group to preservekey personnel and manufacturingcapacity. But lung cancer increased and theydecide to stop all collaboration with potentiel partner for exubera

33. 1990 1997 1995 Pegasys ® : treatment of Hepatitis C

34. 1990 1997 2001 1995 2000 Somavert ® : - human growth hormon receptor antagonist - treatment of acromegaly Micera®: - a continuouserythropoietinreceptoractivator - treatment of anemia associated with chronic kidney disease • Cimzia®: • - at the moment 2 indications • crohndesease • - rheumatoidarthritis Acquisition of • PEG-Intron®: • a pegylatedrecombinanhumaninterferon-alpha • treatment of Hepatitis C

35. Pegylationtechnology

36. PEGylation technology

37. PEGylationinterests • Non-toxic, non-antigenic, non-immunogenic • Improve safety • Different PD and PK properties but the same target Reduceddosingfrequency INCREASE STABILITY / HALF-TIME

38. PEGylation interests

39. PEGylation limitations

40. Nektar: 4 strategies

41. Small MoleculePolymerConjugates • 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 drugcanalsobeengineered to cross cell membranes to reach an intracellulartarget Increase oral bioavailability NKTR-118, NKTR-140 and NKTR-171

42. Pro-Drug Conjugates Several drug molecules attached to a large molecular weight polymer in a multi-arm architecture Programmable releasablelinkers The active parent molecule is cleaved from the prodrug through pH or enzymatic hydrolysis Above all for oncolyticsdrugs NKTR-102 and NKTR-105

43. Large MoleculePolymerConjugates 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 thanbiologics • Nektar has designed a novelhydrolyzable linker • Half life extended • Also for proteins and largermolecules • No drug candidate yet in there pipeline

44. Antibody Fragment Conjugates • Branched PEG conjugated to antibody fragment => become the Fc fragment • Stable or degradable linkage • AVANTAGES • Improvetoxicity profile • Extendhalf-life • Reduceglomerular filtration rate • Reduceantigenicity

45. 1990 1997 2001 1995 2000 2002 Acquisition of Macugen ®: in treating age-related macular degeneration

46. 1990 1997 2001 2005 1995 2000 2002 2003 Inhale Therapeutics Systems change to NEKTAR THERAPEUTIC Acquisition of

47. Acquisition of AEROGEN • Aerogen is a specialty medical device company • NektarTherapeuticsbuydrugdeliveryspecialistAerogen for $32 million boostits position in respiratory technologies.

48. 1990 1997 2001 2005 1995 2000 2002 2007 Acquisition of

49. 2007Collaboration with Bayer HealthCare • NKTR-061 ( inhaledamikacin) • Indication: Gram-negativepneumonias, • used: withconventionalmechanicalventilators or as a hand-held ‘off-vent’. result of complications of other patient conditions or surgeries

50. 1990 1997 2001 2005 2008 1995 2000 2002 2007 Acquisition of