r-m—‘ancan journal of clinical dermatology
`:
`ll no 6 (2010;
`7
`General Collection
`N1 Alvl449V
`2"4""1‘42—07 08:2l 04
`
`0.VOl-11,N0-6(PP~371'443)
`;1175-0561 (Print); 11794888 (Online)
`
`American journal of
`
`Clinical Dermatology
`
`Ethnic Considerations
`1 user 'l‘rcalmcm of Dark Skin
`
`General Interest
`(:lu‘onic Prlll‘illh in the Absence nfSkin Disease
`
`chmridrmis Sucgcxsfull)‘ ’l‘rcatcd with l’mpranolol
`
`Hereditary Disorders
`Novel 'l‘licrapicx for Acme Hereditary Angiocdcma
`
`Inflammatory Disorders
`Contact Dermatitis in Older Adults
`l’mrmxix I humpy and Cardiovascular Risk l'ucmrs
`’\LHL‘ Kclmdnlix lemu
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`lniliximnli
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`llg'JIlnk'nl for ( imnulunm \nnulmc
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`Photodermatology
`l \':\ l’miuliun oi .’\\Ul)L‘H/(HIC. /,im (hidnx and limnium l)l(l\ldL‘
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`PROPEKI‘Y OF THE
`lll\\\§ NATIONAL
`I LIBRARY or
`m MEDICINE
`
`
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`_Dll6llllll|l lllllfilllllllllllll
`
`luwer business
`
`Page 1 of 9
`
`CSL EXHIBIT 1038
`
`CSL V. Shire
`
`
`
`Page 1 of 9
`
`CSL EXHIBIT 1038
`CSL v. Shire
`
`

`

`,,V9.1,,-..1.1,r Ire-"6,201.0",
`
`,,
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`..
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`
`_
`American journal of
`w . .Clinical.,,P.erm.a,t0i9gy
`
`Contents '
`
`AsknOWIedgmem
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`V
`
`.,
`
`.:
`
`.
`
`..
`
`.
`
`..
`
`,,
`
`r
`
`.
`
`.
`
`.
`
`.
`
`..
`
`Review Arlicles
`
`Contact Dermatitis in Older Adults: A Review of the Literature
`AV Prakash, MDP Davis
`
`An Overview of Novel Therapies for Acute Hereditary Angioedema
`R Firszt, MM Frank
`
`Laser Treatment of Dark Skin: An Updated Review
`S Shah, TS Alsi-er
`
`Chronic Pruritus in the Absence of Specific Skin Disease: An Update on
`Pathophysiology, Diagnosis, and Therapy
`N Cassano, G Tessm'i, GA Vena, G Girolomoni
`
`Original Research Articles
`
`Characterization of the UVA Protection Provided by Avobenzone, Zinc Oxide,
`and Titanium Dioxide in Broad-Spectrum Sunscreen Products
`DG Beasley, TA Meyer
`
`Psoriasis Therapy and Cardiovascular Risk Factors: A '12-Week Follow-Up Study
`5 Coimbra, H Olivaira, F Rois, L Bela, S Rocha, A Quintanillm, A Figuciredo, P Teixeira, E Castro,
`P Roclza—Pcreira, A Santos-Silva
`
`Case Reports
`
`Acne Keloidalis Nuchae: Another Cutaneous Symptom of Metabolic Syndrome,
`Truncal Obesity, and Impending/Overt Diabetes Mellitus?
`SB Vermn, U Wollina
`
`Anti-Tumor Necrosis Factor—0c Treatment with Infliximab for Disseminated
`Granuloma Annulare
`G Murdacn, BM Colombo, G Bm‘abino, M Caiti, P Cagnati, F Puppo
`
`A Case of Hematidrosis Successfully Treated with Propranolol
`Z Wang, Z Yu, I Sn, L Cao, X leao, X Bai, S Zlmn, T Wu, L [£71, P Zhon, C Rum:
`
`371-372
`
`373-381
`
`383-388
`
`389-397
`
`399-411
`
`413-421
`
`423-432
`
`433-436
`
`437-439
`
`440-443
`
`Iourilals@0vid,
`
`Register for the free Adis Electronic Table of Contents E-Vlail Alert Service today at hltpz/ /adisonline.com
`American Journal ofCIinical Dermatology is indexed in the following biomedical databases: MEDLINE, EMBASE/Exccrpia Mcdica, International Pharmaceutical Abstracts (IPA),
`Current CoillcnlS/Cliuiral Medicine, SCiSL’IU'Cil, [onrnal Citation Reports/Science Edition, Prons Science Integrity, Sociezind Iberoamoricana dc Informacio’n CiL’nlij’ica (SIIC), and
`
`Page 2 of 9
`
`

`

`$.Adis
`
`a Wolters Kluwer business
`
`American journal of
`Clinical Dermatology
`
`International Editorial Board
`
`D. Abeck, Munich, Germany
`
`T. Alster, Washington, DC, USA
`K.E. Andersen, Odense, Denmark
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`F.F. Belli, Milan, Italy
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`E. Berardesco, Rome, Italy
`C.J. Cockerell, Dallas, TX, USA
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`P.R. Cohen, Houston, TX, USA
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`8. Dreno, Nantes, France
`M. Duvic, Houston, TX, USA
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`P. Eisner, Jena, Germany
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`J.C. English lll, Pittsburg, PA, USA
`V. Folctnga, Providence, RI, USA
`E.R. Former, Norfolk, VA, USA
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`B. Giannotti, Florence, Italy
`A. Gottlieb, Boston, MA, USA
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`C.E.M. Griffiths, Salford, England
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`H.C. Korling, Munich, Germany
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`H.|. Maibach, San Francisco, CA, USA
`R. Marks, Cardiff, Wales
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`U. Mrowietz, Kiel, Germany
`J.P. Ortonne, Nice, France
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`A.S. Puller, Chicago, IL, USA
`T.J. Phillips, Boston, MA, USA
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`G.E. Piérard, Liege, Belgium
`N.S. Scheinfeld, New York, NY, USA
`N. Shear, Toronto, ON, Canada
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`K.S. Smalley, Tampa, FL, USA
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`H. Tagoml, Aoba, Sendai, Japan
`J.M. Weinberg, New York, NY, USA
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`Page 3 of 9
`
`Aim and Scope: The American Iourluzl of Clinical Dermatology promotes rational
`therapy and effective patient management within the discipline of dermatology by
`providing a regular program of independent review articles covering all aspects of the
`management of dermatological conditions, particularly the place in therapy of newer
`and established agents and procedures.
`The Journal includes:
`- leading / current opinion articles providing an overview of contentious or emerging
`areas and key regulatory and ethical issues;
`- definitive reviews on a broad range of topics relating to the management of derma—
`tological conditions;
`- therapy in practice reviews covering optimum management of specific conditions;
`- pictorial diagnosis and treatment articles where illustrations are used to portray
`clinical findings and techniques;
`- Adis Drug Evaluations reviewing the properties and place in therapy of both newer
`and established drugs in dermatology;
`- Adis Drug Profiles reviewing innovations in therapy.
`Original research articles will also be considered for publication.
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`All manuscripts are subject to peer review by international experts. Letters to the editor
`are welcomed and will be considered for publication.
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`Editor: Kathy Fraser
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`Publication Manager: Sheree Bartlett
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`http: / /adisonline.com/ dermatology
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`American Journal of Clinical Dermatology (print ISSN 1175-0561; online ISSN 1179-
`1888) is published as 1 volume with 6 bi-monthly issues by Adis, a Wolters Kluwer
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`Page 3 of 9
`
`

`

`REIEW ARTICLE
`
`ArnJ Clin Dermatol 2010; ll (6) 383-358
`l17570551/lU/m83/84995/D
`
`" " ©1Aa‘ls Dt IntorlB.A| rights reserved.
`
`An Overview of Novel Therapies for Acute
`Hereditary Angioedema
`
`Rafael Firszt and Michael M. Prank
`
`Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA
`
`Abdominal attacks presenting with severe abdominal pain may
`
`Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks
`are characterized by nonpitting edema of external or mucosa] body surfaces. Patients often present with
`swelling ol‘the extremities, abdominal pain, and swelling of the mouth and throat, which can at times lead to
`asphyxiation. The disease is caused by a mutation in the gene encoding the complement Cl-inhibitor protein,
`which leads to unregulated production of bradykinin.
`Long-term therapy has depended on the use of attenuated androgens or plasmin inhibitors but in the US
`there was, until recently, no specific therapy for acute attacks. As well, many patients with hereditary
`angioedema in the US were either not adequately controlled on previously available therapies or required
`doses of medications that exposed them to the risk of serious adverse effects. Five companies have completed
`or are currently conducting phase III clinical trials in the development ofspecific therapies to terminate acute
`attacks or to be used as prophylaxis. These products are based on either replacement therapy with purified
`plasma-derived or recombinant Cl-inhibitor, or inhibition of the kinin—generating pathways with a re-
`combinant plasma kallikrein inhibitor or bradykinin type 2 receptor antagonist. Published studies thus far
`suggest that all of these products are likely to be effective. These new therapies will likely lead to a totally new
`approach in treating hereditary angiocdema.
`
`Contents
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`Abstract .
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`l. Pathophysiology and Diagnosis of Hereditary Angioedema (HAE) .
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`2. Treatment of HAE .
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`2.1 Previously Available Therapies .
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`2.2 Novel Therapies .
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`22.1 Cl-lnhibitor Replacement Therapy .
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`2.2.2 inhibitors of Kinin Generation and Response .
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`. . . . . . . . . . . . . . . . . . . . . . . . , . . . , , . , , _ , . , . . . . . . , . , , , , , , . , . _ . , . . , . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . ......... Conclusions . . 387
`
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`Abstract
`
`The common types ofhereditary angioedema (HA E), type 1
`and 2, are rare autosomal dominant disorders due to either
`deficiency or dysfunction ofCl-inhibitor (Cl-INH). Cl-INH is
`involved in regulating the activation of the complement eas-
`cade. The cause of type 3 HAE is less clear. All are characterized
`
`by recurrent attacks of nonpruritie angioedemai” The edema is
`nonpitting and typically nonpainful and is due to leakage of
`plasma from postcapillary venules into the dermal layers of the
`skin. HAE is often grouped as an allergic disorder, but attacks
`
`are not due to histamine release and patients do not have more
`allergic symptomatology than those in the general pop-
`ulation.[” It primarily involves the extremities (eg. hands and
`feet), face, and genitalia, although patients also commonly have
`swelling of the gastrointestinal tract and it occasionally affects
`the mucosal tissues of the upper airway. In about one-quarter
`of patients, severe abdominal pain may be the presenting fea—
`ture and it is usually the feature that debilitates the patientm
`
`Page 4 of 9
`
`

`

`Subject US {Sapjrright Laws
`
`Factor XII function, but how this may lead to angioedema is
`unknownllu More importantly, the majority are very difficult
`to diagnose with certainty because, although they may have a
`suggestive clinical history,
`they have no clearly identifiable
`blood abnormality.
`Cl-INH is a broadly active serine protease inhibitor in
`A diagnosis of HAE should be considered in patients with
`plasma. It is the principal inhibitor of Clr and C13 and man-
`recurrent angioedema without urticaria, unexplained episodes
`nose binding lectin-associated serine proteases (MASPS) of the
`of recurrent colicky abdominal pain, a family history of angio—
`complement pathway. These are the activated serine proteases
`edema, or unexplained laryngeal edema. It should be noted
`of C I (the first component of the classical complement path-
`that, as with many autosomal dominant diseases, a family
`way) and the proteases that function with mannose binding
`history is frequently not present. Since most cases of HAE are
`lectin. By inhibiting these proteases, Cl-INH can prevent ex-
`due to low functional levels of Cl-INH, Cl protein in the
`This material was copied
`at the N LM 5 rid may be
`
`lead to surgery in patients without an appropriate diagnosis.
`The abdominal pain tends to be more spasmodic than con—
`tinuous and may be associated with vomiting, constipation, or
`diarrhea. In addition, about one-third of patients develop ery-
`thema marginatum at the start of an attack; the rash is usually
`described as red circles on the skin and is flat, erythematous,
`and nonpruritic.
`The age at which attacks begin is variable. Most patients
`have their first attack in childhood and these attacks usually
`
`become more severe at pubertylml However, attacks can begin
`at any time, even as late as 70—80 years ofage. Most often, age at
`onset is identified retrospectively, that is, the diagnosis is made
`years after clinical symptoms manifest, particularly if there is
`no family history. Attacks are often preceded by a prodrome
`consisting of tingling in the area of the skin involved followed
`by swelling within the next several hours. These attacks are
`usually sporadic. However,
`in about one-third of patients,
`minor trauma or psychological stress can initiate an attack.
`Menstruation may precipitate attacks in some women. Other
`
`triggers include the use of ACE inhibitors and estrogens. ACE
`inhibitors precipitate attacks by preventing the breakdown of
`bradykinin, the mediator that has been shown to cause capillary
`leakagelml It is interesting to note that although one would
`expect an equal prevalence of disease among men and women,
`most physicians note a preponderance of women requiring
`care. It is likely that this reflects the influence of estrogen on
`disease severityl‘”
`Typically, attacks grow more severe in the first 24—36 hours
`and then gradually subside over the next 48~72 hours. In some
`patients, abdominal pain can last 4—5 days and peripheral
`swelling can last up to 9 days. Most often the swelling is self-
`limited; however, edema of the upper airway can be life
`threatening. Laryngeal attacks usually develop over hours but
`there have been reports of precipitous airway closurelsl In early
`clinical studies before prophylactic therapy was available, it
`was reported that about one-third of family members with the
`disease had a history of aspliyxiation.[6]
`
`i. Pathophysiology and Diagnosis of Hereditary
`Angioedema (HAE)
`
`to 2010 Adis Data information BV. All rights reserved.
`
`Firszt 8 Frank
`
`cessive activation of the complement pathway by antigen-
`antibody complexes. Cl-INH is also involved in inhibiting
`other mediator cascades in plasma. These include the intrinsic
`
`coagulation cascade, the kinin-generating pathways, and the
`fibrinolytic systems. In the coagulation cascade, Cl-INH inhibits
`all of the active fragments of Factor XII (Hageman Factor) and
`Factor XI, as well as tissue plasminogen activator and plasmin
`in the fibrinolytic pathway. In the kinin-generating pathway,
`Cl-INH functions to inhibit plasma kallikrein. Kallikrein is a
`plasma enzyme that functions to cleave its substrate, high
`molecular weight kininogen, to form bradykinin. Interestingly,
`Factor XII, the first factor involved in the intrinsic coagulation
`cascade, is thought to be involved in activating kallikrein. Re-
`cent studies have shown that bradykinin is the major mediator
`of angioedema and this is released during the activation of the
`inter-related clotting and kinin—generating pathways”
`It was not until the early 1960s that studies indicated that
`HAE was due to abnormally low levels of Cl-INH.[8’°l Later
`studies suggested that there are different types of HAE de-
`pending on the presence and function ofCl-INH.['°] There are
`
`currently three identified types of HAE. Type 1 HAE is char—
`acterized by a mutation in one of the two Cl-INH gene alleles
`leading to low levels of functional and Cl-INH protein. In
`type 1, serum levels ofC l -INH are often <30% ofnormal. On the
`
`other hand, type 2 HAE is characterized by a mutation in one of
`the Cl-INH alleles that affects the active site of the protein.
`These patients often have normal or elevated amounts of
`
`Cl-INH protein circulating, but have levels of function similar
`to those in the patients with type 1 HAE because half the protein
`synthesized is non-functional. Lastly, there is a third form of
`HAE (type 3) that occurs mainly in women and is characterized
`by an angioedema syndrome that is often estrogen dependent.
`These patients have typical symptoms of HAE but thus far no
`clear complement or kinin system abnormality has been identi-
`fied. About one-third of the patients with type 3 HAE are re-
`ported to have mutations in Factor XII that lead to increased
`
`Am J Clin Delmaiol 20l0; ll (6)
`
`Page 5 of 9
`
`

`

`Novel Therapies for Acute Hereditary Angioedema
`
`complement pathway is able to continuously cleave and con-
`sume the next two proteins, C4 and C2. Therefore, patients with
`type 1 and 2 HAE almost always have low levels of C4, even
`between attacks. Cl-INH levels and C4 measurements are the
`
`usual diagnostic tests. In the case where both C4 and Cl-INH
`antigen are low then the patient most likely has type 1 HAE. If
`C4 is low but Cl-INH is normal, then one can obtain tests of
`Cl-INH function. If these are low, the patient most likely has
`type 2 HAE. There is one major caveat. The functional tests
`
`available in the US may be unreliable and give false-positive or
`false-negative values and often the serum C4 is the best func-
`
`tional test. Type 3 HAE requires a strong index of suspicion
`since Cl-INH levels and function are normal and there are no
`
`action typically occurs 48 hours following administration.
`Since danazol, the first of the drugs found to be effective, is
`widely available and generally well tolerated it tends to be the
`androgen of choice. In our management plan,
`the starting
`dosage of danazol is 200 mg three times daily. This dose is then
`titrated downwards until the lowest tolerated dose able to
`
`prevent attacks is achieved.
`Androgen therapy is generally well tolerated but there are
`important adverse effects, which although minor in most
`patients are intolerable in others. These include masculiniza-
`tion, headaches, weight gain, hirsutism, liver function abnor-
`malities, and lipid abnormalities. Only methylated androgen
`derivatives are effective in the treatment of HAE. Un-
`
`alterations in any complement levelsllv‘svm
`There is an acquired form of angiocdema that tends to occur
`in older patients with monoclonal antibodies to Cl-INH or
`
`fortunately, these methylated androgens are only available in
`oral form and are therefore unsuitable for patients with acute
`abdominal attacks with edematous gastrointestinal mucosa.
`
`from malignancy. In addition, some patients with autoimmune
`disorders such as systemic lupus erythematosus appear to
`consume sufficient Cl—INH to induce an HAE-like syndrome.
`These patients have low levels of C4 and low levels of Clq,
`which is the third protein that forms the C1 complex with Clr
`and C15 and which is at normal levels in patients with true
`HAE. The patients with acquired disease may have normal
`levels of C l-INH, although levels are usually low, but their
`functional level is always low. Unlike patients with true HAE,
`their C3 levels may at times be low.[‘3'16] Therapy of these
`patients is not reviewed here.
`
`2. Treatment of HAE
`
`2.1 Previously Available Therapies
`
`Although occasionally used, long—term administration of an-
`drogens is considered unsafe in children since it may cause
`premature closure of bony epiphyses leading to short stat-
`urelzmzl In addition, androgens cannot be used in pregnancy
`because they may lead to ambiguous genitalia in newbornsml
`A second class of agents, the antiflbrinolytics, has been used
`in the long-term treatment of HAE. These agents inhibit the
`conversion of plasminogen to plasmin but it still remains un—
`clear why they reduce attacks of HAE. It has been shown in a
`double-blind, placebo-controlled study that aminocaproic acid
`is effective as long-term therapy?“ Tranexamic acid, a drug
`related to aminocaproic acid, is another example of a plasmin
`inhibitor but it is not generally used for oral therapy of HAE in
`the US. Similar to androgen therapy, in our experience these
`
`agents require 48 hours to take effect. Adverse effects are com-
`mon and may include painful myositis, disturbed color vision in
`the case of tranexamie acid, and gastrointestinal complaints?“
`
`Since androgens and plasmin inhibitors are ineffective in
`treating acute attacks, fresh frozen plasma (FFP) has been
`widely used for acute treatment of HAE. FFP is used to supply
`the needed Cl-INH that is missing or dysfunctional in these
`
`patients. FFP is generally efficacious in treating acute attacks;
`however, FFP can rarely exacerbate attacks of HAE in patients
`and therefore may be dangerous. Since high molecular weight
`
`Subject LIE Sepryrright Laws
`
`Until 2009 treatment strategies for HAE in the US focused
`on long-term therapy and avoidance of possible known trig-
`gers. Although prophylaxis is often effective, treatment of acute
`attacks in the US was unsatisfactory since effective agents that
`terminate attacks were not available. Long-term therapy was
`mainly dependent on the use of attenuated androgens. In the
`19705, it was noted that HAE attacks were made much worse by
`estrogen therapy and that puberty was associated with marked
`exacerbation of disease. Attenuated androgens were subse-
`quently studied in the treatment of HAE attacks. In double-
`blinded studies, it was found that attenuated androgens were
`effective in decreasing the frequency of attacks. In addition,
`these drugs tended to normalize the blood levels ofCl—INH and
`C4.“7‘3°] However, the exact mechanism of action of attenuated
`androgens is still unclear. These agents require long-term ad-
`ministration and are not effective in acute attacks since onset of
`
`kininogen, the substrate for kallikrein, is also present in normal
`plasma, bradykinin generation may increase and a patient’s
`symptoms may actually worsen with infusion of FFP. In the
`absence of effective therapy for acute attacks, this may lead to a
`life-threatening situationml
`In summary, although treatment of HAE is generally well
`accepted, these therapies are not always useful. As mentioned,
`they are not effective in the treatment of acute attacks and they
`Th is- matierlal wasmpiee
`at the NLM and may he
`
`Am J Clin Dermatol 2010; ll (6)
`
`© 20l0 Adls Data information BV. All rights reserved.
`
`Page 6 of 9
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`

`Fir-5:18 Frank
`
`laxis and Berinert® is approved for acute therapy. Similar
`preparations have been on the market in Europe for decades
`and many case reports confirm their effectiveness. CinryzeTM
`for prophylaxis is administered at a dosage of 1000 units intra-
`venously every 374 days. Berinert® for acute treatment is ap-
`proved at a dosage of 20 units/kg, also given intravenously.
`BorkB” first mentioned the use of the Behring Cl-INH to
`terminate an attack of HAE in 1979. Since then, the efficacy
`of this purified Cl-INH to treat acute attacks of HAE has
`
`been well documented. Bork and Barnstedtmiul reported ex—
`tensively on its use in retrospective studies of case reports but
`there were no controlled trials. A large, non-randomized study
`compared purified Cl-INH with conservative management in
`193 episodes of laryngeal angioedema occurring in
`18
`patientsml All treated patients responded, and Cl—INH stop-
`ped progression of symptoms as rapidly as 30 minutes. The
`mean duration of laryngeal edema was 15.3 hours in patients
`who received treatment compared with 101 hours in those who
`did notinl Cicardi and Zingalem] have similarly treated a large
`number of acute attacks of HAE successfully with purified Cl-
`INH. The dose of Cl-INH used to terminate attacks in most
`
`studies has been in the range of 154.5 units/kg.
`The primary concern in treating patients with purified Cl-
`INH from plasma is the theoretical risk of disease transmission.
`
`In the past 2 decades, there have been no reported cases of
`infection with the products of CSL Behring and ViroPharma
`despite being given to hundreds of patients. Other adverse ef-
`fects from this treatment are rare and include headache and
`
`have adverse effects that may be intolerable to some patients.
`As well, some patients do not respond to the above therapies.
`
`2.2 Novel Therapies
`
`There are currently five products newly available or in the
`process of coming to market in the US. Two companies have
`launched purified Cl-INH protein derived from the pooled
`plasma of thousands of donors: CinryzeTM (ViroPharma Inc.,
`Exton, PA, USA)[35’36] and Berinert® (CSL Behring LLC,
`Kankakee, IL, USA).[3’27] CinryzeTM is approved by the US
`FDA for prophylaxis against angioedema attacks in adolescent
`and adult patients with HAE, and Berinert® is approved for the
`treatment of acute abdominal or facial attacks of HAE in adult
`
`and adolescent patients. A third company is producing a re-
`combinant human Cl-INH protein preparation (Rhucin®;
`Pharming Group NV, Leiden, the Netherlands). This product
`is not yet available in the US. The final two products focus
`specifically on the kinin-generating pathways. The first of these
`is ecallantide (Kalbitor®; Dyax Corp, Cambridge, MA, USA),
`which is a kallikrein inhibitor and has recently been approved
`by the FDAIZS] The second, icatibant (Firazyr'a; Shire, Cam-
`bridge, MA, USA) is a bradykinin type 2 receptor antagonist,
`which is currently licensed in numerous European countries but
`not in the US.
`
`2.2. 1 CI -Inhibii‘or Replacement Therapy
`
`Actually, the word novel is somewhat misleading when ap-
`plied to these agents. Cl-INH, prepared by the American Red
`Cross, was reported to be effective in treating attacks in the US
`in 1980 and biochemical data on its effectiveness were pro-
`videdizgl In a double-blind, placebo-controlled trial
`in 11
`patients with HAE reported in 1996, purified Cl-INH prepared
`by the Austrian company Immuno was evaluated in the treat-
`ment of all types of acute attacks. Purified Cl-INH improved
`symptoms in 55 minutes compared with 563 minutes with
`placebo.[301 In addition, in contrast to placebo, the infusions of
`Cl-INH concentrate resulted in close to normal functional
`levels of Cl-INH and C4.
`
`Su-izjett US Copyright Laws
`
`fever. There have also been rare anaphylaetoid reactions re-
`ported. However, since all patients are heterozygotes and syn-
`thesize and have present circulating normal protein, significant
`allergy to the administered product is unlikely. In addition,
`plasma products would be expected to be safe in childhood and
`pregnancy. Unlike the other new products, purified Cl-INH
`has been shown to be effective in short—term prophylaxis for
`surgery and dental procedures.[341 A major disadvantage with
`purified Cl-INI-I is that it has only been studied for use via
`intravenous administration. Up to new, studies have shown
`that self-administration of these products at home is effective
`and can reduce the need for going to hospital.[35’3(‘] As well,
`these studies have shown that self-administration of purified
`Cl-INI-l on a regular basis can decrease attack frequencies and
`is effective as prophylaxis. It is likely that subcutaneous ad-
`ministration of these products will be examined.
`A third Cl-INH product is being introduced by the Dutch
`company Pharming. It is a recombinant human Cl-INH iso—
`
`Purified Cl-INH has been on the market and successfully
`used in Europe since the early 19803, but has only recently been
`submitted to the FDA for approval and distribution in the US.
`As mentioned, two companies have now received FDA ap-
`proval for purified Cl-INH from plasma. Both provide Cl—
`INH replacement protein obtained from pooled human plasma
`that has been pasteurized and has undergone multiple purifica-
`tion procedures. Both are administered intravenously. Although
`they are similar products, CinryzeTM is approved for prophy-
`This material was «copied
`at the NLM and may“ be
`
`© 2010 Adis Data information BV. All rights reserved.
`
`Am J Ciin Dermotol 2010: ll (6)
`
`lated from milk of transgenic rabbits. The human gene for
`C1~INH is cloned and introduced into rabbits with a bovine
`
`Page 7 of 9
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`

`

`Novel Therapies for Acute Hereditary Angioedema
`
`casein promoter. The human protein is secreted in milk of
`lactating rabbits and the protein is subsequently isolated. Choi
`et 211.97] treated 13 severe angioedema attacks in nine patients
`with this recombinant Cl-INH. They found that there was
`rapid improvement of clinical conditions in all attacks, with
`approximately 80% of treated patients experiencing symptom
`relief within 2 hours and minimal symptoms within 12 hours.
`There are two major advantages ofthis product. The first is that
`since it is made in rabbits the supply of recombinant Cl-INH
`can be essentially limitless. The other major advantage is that it
`is not prepared from pooled human plasma thus decreasing any
`infectious risk. However, the product has a major limitation.
`Cl-INH is one of the most heavily glycosylated proteins in
`plasma. It is thought that, because proteins are glycoslyated
`differently in humans and rabbits, it has a short half-life in the
`circulation and has to be used in higher doses.
`
`2.2.2 Inhibitors of Kinin Generation and Response
`
`The above three products replace Cl-INH and presumably
`restore normal control of kallikrein inhibition. There are two
`
`additional products that target the kinin-generating pathways.
`These products directly affect the bradykinin pathway, which is
`thought to be directly responsible for angioedema formation.
`The first of these products is ecallantide. It is produced by
`Dyax, an American company, and it is a potent reversible in-
`hibitor of the enzyme kallikreinflzwsl Ecallantide is a 60 amino
`acid peptide with seven unique amino acids derived on a
`KunitZ-type enzyme inhibitor domain that is prepared by re-
`combinant technology in the yeast Pic/rig pastoris. It has the
`advantage of being administered either intravenously or sub-
`cutaneously. Recently reported are the results of a double-blind,
`placebo-controlled trial with 71 patients. Using both treatment
`outcome scores as well as time to improvement, the drug was shown
`to be highly effective in the treatment of acute attacks of HAEl-w]
`Because it has a short half-life, ecallantide is not used in
`
`prophylactic therapy. The drug has been approved by the FDA
`for acute therapy at a dose of 30mg subcutaneously. One
`concern is that about 4% of patients had an anaphylactic event
`following the administration of this 60 amino acid peptide and
`the FDA has required a black-box warning and requires the
`drug to be administered by medical personnel?“
`The final product, icatibant,
`is a small synthetic peptide
`marketed by Shire (Cambridge, MA, USA). It is a potent,
`reversible, competitive antagonist of the bradykinin type 2
`receptor. Two double-blind trials have been completed that
`examine the use ofthis agent in the treatment ofacute attacks of
`HAE — FAST-l and FAST-2W] The FAST-l trial was con-
`
`FAST-2 trial was conducted in Europe and Israel. The two
`
`trials had a similar study design with one major difference. In
`the FAST-l trial the drug was compared with placebo. How-
`ever, for the FAST-2 trial the relevant agency in Europe asked
`that the drug be compared with tranexamic acid, a fibrinolysis
`inhibitor that is available for the treatment of HAE in Europe.
`
`3. Conclusions
`
`Many patients with HAE in the US have either