XP-828L in the Treatment of Mild-to-Moderate Psoriasis: A ...

OriginalResearchAlternative Medicine Review Volume 12, Number 4 2007Reprint by permission from J Cutan Med Surg 2006;10(5):241-248.XP-828L in the Treatment ofMild-to-Moderate Psoriasis:A Randomized, Double-blind,Placebo-controlled StudyYves Poulin, MD; Robert Bissonnette, MD;Christina Juneau, PhD; Kim Cantin, BSc;Rejean Drouin, PhD; Patrice E. Poubelle, MD, DScAbstractBackground: XP-828L, a protein extract obtained from sweetwhey, has demonstrated potential benefit for the treatment ofmild to moderate psoriasis in an open-label study. Objective:To study in a randomized, double-blind, placebo-controlledstudy the safety and efficacy of XP-828L in the treatment ofmild to moderate psoriasis. Design: XP-828L 5 g/d (group A,n=42) or placebo (group B, n=42) was given orally for 56 daysfollowed by XP-828L 5 g/d in group A and by XP-828L 10 g/din group B for an additional 56 days. Results: Patients receivingXP-828L 5 g/d for 56 days had an improved Physician’sGlobal Assessment (PGA) score compared with patients underplacebo (p

Alternative Medicine Review Volume 12, Number 4 2007Psoriasis StudyEfficacy AssessmentsEfficacy was basedprimarily on the Physician’sGlobal Assessment(PGA), an assessment ofoverall lesion severity comprisingsix categories, rangingfrom none (category 0)to very severe (category 5),based on plaque elevation,scaling, and erythema. 9,10Other efficacy assessmentsincluded the Psoriasis Areaand Severity Index (PASI),body surface area (BSA)covered with psoriasis, anditch severity (0=no itch and3=severe, bothersome withdifficulty in performingdaily activities and causingsleep disturbances).The PASI is a physicianassessedoutcome based onthe extent of involved skinFigure 1. Patient DispositionDay 1 - 56Double-blindPlacebo-controlledDay 56 - 112Double-blindDose comparisonsurface and severity of erythema, desquamation, andplaque induration, with a score ranging from 0 to 72. 9,10Efficacy assessments were done at day 1 (baseline), day56, and day 112. If a value was missing, the last availableobservation was carried forward for analysis.Safety AssessmentSafety was assessed by evaluating adverseevents at each visit. Blood samples for hematology andchemistry analysis and urine samples were collected beforerandomization and at days 4, 7, 28, 56, 59, 62, 84,and 112 and were analyzed by a central laboratory.Statistical AnalysisPGA and PASI scores for patients who receivedXP-828L were compared with those from patientsunder placebo at days 56 and 112 for each testeddose. Gender, age, and baseline PASI score were includedas covariables when appropriate.Continuous end-point variables were analyzedusing mixed-model analyses of variance or analyses ofGroup A42 received XP-828 5 g/day38 completed day 564 discontinued1 Patient’s request1 Disease progression2 OtherGroup A38 received XP-828 5 g/day35 completed day 1123 discontinued1 Patient’s request2 OtherRandomized (n=84)Group B42 received placebo38 completed day 564 discontinued2 Adverse events1 Patient’s request1 OtherGroup B38 received XP-828 10 g/day34 completed day 1124 discontinued2 Patient’s request1 Disease progression1 Othercovariance, controlling for baseline values. Score changesover time were analyzed using two-tailed Student’sunpaired t-tests. Dichotomous end points and safetyparameters were analyzed using chi-square tests. Allstatistical analyses were performed on an intent-to-treatand on a per protocol basis (completers with ≥80%compliance). In all cases, a p value

Original ResearchAlternative Medicine Review Volume 12, Number 4 2007not complete the entire study. Five patients discontinuedfollowing consent withdrawal, two patientsbecause of unrelated adverse events, and two patientsdiscontinued owing to disease progression.Compliance with the test product was 93% in bothgroups. The per protocol data set excluded six patientsfor whom compliance with testing the productwas less than 80%.Treatment EfficacyA clinical improvement in the psoriasisplaque severity was associated with a decrease inPGA, PASI, BSA, and the severity of the itch.Physician’s Global Assessment: IntergroupAnalysisIn the intent-to-treat data set, the PGAscore at day 56 was lower in XP-828L-treated patientsthan in the placebo group (p

Alternative Medicine Review Volume 12, Number 4 2007Psoriasis StudyPsoriasis Area and Severity Index: IntragroupAnalysisIn the intent-to-treat data set of group A, thePASI score decreased from 8.94 ± 3.97 at day 1 to 8.36± 4.31 at day 56 (p

Original ResearchAlternative Medicine Review Volume 12, Number 4 2007Table 5. Biochemical DataDay 1 Day 56 Day 112Ref. values Group A Group B Group A Group B Group A Group(n=42) (n=42) (n=39) (n=38) (n=35) (n=34)Creatinine(µmol/L) (44-106) 78.7 ± 12.6 75.5 ± 14.6 73.0 ± 11.6 72.3 ± 12.2 73.4 ± 12.4 71.1 ± 11.9Total Bilirubin(µmol/L) (0-20) 9.9 ± 4.8 9.9 ± 4.6 9.3 ± 3.6 9.0 ± 3.2 8.6 ± 2.8 8.8 ± 2.7AST(U/L) (10-35) 24.1 ± 10.1 21.7 ± 5.9 24.3 ± 6.7 22.5 ± 5.6 24.2 ± 7.7 21.8 ± 6.0ALT(U/L) (5-40) 30.8 ± 23.2 25.1 ± 12.7 29.0 ± 13.1 24.8 ± 11.2 29.0 ± 16.5 24.3 ± 12.8Data are expressed as mean ± SD. ALT = alanine transferase; AST = aspartate transaminaseDiscussionWhey used to be considered a waste productfrom cheese and curd manufacturing. However, withits discovery as a functional food with potential healthbenefits, whey is now considered a coproduct of cheesemanufacturing. 8 Proteins contained in whey, such asβ-lactoglobulin, α-lactalbumin, bovine serum albumin,lactoferrin, immunoglobulins, glycomacropeptide, andgrowth factors, are known to have health benefits 8 andto modulate the immune system. 11,12In this study, the clinical benefit of XP-828Ltherapy in patients with mild to moderate psoriasis wasshown mainly by the PGA score (primary efficacy variable),which was improved at day 56 in patients whoreceived 5 g/d of the product. Also, the intragroup analysisrevealed that both PGA and PASI scores were improvedat day 56 in patients using XP-828L (Tables 1and 2), whereas no change was observed in the placebogroup. These data suggest that a period of 56 days oftreatment with 5 g/d of XP-828L is sufficient to induceand maintain a clinical improvement of mild to moderatepsoriasis insofar as 112 days of treatment did notadditionally improve PGA scores (Table 1). Duringthe second phase of the study, in which the patients ingroup B received 10 g of XP-828L daily, no additionaleffect on PGA or PASI scores was observed with thedouble dose of XP-828L. The initial improvement wasmaintained by continuing to receive 5 g/d XP-828L,but future studies would be required to evaluate howlong the improvement can be maintained and how fastthe disease will return following treatment interruption.At the present time, although a strong tendency of improvementhas been observed, the reason why a dose of10 g/d of XP- 828L did not statistically improve psoriasisis unknown. No studies on efficacy-dose relationshipstudies have been performed on humans with XP-828L.Further studies should be conducted to determine theoptimal dose of XP-828L for the treatment of psoriasis.However, the fact that the placebo group had beenuntreated for 56 days prior to XP-828L treatment mayhave worsened their condition, even though it was notrevealed by BSA or PASI or PGA scores. During theentire 112-day study, no related serious adverse eventwas reported under XP-828L treatment, and no statisticallysignificant difference was observed between theXP-828L group and the placebo group for laboratoryvalues or for the total number of adverse events.As there is no cure for psoriasis, the multipletreatment options currently available are only attemptingto control the severity of signs and symptoms. Thetherapeutic challenge is to find an ideal compromise betweenthe effectiveness and the side effects of a productto increase the general well-being of the patients. Thenature, extent, location, side effects, and convenience areall factors that influence the choice of treatment for patients,particularly for patients with mild psoriasis. Ingeneral, therapies with the fewest side effects are preferredby these patients. 13 One potential option is theuse of natural products or nutraceuticals with clinicalproof of efficacy and safety. As such, clinical trials onpsoriasis against a placebo present a great challenge for aPage 357Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 4 December 2007

Alternative Medicine Review Volume 12, Number 4 2007Psoriasis Studynutraceutical product. The only clinicaldata against a placebo concerningthe potential efficacy of a naturalor nutraceutical product for chronicplaque psoriasis are data on fish oilsupplementation (omega-3 fatty acid).Mayser and colleagues demonstratedthat intravenous administration ofomega-3-fatty acid for 14 days was efficaciousin the treatment of chronicplaque psoriasis. 1 The main result ofthis study was a decrease in the PASIscore in the omega-3 group (11.2 ±9.8) compared with placebo (7.5 ±8.8). Also, a PASI score of 50 wasreached in 37% of patients receivingthe omega-3 fatty acid solution comparedwith 27% for those receivingthe placebo lipid emulsion. Althoughthese results look promising, the needfor intravenous administration remainsa deterrent for the treatmentof mild to moderate psoriasis. Guptaand colleagues also demonstrated thehealth-promoting features of fish oilfor psoriasis. 4 In this study, oral administrationof fish oil was used inaddition to phototherapy (UVB) andthe improvement in the fish oil groupwas statistically greater for all parameters comparedwith placebo with UVB. This study suggests that anatural product, taken orally, could support traditionaltherapies for psoriasis. Conversely, used alone 2,3,14 orwith topical corticosteroids, 5 the efficacy of fish oil forpsoriasis was not confirmed. Thus, data on the use offish oil for psoriasis treatment remain inconsistent. Thepresent study demonstrated that XP-828L can reducethe symptoms associated with mild to moderate psoriasis.Additional studies would be required to evaluate thepotential of XP-828L to complement traditional treatmentsfor psoriasis. From its safety and efficacy profiles,a natural product such as XP-828L could be a goodaddition to traditional therapies for mild to moderatepsoriasis.Figure 2. Two patients treated with XP-828L (2.5 g twice daily).A) Patient MB001 of Group A. B) Patient LT036 of group A.ABDay 1 Day 56 Day 112Day 1 Day 56 Day 112Psoriasis has a T lymphocyte-based immunopathogenesis.15 The response of psoriasis to treatmentcompounds that act on lymphocytes such ascyclosporine, 16 DAB389IL-2, 17 alefacept, 18 efalizumab, 19or, in some cases, CD4 antibodies 20 confirms the majorrole of T cells in the pathogenesis of psoriasis. Anti-tumornecrosis factor agents (etanercept, infliximab, adalimumab)also have a proven efficacy. 21 However, thesespecific products are not appropriate for mild psoriasisowing to potential side effects and the high costs of treatment.There is a need for a safer and more appropriatetherapy for patients with psoriasis. The bioactive profileof XP-828L could be related to the presence of growthfactors, active peptides, and immunoglobulins in the extract.In vitro experiments showed that XP-828L inhibitsthe production of T helper 1 cytokines (IFN-γ andIL-2), suggesting that XP-828L could improve T helperPage 358Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 4 December 2007

Original ResearchAlternative Medicine Review Volume 12, Number 4 20071-related disorders, such as psoriasis. 6 The exact mechanismof action of XP-828L is still unknown. However,we suspect that the high concentration of transforminggrowth factor (TGF)-β2 could be, at least in part, responsiblefor the inhibition of T helper 1 cytokines bylymphocytes. In fact, TGF-β plays an essential role inT-cell homeostasis, and its abrogation leads to autoimmunedisease. 22 For instance, TGF-β-based diets havebeen shown to reduce the symptoms associated withinflammatory bowel disease. 23-25In conclusion, oral administration of XP-828Lat a dose of 2.5 g twice daily for 56 days reduced PGAand PASI scores compared with day 1, whereas nochange was observed in the placebo group. Furthermore,XP-828L is safe and well tolerated by patients withmild to moderate stable psoriasis. It is a novel therapeuticagent to add to the armamentarium to be used as acomplement for long-term treatment of psoriasis.AcknowledgmentsWe gratefully acknowledge the contribution ofDaniel Croteau, MSc Pharm, to the development of themanuscript and the contribution of Charles Dupontfrom DataMed to the statistical analyses.References1.2.3.4.5.6.Mayser P, Mrowietz U, Arenberger P, et al. Omega-3fatty acid-based lipid infusion in patients with chronicplaque psoriasis: results of a double-blind, randomized,placebo-controlled, multi-center trial. J Am Acad Dermatol1998;38:539-547.Veale DJ, Torley HI, Richards IM, et al. A double-blindplacebo controlled trial of Efamol Marine on skin andjoint symptoms of psoriatic arthritis. Br J Rheumatol1994;33:954-958.Soyland E, Funk J, Rajka G, et al. Effect of dietarysupplementation with very-long-chain n-3 fatty acids inpatients with psoriasis. N Engl J Med 1993;328:1812-1816.Gupta AK, Ellis CN, Tellner DC, et al. Double-blind,placebo-controlled study to evaluate the efficacy of fishoil and low-dose UVB in the treatment of psoriasis. Br JDermatol 1989;120:801-807.Gupta AK, Ellis CN, Goldfarb MT, et al. The role of fishoil in psoriasis. A randomized, double-blind, placebocontrolledstudy to evaluate the effect of fish oil andtopical corticosteroid therapy in psoriasis. Int J Dermatol1990;29:591-595.Aattouri N, Gauthier SF, Santure M, et al.Immunosupressive effect of a milk-derived extract[abstract]. Clin Invest Med 2004;27.7. Poulin Y, Pouliot Y, Lamiot E, et al. Safety and efficacy of amilk-derived extract in the treatment of plaque psoriasis: anopen-label study. J Cutan Med Surg 2006.8. Marshall K. Therapeutic applications of whey protein.Altern Med Rev 2004;9:136-156.9. Langley RG, Ellis CN. Evaluating psoriasis with PsoriasisArea and Severity Index, Psoriasis Global Assessment, andLattice System Physician’s Global Assessment. J Am AcadDermatol 2004;51:563- 569.10. Feldman SR, Krueger GG. Psoriasis assessment tools inclinical trials. Ann Rheum Dis 2005;64:65-68.11. Afuwape AO, Turner MW, Strobel S. Oral administrationof bovine whey proteins to mice elicits opposingimmunoregulatory responses and is adjuvant dependent.Clin Exp Immunol 2004;136:40-48.12. Kilara A, Panyam D. Peptides form milk proteins and theirproperties. Crit Rev Food Sci Nutr 2003;43:607-633.13. Linden KG, Weinstein GD. Psoriasis: current perspectiveswith an emphasis on treatment. Am J Med 1999;107:595-605.14. Bjorneboe A, Soyland E, Bjorneboe GE, et al. Effect of n-3fatty acid supplement to patients with atopic dermatitis. JIntern Med Suppl 1989;731:233-236.15. Christophers E. The immunopathology of psoriasis. IntArch Allergy Immunol 1996;110:199-206.16. Mueller W, Herrmann B. Cyclosporin A for psoriasis. NEngl J Med 1979;301:555.17. Gottlieb SL, Gilleaudeau P, Johnson R, et al. Response ofpsoriasis to a lymphocyte-selective toxin (DAB389IL-2)suggests a primary immune, but not keratinocyte,pathogenic basis. Nat Med 1995;1:442-447.18. Ellis CN, Krueger GG, Alefacept Clinical Study Group.Treatment of chronic plaque psoriasis by selective targetingof memory effector to T lymphocytes. N Engl J Med2001;345:248-255.19. Lebwohl M, Tyring SK, Hamilton TK, et al, EfalizumabStudy Group. N Engl J Med 2003;349:2004-2013.20. Nicolas JF, Chamchick N, Thivolet J, et al. CD4 antibodytreatment of severe psoriasis. Lancet 1991;338:321.21. Krueger JG. The immunologic basis for treatment ofpsoriasis with new biologic agents. J Am Acad Dermatol2002;46:1-23.22. Gorelik L, Constant S, Flavell RA. Mechanism oftransforming growth factor beta-induced inhibition of Thelper type 1 differentiation. J Exp Med 2002;195:1499-1505.23. Beattie RM, Schiffrin EJ, Donnet-Hughes A, et al.Polymeric nutrition as the primary therapy in childrenwith small bowel Crohn’s disease. Aliment Pharmacol Ther1994;8:609-615.24. Oz HS, Ray M, Chen TS, McClain CJ. Efficacy of atransforming growth factor beta 2 containing nutritionalsupport formula in a murine model of inflammatory boweldisease. J Am Coll Nutr 2004;23:220-226.25. Schiffrin EJ, Yousfi ME, Faure M EP, et al. Milk caseinbaseddiet containing TGF-beta controls the inflammatoryreaction in the HLA-B27 transgenic rat. JPEN J ParenterEnteral Nutr 2005;29:S141-S148.Page 359Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 4 December 2007