ADPresentations All FINAL FLS

Investor Day Meeting

June 27, 2013

This presenta4on contains forward-‐looking statements, including, but not limited to, statements related to the process and 4ming of an4cipated future clinical development of our product candidates, including the release of the top-‐line clinical data in the final pivotal Phase 3 study of NanoTab System, the poten4al filing of an NDA for the NanoTab System and the 4ming thereof, therapeu4c and commercial poten4al of the Nanotab System and the an4cipated 4ming and therapeu4c and commercial poten4al of our other product candidates, our poten4al commercial market opportunity, the patent protec4on for our product candidates, and our cash and use of proceeds es4mates. Forward-‐looking statements represent our es4mates and assump4ons only as of the date of this presenta4on. Actual results may differ materially due to the risks and uncertain4es inherent in our business, including the outcome, cost and 4ming of our product development ac4vi4es and clinical trials; the uncertain clinical development process, including the risk that clinical trials may not have an effec4ve design; our ability to obtain and maintain regulatory approval of our product candidates; our ability to obtain funding for our opera4ons; our plans to research, develop and commercialize our product candidates; our ability to aMract collaborators with development, regulatory and commercializa4on exper4se; the size and growth poten4al of the markets for our product candidates; our ability to successfully commercialize our product candidates and the 4ming of commercializa4on ac4vi4es; the rate and degree of market acceptance of our product candidates; our ability to develop sales and marke4ng capabili4es; the accuracy of our es4mates regarding expenses, future revenues, capital requirements and needs for financing; our ability to con4nue obtaining and maintaining intellectual property protec4on for our product candidates; and other risks detailed in our filings and reports with the SEC including our Quarterly Report on Form 10-‐Q filed with the SEC on May 8, 2013. You may obtain these documents for free by visi4ng EDGAR on the SEC’s website at www.sec.gov. The statements presented in this presenta4on speak only as of May 21, 2013. We undertake no duty or obliga4on to update publicly any forward-‐looking statements contained in this presenta4on for any reason.

Forward Looking Statements

Agenda

•  9:00am Introduc4on Richard King, CEO AcelRx Pharmaceu4cals

•  9:05am The Future of Post-‐Opera4ve Pain Management Dr Richard Berkowitz, Orthopedic Surgeon. Medical Director, Total Joint Program, Coral Springs Medical Center, FL

•  9:20am Sufentanil – A Fresh Perspec4ve Dr Eugene Viscusi, Anesthesiologist. Professor of Anesthesiology, Director of Acute Pain Management, Thomas Jefferson University Hospital

•  9:35am The Sufentanil NanoTab PCA System – Phase 3 Insights Dr Pamela Palmer, Anesthesiologist. Chief Medical Officer, AcelRx Pharmaceu4cals

3

Agenda

•  9:55am Q&A Panel Dr Richard Berkowitz, Dr Eugene Viscusi, Dr Pamela Palmer, Pam Lindley, RN (Study Nurse, Memorial Hermann Memorial City Hospital, Houston, TX)

•  10:15am Hospital Formulary Adop4on Dr Mike Royal, Anesthesiologist. Chief Clinical Affairs, AcelRx Pharmaceu4cals

•  10:30am Commercializa4on Richard King, CEO AcelRx Pharmaceu4cals

•  10:45am Open Ques4on Session

4

Post-Operative Pain Management: Looking to the Future

Richard Berkowitz, MD, FAAOS Medical Director, Total Joint Program

Coral Springs Medical Center

Optimizing the Patient’s Surgical Experience

LMNOP Approach Less invasive surgery followed by Mul4modal, NOn-‐invasive, Pa4ent-‐controlled analgesic therapy: •  Less invasive surgery results in less severe pain and early discharge •  Mul4modal approach simultaneously aMacks mul4ple pain pathways,

while also reducing excessive dosing of a single pathway •  Non-‐invasive modali4es allow ease of ambula4on and promotes early

discharge •  Pa4ent-‐controlled analgesia allows flexibility and enhances pa4ent

sa4sfac4on

6

Current Post-Operative Analgesia Modalities

IV PCA pump with opioid (usually morphine or hydromorphone) Regional anesthesia techniques depending on type/locaBon of surgery

•  Epidural catheter with local anesthe4c and opioid •  Nerve block: single-‐shot or con4nuous catheter infusion •  Field/wound block with local anesthe4c

MulB-‐modal oral analgesics: CombinaBon of oral extended-‐ and immediate-‐release opioids with oral gabapenBnoids (NeuronBn or Lyrica) and oral anB-‐inflammatory agents

7

50-Year Old Technology While paBent-‐controlled modaliBes are preferred, the complex technology used for IV/epidural PCA can lead to medicaBon errors

•  From 2005–2009: •  56,000 reported adverse events due to

infusion pumps •  87 pump recalls ins4tuted1

•  Es4mated 407 errors per 10,000 IV PCA pa4ents per year2

•  80% of IV PCA errors due to human factors (programming errors) 2,3

1 FDA / AAMI Summit Meeting held October 2010; http://www.aami.org/infusionsummit/AAMI_FDA_Summit_Report.pdf 2 Meissner, Hospital Pharmacy 44:312, 2009 3 ISMP: http://www.ismp.org/Newsletters/acutecare/articles/20070222.asp

8

Smart Pumps?

A variety of smart pump technologies have been introduced

•  Over 5 years of observa4on (2000-‐2004, inclusive) PCA error rates remain unchanged in spite of technological improvements

•  Pumps may be “smart”, but…. humans remain a weak link

Hankin CS, Zhang M: Abstract at: American Society of Health-System Pharmacists Summer Meeting. June 11-15, 2005. Boston, Mass. Institute for Safe Medication Practices. Available at: www.ismp.org. USP Quality Review, No. 81. 2004. Sikirica V et al. presented at The 41st American Society of Health-System Pharmacists Midyear Clinical Meeting. December 3-7, 2006. Anaheim, Calif. FDA / AAMI Summit Meeting held October 2010; http://www.aami.org/infusionsummit/AAMI_FDA_Summit_Report.pdf

9

IV Drug Delivery Challenges

•  IV drug delivery necessitates conversion to oral therapy to allow discharge from hospital

•  Analgesic gaps occur in 12% of pa4ents with IV PCA, mostly due to IV infiltra4on 1

•  Risk of phlebi4s with peripheral catheters is 7–9% 2

•  Bacteremia due to a peripheral venous catheter occurs at a rate of 0.2–0.4% 2

1 Panchal et al., Anesth Analg 105:1437–41, 2007 2 Webster et al., Cochrane Database Syst Rev 3:CD007798, 2010

10

Regional Anesthesia Challenges

Epidural success rate is only 70% and can oPen cause lower extremity weakness 1

ConBnuous peripheral nerve blocks also limit ambulaBon and have been reported to have a 7% rate of paBents falling2

•  Reducing risk of falls is a Joint Commission Na4onal Pa4ent Safety Goal3

•  42% of inpa4ent falls result in injury,4 cos4ng hospitals an average of $4,200 more per stay5

1 Ready : Reg Anesth Pain Med 24:499-505, 1999 2 Ilfeld et al., Anesth Analg 111:1552–54, 2010 3 http://www.jointcommission.org/assets/1/18/ 2011-2012_npsg_presentation_final_8-4-11.pdf 4 Hitcho et al., J Gen Intern Med 19:732–9, 2004 5 Bates et al., Am J Med 99:137–43, 1995

11

Current PCAs require IV pole and pump connecBon at all Bmes, restricBng mobility, hampering physical therapy

Regional anesthesia techniques cause lower extremity weakness

Both of these issues limit mobility

•  Early mobiliza4on may decrease the risk of postopera4ve complica4ons, including pneumonia, atelectasis, ileus and venous thrombosis 1

Invasive Therapies Restrict Mobility

1 Canavarro et al., Ann Surg 124:180–1, 1946 12

Multi-Modal Oral Analgesics

13

•  CombinaBon of oral extended-‐ and immediate-‐release opioids with oral gabapenBnoids (NeuronBn or Lyrica) and oral anB-‐inflammatory agents

•  OPen requires IV opioids administered by nurse for breakthrough pain in first 24 hours

•  Nurse Bme-‐intensive regimen

•  Fixed, one-‐size-‐fits-‐all dosing intervals of medicaBons

•  Not paBent-‐controlled

14

Can We Do Better?

Maintain paBent control and provide rapid onset of analgesia with beYer aYributes •  Less tethering •  Enhanced mobility •  Improved physical therapy •  Avoid prescribing errors •  Eliminate programming errors •  Less nursing Bme with technology •  Enhanced paBent saBsfacBon

14

15 15

How About an Oral Opioid Delivery System that is Patient-Controlled, Non-Invasive and Preprogrammed?

15

Non-‐invasive (sublingual) delivery •  Eliminates IV infec4on risk •  Enhances ease of ambula4on

Pre-‐programmed delivery •  Single-‐strength 15 mcg NanoTab

with fixed 20-‐minute lockout •  Eliminates medica4on prescribing

errors •  Eliminates programming errors

NOT FDA APPROVED

Sufentanil – A Fresh Perspective

Eugene Viscusi, MD Professor of Anesthesiology

Director of Acute Pain Management Thomas Jefferson University

Opioid Analgesia

•  Opioids, such as morphine, hydromorphone, fentanyl and sufentanil, are powerful analgesics which bind mainly to mu-‐opioid receptors in the central nervous system (brain and spinal cord)

•  Opioids produce powerful analgesia and are reserved for treatment of moderate-‐to-‐severe pain

17

History of Sufentanil

Sufentanil first synthesized by Janssen in 1974 First approved in US for IV delivery in 1984 •  Approved for induc4on of anesthesia •  Later approved for epidural delivery as an analgesic in combina4on with bupivacaine

Physico-‐Chemical Proper4es •  Lipophilic –1500 4mes more fat-‐soluble than morphine •  20% non-‐ionized at physiological pH •  Fat-‐loving, non-‐ionized molecules can penetrate 4ssue membranes quickly, allowing a

non-‐IV route of administra4on and rapid brain penetra4on

•  Highly protein bound and fairly rapidly excreted, with a half-‐life of 2-‐4 hours

18

Why Sufentanil?

•  Animal studies have evaluated the Therapeu4c index = median lethal dose (LD50)/

median effec4ve dose (ED50)

•  Rapid t1/2ke0 = 6 minutes to brain:plasma equilibra4on

•  No ac4ve metabolites

1 Mather, Clin Exp Pharmacol Physiol 1995; 22:833. 2 Kumar, Eur J Pharmacol 2008; 597:39 (ED50) and Purdue Pharma MSDS, 2009 (LD50)

OPIOID THERAPEUTIC INDEX

Meperidine 51

Methadone 121

Morphine 711

Hydromorphone 2322

Fentanyl 2771

Sufentanil 26,7161

19

Is the Differentiated Therapeutic Index Related to MOR-1 Splice Variants?

•  The single mu opioid receptor (MOR) gene has a series of introns and exons

•  How these are aMached together to create the messenger RNA that makes the receptor protein can vary

•  Different opioids bind to these MOR splice variants in a unique way, possibly explaining the differen4al side effect profile and therapeu4c index value for the various opioids

Ravindranathan et al, Proc. Nat. Acad. Sci, 106 :10811–16, 2009 20

Clinical Experience with IV Sufentanil

•  When used intra-‐opera4vely, sufentanil demonstrated less post-‐opera4ve respiratory depression and improved analgesia rela4ve to fentanyl1

•  Sufentanil-‐based IV PCA demonstrated equal levels of analgesia, less seda4on and less oxygen desatura4on compared to IV PCA groups treated with morphine or alfentanil2

•  In healthy volunteers, IV sufentanil produced less respiratory depression and more effec4ve analgesia compared to IV fentanyl3

•  Plasma levels of sufentanil that produce seda4on and analgesia did not have any effect on eight different parameters of respiratory or pulmonary func4on in an ICU sewng4

1Clark NJ et al. Anesthesiology 1987; 66:130-‐135 2Ved SA, et al. Clin J Pain 1989; 5(S1):S63-‐S70 3Bailey PL, et al. Anesth Analg 1990;70(1):8-‐15 4Con4 G, et al. Can J Anesth 2004; 51(5):494-‐499 21

22

Opioid Analgesia Results from a Two-Stage Process •  Achieving a Plasma Level

•  Distribu4on of drug to plasma, affected primarily by lipophilicity, ioniza4on of molecule

•  Elimina4on from plasma, affected by metabolism to hydrophilic ac4ve or inac4ve metabolites

•  Ge[ng to the CNS Effector Site •  Influx across blood-‐brain barrier, affected by

lipophilicity, ioniza4on

•  Countered by efflux via P-‐glycoprotein (PGP) transporter mechanisms

•  Unlike morphine, sufentanil is not a PGP substrate

Sufentanil Has a 6 Minute t1/2ke0

Commonly used IV opioids have a delayed transit and equilibraBon Bme from plasma to the CNS (t½ke0) •  Morphine (t½ke0) = 2.8 hours1

•  Hydromorphone (t½ke0) = 46 minutes2

•  Factors that increase t½ke0: •  low lipid solubility •  high degree of ioniza4on •  drug acts as a substrate for CNS

efflux transporters

1 Lotsch et al., Anesthesiol 95:1329-38, 2001 2 Shafer et al., Geriatric Anesthesiology. 2nd ed. New York, NY: Springer; Chapter 15:209–28, 2007 23

Active Metabolites Can Enhance Risk for AEs Poor renal function enhances this risk

Meperidine metabolized to normeperidine can cause seizures1

Morphine’s acBve metabolites M3G, M6G can rapidly accumulate2,3

•  M6G has a t½keo of 6.5 hours,4 is equianalgesic to morphine and is present at the same concentra4on as morphine

•  M3G can reach levels higher than morphine and has been linked to neuroexcitatory effects

Hydromorphone metabolite H3G linked to neuroexcitaBon, H6G linked to mu-‐opioid mediated analgesia

•  H3G and H6G can accumulate with renal insufficiency following surgery3,5

1 Clark et al., J Emerg Med 1995;13:797–802 2 Smith et al., Clin J Pain 2011; 27:824–38. 3 Smith et al., Clin Exp Pharmacol Physiol 2000; 27:524–8. 4 Lotsch et al., Anesthesiol 2001; 95:1329–38. 5 Wright et al., Life Sci 2001; 69:409–20.

24

Sufentanil NanoTab 15 mcg

•  Novel, proprietary sublingual dosage form that is bioadhesive

•  Rapid drug uptake from sublingual mucosa

•  Low salivary response= minimal drug swallowing thereby avoiding erra4c GI uptake

•  Non-‐invasive route with no infusion or pump required •  Avoids IV peaks and troughs •  In Phase 3 head-‐to-‐head study, two-‐fold longer

interdosing interval than IV PCA morphine

25 NOT FDA APPROVED

Sufentanil NanoTab PCA System Preprogrammed, Non-Invasive Sublingual Delivery

26 NOT FDA APPROVED

Sufentanil NanoTab PCA System Phase 3 Insights

Pamela Palmer, MD, PhD Professor of Anesthesiology,

Chief Medical Officer, AcelRx Pharmaceu4cals, Inc.

Sufentanil NanoTab PK Single-Dose and Multiple-Dose

28

•  Repeat Dose: PaBents dosed 1 NanoTab every 20 minutes

•  Total 40 NanoTabs consumed in 13.3 hours

•  For reference, single IV dose

of 15 mcg results in: •  Cmax: 445 pg/ml •  Tmax: 4 minutes

Sufentanil 15mcg Mul4ple Dose

Sufentanil 15mcg Single Dose

Time Post-‐dose (hours)

Sufentanil Plasma Co

ncen

tra4

on (p

g/ml)

Therapeu4c Range

ARX-01 Phase 3 Program

29

Surgery Type Study Type Sites N Data Abdominal & Orthopedic Surgery (IAP309)

Open-‐label, Ac4ve-‐comparator 1o EP: PaBent Global

Assessment of Method of Pain Control over 48 hrs

26 359 1:1 Nov 2012

Abdominal Surgery (IAP310)

Double-‐blind, Placebo-‐controlled

1o EP:Sum of Pain Intensity Difference over 48 hrs

13 178 2:1 Mar 2013

Orthopedic Surgery (IAP311)

Double-‐blind, Placebo-‐controlled

1o EP:Sum of Pain Intensity Difference over 48 hrs

34 426 3:1 May 2013

IAP309: Primary Endpoint PaBent Global Assessment – 48 hours (ITT PopulaBon)

•  PGA 48 demonstrates non-‐inferiority and superiority for NanoTab (ITT PopulaBon)

•  PGA 48 among completers demonstrates superiority for NanoTab

•  PGA 24 and 72 hr (ITT populaBon) also staBsBcally superior in favor of NanoTab 30

78.5

65.6 60

64

68

72

76

80

Sufentanil NanoTab (n=177)

IV PCA Morphine (n=180) %

of P

aBen

ts in each Group

Good/Excellent RaBng

22.1

3.7

12.9

-‐20

-‐10

0

10

20

30

p<0.001

p=0.007

Primary Endpoint Non-‐Inferiority Comparison

IAP309: PGA-48 – Completer Population

31

50.7

39.7 42.5 41.9

6.8

17.6 0 0.7

0

10

20

30

40

50

60

Sufentanil NanoTab (n=146) IV Morphine (n=136)

% of P

aBen

ts

Excellent Good Fair Poor

Comparison between two groups (p=0.03)

IAP309: SPID-48 and TOTPAR-48 Scores

32

76.5

70.4

60

70

80


IV PCA Morphine (n=180)

SPID over 4

8 ho

urs

LS Mean SPID-‐48

98.3

90.2

80

90

100


IV PCA Morphine (n=180)

TOTP

AR over 4

8 ho

urs

LS Mean TOTPAR-‐48 P=0.546

P=0.058

IAP309: PGA-48 and SPID-48 by Surgery Type

33

81.1 83.3

69.6 66.7 66.7

63.3

50

60

70

80

Abdominal (n=79)

Hip (n=162)

Knee (n=116)

% Pts Scorin

g Goo

d/Excellent PGA-‐48

Sufentanil NanoTab Morphine IV PCA

108 106

42

122 97

29

0

25

50

75

100

125

Abdominal (n=79)

Hip (n=162)

Knee (n=116)

48 hou

r SPID

SPID-‐48


*

* p<0.05

IAP309: Speed of Onset and Drop-out due to Inadequate Analgesia

34

3

4

5

6

0

0.25

0.5

0.75 1 2 4 6 8 10

12

PaBe

nt Rep

orted Pa

in In

tensity

ReducBon in Pain Intensity


* * *

Time from first dose of study drug (hours) 0

2

4

6

8

10

4 8 12 16 20 24 28 32 36 40 44 48

K-‐M EsBmated

Event Rate (%

)

Time aPer first study drug dosing (hrs)

Drop-‐out -‐ Inadequate Analgesia


* p<0.01

3

4

5

6

7

0 0.5 1 4 8 12

Abdominal (n=37 Suf; 42 Mor)

*

IAP309: Speed of Onset in Each Population

35

Time from first dose of study drug (hours)

3

4

5

6

7

0 0.5 1 4 8 12

Hip (n=84 Suf; 78 Mor)

Sufentanil NanoTab

Morphine IV PCA

* 3

4

5

6

7

0 0.5 1 4 8 12

Knee (n=56 Suf; 60 Mor)

* *

* p<0.05 * p<0.05 * p<0.05

IAP309: Doses Used by Time Period

36

28.2 36.2

28.2

7.3 0 10 20 30 40 50

<24 24-‐<48 48-‐72 >72

% of P

aBen

ts Sufentanil (Doses in 48 hours)

15.6 22.2 21.1

41.1

0 10 20 30 40 50

<24 24-‐<48 48-‐72 >72

% of p

aBen

ts

Morphine (Doses in 48 hours)

13 9 12

0 5 10 15 20 25 30

0-‐12 hr 12-‐24 hr 24-‐48 hr

Med

ian Do

ses U

sed

Sufentanil (Doses/Study Period)

25

17 19

0 5 10 15 20 25 30

0-‐12 hr 12-‐24 hr 24-‐48 hr

Med

ian Do

ses U

sed

Morphine (Doses/Study Period)

IAP309: Sufentanil Doses by Time Period/Surgery

37

17 15 17.5

0

5

10

15

20

0-‐12 hr 12-‐24 hr 24-‐48 hr

Knees (Median 51)

11 9 12

0

5

10

15

20

0-‐12 hr 12-‐24 hr 24-‐48 hr

Hips (Median 31)

11 11 16

0

5

10

15

20

0-‐12 hr 12-‐24 hr 24-‐48 hr

Abdominal (Median 40)

12 10

15

0

5

10

15

20

0-‐12 hr 12-‐24 hr 24-‐48 hr

Overall (Median 39.5)

IAP309: Patient and Nurse Ease of Care

38

4.45

4.07

3.6 3.8 4

4.2 4.4 4.6

Sufentanil NanoTab IV PCA Morphine

PaBent Ease of Care

4.27

3.82 3.6 3.8 4

4.2 4.4 4.6


Nurse Ease of Care

4.15 3.84

3.2 3.4 3.6 3.8 4

4.2


PaBent SaBsfacBon

3.92

3.35 3.2 3.4 3.6 3.8 4

4.2


Nurse SaBsfacBon

P<0.001 P=0.017

P=0.004 P<0.001

IAP310 & IAP311 Primary Endpoint: SPID-48 – ITT Population

39

0

20

40

60

80

100

120

0.25 0.75 2 6 10 16 24 32 40 48

Time-‐Weighted SPID IAP 310 – Abdominal

Sufentanil NanoTab Placebo

-‐20

0

20

40

60

80

100

0.25 0.75 2 6 10 16 24 32 40 48

Time-‐Weighted SPID

Time aPer first study drug dosing (hrs)

IAP 311 -‐ Orthopedic

Sufentanil NanoTab Placebo

p=0.001

P<0.001

AE Profile vs Meta Analysis of IV PCA opioid

40

Study Sufentanil – 310 & 311

Placebo – 310 & 311

Cashman & Dolin, ’94 &’95 (95% CI)

Abdominal:Hip:Knee (%) 27:38:35

Nausea 46.9% 36% 26.8-‐37.6%

VomiBng 11.7% 6.1% 17.1-‐24.8%

ConsBpaBon 5.1% 2.4%

Oxygen DesaturaBon 7.7% 3% 5.6-‐22%

Itching 6.8% 0% 10.7-‐17.5%

Urinary RetenBon 1.2% 0% 6.6-‐25%

Confusional State 2.1% 1.2%

SedaBon/Somnolence 2.3% 0.6% 4.6-‐6.4%

IAP309: Rate of Oxygen Desaturation Events

41

19.7

12.4 9.6

30

20 16.1

0

5

10

15

20

25

30

35 % Pts with

O2 De

sat

Even

ts

Sufentanil

Morphine

O2 <95% O2 <94% O2 <93%

p=0.028

Conclusions

42

Sublingual sufentanil provides ideal PK profile for PRN dosed opioid •  High lipophilicity allows non-‐IV delivery, rapid transit to brain •  Sublingual depot enables 90-‐minute re-‐dosing vs 40-‐minute for IV •  No ac4ve metabolites, rapid t1/2ke0 eliminates dose-‐stacking risk Strong Sufentanil NanoTab PCA System Clinical Profile Emerging •  Excellent acute pain control, early pain control superior to IV morphine •  AMrac4ve AE profile with low rate of oxygen desatura4on events •  Superior Pa4ent Sa4sfac4on and Nurse Ease of Care to IV morphine •  Device eliminates programming errors, facilitates pa4ent ambula4on

Panel Q&A

•  Dr Richard Berkowitz •  Dr Eugene Viscusi •  Dr Pamela Palmer •  Pam Lindley, RN

43

Formulary Adoption

Mike A. Royal, MD, JD, MBA Chief Clinical Affairs,

AcelRx Pharmaceu4cals, Inc.

45

•  From inventory control to ra4onal use

•  Ensure that safe and effec4ve drugs are available •  Iden4fy preferred drugs and avoid therapeu4c duplica4on •  Cost control: aggressive contrac4ng and control mechanisms

–  Formulary management with strict P&T controls

–  Drug use policy making

–  Drug use monitoring

Hospital Formularies and the Modern P&T Process

46

The Old Days: Formulary Review

New Request by any MD

Fill out application

Approved

Formulary Inclusion

•  Pharmacy open to see sales reps/MSLs

•  Turnaround 4me: days to a few weeks

•  Use off formulary simple and frequent

•  End user training could occur before approval

Cost Focus has Shifted Power to Pharmacy in P&T Process

47

•  Advantage to new products which sa4sfy unmet needs or have pharmacoeconomic benefits

•  Several physicians may need to advocate for new addi4on

•  Process is more deliberate

American College of Clinical Pharmacy

Resulting in Today’s Multilayered Process

48

New Drug Requests by multiple MD; Department Chiefs helpful

Fill out applications; write letters Get on P&T schedule

Formal Pharmacy Review

Not Approved

To Med/Exec Cmte Review

Final Approval

Formulary Inclusion

Decision by Med/Exec Cmte Pharmacy Preparation of Monograph Without Pharma input

Approved

Key Influencers of Speed of P&T Approvals

49

•  Chat rooms to share info about new products •  Counter-‐detailing •  Restricted access to P&T members/process •  Lack of published ac4ve comparator and pharmacoeconomic data •  Mandatory wai4ng periods post FDA approval •  Periodic P&T scheduling with limited # of products reviewed •  Pharmacy control of presenters at P&T mee4ngs •  Device analysis may require another commiMee input

Sufentanil NanoTab Formulary Expectations

50

•  IV PCA costs and challenges already well understood •  Non-‐invasive, pre-‐programmed PCA System automa4cally aMrac4ve •  Ac4ve comparator data to current Standard of Care with comparable efficacy

expected by P&T CommiMees in research, but exceeding expecta4ons are: •  Demonstra4on of superiority to IV PCA morphine •  Faster onset and reduced percentage of oxygen desatura4on events

•  Cost as a factor is manageable •  Expect comparable pricing to current IV PCA •  Differen4a4on based on pa4ent sa4sfac4on, clinical benefits, and

overall cost reduc4on expected to encourage adop4on •  Overall, expect formulary adop4on to be rapid

Publication Strategy Supporting Formulary Assessment

51

2013 •  create awareness of IV PCA limita4ons and problems •  benefits of sufentanil, especially when given sublingually •  sophis4ca4on and inherent controls of the System •  posi4ve results from trials (poster and satellite presenta4ons)

2014 •  shi} to publica4ons in pharmacy journals with a focus on cost

savings, pa4ent sa4sfac4on, and poten4al reduc4on in error rates and AEs with a switch from IV PCA

2015 •  return focus on posi4ve results from the System •  messaging to end users

Medical Affairs Strategy

52

•  Coordinate with commercial to op4mize reach/frequency and iden4fy early targets

•  Focus on pharmacoeconomic value with pharmacy directors; lead with 309 ac4ve comparator (IV PCA) data in Dossier and presenta4ons

•  Use a blended team of PharmDs (for difficult P&Ts) and RN Educators (for educa4on, assistance with pull through) to start early on

•  Capitalize on inves4ga4onal sites as “centers of excellence” for regional ripple effect – early posi4ve trial experience predicts P&T approval

•  Focus phase 4 ac4vi4es on developing “best prac4ces” for specific surgeries that include the System as part of mul4modal approaches

•  Facilitate development of standing orders •  Assist pharmacy depts in MUE/DUE designs that augment

pharmacoeconomic data

Commercialization

Richard King Chief Execu4ve Officer,

AcelRx Pharmaceu4cals, Inc.

The Post-Operative Pain Market is Dynamic

Trends

•  PoliBcal •  Economic •  Sociological •  Technological

Macro Influences •  Length of Stay/Se[ng •  Types of Procedures •  Pain Management •  Stakeholders •  Reimbursement and Cost

PotenBal Drivers of AdopBon for Any Product in this Area

•  Cost-‐effecBveness (relaBve to current standard of care) •  PaBent saBsfacBon, leading to insBtuBonal focus on pain management

54

Source: RoseMa Qualita4ve Interviews, Fall 2011.

Pain Management Focus and Trends in US

55

Length of Stay •  Opportunity for product that helps to reduce length of stay is high •  Push for shorter length of stay implies pain being pushed to home sewng Procedure Mix and Invasiveness •  Opportunity for products with effec4ve pain relief for 6-‐23 hr post-‐op stay MulBmodal Analgesia •  Opportunity for non-‐invasive, pa4ent-‐controlled analgesia delivery as component

of otherwise fixed dosing regime Emergence of InsBtuBonal Pain Teams •  In addi4on to surgeons, support from anesthesiologists/pain specialists cri4cal •  Pa4ents emerging as stakeholder, as pa4ent sa4sfac4on more important Cost •  23-‐hour stay support and cost effec4veness key foci

Sources: RoseMa Mini-‐quant Survey fielded to 29 physicians (15 hospitalists and 14 anesthesiologists) in Winter 2011. RoseMa Qualita4ve Interviews, Fall 2011.

Introducing……………..

56

(sufentanil sublingualmicrotablet system)

For use in hospitals only.For use only with ZALVISO™ Sufentanil sublingual microtablet systemND

C XX

XX-Y

YYY-

PP

LOT

NO. X

XXXX

E

XP D

ATE

DDM

MYY

P ONLY

CONTENTS cartridge1 40 *equals 22.5 mcg sufentanil citrate

For management of moderate to severe acute pain.

0 1 2 3 4 5 6 7 8 9

(sufentanil sublingualmicrotablet system)

15mcg* sufentanil/microtablets

376170 431

1 inch

BLACK

(sufentanil sublingualmicrotablet system)CONTROLLER


1 inch



Pouched Cartridge Label

Label on Controller Packaging

Product Logo

Regulatory Pathways

57

•  NDA Pathway –  Submit NDA (Q3 2013) –  FDA Files NDA (Q4 2013) –  DAAAP Division review

–  CDER Leads (Drug) –  CDRH Consulta4on (Device)

–  Approval (Q3 2014) for single label for use of drug and device for moderate to severe acute pain management in hospital sewng

–  No AdComm Expected (Hospital use product, not to go home)

•  MAA Pathway –  AcelRx to determine Central vs

Mutual Recogni4on Pathway –  MAA submission will be for drug

product (Q2 2014) –  Device will be presented to No4fied

Body to pursue CE mark (Q2 2014) –  Approval (Q2 2015) for drug product

and CE mark for device granted –  AcelRx can translate GUI / IFU

languages to EU specific requirements

US Surgical Procedures – Evolving Settings

58

Strategic Importance

Post-‐operaBve Length of Stay

Inappropriate Pa4ent Types

Appropriate Pa4ent Types (# Procedures with Moderate to Severe Pain)

6-‐12 hours 23 hours 1-‐2 days 2+ days

Treatm

ent S

e[ng

Inpa4ent Post-‐op Surgical

Procedures (31,680k)

Cogni4ve or p

hysic

al im

pairm

ent that

preven

ts pa4

ents from

usin

g a pa4e

nt-‐

controlled de

vice

Low (1,679k)

Medium/High (3,071)

High (8,047)

Hospital Ambulatory Surgery (HOPD) (24,890k)

Low (935k)

Medium (950k) N/A N/A

ASC (18,813k)

Low (1,367k)

Low (212k) N/A N/A

Low Opportunity

High Opportunity

Sources: RoseMa Mini-‐quant Survey fielded to 29 physicians (15 hospitalists and 14 anesthesiologists) in Winter 2011.

Moderate-to-Severe Pain in US Hospital Settings

59

Hospital in-‐paBent, moderate-‐to-‐severe acute pain, post-‐operaBve 12M procedures per annum, Zalviso poten4ally usable in ~95% cases

Hospital in-‐paBent, moderate-‐to-‐severe acute pain, not post-‐operaBve 7.4M pa4ents per annum, Zalviso poten4ally usable ~66-‐80% cases

•  Indica4on likely to cover this pa4ent popula4on •  IV push opioid medica4on is standard for acute non-‐post-‐opera4ve pain, not IV PCA • Physicians reported Zalviso may be supplementary to IV push, rather than a replacement

Hospital affiliated hospice, moderate-‐to-‐severe acute pain Est. 300k pa4ents per annum, Zalviso usable in ~40% cases

•  Indica4on likely to cover this pa4ent popula4on • ARX-‐01 is poten4al replacement for liquid morphine, measured by nurse when dosed

Sources: RoseMa Mini-‐quant Survey fielded to 29 physicians (15 hospitalists and 14 anesthesiologists) in Winter 2011. RoseMa Qualita4ve Interviews, Fall 2011.

8.3 9.2

8.3 7.9

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0

10.0

Ortho OBGYN Gen Surgeon Anes

AYracBveness RaBng of ARX-‐012

Ortho OBGYN Gen Surgeon Anesth

8.8 8.1 7.8 7.8

8.8

7.4

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

Gastro OBGYN Gen Surgeon

AYracBveness RaBng of ARX-‐011

Gastro Ortho OBGYN Cardio Gen Surg Anesth

Physician Reaction to Acute Pain Product Profile

60

US Physicians1 EU Physicians2

1. RoseMa: Mini-‐quant Survey of 29 US physicians (15 hospitalists and 14 anesthesiologists) in Winter 2011. 2: RoseMa: Qualita4ve Interviews with 35 EU physicians (9 anesthe4sts/22 surgeons/4 KOLs) in Spring 2013

Physician Reaction to Product Profile

61

“This is a big improvement because the pa:ent can get out of bed quicker.” – OB/GYN1

“It’s a 10 if I’m using PCAs and want to switch. It’s an 8 because it’s s:ll a narco:c medica:on. In an ideal world, I’m looking for something other than a narco:c.” – Orthopedic Surgeon1

It gives a pa:ent possibility to move around, he or she doesn’t have to be :ed up to their bed.

– Anesthe4st, Poland2

“It’s very aIrac:ve. Anything that would give pa:ents power to control their pain, and less work for nurses is highly aIrac:ve.” Anesthesiologist1

“Sufentanil is the perfect drug; I use it all the :me.” – Cardiothoracic Surgeon1

“There are many advantages here combined. You will have a great compliance here… I think that pa:ents will accept it very well, I guess much more as the IV PCA.”

– Orthopedic Surgeon, Germany2

1. RoseMa: Mini-‐quant Survey of 29 US physicians (15 hospitalists and 14 anesthesiologists) in Winter 2011. 2: RoseMa: Qualita4ve Interviews with 35 EU physicians (9 anesthe4sts/22 surgeons/4 KOLs) in Spring 2013

62

Segmentation

•  All physicians interviewed have strong interest in Zalviso •  First segmenta4on filter will be formulary approval •  Market segmenta4on will focus on likely sequence of adop4on

•  Orthopedic surgeries first (1.5M per annum1) •  23-‐hour stay surgeries also early (4M p.a2) •  GI and GYN surgeries, supported by abdominal data set (4.5M p.a1) •  CT (1M p.a1), OB (2M p.a1), fusion/fracture surgeries (1M p.a1) as

familiarity with Zalviso grows •  Burns, other acute in-‐hospital pain (7M p.a2) opportunis4cally

1. Na4onal Hospital Discharge Survey, 2010 2. RoseMa Mini-‐quant Survey fielded to 29 physicians (15 hospitalists and 14 anesthesiologists) in Winter 2011.

Building Commercial Infrastructure

63

H2 2013: Marke4ng team established (2 Senior, 2 Mid-‐management) H1 2014: MSL team established / deployed (6-‐8 MSLs); Sales Structure Finalized Q3 2014: Sales Management Team Employed (6-‐8 Regional Directors) Q4 2014: MSL’s, Sales Management, Contrac4ng team push for Formulary Review and Approval Q1 2015: Sales Reps deployed (up to 65, dependent on formulary adop4ons), Product Sale ini4ated, Phase 3 publica4ons appearing

Pricing and Pharmacoeconomics

64

0 50

100 150 200 250 300 350

Lo IV PCA Hi IV PCA Zalviso Range Co

st per paB

ent for 2 days ($)

Drug Tubing Device

Pharmacoeconomic value created by: –  Elimina4on of programming errors –  Elimina4on of excess dosing due pump failure –  Elimina4on of IV site infec4on risk for IV PCA –  Earlier and easier ambula4on poten4ally

accelerates hospital release –  Early onset pain relief results in lower opioid

dosing, less overshoot –  Reduced SAEs (par4cularly oxygen

desatura4on) results in lower ICU visits/costs –  Enhanced Pa4ent Sa4sfac4on results in

improved CMS reimbursement, higher hospital market share

Cost of Managing IV PCA - 2 days of therapy Cost Per Patient

Staff Time and Labor 1,2,3,4 $85.82

Medical Cost of Adverse Events Caused by IV PCA Errors 5,6 $50.05

Administrative Costs due to Adverse Events Caused by IV PCA Errors 7,8 $96.85

TOTALS $230

Pharmacoeconomics Literature identifies cost of managing IV PCA

Does not account for: •  Poten4al benefit of early ambula4on resul4ng in higher bed turnover •  Improved Pa4ent Sa4sfac4on impact on reimbursement or pa4ent volume •  Cost of pump maintenance in Biomedical Engineering

65

1.  Average of nurses 4me es4mates by Evans et al 2007, Bonnet et al 2009, Mordin et al 2007 and Choniere et al 1998 2.  Expert opinion by Alex Macario MD from discussions with Hospital Pharmacists 3.  Median Base Salary + Bonus + Benefits obtained from SalaryCenter.com, HR Salary Wizard 4.  A Comparison of Nurse Tasks and Time associated with two pa4ent-‐controlled analgesia modali4es using delphi panels; Evans C, et al Pain Man Nurs 2007; 8;2; 86-‐95 5.  Meissner B, et al. Hosp Pharm 2009;44:312-‐324. 6.  Campbell Alliance Market Research Study -‐ 2005 es4mate of US pa4ents that use IV PCA Pumps 7.  Source.: Toby Gordon Sc D – Expert opinion interviews and literature review -‐ Dec 2009 8.  BiomedEcon Analysis of Hankin et al 2007 reports of IV PCA Errors

Conclusion

66

Strong Zalviso Clinical Profile Emerging •  Excellent acute pain control, early pain control superior to IV morphine •  AMrac4ve AE profile with low rate of oxygen desatura4on events •  Superior Pa4ent Sa4sfac4on and Nurse Ease of Care to IV morphine •  Device eliminates programming errors, facilitates pa4ent ambula4on Working towards Q3 2013 NDA Submission Commencing Commercial Prepara4on •  Plans in hand to build commercial infrastructure •  Significant amount of market understanding work completed •  Defini4ve posi4oning and branding work underway

Closing Q&A

•  Mike Royal •  Richard King •  Pam Palmer

67

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