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CHONDROITIN SULFATE CLINICAL REVIEW IN
OSTEOARTHRITIS

• José Vergés MD, MSc, PhD
• Clinical Pharmacologist
• Scientific Director
• BIOIBERICA S.A.
• Barcelona, Spain

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DESCRIPTION

• Chondroitin sulfate (CS) belongs to the group of
  glycosaminoglycans, important constituents of
  cartilage extracellular matrix1.
• Chondroitin sulfate (Condrosan / Condrosulf) is
  a symptomatic slow acting drug for osteoarthritis
  (SYSADOA) in Europe2, where it has been approved
  as a drug for more than ten years in several
  countries.

(1). Hardingham T. Osteoarthritis Cart
(1998) 6, (Supplement A), 3-5. (2) Lequesne M. G.
Rev Rhum (Eng/Ed) 1994 61 69-73.
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CHONDROITIN SULFATE ACTION MECHANISMS3-4
STIMULATES ? proteoglycans ? HA
INHIBITS ? cartilage degradative enzymes
(collagenase,elastase, proteoglycanase,
fosfolipase A2, N-acetylglucosaminidase, etc.) ?
cartilage damaging substances (free radicals) ?
apoptosis ? NO ? Stromelysin (MMP-3) ? NF-kB

• EFFECT
• anti-inflammatory activity
• Membrane stabilising action

(3) Ronca F et.al. Osteoarthritis Cart (1998) 6,
(Supplement A), 14-21. (4) Blanco FJ. et. al.
Rev. Esp. Reumatol 2001 28, 1 12-17.
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CLINICAL EVIDENCE

• 9 randomized, controlled, clinical trials have
  been conducted in Europe with Condrosan /
  Condrosulf, comparing its effect against placebo
  (PBO) and sodium diclofenac (SD) (150 mg) in 1163
  patients with knee and hand osteoarthritis
  (OA)5-13.
• The results from these clinical trials conclude
  that CS is as effective as SD and around 50 more
  effective than PBO (p lt 0.05) in the reduction of
  OA symptoms5,14,15. Besides, its efficacy lasts
  for at least 3 months after treatment suppression
  (carry-over effect).

(5) Morreale, et al. J. Rheumatol. 1996, 23
1385-1391. (6) Kissling R. et al. Osteoarthritis
Cart 1997, 5 (Supplement A), 9 70. (7) Bucsi L,
et.al. Osteoarthritis Cart 1998, 6 (supplement
A)31-36. (8). Pavelka K, et al. Litera
Rheumatologica 1998, 2421-30. (9). Uebelhart D,
et.al. Osteoarthritis Cart 1998, 6, (Supplement
A), 39-46. (10). Uebelhart D, et al.
Osteoarthritis Cart 2004, 12269-276. (11) Michel
B, et al.. Osteoarthritis Cart 2001, 9
(supplement B), LA2. (12) Verbruggen G, et al.
Osteoarthritis Cart (1998) 6, (Supplement A),
37-38. (13) Vebruggen G. et al. Clinical
Rheumatology 2002, 21 231-241. (14) Leeb F, et
al. J. Rheumatol. 2000 27 1 205 211. (15) du
Souich P, Vergés J. Clin. Pharm. Ther. 2001 70
5-9.
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S/DMOAD

• CS may act as a structure disease modifying OA
  drug (S/DMOAD), that is, it may slow down disease
  progression16.

• 3 clinical trials in knee OA have evidenced a
  stabilization of joint space width with CS
  treatment as opposed to a narrowing of joint
  space with PBO9-11.
• 2 clinical trials in hand OA concluded that
  disease progression was lower in CS-treated
  patients and less patients from this group
  developed erosive OA12-13.

(9). Uebelhart D, et.al. Osteoarthritis Cart
1998, 6, (Supplement A), 39-46. (10). Uebelhart
D, et al. Osteoarthritis Cart 2004, 12269-276.
(11) Michel B, et al.. Osteoarthritis Cart 2001,
9 (supplement B), LA2. (12) Verbruggen G, et al.
Osteoarthritis Cart (1998) 6, (Supplement A),
37-38. (13) Vebruggen G. et al. Clinical
Rheumatology 2002, 21 231-241. (16). Jordan KM,
et al.Ann Rheum Dis 2003 621145-1155
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SAFETY PROFILE

• The tolerance of the product is very well
  documented equivalent to PBO and much higher
  than that of SD14.
• It is not metabolized by enzymes from cytochrome
  P450.
• It can not present drug interactions at this
  level.
• Pharmacosurveillance data from Europe, where no
  serious adverse events have been reported for
  more than 10 years, support the safety of the
  product.

(14) Leeb F, et al. J. Rheumatol. 2000 27 1
205 211.
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EULAR RECOMMENDATIONS 200416 Evidence based
medicine
(16). Jordan KM, et al.Ann Rheum Dis 2003
621145-1155.
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CS ADVANTAGES

• Clinical efficacy on symptom reduction and
  improvement of functional capacity
• Persistent clinical effect after treatment
  suppression (evidenced for at least 3 months)
• Greater safety than conventional therapy
  (analgesics, NSAIDs). It does not cause drug
  interactions.

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CLINICAL BIOEQUIVALENCE I

• There is only one CS approved as a drug in
  several European countries, which is therefore
  considered as the reference product17.
• This CS is manufactured by BIOIBERICA
  (CSdBio-Active) and marketed in Europe by IBSA
  and BIOIBERICA and in the the U.S.A. by Nutramax
  Laboratories, Inc. (under the trademark
  Cosamin).
• This CS is being used by the NIH for its
  Glucosamine/Chondroitin Arthritis Intervention
  Trial (GAIT). Its IND number is 59,181.

• (17). Vergés J., et al. Proceeding of the Western
  Pharmacology Society 2004 (submitted for
  publication). Poster Presentation, 47th Annual
  Meeting of the Western Pharmacology Society,
  Hawaii, 25-29 January (poster N. W-20).

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CLINICAL BIOEQUIVALENCE II

• A study analysing the contents of glucosamine and
  CS of several US products, concluded that the
  amounts found were significantly different from
  label claim in some products, with deviations
  from 0 to 11518.
• It also evidenced that characteristics such as
  molecular weight, flexibility of structure,
  sulfation and method of manufacture may influence
  oral absorption.
• Among all products compared, the one from
  Bioibérica evidenced the highest permeability
  rate.

Raw material Permeability coefficient (x 10-6) (n3) (cm/sec)
A1 B C D E F 10.1 (? 0.6) 8.73 (? 9.07) 7.94 (? 7.35) 0.00 (? 0.00) 3.63 (? 2.07) 1.03 (? 1.78)
1mol Wt 16,900 dalton (95 Bioiberica)
(18) Adebowale A, et al. JANA 2000, 3 (1) 37-44.
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CONCLUSION

• In order to ensure equivalent clinical results in
  terms of efficacy and safety, other CS products
  must show their bioequivalence to the reference
  formulation17.
• For this purpose, we propose the following method
  to determine the bioequivalence of two CS
  formulations
• Only the CS (product b) presenting an equivalent
  clinical effect to the reference CS (product a)
  within a variation range of 0.8 to 1.2 in the a/b
  ratio for the Emax, T50 and ? values for the 3
  following parameters Lequesne Index, Visual
  Analogue Scale (VAS) and pain on load, can be
  considered bioequivalent.

• (17). Vergés J., et al. Proceeding of the Western
  Pharmacology Society 2004 (submitted for
  publication). Poster Presentation, 47th Annual
  Meeting of the Western Pharmacology Society,
  Hawaii, 25-29 January (poster N. W-20).

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