Hyalobarrier

Fidia Advanced Biopolymers Srl
HYALOBARRIER GEL
Product technology & preclinical data
Enrico Tognana, PhD
Head of R&D Unit
FAB-Nordic Pharma kick-off meeting, Abano terme - 18 March 2008

HYALURONAN:
CLINICAL AND SURGICAL APPLICATIONS
 Wound healing
 Scaffold for tissue engineering
 Used in treatment of osteoarthritis
 Ocular surgery
 Anti-adhesive barrier

HYALURONAN:
IN ADHESION PREVENTION
Why?
Biocompatible
Barrier function
(viscosity)
Bio-absorbable
Role in modulation of
inflammatory phase in
wound healing
Role in scarless wound
healing
Inadequacy because of:
Quickly cleared
Inadequately
viscous
Low residence time
 Yarali H J Reprod Med 1994;39:667-670
 Hill-West J Fertil Steril 1994;62:630-4
 Burns JW Surg Res 1995;59:644-52
 Urman B Fertil Steril 1991;56:563-7
BUT…

HYALURONAN DERIVATIVES
IN POST-SURGICAL ADHESION PREVENTION
FAB developed a hyaluronan derivative
which overcomes the limits of native
hyaluronan
Characteristics:
 Prolonged residence time
 Prolonged barrier effect
 High viscosity
 High biocompatibility
 Pure HA is the result of degradation process
…THEN…
ACP®

WHAT IS HYALOBARRIER® GEL?
Hyalobarrier® Gel is a selective barrier made up of pure auto-cross-
linked Hyaluronan with increased density, viscosity, and adhesive
properties.
 Hyaluronan (HA) is a major component of Extra-cellular Matrix
 Hyaluronan is part of all connective tissues in the body
 Hyaluronan is present in high concentration in the vitreous humour and
synovial fluid providing lubrication and gliding effects

WHAT IS HYALOBARRIER® GEL?
Classification
Medical device, class III.
Indications for use
 Prevention and reduction of post-surgical adhesion formation in the
abdominal pelvic area
Intended use
 Mechanical barrier to prevent or minimize post-surgical adhesions after
surgical interventions.

REGULATORY STATUS
EUROPE
 Approved CE mark 0459
(notified body G-Med)
USA
 Medical Device with PMA registration
OTHER COUNTRIES
 Medical Device

 ACP gel: EP 0614914
 Anti-adhesion gel: WO 97/07/833
PATENTS

WHAT IS HYALOBARRIER® GEL
MADE OF?
ACP® is obtained by inter- and intramolecular reaction of the alcohol and
carboxyl group which are present in the native HA molecule.
ACP is manufactured from fermented hyaluronan (no animal source).
Autocross-linked HA (ACP®)

HOW IS HYALOBARRIER® GEL
DEGRADED?
Metabolic pathway
Hydrolysis Natural
metabolic
degradation
HYALOBARRIER
(ACP gel)
Hyaluronic Acid Oligomers
GluA
GlNAc
CO2 + H2O
Renier D. et al. Pharmacokinetic behaviour of ACP gel, an auto-crosslinked hyaluronan derivative, after
intraperitoneal administration. BIOMATERIALS, 26:5368-74, 2005

WHAT IS HYALOBARRIER® GEL
MADE OF?
Hyalobarrier® is like Natural HA because no foreign cross-linking
molecules inside
 Different physicochemical properties
 Increasing bio-adhesiveness
 Longer degradation time & residence time
 Biological barrier effect
BUT IT HAS

 Hyalobarrier® is resorbed in 3 to 7 days
 Hyalobarrier® therefore covers the critical period of
postoperative adhesion onset
WHEN IS HYALOBARRIER® GEL
DEGRADED?

Due to higher adhesivity and prolonged residence time vs unmodified HA,
Hyalobarrier Gel seems particularly suitable for preventing adhesion formation
(Mensitieri et al. 1996)
HOW DOES HYALOBARRIER® GEL
WORK?
 Keep tissue separated during the critical period following injury
 Protects traumatized and ischemic serous membranes
 Hydrates underlying tissues
 Modulates the peritoneal wound healing process
Clinical use
Prevention and reduction of post-surgical adhesion formation in
gynecological and abdomino-pelvic surgery, both in laparoscopy and
laparotomy

 Efficacy and safety in different types of surgery:open
and close
 Determine kinetics of in vivo degradation
 Answers to questions relevant in a clinical setting:
Behaviour in case of inadequate hemostasis
Effect on tumour growth
PRECLINICAL STUDIES

IS HYALOBARRIER® GEL SAFE?
 The safety of Hyalobarrier® Gel was evaluated through a series of
toxicological tests. All these evaluations demonstrated that
Hyalobarrier® is:
 Non toxic
 Non irritant
 Non sensitizing
 Non cytotoxic
 Non pyrogenic
 Non mutagenic
 Non carcinogenic
Yes

DeIaco P.A. et al.Fertility Sterility 1998;69 (2):318-323
Belluco C. et al. J Surg Res. 2001; 100:217-221
Kocak I , Unlü C., Akcan Y et al. Fertility Sterility 1999, vol.72. N°5
Wallwiener M., Brucker S.,Hierlemann H et al. Fertility and Sterility 2006;86 (3):1266-1276
Binda MM, Molinas CR, Bastidas A et al. The Journal of Minimally Invasive Gynecology 2007;14:591-599
 In experimental studies (rabbit, rat, mouse), uterine horn in laparoscopy
and abdominal model in laparotomy it was detected a statistically
significant difference between Hyalobarrier and Control group with
respect to the incidence and severity of adhesions formation
IS HYALOBARRIER® GEL EFFECTIVE?
Yes

HYALOBARRIER® GEL ADVANTAGES
 Pure hyaluronan derivative containing no foreign substances
 High viscosity, site-specific for the intended use
 Excellent conformability
 Prolonged residence time in the application site
 Excellent bio-compatibility
Major Advantages

CAN HYALOBARRIER BE USED IN
PRESENCE OF MALIGNANCIES?
PRECLINICAL STUDY
The safety of Hyalobarrier
was demonstrated in presence
of malignancies in preclinical study
Hyalobarrier gel does not potentiate HT 29 colorectal human
intraperitoneal tumour cells growth in an experimental model of
tumour induction

CAN HYALOBARRIER BE USED IN
PRESENCE OF INADEQUATE HAEMOSTASIS?
PA De Iaco* M.D., G Muzzupapa * M.D., E Bigon §,
D Pressato §, M Donà §, A Pavesio § and L Bovicelli* M.D.
*Ob&Gyn Clin. S. Orsola Hospital , University of Bologna - Italy
§Fidia Advanced Biopolymers, Abano T. Padova - Italy
SURGERY 2001; 130:60-4

 Safety and efficacy in reducing postsurgical adhesions
DeIaco P.A. et al. Fertility Sterility 1998;69 (2):318-323 (Laparoscopy)
Belluco C. et al. J Surg Res. 2001; 100:217-221 (Laparotomy)
Kocak I et al. Fert.Ster.1999, vol.72. N°5 (Laparotomy)
Wallwiener M et al. Fertility and Sterility 2006;86 (3):1266-1276 (Laparotomy)
Binda MM et al. The J Minimal Inv Gynecology 2007;14:591-599 (Laparoscopy)
 Pharmacokinetic behaviour of ACP gel, an autocrosslinked hyaluronan derivative, after
intraperitoneal administration
Renier D, Bellato P, Bellini D. et al. Biomaterials 2005; 26: 5368-5374.
 Efficacy in presence of inadequate hemostasis
De Iaco P.A. Surgery 2001; 130 (1): 60-64 (Laparotomy)
 No effect on colon-rectal tumour growth
Pucciarelli S. et al. British Journal Surgery 2003;90:66-71 (Laparotomy)
PRECLINICAL PUBLICATIONS

To date, the preclinical data
indicate that
HYALOBARRIER® can be
considered a safe and
effective bio-absorbable
device for the prevention of
postoperative adhesions in
abdomino-pelvic surgery
CONCLUSIONS

Kickoff Meeting NordicPharma-FAB
March 18th, 2008
F.Torasso

CLINICAL NEED
Adhesions in the abdomino-pelvic cavity
Courtesy from: International Adhesion Society web site
Abnormal attachments between tissues
and organs and may be congenital or
acquired.
The development of acquired adhesions
is a generalised phenomenon in
response to trauma to the peritoneum
(mechanical trauma, foreign materials,
surgery, infection, inflammation or
ischaemia)

Peritoneal trauma
Inflammatory exudate
Fibrin clot
Normal fibrinolitic activity
Resolution of fibrin
New mesothelium
Repair
Suppressed fibrinolytic activity
Persistence of fibrin
Fibroblasts proliferation and
deposition of collagen
.
Organisation of fibrin matrix
and adhesion formation
Normal peritoneal tissue repair
Adhesion formation
Ischaemia

Adhesion-related complications
For the patient
 Small bowel obstruction: 49%-74%
 Intestinal obstruction :22%
 Infertility: 15% - 20%
 Chronic pelvic pain: 20% - 50%
For the surgeon
 Increase the risk of any future
surgery
 Prolong a future surgery (an
average of 24 minutes)
Ray NF. J Am Coll Surg 1998; 186: 1-9.;Holmdahl, Eur J Surg 1997;Suppl 577:56-62;
Ellis H. Lancet 1999; 553: 1476-1480.

Recommendations for reduction or prevention
of adhesions
 Adjusting surgical practice
 Applying adjuvants
 Anti-inflammatories (eg. corticosteroids or antihistamines).
 Anti coagulants (e.g.heparin)
 Fibrinolytic agents (e.g. urokinase, pepsin)
 Barriers:
 separate adjacent organ/tissue surfaces after surgery (site specific or broad
coverage)
 Only class of products shown to be effective in clinical trials

Efficacy Clinical Evidence

1. Pellicano M, Bramante S, Cirillo D. et al. Effectiveness of autocrosslinked hyaluronic acid gel after laparoscopic
myomectomy in infertile patients: a prospective, randomized, controlled study. Fertil Steril. 2003 Aug;80(2):441-4
2. Acunzo G, Guida M, Pellicano M et al. Effectiveness of auto-cross-linked hyaluronic acid gel in the prevention of
intrauterine adhesions after hysteroscopic adhesiolysis: a prospective, randomised, controlled study. Hum Reprod.
2003 Sep;18(9):1918-21.
3. DeIaco P.A., Muzzupapa G., Bovicelli A. et al. Hyaluronan derivative gel (Hyalobarrier gel) in intrauterine adhesion
(IUA) prevention after operative hysteroscopy. Ellipse 2003; 19 (1):15-18.
4. Carta G., Cerrone L, Iovenitti P. Postoperative adhesion prevention in gynecologic surgery with hyaluronic acid Clin
Exp Obstet Gynecol. 2004;31(1):39-41.
5. Guida M., Acunzo G., Di Spiezio Sardo A.et al.Effectiveness of auto-crosslinked hyaluronic acid gel in the prevention
of intrauterine adhesions after hysteroscopic surgery: a prospective, randomized, controlled study. Hum Reprod. 2004
Jun;19(6):1461-4. Epub 2004 Apr 22.
6. Pellicano M., Guida M., Bramanti S.et al. Reproductive outcome after autocrosslinked hyaluronic acid gel application
in infertile patients who underwent laparoscopic myomectomy. Fertil Steril. 2005 Feb;83(2):498-500.
7. Mais V., Bracco G.L., Litta P.et al. Reduction of postoperative adhesions with an auto-crosslinked hyaluronan gel in
gynaecological laparoscopic surgery: a blinded, controlled, randomized, multicentre study Hum Reprod. 2006
May;21(5):1248-54. Epub 2006 Jan 26.
8. Metwally M, Gorvy D, Watson A, Li TC. Hyaluronic acid fluid agents for the prevention of adhesions after fertility-
preserving gynecological surgery: a meta-analysis of randomized controlled trials. Fertil Steril. 2007 May;87(5):1139-
46.
Clinical Publications

 5 RCT, randomized controlled clinical trials, in gynecological endoscopy.
 1 clinical trial showed as efficacy date the significant increase in
pregnancy rate
 1 clinical trial in gynecologic laparotomy
 Hyalobarrier® was included in an indipendent Cochrane meta-analysis on
hyaluronan based anti-adhesion products in the conservative gynecologic
surgery.
To highlight

• LAPAROSCOPIC Surgery (Myoma): Hyalobarrier® was effective
in the prevention of de-novo adhesions, reducing the incidence
(Pellicano, 2003) and severity (Mais, 2006).
in infertile patients resulting in a significant increase in the pregnancy
rate (Pellicano 2005)
Key findings from clinical trials

28%
78%
0
10
20
30
40
50
60
70
80
90
100
% denovo
adhesions
(n=36)
Hyalobarrier Control
P <0.01
1,5
2,7
0
1
2
3
Mean score at
secondlook
(n=23)
P <0.05
Laparoscopic Surgery (I)
Reduction of the incidence of denovo
adhesions (Pellicano, 2003)
Reduction of the severity of de-novo adhesions (Mais,
2006)

44,4
22,2
77,8
38,8
0
10
20
30
40
50
60
70
80
%
pregnancy
(n=36)
6 months 12 months
Infertile patients: increase the pregnancy
rate (Pellicano, 2005)
P <0.01
P <0.01
Laparoscopic Surgery (II)

• HYSTEROSCOPIC Surgery (Polyps, Myomas, Uterine Septae,
Adhesions): Hyalobarrier® was effective
in the prevention of denovo uterine adhesions, resulting in reduction of
both the incidence and the severity (Guida, 2004) and
in the prevention of the reformed uterine adhesions, resulting in reduction
of both the incidence and the severity (Acunzo, 2003)
Key findings from clinical trials

10
26
0
10
20
30
40
50
%
adhesions
de-novo
(n=138)
P< 0.05
Hysteroscopic Surgery
2,42
3,83
0
1
2
3
4
5
AFS score
at second
look
P< 0.05
Reduction of the incidence
Reduction of the severity
Prevention of intra-uterine de-novo adhesions (Guida, 2004)

14
32
0
10
20
30
40
50
% reformed
adhesions
(n=92)
P< 0.05
Prevention of the intrauterine ahesions reformation (Acunzo, 2003)
2,0
5,3
0
1
2
3
4
5
AFS score
at second-
look
P< 0.05
Reduction of the incidence
Reduction of the severity

Ultrasonographic data showed that Hyalobarrier ® was able to keep
uterine walls separated for more than 72h.
0h 24h. 48h. 72h.
101.2 7.9 0.2 5.20.3 2.70.4
0,0
2,0
4,0
6,0
8,0
10,0
12,0
0 h 24 h 48 h 72 h
Thickness
(
mm)
The product hyperechoic
thickness was (mm):

Five RCT published studies on Hyalobarrier® .
(235 patients,167 treated with Hyalobarrier® and 168 patients of the control group)
The combined meta-analysis showed evidence for a lower incidence of
adhesions in patients treated with Hyalobarrier® compared with those
without adhesion prevention.
odds ratio=0.350 (95% CI=0.208-0.589)
Z value for overall effect=-3.952, p<0.001.
Clinical meta-analysis
(to be submitted for publication)

Group by
SurgeryType
Studyname Statisticsfor each study MH oddsratio and 95% CI
MH odds Lower Upper Relative
Treated Control ratio limit limit Z-Value p-Value weight
Hysteroscopy Acunzo 6/43 13/41 0.349 0.118 1.033 -1.901 0.057 36.41
Hysteroscopy Guida 7/67 17/65 0.329 0.126 0.859 -2.271 0.023 49.13
Hysteroscopy DeIaco 5/18 7/22 0.824 0.210 3.234 -0.277 0.782 14.46
Hysteroscopy 0.408 0.217 0.766 -2.788 0.005
Laparoscopy Pellicano 5/18 14/18 0.110 0.024 0.500 -2.855 0.004 56.26
Laparoscopy Mais 8/21 13/22 0.426 0.125 1.449 -1.366 0.172 43.74
Laparoscopy 0.248 0.098 0.628 -2.940 0.003
Overall 0.350 0.208 0.589 -3.952 0.000
0.01 0.1 1 10 100
Favours Treatment Favours Control
Figure 3: Meta Analysis on RCTs - Forest Plot
Clinical meta-analysis
(to be submitted for publication)

Metwally M. et al. Cochrane Database Rev 2006

in laparoscopy
(Pellicano 2003, Hyalobarrier®)
in laparotomy
(Lundorff 2001; Johns 2001
Intergel;
Diamond 1998, Sepracoat)
 Four studies analyzed
Focus on HYALURONAN adhesion prevention

Hyaluronic acid agents showed evidence for a decreased prevalence of adhesions
compared with placebo or no treatment (odds ratio, 0.31;95% CI0.19-0.51;Fig.2):
Results

Safety Evidence

Safety in preclinical studies
 Biocompatibility was confirmed by toxicological tests
(irritation, sensitization, cytotoxicity, acute systemic toxicity,
haemolysis, pyrogenicity, implantation, mutagenesis, subchronic
toxicity, chronic toxicity, carcinogenicity, ADME test)
 All in vivo experimental studies had an excellent
safety profile of Hyalobarrier®.

All patients treated in clinical trials with
Hyalobarrier® had no adverse event related to the
product
Safety in clinical trials

More than 20.000 patients have been treated
with Hyalobarrier® in Europe since 2002.
No reports of adverse events related to the product
Safety in Postmarketing surveillance

Hyalobarrier® is recognized by the
European Scientific Community
as a technology leader
in the site-specific adhesion prevention.

Hyalobarrier® gel
Indicated for laparotomic
procedures.
• 40 mg/ml ACP Gel
• 3 pre-filled syringes with 10 ml
• 3 needle-cannulas 5 cm long
Store 2-8°C
Hyalobarrier® gel ENDO
Indicated for laparoscopic and
hysteroscopic procedures.
• 30 mg/ml ACP Gel
• 3 pre-filled syringes with 10 ml
• 3 needle –cannulas 30 cm long
Store 2-8°C
LAPAROTOMY
LAPAROSCOPY
&
HYSTEROSCOPY
Hyalobarrier Presentations

Highly viscous - effective barrier function
Autocrosslinked HA – no bridge molecules
HA of fermentative origin
Safe and biocompatible
Easy to use: applicable in laparotomy, laparoscopy and hysteroscopy
Completely bio-absorbable – same metabolic pathway as native HA
Residence time of 7 days
Mucoadhesive - adheres to surfaces even in vertical position
Costs within cost-benefit range – ESGE Consensus
Hyalobarrier - Characteristics

Hyalobarrier Product Positioning
 A natural site-specific adhesion prevention product that can
be positioned where you need it
 Safe and Effective
 Easy to handle
 Presentations specifically designed for Laparoscopic &
Laparotomic surgery

FAQs

Can I use HB in a tumor patient?
 Although preclinical evidence shows no effect of HB on tumor
growth and tumor implantation, HB gel has not been evaluated
in patients affected by malignant tumors.

How many syringes per procedure do I
have to use?
 Generally in case of adnexal surgery, 1 syringe / adnexus is
indicated.
 The content of a syringe (10 ml) covers approximately 100 cm2

How long can HB be kept out of the
fridge?
 “Storage at room temperature is allowed only for a limited
period of time, after which the product can be refrigerated
again”
 In our experience, the product can be left at RT for some hours
and then refrigerated again

How does HB stick to tissues?
 Thanks to the mucoadhesive properties of the ACP gel, HB
remains in situ for the proper time.

What is the thickness of the gel layer
needed to coat the viscera?
 It is not necessary to “overcoat” the surface of the application
site since HB is mucoadhesive and remains in situ quite well.

Can I use the product in case of
incomplete haemostasis?
 Based on preclinical studies, HB can be used in case of
incomplete haemostasis since its efficacy is not compromised
by the blood presence

Why the surgical field should not be
irrigated after application of HB?
 Irrigation with ringer lactate or saline is a recommended
procedure for any gynecological surgery, at the very end of the
intervention there is no need of further irrigation, at this time
HB is applied. Irrigation after application could partially
dislodge the product from the application site.

Can I use a drainage in presence of HB?
 Catheter or drainage can be use in combination with HB, simply
do not place the end of the drainage very close to the gel layer.

Hyalobarrier

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