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Reducing Prescription Drug Abuse with Abuse-Resistant and Use-Reducing Technologies: REMOXY & POSIDUR CONFIDENTIAL1 Jim Brown, D.V.M. President and CEO, DURECT Corporation

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Prescription Opioid Abuse and DURECT Development Candidate: REMOXY Development Candidate: POSIDUR Summary & Next Steps CONFIDENTIAL2

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3 1. Institute of Medicine, 2011 survey of U.S. adults reporting that they had pain in the past three months 2. Archives of Internal Medicine, 2011: Office of National Drug Control Policy 100 Million Americans Suffer from Chronic Pain Chronic pain affects 100 million Americans 1 4 million Americans per year are prescribed a long-acting opioid 2 KEY OBSERVATIONS

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CONFIDENTIAL4 1. Drug Abuse Warning Network (DAWN) SOURCE: Atluri et al. Pain Physician 2014; 17:E119-E128 Opioid Misuse Thousands of DAWN 1 visits Opioid Misuse Thousands of DAWN 1 visits Opioid Use Billions of grams Opioid Use Billions of grams Opioid Misuse 3x Opioid Use and Growing Opioid Use increased by 1,349% in 15 years Concurrently, Opioid Misuse has increased by 4,680% KEY OBSERVATIONS 1996 2004 2011

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CONFIDENTIAL5 Opioid Misuse Thousands of DAWN 1 visits Opioid Misuse Thousands of DAWN 1 visits Opioid Use Billions of grams Opioid Use Billions of grams Opioid Misuse 3x Opioid Use and Growing Opioid Misuse grew at 3X the rate of Opioid Use KEY OBSERVATIONS 1996 2004 2011 1. Drug Abuse Warning Network (DAWN) SOURCE: Atluri et al. Pain Physician 2014; 17:E119-E128

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SOURCE: Centers for Disease Control and Prevention. Unintentional Drug Poisoning in the United States (July 2010). CONFIDENTIAL6 Opioid Deaths 3-6x More Common than Cocaine Deaths or Heroin Deaths Opioid Overdose Deaths are: 3x Cocaine Deaths 6x Heroin Deaths KEY OBSERVATIONS OPIOIDS COCAINE HEROIN

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Leading Causes of Injury Death Thousands of Deaths CONFIDENTIAL7 SOURCE: National Center for Health Statistics. Data Brief: Drug Poisoning Deaths in the United States, 1980-2008. December 2011. No.81. Updated with 2009 and 2010. Drug Poisoning surpassed motor vehicle traffic-related injuries as the leading cause for injury death in U.S. KEY OBSERVATIONS Motor Vehicle Traffic Drug Poisoning: Leading Cause For Injury Death

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CONFIDENTIAL8 REMOXY POSIDUR Abuse-Resistant Formulations Our focus is on developing technologies to reduce prescription drug abuse Reduce Opioid Use and Exposure DURECTs Commitment to the Patient

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Prescription Opioid Abuse and DURECT Development Candidate: REMOXY Development Candidate: POSIDUR Summary & Next Steps CONFIDENTIAL9

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10 Automobiles: Setting The Standard for Safety Photo: http://eblog.mercedes-benz-passion.com/2011/03/diesel-engines-in-mercedes-benz-passenger-cars/

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CONFIDENTIAL11 Automobiles: Setting The Standard for Safety Photo: Courtesy of the Boston Public Library, Leslie Jones Collection.

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CONFIDENTIAL12 Automobiles: Setting The Standard for Safety Photo:: car.mitula.us

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CONFIDENTIAL13 Automobiles: Setting The Standard for Safety

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AUTOMOBILEAUTOMOBILE Seatbelt: Lap Seatbelt: Shoulder Front Airbags Side Airbags Crumple Zones CONFIDENTIAL14 REMOXY Sets Standard for Safety Automobile Safety Measures vs. Common Methods of Drug Abuse REMOXYREMOXY Snort Inject Chew Smoke Combine with Alcohol

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CONFIDENTIAL15 OXYCONTIN Photo: Copyright 2011 The New York Times Company

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CONFIDENTIAL16 REMOXY Sets Standard for Safety Photo: Copyright 2011 The New York Times Company OXYCONTIN OXYCONTIN TR

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CONFIDENTIAL17 REMOXY Sets Standard for Safety Photo: Copyright 2011 The New York Times Company OXYCONTIN OXYCONTIN TR REMOXYREMOXY Snort Inject Chew Smoke Combine with Alcohol REMOXY

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CONFIDENTIAL18 Clinical Data Demonstrate that REMOXY Reduces Abuse-Potential Compared to Oxycodone Drug Liking was significantly lower* for REMOXY Time to Peak Drug Liking was significantly delayed* for REMOXY No patient could chew REMOXY for more than 1.5 minutes due to taste and texture * p

*p=0.0664 ; derived using CMH Chi-Square test adjusted by study sites **p=0.0309 ; derived using CMH Chi-Square test adjusted by study sites POSIDUR May Reduce Opioid Prescriptions After Surgery Hernia Surgery Percent Patients Not Taking Opioids Shoulder Surgery Percent Patients Not Taking Opioids >20% MORE patients did not require a single opioid +24% p = 0.0309*

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CONFIDENTIAL27 Hernia Surgery Shoulder Surgery > 20% more patients didnt require a single opioid p = 0.0664* p = 0.0309* Original from Corporate Slides POSIDUR : Proportion of Patients NOT Taking ANY Supplemental Opioid 0-72 Hrs

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CONFIDENTIAL28 Over 20% MORE PATIENTS DID NOT REQUIRE A SINGLE OPIOID POST-SURGERY

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CONFIDENTIAL29 800,000 Surgeries 800,000 Patients 160,000 Avoided Prescriptions Prevalence of Hernia Surgeries per year in U.S. 100% of patients exposed to opioid prescription 20% of Prescriptions Avoided 5-10% of population genetically susceptible to opioid abuse 1 SOURCE: Hoffman, Matthew. Prescription Drug Abuse: Who Gets Addicted and Why?. www.webmd.com. Accessed May 1, 2014.www.webmd.com Potential Impact 8,000-16,000 8,000-16,000 FEWER ABUSERS PER YEAR 8,000-16,000 8,000-16,000 FEWER ABUSERS PER YEAR POSIDUR Potentially Prevents Thousands of Abusers Per Year

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CONFIDENTIAL30 70M Surgeries 35M Patients 7 Million Avoided Prescriptions SOURCE: Hoffman, Matthew. Prescription Drug Abuse: Who Gets Addicted and Why?. www.webmd.com. Accessed May 1, 2014.www.webmd.com Prevalence of Surgeries per year in U.S. 20% of Prescriptions Avoided 5-10% of population genetically susceptible to opioid abuse 1 POSIDUR Potentially Prevents Thousands of Abusers Per Year Potential Impact 50% of patients exposed to opioid prescription 350,000-700,000 FEWER ABUSERS PER YEAR

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CONFIDENTIAL31 FDA is Committed to Reducing the Abuse of Opioids Let me say, in no uncertain terms: the prevention of prescription opioid abuse is of the highest priority for the FDA. Nothing can erase the tragedy so many people have had to face as a result of abuse, addiction, or misuse of opioids. But we can make meaningful progress to reduce and prevent our nations prescription drug crisis. FDA is committed to reducing abuse of opioids and ensuring appropriate access to pain medicines for patients in need. Margaret A. Hamburg, M.D., Commissioner of the U.S. Food and Drug Administration, stated on April 29, 2014:

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CONFIDENTIAL32 FDA has determined that they cannot approve the NDA in its present form, stating the NDA does not contain sufficient information to demonstrate that POSIDUR is safe when used in the manner described in the proposed label, and the FDA has indicated that additional clinical safety studies need to be conducted. POSIDUR Complete Response Letter POSIDUR Complete Response Letter Food and Drug Administration February 12, 2014

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Prescription Opioid Abuse and DURECT Development Candidate: REMOXY Development Candidate: POSIDUR Summary & Next Steps CONFIDENTIAL33

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REMOXY and POSIDUR have both been submitted to the FDA for approval, and both approvals have been delayed. DURECT is committed to reducing pain and opioid abuse. DURECT continues to engage with FDA to bring these two critical products to market. How you can help CONFIDENTIAL34 Summary and Next Steps

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Opioid use and abuse is a fast-growing and critical concern in the U.S. Medical providers can impact these trends by turning to smarter drug technology FDA claims that introducing drug formulations to reduce prescription drug abuse is their top priority Novel medications in development with abuse-resistant technology, such as REMOXY and POSIDUR, are direly needed to address the prescription drug abuse epidemic in the United States. CONFIDENTIAL35 Summary and Next Steps Alternative 1

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CONFIDENTIAL36 REMOXY has been delayed since 2008 by 2 Complete Response Letters: Due to primarily manufacturing concerns Pfizer expects to resubmit mid-2015 POSIDUR Complete Response Letter in February 2014 FDA requesting additional safety data surrounding surgical side-effects DURECT continues to engage with FDA senior management to bring these products to market, so patients realize their clear benefits REMOXY and POSIDUR Approval Delayed Alternative 2