FORM 8-K/A

 

 

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

 

 

FORM 8-K/A

(Amendment No. 1)

 

 

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

Date of Report (Date of earliest event reported): June 21, 2018

 

 

Heron Therapeutics, Inc.

(Exact name of registrant as specified in its charter)

 

 

 

Delaware   001-33221   94-2875566

(State or other jurisdiction

of incorporation or organization)

 

(Commission

File Number)

 

(I.R.S. Employer

Identification No.)

4242 Campus Point Court, Suite 200,

San Diego, CA

    92121
(Address of principal executive offices)     (Zip Code)

Registrant’s telephone number, including area code (858) 251-4400

N/A

(Former name or former address, if changed since last report)

 

 

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):

 

Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

 

Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

 

Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

 

Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).

Emerging growth company  ☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.  ☐

 

 

 


Explanatory Note.

On June 21, 2018, Heron Therapeutics, Inc. (the “Company”) furnished a Current Report on Form 8-K (the “Current Report”). This Amendment No. 1 to Current Report on Form 8-K/A is being filed to reflect the disclosures included in the Current Report under Item 8.01, rather than Item 7.01. For the avoidance of doubt, the information contained in Exhibits 99.1, 99.2 and 99.3 filed herewith is identical to the information furnished in the Current Report.

 

Item 8.01 Other Events.

On June 21, 2018, the Company issued a press release announcing positive topline results from its Phase 2b study of HTX-011 in patients undergoing total knee arthroplasty and breast augmentation, as described in the press release filed herewith as Exhibit 99.1.

The Company also issued a press release announcing that the U.S. Food and Drug Administration has granted Breakthrough Therapy designation to the Company’s investigational agent, HTX-011, for postoperative pain management, as described in the press release filed herewith as Exhibit 99.2.

A copy of presentation materials describing a Company update, all or a part of which may be used by the Company in investor or scientific presentations from time to time, is filed as Exhibit 99.3 hereto. The attached materials have also been posted on the Company’s website at www.herontx.com. The Company does not undertake any obligation to update this presentation.

The information in Item 8.01 of this Amendment No. 1 to Current Report on Form 8-K/A, including the information contained in Exhibits 99.1, 99.2 and 99.3 filed herewith, shall be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934.

 

Item 9.01 Financial Statements and Exhibits.

(d) Exhibits.

 

Exhibit
No.
  

Description

99.1    Press Release, dated June 21, 2018.
99.2    Press Release, dated June 21, 2018.
99.3    Corporate Presentation, dated June 21, 2018.


SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the Registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

 

      Heron Therapeutics, Inc.
Date: June 25, 2018      

/s/ David L. Szekeres

      David L. Szekeres
Senior Vice President, General Counsel,
Business Development and Corporate Secretary
EX-99.1

Exhibit 99.1

 

LOGO

Heron Announces Positive Topline Results from Phase 2b Clinical Studies of HTX-011 in

Total Knee Arthroplasty and Breast Augmentation

-HTX-011 Significantly Reduced Both Pain Intensity and Opioid Use in Patients Undergoing

Total Knee Arthroplasty-

-HTX-011, Administered via Either Instillation or Nerve Block, Significantly Reduced Both Pain

Intensity and Opioid Use in Patients Undergoing Breast Augmentation-

-Conference Call and Webcast Today at 8:30 a.m. ET-

SAN DIEGO, Calif.—(BUSINESS WIRE)—June 21, 2018—Heron Therapeutics, Inc. (NASDAQ: HRTX), a commercial-stage biotechnology company focused on improving the lives of patients by developing best-in-class treatments to address some of the most important unmet patient needs, today announced positive topline results from two completed Phase 2b studies of HTX-011: Study 209 (local administration in total knee arthroplasty) and Study 211 (instillation or pectoral pocket nerve block in breast augmentation). HTX-011 achieved the primary endpoints in both studies.

Total Knee Arthroplasty (Study 209) Results

Study 209 was a randomized, placebo- and active-controlled, double-blind, Phase 2b clinical study in patients undergoing primary unilateral total knee arthroplasty to evaluate the analgesic efficacy, safety and pharmacokinetics of HTX-011 locally administered into the surgical site. Following a dose-escalation phase, 222 patients were randomized to receive: (1) HTX-011 400 mg administered via instillation into the surgical site (HTX-011 alone); (2) HTX-011 400 mg administered via instillation into the surgical site with a low dose of ropivacaine injected into the posterior capsule (HTX-011 combination); (3) bupivacaine 125 mg administered via multiple injections into the surgical site; and (4) placebo. Ropivacaine and bupivacaine are generically available standard-of-care local anesthetics used in the management of postoperative pain. This study included a pre-specified hierarchical testing strategy for the primary and key secondary endpoints for the HTX-011 400 mg treatment groups. The primary endpoint was pain intensity as measured by the Area Under the Curve (AUC) from 0 to 48 hours post-surgery (AUC 0-48) for HTX-011 compared to placebo. The key secondary endpoint was pain intensity as measured by the AUC from 0 to 72 hours post-surgery (AUC 0-72) for HTX-011 compared to placebo. The primary and key secondary endpoints were achieved:

 

    The HTX-011 combination and HTX-011 alone resulted in reductions of 23% and 19%, respectively, in pain intensity measured at rest through 48 hours when compared to placebo (p<0.0001 and p=0.0002, respectively). These pain reductions from HTX-011 were approximately double that of bupivacaine, which resulted in a reduction of 11%. The HTX-011 combination reduction was significantly better than that of bupivacaine (p=0.0212).

 

    The HTX-011 combination and HTX-011 alone resulted in reductions of 22% and 19%, respectively, in pain intensity measured at rest through 72 hours when compared to placebo (p<0.0001 and p=0.0004, respectively). These pain reductions from HTX-011 were also approximately double that of bupivacaine, which resulted in a reduction of 11%. The HTX-011 combination reduction was significantly better than that of bupivacaine through 72 hours (p=0.0325).

 

1


LOGO

 

    With the more conservative assessment of pain with activity, the HTX-011 combination and HTX-011 alone resulted in reductions of 16% and 12%, respectively, in pain intensity measured with activity through 48 hours when compared to placebo (p<0.0001 and p=0.0017, respectively). These pain reductions from HTX-011 were significantly better than that of bupivacaine, which resulted in a reduction of 4% (p=0.0012 and p=0.0366, respectively). Both the HTX-011 combination and HTX-011 alone maintained control of pain with activity through 72 hours with a 15% (p=0.0002) and 11% (p=0.0058) reduction compared to placebo, respectively.

 

    The HTX-011 combination significantly reduced opioid use through 48 and 72 hours compared to placebo (p=0.0091 and p=0.0253, respectively).

Breast Augmentation (Study 211) Results

Study 211 was a randomized, placebo- and active-controlled, double-blind, Phase 2b dose-finding study in patients undergoing augmentation mammoplasty to evaluate the analgesic efficacy, safety and pharmacokinetics of HTX-011 when administered by instillation into the surgical site or via ultrasound-guided lateral and medial pectoral nerve block before surgery. The study consisted of three cohorts comparing HTX-011 nerve block (60 mg, 120 mg, 240 mg) to the standard dose of bupivacaine 50 mg, administered as a nerve block, and placebo, and a final cohort comparing both HTX-011 400 mg administered by instillation and HTX-011 400 mg administered as a nerve block to the same two control groups. A total of 243 patients were enrolled. The primary endpoint was pain intensity as measured by the AUC from 0 to 24 hours post-surgery (AUC 0-24) compared to placebo. The primary endpoint of the study was achieved:

 

    HTX-011 400 mg administered by instillation into the surgical site and HTX-011 400 mg administered as a nerve block both resulted in reductions of 22% in pain intensity measured at rest through 24 hours when compared to placebo (p=0.0023 and p=0.0055, respectively). These pain reductions from HTX-011 were approximately triple that of bupivacaine administered as a nerve block, which resulted in a reduction of 8%. The HTX-011 400 mg instillation reduction was significantly better than that of bupivacaine (p=0.0383).

 

    With the more conservative assessment of pain with activity, HTX-011 400 mg instillation and HTX-011 400 mg nerve block resulted in reductions of 24% and 23%, respectively, in pain intensity measured with activity through 24 hours when compared to placebo (p=0.0004 and p=0.0015, respectively). These pain reductions from HTX-011 were approximately double that of bupivacaine administered as a nerve block, which resulted in a reduction of 12%.

 

    HTX-011 400 mg instillation and HTX-011 400 mg nerve block resulted in reductions in total opioid use of 33% and 26%, respectively, when compared to placebo (p=0.0093 and p=0.0435, respectively). These reductions from HTX-011 were approximately triple that of bupivacaine administered as a nerve block, which resulted in a reduction of 10%. The HTX-011 400 mg instillation reduction was significantly better than that of bupivacaine (p=0.0455).

 

2


LOGO

 

There was a strong correlation between pain reduction and the pharmacokinetics of HTX-011 in both studies.

HTX-011 was well tolerated in both studies, with a safety profile comparable to placebo and bupivacaine solution. There were no deaths and no clinically meaningful differences in overall adverse events, serious adverse events, premature discontinuations due to adverse events, potential local anesthetic systemic toxicity related adverse events or wound healing.

“Without appropriate pre-emptive pain management, certain total joint replacement procedures such as a total knee arthroplasty can be very painful for patients,” said Paul F. Lachiewicz, M.D., Consulting Professor, Department of Orthopedic Surgery, Duke University; Chapel Hill Orthopedic Surgery and Sports Medicine. “The superior pain relief provided by HTX-011 compared to the current standard of care may provide a significant clinical benefit for patients and, as part of a multimodal pain management regimen, has the potential to significantly reduce the amount of opioid medication required for patients in the early postoperative recovery period.”

“With postoperative opioids serving as a gateway to addiction, there is a large unmet need for non-opioid pain alternatives,” said Barry D. Quart, Pharm.D., Chief Executive Officer of Heron Therapeutics. “With the results reported today, we have seen positive results across 7 controlled clinical studies and 5 diverse surgical models, including hernia repair, abdominoplasty, bunionectomy, total knee arthroplasty and breast augmentation. We look forward to submitting an NDA to the FDA for HTX-011 in the second half of 2018.”

Conference Call and Webcast

Heron Therapeutics will host a conference call and webcast today, June 21, 2018, at 8:30 a.m. ET (5:30 a.m. PT). The conference call can be accessed by dialing 877-311-5906 for domestic callers and 281-241-6150 for international callers. Please provide the operator with the passcode 9387615 to join the conference call. A slide presentation accompanying today’s press release and conference call may also be found on Heron’s website at www.herontx.com under the Investor Relations section. The conference call will also be available via webcast under the Investor Relations section of Heron’s website. An archive of today’s teleconference and webcast will be available on Heron’s website for 60 days following the call.

About HTX-011 for Postoperative Pain

HTX-011, which utilizes Heron’s proprietary Biochronomer® drug delivery technology, is an investigational, long-acting, extended-release formulation of the local anesthetic bupivacaine in a fixed-dose combination with the anti-inflammatory meloxicam for the management of postoperative pain. By delivering sustained levels of both a potent anesthetic and a local anti-inflammatory agent directly to the site of tissue injury, HTX-011 was designed to deliver superior pain relief while reducing the need for systemically administered pain medications such as opioids, which carry the risk of harmful side effects, abuse and addiction. HTX-011 has been shown to reduce pain significantly better than placebo or bupivacaine alone in five diverse surgical models: hernia repair, abdominoplasty, bunionectomy, total knee arthroplasty and

 

3


LOGO

 

breast augmentation. HTX-011 was granted Fast Track designation from the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2017 and Breakthrough Therapy designation in the second quarter of 2018. In the second half of 2018, Heron expects to submit a New Drug Application (NDA) to the FDA for HTX-011.

About Heron Therapeutics, Inc.

Heron Therapeutics, Inc. is a commercial-stage biotechnology company focused on improving the lives of patients by developing best-in-class treatments that address some of the most important unmet patient needs. Heron is developing novel, patient-focused solutions that apply its innovative science and technologies to already-approved pharmacological agents for patients suffering from cancer or pain. For more information, visit www.herontx.com.

Forward-Looking Statements

This news release contains “forward-looking statements” as defined by the Private Securities Litigation Reform Act of 1995. Heron cautions readers that forward-looking statements are based on management’s expectations and assumptions as of the date of this news release and are subject to certain risks and uncertainties that could cause actual results to differ materially, including, but not limited to, those associated with the timing of the HTX-011 NDA filing and review process and other risks and uncertainties identified in the Company’s filings with the Securities and Exchange Commission. Forward-looking statements reflect our analysis only on their stated date, and Heron takes no obligation to update or revise these statements except as may be required by law.

Investor Relations and Media Contact:

David Szekeres

Senior VP, General Counsel, Business Development and Corporate Secretary

Heron Therapeutics, Inc.

dszekeres@herontx.com

858-251-4447

 

4

EX-99.2

Exhibit 99.2

 

LOGO

HTX-011 for Postoperative Pain Management Receives

Breakthrough Therapy Designation from FDA

-Conference Call and Webcast Today at 8:30 a.m. ET-

SAN DIEGO, Calif.—(BUSINESS WIRE)—June 21, 2018—Heron Therapeutics, Inc. (NASDAQ: HRTX), a commercial-stage biotechnology company focused on improving the lives of patients by developing best-in-class treatments to address some of the most important unmet patient needs, today announced that HTX-011 for postoperative pain management has received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA). HTX-011 is an investigational, long-acting, extended-release formulation of the local anesthetic bupivacaine in a fixed-dose combination with the anti-inflammatory meloxicam for the management of postoperative pain.

Breakthrough Therapy designation is designed to expedite the development and review of drugs that are intended to treat serious conditions and for which preliminary clinical evidence indicates substantial improvement over available therapies on clinically significant endpoint(s). Breakthrough Therapy designation was granted for HTX-011 based on the results of Phase 2 studies and two recently completed Phase 3 studies, which showed that HTX-011 produced significant reductions in both pain intensity and the need for opioids through 72 hours post-surgery compared to placebo and bupivacaine solution, the standard of care.

“We are pleased that HTX-011 has received Breakthrough Therapy designation from the FDA,” said Barry D. Quart, Pharm.D., Chief Executive Officer of Heron Therapeutics. “HTX-011 is the only long-acting local anesthetic to demonstrate significantly reduced postoperative pain and opioid use through 72 hours compared to bupivacaine solution, the standard-of-care local anesthetic for postoperative pain management, in Phase 3 studies. We look forward to working towards the submission of an NDA to the FDA for HTX-011 in the second half of 2018.”

Conference Call and Webcast

Heron Therapeutics will host a conference call and webcast today, June 21, 2018, at 8:30 a.m. ET (5:30 a.m. PT) to discuss the receipt of Breakthrough Therapy designation and the positive HTX-011 Phase 2b study results that were also announced today in a separate press release. The conference call can be accessed by dialing 877-311-5906 for domestic callers and 281-241-6150 for international callers. Please provide the operator with the passcode 9387615 to join the conference call. A slide presentation accompanying today’s press release and conference call may also be found on Heron’s website at www.herontx.com under the Investor Relations section. The conference call will also be available via webcast under the Investor Relations section of Heron’s website. An archive of today’s teleconference and webcast will be available on Heron’s website for 60 days following the call.

About HTX-011 for Postoperative Pain

HTX-011, which utilizes Heron’s proprietary Biochronomer® drug delivery technology, is an investigational, long-acting, extended-release formulation of the local anesthetic bupivacaine in a fixed-dose combination with the anti-inflammatory meloxicam for the management of postoperative pain. By delivering sustained levels of both a potent anesthetic and a local anti-inflammatory agent directly to the site of tissue injury, HTX-011 was designed to deliver superior

 

1


LOGO

 

pain relief while reducing the need for systemically administered pain medications such as opioids, which carry the risk of harmful side effects, abuse and addiction. HTX-011 has been shown to reduce pain significantly better than placebo or bupivacaine alone in five diverse surgical models: hernia repair, abdominoplasty, bunionectomy, total knee arthroplasty and breast augmentation. HTX-011 was granted Fast Track designation from the FDA in the fourth quarter of 2017 and Breakthrough Therapy designation in the second quarter of 2018. In the second half of 2018, Heron expects to submit a New Drug Application (NDA) to the FDA for HTX-011.

About Heron Therapeutics, Inc.

Heron Therapeutics, Inc. is a commercial-stage biotechnology company focused on improving the lives of patients by developing best-in-class treatments that address some of the most important unmet patient needs. Heron is developing novel, patient-focused solutions that apply its innovative science and technologies to already-approved pharmacological agents for patients suffering from cancer or pain. For more information, visit www.herontx.com.

Forward-Looking Statements

This news release contains “forward-looking statements” as defined by the Private Securities Litigation Reform Act of 1995. Heron cautions readers that forward-looking statements are based on management’s expectations and assumptions as of the date of this news release and are subject to certain risks and uncertainties that could cause actual results to differ materially, including, but not limited to, those associated with the timing of the HTX-011 NDA filing and review process, and other risks and uncertainties identified in the Company’s filings with the Securities and Exchange Commission. Forward-looking statements reflect our analysis only on their stated date, and Heron takes no obligation to update or revise these statements except as may be required by law.

Investor Relations and Media Contact:

David Szekeres

Senior VP, General Counsel, Business Development and Corporate Secretary

Heron Therapeutics, Inc.

dszekeres@herontx.com

858-251-4447

 

2

EX-99.3
HTX-011
Postoperative Pain Program
Topline Results from Phase 2b Studies
June 21, 2018
Exhibit 99.3


2
Forward-Looking Statements
This presentation contains "forward-looking statements" as defined by the Private Securities Litigation Reform Act
of 1995. We caution investors that forward-looking statements are based on management’s expectations and
assumptions as of the date of this presentation and involve substantial risks and uncertainties that could cause our
clinical development programs, future results, performance or achievements to differ significantly from those
expressed or implied by the forward-looking statements. These risks and uncertainties include, but are not limited
to, those associated with: the potential market opportunity for HTX-011; the timing of the NDA filing for HTX-011;
the timing of completion and results of clinical studies for HTX-011; and other risks and uncertainties identified in
the Company's filings with the Securities and Exchange Commission. Forward-looking statements reflect our
analysis only on their stated date, and we take no obligation to update or revise these statements except as may
be required by law.


3
Preclinical
Clinical
NDA
Approved
SUSTOL
®
(granisetron) extended-
release injection
CINVANTI
®
(aprepitant)
injectable
emulsion
HTX-011 bupivacaine
+ meloxicam
ER
Local Administration
HTX-011 bupivacaine
+ meloxicam
ER
Nerve Block
Approved by U.S. FDA for CINV Prevention
Status of Product Portfolio
Approved by U.S. FDA for CINV Prevention
Postoperative Pain with Local Administration
Fast Track and Breakthrough
Therapy designations granted
Positive Phase 2, 2b and 3 results
CINV
Pain
Positive Phase 2b results in breast augmentation
Postoperative Pain with Nerve Block


4
HTX-011 for Postoperative Pain Management Has
Received Breakthrough Therapy Designation
Breakthrough Therapy designation designed to expedite development and
review of drugs:
Intended to treat serious conditions; and
For which preliminary clinical evidence indicates substantial improvement over
available therapies on clinically significant endpoint(s)
Designation granted based on results of Phase 2 studies and two recently
completed Phase 3 studies
HTX-011 produced significant reductions in both pain intensity and need for
opioids through 72 hours post-surgery compared to placebo and bupivacaine
solution, the standard of care
HTX-011 was also granted Fast Track designation in November 2017


5
Postoperative Opioids Are a Gateway to Addiction
AS MANY AS 2.6 MILLION
patients that take opioids to manage pain after
surgery may become persistent opioid users
each year
.
MORE THAN 40 MILLION
patients undergoing surgical procedures are
prescribed opioids for pain management
in the United States each year
UP TO 440,000
patients will become addicted to
opioids each year
In addition
>1 BILLION OPIOID PILLS
are taken home from the hospital after surgery each year
70% of all these
opioid pills
go unused
90% of these pills remain inside
the home in unsecured locations
>$15 BILLION
of the annual healthcare costs
associated with addiction can
be attributed to postoperative
pain management
32% of all opioid addicts report
first opioid exposure
through leftover pills


6
HTX-011 ACHIEVED STATISTICALLY SIGNIFICANT
REDUCTIONS IN PAIN AND THE NEED FOR
OPIOIDS VS. BUPIVACAINE IN EVERY PHASE 2
STUDY AND BOTH PHASE 3 STUDIES


7
Seven Positive Controlled Studies to Be Included in
HTX-011 New Drug Application (NDA)
Study
Phase
Surgical Model
Tissue
Type
Significant for
Pain Reduction
vs. PBO
Significant for
Pain Reduction
vs. BPV
Significant
Reduction in
Opioid Use
PK –
PD
Relation-
ship
202
2
Hernia Repair
Soft
203
2
Abdominoplasty
Soft
208
2
Bunionectomy
Bony
209
2b
TKA
Bony
211
2b
Breast
Augmentation
Soft
301
3
Bunionectomy
Bony
302
3
Hernia Repair
Soft
NDA, planned in 2H 2018, will request broad label for reduction of postoperative pain
and opioid analgesics for 72 hours after surgery
PBO = placebo; BPV = bupivacaine solution; PK = pharmacokinetic; PD = pharmacodynamics; TKA = total knee arthroplasty 


8
RECENTLY COMPLETED PHASE 2B STUDIES


9
Study 209: Phase 2b Total Knee Arthroplasty (TKA)
Study Design
HTX-011 400 mg
Instillation
N=58
HTX-011 400 mg
Instillation + Ropivacaine
Injection
N=56
Saline Placebo
Injection
N=53
Bupivacaine 125 mg
Injection
N=55
Cohort
1
HTX-011 200 mg
Instillation
N=20
HTX-011 200 mg
Instillation + Injection
N=22
Saline Placebo
Injection
N=11
Bupivacaine 125 mg
Injection
N=10
IRC
Cohort 2
Stand-alone, adequate and well-
controlled study cohort


10
Study 209: Subject Demographics (ITT)
Saline
Placebo
(N=53)
Bupivacaine Solution 125 mg
(N=55)
HTX-011 400 mg
(N=114)
Total
(N=222)
Age (years) –
mean (SD)
61.5 (8.3)
61.4 (9.4)
62.8 (9.0)
62.1 (8.9)
Sex –
n (%)
Female
25 (47.2%)
35 (63.6%)
53 (46.5%)
113 (50.9%)
Male
28 (52.8%)
20 (36.4%)
61 (53.5%)
109 (49.1%)
Race –
n (%)
Asian
0
1 (1.8%)
1 (0.9%)
2 (0.9%)
American Indian
or
Alaska Native
0
0
2 (1.8%)
2 (0.9%)
Black or African Descent
8 (15.1%)
7 (12.7%)
11 (9.6%)
26 (11.7%)
White
45 (84.9%)
47 (85.5%)
100 (87.7%)
192 (86.5%)
Ethnicity –
n (%)
Hispanic
or Latino
12 (22.6%)
16 (29.1%)
25 (21.9%)
53 (23.9%)
Not Hispanic or Latino
41 (77.4%)
39 (70.9%)
89 (78.1%)
169 (76.1%)


11
Study 209: Phase 2b TKA Results Hierarchy
AUC
0-48
HTX-011 400 mg vs. Placebo
AUC
0-72
HTX-011 400 mg + Ropivacaine
vs. Placebo
AUC
0-48
HTX-011 400 mg + Ropivacaine
vs. Placebo
p < 0.0001
AUC
0-72
HTX-011 400 mg vs. Placebo
p = 0.0002
p < 0.0001
p = 0.0004
HTX-011 via instillation achieved primary and key secondary endpoints for pain


12
Study 209: Pain Reduction from HTX-011 at Rest
Approximately Double that of Bupivacaine
Windowed-worst observation carried-forward (wWOCF) for use of opioid rescue medication and last-observation carried-forward (LOCF) for missing pain data
HTX-011 achieved primary endpoint for AUC
0-48


13
Study 209: Both HTX-011 Arms Significantly Reduce
Pain at Rest Compared to Placebo through 72 Hours
wWOCF
for use of opioid rescue medication and LOCF for missing pain data


14
Study 209: Significant Separation between HTX-011
Arms and Placebo through 72 Hours
wWOCF
for use of opioid rescue medication and LOCF for missing pain data


15
Study 209: Both HTX-011 Arms Reduce Pain with Activity
Significantly Better than Placebo and Bupivacaine
through 48 Hours 
wWOCF
for use of opioid rescue medication and LOCF for missing pain data


16
Study 209: HTX-011 plus Ropivacaine
Significantly
Reduces Opioid Use vs. Placebo through 72 Hours
Opioid consumption is presented in mean milligrams of morphine equivalents


17
Study 209: Strong Correlation between Pain
Reduction and Pharmacokinetics of HTX-011 in TKA
HTX-011 400 mg Via Instillation


18
Study 209: HTX-011 Well Tolerated in TKA
HTX-011 was well tolerated, with a safety profile comparable to placebo
and bupivacaine solution:
No clinically meaningful differences in overall adverse events
No difference in the incidence of serious adverse events
No difference in premature discontinuations due to adverse events
No deaths
No clinically meaningful differences in potential local anesthetic systemic
toxicity (LAST) adverse events in this highly vascular model
No increase in potential LAST when given with another local anesthetic,
ropivacaine
No difference in wound healing


19
Study 209: TKA Summary
HTX-011 achieved primary and key secondary endpoints
Both HTX-011 arms achieved significant reductions in pain at rest vs. placebo
through 48 hours
Also significantly reduced pain at rest through 72 hours vs. placebo
Both HTX-011 arms achieved significant reductions in pain with activity (the
most conservative assessment) vs. placebo and bupivacaine through 48 hours
HTX-011 plus ropivacaine
maintained superiority to both placebo and bupivacaine
through 72 hours                 
There was significant separation of the HTX-011 mean pain curves vs.
placebo through 72 hours
Strong correlation between PK and PD in TKA
HTX-011 with or without ropivacaine
was generally
well tolerated                   
in TKA


20
HTX-011 60 mg
Nerve Block
N=12
Saline Placebo
Nerve Block
N=6
Study 211: Phase 2b Breast Augmentation
Study Design
Cohort 1
Cohort 2
Interim Review
Committee (IRC)
Cohort 2 dose
decision
HTX-011 120 mg
Nerve Block
N=27
Saline Placebo
Nerve Block
N=12
Bupivacaine 50 mg
Nerve Block
N=11
HTX-011 240 mg
Nerve Block
N=25
Saline Placebo
Nerve Block
N=11
IRC
Cohort 3 dose
decision
IRC
Cohort 4 dose
decision
Bupivacaine 50 mg
Nerve Block
N=12
HTX-011 400 mg
Nerve Block
N=47
HTX-011 400 mg
Instillation
N=50
Saline Placebo
Nerve Block
N=12
Bupivacaine 50 mg
Nerve Block
N=12
Cohort 4
Cohort 3
Protocol includes additional optional cohorts to evaluate other doses and administration techniques
Bupivacaine 50 mg
Nerve Block
N=6


21
Study 211: Subject Demographics (ITT)
Saline
Placebo
(N=41)
Bupivacaine HCL 50 mg
(N=41)
HTX-011
(N=161)
Total
(N=243)
Age (years) –
mean (SD)
31.3 (9.0)
30.4 (7.8)
31.4 (7.8)
31.2 (8.0)
Sex –
n (%)
Female
41 (100%)
41 (100%)
161 (100%)
243 (100%)
Race –
n (%)
Asian
2 (4.9%)
2 (4.9%)
7 (4.3%)
11 (4.5%)
Black or African Descent
7 (17.1%)
3 (7.3%)
26 (16.1%)
36 (14.8%)
White
32 (78.0%)
35 (85.4%)
127 (78.9%)
194 (79.8%)
Multiple
0
1 (2.4%)
1 (0.6%)
2 (0.8%)
Ethnicity –
n (%)
Hispanic
or Latino
16 (39.0%)
17 (41.5%)
61 (37.9%)
94 (38.7%)
Not Hispanic or Latino
25 (61.0%)
24 (58.5%)
100 (62.1%)
149 (61.3%)


22
Study 211: Pain Reduction from HTX-011 at Rest
Approximately Triple that of Bupivacaine
HTX-011 achieved primary endpoint for AUC
0-24


23
Study 211: HTX-011 Instillation Shows Superior Reduction in
Pain Intensity Early and HTX-011 Nerve Block Shows Durable
Response
Notes:
Pain intensity collected at rest
wWOCF, windowed-worst observation carried-forward for use of opioid rescue medication and LOCF for missing pain data


24
Study 211: Raw Pain Scores in All Arms Drop Quickly;
Difficult to Discriminate between Arms after 24 Hours
Notes:
Raw pain intensity collected at rest
Scores not adjusted for opioid use


25
Study 211: Both HTX-011 Arms Reduce Pain with Activity
Significantly Better than Placebo through 24 Hours


26
Study 211: Both HTX-011 Arms Significantly Reduce
Opioid Use vs. Placebo through 24 Hours
Opioid consumption is presented in mean milligrams of morphine equivalents


27
Study 211: Strong Correlation between Pain Reduction
and Pharmacokinetics of HTX-011 Instillation in Breast
Augmentation


28
HTX-011 Well Tolerated in Breast Augmentation
HTX-011 was well tolerated, with a safety profile comparable to placebo
and bupivacaine solution:
No clinically meaningful differences in overall adverse events
No difference in the incidence of serious adverse events
No premature discontinuations due to adverse events
No deaths
No clinically meaningful differences in potential LAST adverse events
No evidence of wound healing issues with local administration into the
breast pocket


29
Study 211: Breast Augmentation Summary
HTX-011 achieved the primary endpoint
Both HTX-011 arms achieved significant reductions in pain at rest vs.
placebo through 24 hours
Both HTX-011 arms achieved significant reductions in pain with activity
(the most conservative assessment) vs. placebo through 24 hours
HTX-011 instillation (the most commercially relevant route for cosmetic
surgery) produced the greatest reduction in pain and opioid use, beating
both placebo and bupivacaine nerve block
Strong correlation between PK and PD in breast augmentation with
instillation
HTX-011 administered via instillation or as a nerve block was generally
well tolerated in breast augmentation with no wound healing issues


30
CONSISTENT PHARMACOKINETICS


31
HTX-011 Pharmacokinetics Across 5 Diverse Surgical
Models Are More Dose-Linear than Bupivacaine Solution
R² = 0.8103
0
100
200
300
400
500
600
700
800
0
100
200
300
400
Bupivacaine C
max
(ng/mL)
Bupivacaine Dose (mg)
Bupivacaine C
max
Bunionectomy
Herniorrhaphy
Abdominoplasty
Total Knee Arthroplasty
Augmentation Mammoplasty
R² = 0.0349
0
100
200
300
400
500
600
700
25
50
75
100
125
Bupivacaine C
max
(ng/mL)
Bupivacaine Dose (mg)
Bupivacaine C
max
Bunionectomy
Herniorrhaphy
Abdominoplasty
Total Knee Arthroplasty
Augmentation Mammoplasty
Bupivacaine Cmax
With HTX-011
Bupivacaine Cmax
With Bupivacaine HCl


32
Phase 2b Conclusions
HTX-011 plus ropivacaine
was significantly superior to both placebo and
bupivacaine in TKA
HTX-011 demonstrated significant activity via both instillation and nerve
block in breast augmentation
Pharmacokinetics of HTX-011 remained consistent across 5 diverse
surgical models with consistent correlation between PK and PD
HTX-011 has been generally well tolerated up to 400 mg by instillation
and as a nerve block
Results from 7 positive Phase 2/3 studies across 5 surgical models are
intended to support broad use of HTX-011 across a full range of surgical
procedures


33
Large US Market Opportunity
Target Market Opportunity
Initial Targets
Higher volume procedures across 4 major specialties
~6.5M Orthopedic procedures
~4.3M General Surgery procedures
~3.3 M OB/GYN procedures
~1.1M Plastic Surgery procedures
Secondary Targets
Higher volume procedures in
non-core specialties (e.g.,
ENT, urology, hand, others)
Tertiary Targets
Lower volume procedures
and procedures where local
anesthetics are not widely
used today
~28M Annual US Surgical Procedures Requiring Postoperative Pain Management That
Were Considered Potentially Suited for HTX-011
~15M procedures
~6M procedures
~7M procedures
Target Market Opportunity Size*
$4.9B
$1.9B
$2.3B
*Based on the current WAC of Exparel


34
HTX-011 Has Demonstrated Significant Clinical Benefit in
Several of the High-Value Procedures in Initial Target Market
Completed
studies
Procedure
Annual
Volume
(‘000s,
US, 2015)
Overall % Local
Anesthetic Use
HTX-011 Significantly
Superior to Bupivacaine
Claims
Survey
Ortho
Surgery
Knee arthroplasty
815
85%
YES
Hip arthroplasty
337
78%
Shoulder arthroplasty
107
98%
Rotator cuff repair
550
90%
Spine procedures
750
100%
General
Surgery
Hernia repair
1,096
67%
YES
Hemorrhoidectomy
504
86%
Colon and small bowel
resection
483
69%
Plastic
Surgery
Abdominoplasty
160
73%
YES
Mammoplasty
>300
86%
YES
OB/GYN
C-Section
1,285
TBD


35
Positive Response by Physicians and Pharmacists
to HTX-011’s Target Product Profile
48%
55%
60%
60%
66%
67%
69%
73%
79%
80%
87%
88%
50%
43%
37%
38%
31%
31%
30%
23%
20%
19%
13%
11%
1%
Phase 3 Procedures
Dosing Regimen
Overall Safety
No Impact on Implantables
Compatability with NSAIDs
Indication
No Impact on Wound Healing
Mechanism of Action
Analgesia Duration
Reduction in Opioid AEs*
Reduction in Pain Score
Reduction in Opioid Consumption
Strength
Neither a Strength Nor Weakness
Weakness
HTX-011 Target Product Profile: Strengths
N = 376 total (101 anesthesiologists, 51 general surgeons, 122 orthopedic surgeons, 50 plastic surgeons, 52 pharmacy directors)
*Opioid AE’s are assumed to be reduced with significant reduction in use