SYMPOSIUM REPORT SUPPLEMENT
`
`Recombinant and Plasma-Purified Human C1 Inhibitor for
`the Treatment of Hereditary Angioedema
`
`Michael M. Frank, MD
`
`Background: Agents for prophylaxis of hereditary angioedema
`(HAE) have been available in the United States for several decades,
`but their usefulness is limited by side effects and they cannot be used
`at all in some patients. No agents have been available in the United
`States to specifically treat acute attacks. HAE types I and II are
`associated with low functional levels of C1 inhibitor, and evidence
`accumulated over decades suggests that intravenous infusion of C1
`inhibitor is useful for terminating angioedema attacks and for
`prophylaxis.
`Key Points: C1 inhibitor derived from pooled human plasma has
`been available for decades in Europe, and 2 preparations have been
`recently introduced into the United States. Both have been effica-
`cious in carefully controlled double-blind studies. One preparation,
`Cinryze, was approved by the U.S. Food & Drug Administration
`(FDA) for prophylaxis of HAE attacks in October 2008, and the
`second, Berinert, was approved by the FDA for treatment of acute
`attacks in October 2009. A third preparation,
`the recombinant
`human C1 inhibitor Rhucin, is completing clinical trials. Although
`not yet approved by the FDA, preliminary results made available
`suggest that Rhucin, too, is effective in terminating attacks of HAE.
`Conclusions: Americans will now have access to effective acute
`and prophylactic treatments with C1 inhibitor for hereditary
`angioedema.
`
`Key Words: HAE, contact system, C1INH
`
`(WAO Journal 2010; 3:S29 –S33)
`
`Hereditary angioedema (HAE) is an episodic swelling
`
`disorder that involves the subcutaneous tissues of the
`extremities or the mucosa of the bowel and occasionally the
`tissues of the face, mouth, and pharynx or the genital area.1,2
`Attacks most commonly increase in severity for about 1.5
`days and then resolve during about the same period of time.
`Patients are usually most bothered by the painful abdominal
`attacks, which can be very severe and can lead to abdominal
`
`From the Duke University Medical Center, Durham, North Carolina.
`Presented as part of “New Perspectives in Hereditary Angioedema: Molec-
`ular Mechanisms and Therapeutic Choices,” A CME Symposium pre-
`sented at the 2009 World Allergy Congress, Buenos Aires, Argentina,
`December 9, 2009.
`Correspondence to: Michael M. Frank, MD, Duke University Medical
`Center, 131 MSRB 1, 571 Research Drive, DUMC Box 2611, Durham,
`NC 27710.
`Phone: (919) 684-2922. E-mail: frank007@mc.duke.edu.
`Copyright © 2010 by World Allergy Organization
`
`WAO Journal ● September 2010, Supplement
`
`surgery; however, the development of laryngeal angioedema
`can lead to asphyxiation and death. HAE types I and II are
`caused by mutations in 1 of the 2 gene alleles that code for the
`plasma protein C1 inhibitor. This protein was named for its
`ability to regulate the activity of the complement protein C1,
`but C1 inhibitor has been found to act as a regulator or
`inhibitor of the clotting, fibrinolytic, and kinin-generating
`systems in plasma as well. It is now believed that comple-
`ment is not the major system responsible for HAE attacks,
`although the failure of C1 inhibitor to regulate activation of
`the complement system in these patients has led to the most
`commonly used diagnostic test other than the level or function
`of C1 inhibitor itself, the plasma concentration of C4; the level
`of the complement protein C4 is almost always low in these
`patients. The failure to adequately regulate the kinin system
`leads to the unregulated formation of bradykinin, which in turn
`leads to angioedema.3
`Identification of the elements of the kinin pathway has
`led to the development of highly specific therapy; however,
`even before this information was available, considerable
`progress was made in attempts to provide long-term prophy-
`laxis for patients with HAE. Epsilon aminocaproic acid, the
`first agent found to be effective in prophylactic treatment of
`HAE,4,5 was identified during a random screen of diseases
`that may respond to treatment with this agent. Frank and
`colleagues at the National Institutes of Health performed a
`small double-blind trial that confirmed the effectiveness of
`the drug in preventing HAE.6 Over time, it became clear that
`epsilon aminocaproic acid, a fibrinolysis inhibitor, has many
`side effects that limit its use. A related drug, tranexamic acid,
`was developed that is less toxic and has been used with
`success in Europe, but it has not been widely used in the
`United States.7 Several years after the identification of the
`antifibrinolytics as useful in prophylaxis, the androgens were
`shown to be effective in the prophylaxis of HAE.8 Their
`mechanism of action is still not completely clear, but patients
`with HAE are heterozygous for the defective C1 inhibitor
`gene allele, and androgens seem to increase synthesis of C1
`inhibitor by the normal gene allele. Androgens have proven
`very useful, but they are not effective in everyone, cannot be
`used in children or pregnant women, and have a great many
`side effects that, although generally mild, preclude their use
`in some people.9 Furthermore, they regularly induce weight
`gain and alterations in blood lipids that may predispose
`patients taking them for decades to atherosclerosis and car-
`diovascular disease.10 None of these prophylactic drugs are
`effective as acute therapy and it is clear that new, more-
`
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`WAO Journal • September 2010, Supplement
`
`specific agents are needed. Fresh-frozen plasma has been
`widely used in acute attacks.11 However, it rarely can in-
`crease angioedema during attacks because it supplies the
`precursor proteins for kinin generation.
`
`DEVELOPMENT OF C1 INHIBITOR THERAPY
`In 1963, Donaldson and Evans reported that HAE
`patients have a specific inherited defect in the plasma protein
`C1 inhibitor.12 Patients with type I HAE were later shown to
`have low levels of this protein because its synthesis or
`secretion was prevented by mutations in one of the gene
`alleles; in general, patients with type II HAE have a defect in
`a gene allele that results in secretion of a nonfunctioning
`protein.13 Infusion of the missing functional protein C1 in-
`hibitor was an obvious approach to specific therapy. Three
`groups, the American Red Cross, the Dutch Red Cross, and
`the Behring Company in Germany all set out to purify C1
`inhibitor from plasma. All of these groups already had facil-
`ities for collecting and pooling plasma from thousands of
`donors and purifying individual plasma proteins because all
`were suppliers of gamma globulin for patient use. The au-
`thor’s own group had access to the American Red Cross
`preparation and in 1980 reported that C1 inhibitor infusion
`raised plasma C1 inhibitor levels as expected in 8 patients
`and, as a consequence of its action in inhibiting activated C1,
`also raised the levels of serum C4.14 We reported that this
`treatment terminated angioedema attacks in 5 of our patients
`who were having attacks at the time of their infusion.14 At
`about the same time, the Dutch Red Cross developed a
`preparation of C1 inhibitor, and Agostoni et al reported that
`it was effective in terminating attacks of angioedema.15 Bork
`and Witzke also reported that the German preparation was
`effective in terminating an attack of HAE.16
`
`DEVELOPMENT OF THE CURRENTLY USED C1
`INHIBITOR PREPARATIONS
`In 1980, the importance of blood transfusion in trans-
`mitting the newly discovered disease AIDS became clear.
`The American Red Cross turned its attention to developing
`procedures to make the blood supply safe, and they prepared
`no further batches of C1 inhibitor. However, both the Dutch
`Red Cross and Behring continued to prepare batches of C1
`inhibitor for therapeutic purposes. The manufacturing arm of
`the Dutch Red Cross was merged into the company Sanquin
`in 2003. In 1989, heat treatment was added to the preparation
`of this product, and now nanofiltration has also been added as
`an extra step to ensure the absence of contaminating viruses.
`The Behring product was first licensed as a unpasteurized
`product in Germany in 1979 and as a pasteurized product in
`1985. Thus, these 2 products are available in Europe and have
`been used in patients for decades and, since the introduction
`of further purification steps 2 decades ago, have not been
`noted to transmit any infectious agents. The purification
`procedure in both cases is designed to remove viral contam-
`inants. Some years after the initial reports of successful
`therapy, the Austrian company Immuno, another supplier of
`gamma globulin, also began to prepare a C1 inhibitor and to
`make it available in Europe. Waytes et al examined this
`
`S30
`
`preparation in a double-blind study reported in 1996 and
`demonstrated that it was effective for both prophylaxis and
`acute treatment of angioedema attacks17; however, this prod-
`uct is no longer available. Many subsequent reports have
`testified to the efficacy of the European preparations. In
`particular, Bork and colleagues have published extensively
`on the effect of the Behring preparation in terminating acute
`attack.18,19 Because prevention using attenuated androgens
`was less common in Germany, an enormous number of
`attacks were treated. For example, Bork et al reported the
`effect of C1 inhibitor on symptoms in thousands of HAE
`abdominal attacks. Many patients began to recover at about
`30 minutes, and by 1 hour after treatment began most patients
`were well on the road to recovery.19
`
`INTRODUCTION OF C1 INHIBITOR INTO THE
`AMERICAN MARKET
`Several years ago, Behring and Sanquin made the
`decision to bring their European plasma-derived products to
`the United States. Over the years the original Behring Com-
`pany was first divided and then acquired by a number of
`companies, and now it is part of the larger company CSL
`Behring. The pharmaceutical company Lev was organized in
`the United States to test and bring to market the Sanquin
`product. More recently, Lev was acquired by Viropharma.
`
`RECOMBINANT C1 INHIBITOR
`A new approach for the development of a human C1
`inhibitor for treatment of HAE attacks was developed by a
`second Dutch company, Pharming.20 This company pio-
`neered the concept of isolating the human gene for a plasma
`protein and fusing it to a bovine casein promoter. The new
`gene was transduced into rabbits, and the animals secrete the
`human gene product in their milk after pregnancy and deliv-
`ery. The human protein is then isolated from the milk. This
`company is in the late stages of testing their product, called
`Rhucin, in treatment of HAE attacks.21
`
`TESTING OF THE NEW PREPARATIONS
`A series of double-blind studies of treatment of acute
`attacks were initiated in the United States to fulfill Food and
`Drug Administration (FDA) requirements. The studies per-
`formed had much in common. All were placebo-controlled
`trials, with each subject receiving one dose of either drug or
`placebo. All patients had a preliminary screening visit at
`which the diagnosis was confirmed. Patients must have had
`low actual or functional amounts of plasma C1 inhibitor and
`low C4 with a normal C1q. There were also details that
`differed between the studies. For example, the type of attack
`acceptable for the treatment protocol varied from study to
`study: some allowed peripheral edema attacks, but some did
`not, and some allowed facial attacks, but some did not. For
`some studies, the FDA allowed C1 inhibitor to be used as the
`rescue medication. In all studies the C1 inhibitor was admin-
`istered intravenously. The only prophylaxis trial had a cross-
`over design, as discussed below. The Behring study examined
`responses to abdominal and facial attacks, and the Lev study
`examined responses to abdominal, facial, and genital attacks. In
`
`© 2010 World Allergy Organization
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`

`WAO Journal • September 2010, Supplement
`
`C1 Inhibitors for HAE
`
`the Lev study, the product, now called Cinryze, was used at
`1000 units per patient with the possibility of the dose being
`repeated if the patient did not respond.22 In the Behring study,
`the product, now known as Berinert, was used at either 10 or 20
`units/kg.23 In the Pharming study the product was used at 50 or
`100 units/kg21; a higher dose was used because the recombinant
`protein has a much shorter half-life in the circulation than the
`plasma-derived protein. This is presumably because the rabbit
`glycosylates proteins differently from humans, and the C1 in-
`hibitor is a heavily glycosylated protein.
`All 3 preparations of C1 inhibitor seem to be effective
`in terminating attacks of angioedema (Fig. 1). Response is
`dose-dependent, and it is likely that small differences are
`
`FIGURE 1.
`Two plasma-derived C1 inhibitor preparations,
`Cinryze (A) and Berinert (C), and a recombinant protein,
`Rhucin (B), provide faster symptom relief for acute HAE at-
`tacks than placebo. Reprinted with permission from (A) New
`England Journal of Medicine,22, (B) Pharming Group NV, (C)
`Journal of Allergy and Clinical Immunology.23
`
`© 2010 World Allergy Organization
`
`determined by differences in the dose administered and the
`severity and type of attack. Dose-finding studies were con-
`ducted by Pharming (personal communication) and CSL
`Behring.23 Patients with moderate disease started to recover
`in a mean of about 9 hours with placebo and recovered in
`about 5 hours when given C1 inhibitor. CSL Behring found
`that 20 units/kg Berinert, not 10 units/kg, was significantly
`effective in terminating attacks. Although fewer patients in
`this group were studied, with severe disease the difference
`was even more striking with severe attacks, which showed
`relief in 12 hours with placebo and in 2 hours with C1
`inhibitor. Patients responded to both the 50 and 100 unit/kg
`dose of Rhucin. In general, abdominal and throat attacks
`responded much more rapidly than peripheral attacks. This
`may be a reflection of the fact that resorption of peripheral
`edema is slow. The amount of edema that it takes to com-
`promise the airway is small and the amount of edema that it
`takes to stretch the gut mucosa is relatively small or relatively
`easily absorbed in this area of high vascularity. In earlier studies,
`clear responses were seen at 30 minutes, but in no case did the
`agent lead to complete recovery in this time frame.19 All the
`patients receiving placebo also recovered; HAE is a self-limited
`disease and in all cases attacks resolve spontaneously.1,2 Part of
`the speed of response is determined by the stage of attack when
`the patient is treated. If the patient is treated early in an attack,
`resolution may be quick. If he or she is at the peak of the attack,
`resolution may occur more slowly. If the patient has started
`to recover and is no longer generating bradykinin, the recovery
`may be rapid. There is no biochemical test that allows the
`physician to grade the severity of an angioedema attack or to
`determine whether an attack is becoming more severe or is in the
`recovery phase, and so many of these decisions are based on
`experience and judgment.
`It appears that both of the plasma-derived products,
`Cinryze and Berinert, are effective in acute therapy. The
`Behring product was approved by the FDA for treatment of
`acute attacks of HAE in October 2009. The recombinant
`product is reported to be effective but has not yet been
`approved for therapy.
`
`PROPHYLAXIS OF ATTACKS
`Perhaps 20% of patients have attacks that are suffi-
`ciently frequent or sufficiently severe that prophylaxis is
`needed. As noted above, the drugs that have been tradition-
`ally used for prophylaxis are not suitable in all situations and
`are associated with side effects that in some patients may be
`intolerable. In October 2008, the C1 inhibitor preparation
`Cinryze (Viropharma) was approved by the FDA for prophy-
`laxis against HAE angioedema attacks. Approval followed a
`double-blind study that had a crossover design.22 Patients
`received 1000 units of Cinryze or an equal volume of placebo
`as an intravenous infusion 2 times per week. If the patient’s
`symptoms were not controlled on 2 infusions per week, a
`third infusion of Cinryze as open-label treatment was permit-
`ted. After 12 weeks of treatment with drug or placebo, there
`was a crossover so that patients receiving drug were switched
`to placebo and patients on placebo were switched to drug.
`The number, location, duration, and severity of attacks were
`
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`Frank
`
`WAO Journal • September 2010, Supplement
`
`recorded, as was the number of times that rescue medication
`was administered. The results were clear cut: on all of these
`parameters patients did better on drug, and the results were
`statistically highly significant. Most patients had fewer at-
`tacks, although attacks were not eliminated altogether, but in
`some patients the attack frequency did decrease to zero. One
`patient had a markedly increased frequency of attacks on
`Cinryze compared with placebo. These results point out
`several things. In none of these studies did the amount of drug
`given lead to complete normalization of C1 inhibitor levels,
`and it seems reasonable to expect that in some patients attacks
`may continue. It had previously been noted before that there
`is no relationship between C1 inhibitor levels and the inci-
`dence or severity of attacks.1 Patients with relatively high
`levels of C1 inhibitor may have severe and frequent attacks,
`and patients with relatively low levels may have mild disease.
`Because the level of bradykinin is determined not only by the
`rate of generation of the peptide but also by its rate of
`degradation, it is reasonable to hypothesize, but has not been
`shown experimentally, that differences in the rate of brady-
`kinin degradation may explain this finding. Psychologic fac-
`tors also have a marked influence on the frequency and
`severity of attacks.22 The individual with increased attack
`frequency had a series of major personal problems during the
`12-week period when she was receiving Cinryze. During the
`period when she was receiving placebo her life situation was
`much improved and her attack frequency was much lower.
`
`ADVANTAGES AND DISADVANTAGES OF THE
`VARIOUS AGENTS
`There are theoretical problems with all products. The
`plasma products carry some risk of infection. Hepatitis was
`transmitted by plasma-purified C1 inhibitor in the very early
`days of its use, but with the introduction of more highly
`refined purification and pasteurization techniques there have
`been no cases of infectious disease transmission by these
`agents for decades, and they are used extensively in Europe.
`Plasma-derived inhibitors have the advantage that because
`all patients are heterozygous for deficient C1 inhibitor
`function, they have one normal gene producing normal
`secreted protein, and allergy to the administered product is
`unlikely unless it is modified during the purification. Fur-
`thermore, because this is the normal physiologic protein, it
`is expected to work in the normal way to restore patients
`to physiologic balance.
`Recombinant C1 inhibitor carries less risk of infection,
`although rabbits do have some retroviruses. However, glyco-
`sylation of the recombinant protein differs from that of the
`normal C1 inhibitor, resulting in a shorter half-life. As a
`result, it is unlikely to be of use in prophylaxis. Because of
`the difference in sugars, there is some risk of allergy; al-
`though some allergy has been noted to rabbit proteins, the
`author is not aware of any allergy to the purified human C1
`inhibitor. Because it is not a serum product, in theory the
`supply is limitless. All of the reported testing has used
`intravenous administration and only intravenous products are
`FDA-approved. This limits self-administration and is there-
`fore inconvenient for the patient.
`
`S32
`
`COST OF THE NEW THERAPIES FOR
`HEREDITARY ANGIOEDEMA
`HAE has been designated an “Orphan Disease”, mean-
`ing that there are so few patients that a drug manufacturer is
`unlikely to see the development of therapy as profitable. For
`that reason the U.S. Congress some years ago gave manufac-
`turers an incentive to develop drugs for this group of diseases
`by providing for 7 years of exclusivity; that is, the develop-
`ment of new effective therapy for an Orphan Disease guar-
`antees the developers that no other manufacturer will be able
`to market the same product for 7 years. This has led directly
`to an effort to have new drugs approved for the treatment of
`HAE for the American market. Interestingly, multiple ap-
`proaches to this problem have led to the almost simultaneous
`development of effective agents. Development and testing of
`drugs is expensive and the developers want to assure their
`investors of a profit. As is often the case with new drugs
`developed through the Orphan Disease program, the drugs
`are expensive. Thus far, we know the cost of the plasma-
`derived C1 inhibitor products and of Ecallantide. All are
`marketed at well over $1000 dollars a dose and are far more
`expensive than danazol, but all seem to have a better safety
`profile. With so many new effective agents on the market, it
`is not clear how pricing will proceed in the future.
`
`CONCLUSIONS
`The development of C1 inhibitor prophylaxis and ther-
`apy for acute treatment represents an enormous milestone in
`the history of HAE treatment. For the first time, Americans
`have drugs available that clearly will terminate attacks. Fur-
`thermore, there is now effective prophylactic therapy as well.
`It
`is likely that some patients will continue to take the
`androgens for cost reasons and because they are relatively
`low in toxicity. Clearly, the toxicity profile of the new agents
`is preferable. Nevertheless, pregnant women and children
`have therapeutic alternatives that were not available in this
`country in the past, and their lives will be greatly improved.
`
`ACKNOWLEDGEMENT
`This CME satellite symposium was kindly supported by
`an educational grant from ViroPharma Incorporated, and
`sponsored by the World Allergy Congress 2009 and Robert
`Michael Educational Institute LLC. In addition, the authors
`and editors would like to thank Naomi Ruff, PhD, for her
`editorial contribution.
`
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