conestat alfa - Rhucin; Ruconest; rhC1INH; C1-INH; human complement C1 esterase inhibitor, recombinant, transgenic rabbits
Status: MAA approved in the EU; BLA filed in Dec. 2010, refiled in April 2013
Organizations involved:
Pharming B.V. – Manuf.; R&D; Tech.; Intl. Mark.
Santarus Inc. – USA mark.
Fuji Diosynth Biotechnology –Manuf.
Akzo Nobel NV – Parent
Swedish Orphan Biovitrum AB (Sobi) – Europe mark.
Advanced Cell Technology (ACT) – Tech.
Infigen, Inc. – Tech.
Cross ref.: See the human-derived C1-esterase inhibitor (Cetor) entry (#714). See also the entry for Kallikrein inhibitor, rDNA (DX-88) also used for treatment of hereditary angioedema (HAE).
Description: Rhucin is a formulation of recombinant human C1 inhibitor (rhC1INH; C1-INH) glycoprotein obtained from the milk of transgenic rabbits, The rabbits’ DNA has been modified by insertion of a bovine alpha-S1 casein milk-specific promoter sequence functionally linked to the gene encoding human C1 inhibitor. This allows the rabbits to express rhC1INH in their milk at levels of 12 g/L. The protein has a molecular weight of about 105 kDa.
rhC1INH is Pharming’s lead in-house-developed product. If approved, Rhucin(R) will represent the first new therapy for hereditary angioedema (HAE) in over thirty years.
Biological.: Human C1 inhibitor, also known as C1 esterase inhibitor (C1-INH), belongs to the superfamily of serine proteinase inhibitors (i.e., it’s a protease inhibitor). Human C1 inhibitor is the only inhibitor of C1r and C1s of the complement system, and is the major inhibitor of factor XIIa and kallikrein of the contact system. C1 inhibitor also inhibits other serine proteases of the coagulation and fibrinolytic systems like factor XI, tissue type plasminogen activator and plasmin..
Human C1 inhibitor (C1-INH) is encoded by a single gene on chromosome 11 and consists of 8 exons and 7 introns. The entire genomic sequence codes for a protein of 500 amino acids, including a 22 amino acid signal sequence. Plasma C1 inhibitor is a glycoprotein of ~105 kDa and is heavily glycosylated, up to 50% of its molecular mass consists of carbohydrate. This high level of glycosylation, which is required for activity, necessitates recombinant expression of hC1NH in mammalian cells or animals (or expression systems substantially mimicking mammalian glycosylation).
In humans, C1-INH helps to regulate the complex biochemical interactions of blood-based systems involved in inflammation and coagulation. C1-INH is known to be either a major or minor inhibitor of at least seven proteins involved in these systems. C1-INH is known to inhibit three key biochemical pathways underlying inflammation and/or coagulation – the complement system, the contact pathway of intrinsic coagulation, and the fibrinolytic system. Excessive activity of each of these systems has been demonstrated in hereditary angioedema (HAE; see the Disease section below), as evidenced by increased levels of components of the complement system, kallikrein, coagulation Factors XIa and XIIa, and plasmin.
The biochemical imbalance that results from reduced levels of functional C1-INH leads to the production of proteins and peptides that cause fluids to be released from the capillaries into surrounding tissues, causing edema. C1-INH is a multifunctional regulator of all major kinin-generating protein cascade systems. Besides use for treatment of hereditary angioedema, C1-INH may also be useful for treatment of complement-mediated inflammatory tissue damage such as capillary leak syndrome, septic shock, multiple organ failure, and hyperacute graft rejection.
Nomenclature: C1-esterase inhibitor, rDNA [BIO]
Rhucin [TR]; Ruconest [TR EU]; 80295-38-1 [RN for the human C1NH]; C1 esterase inhibitor [SY]; complement C1 esterase inhibitor, recombinant, transgenic rabbits [SY]; rhC1INH [SY]
Companies.: Rhucin was developed by Pharming Group N.V. Pharming manufactures rhC1NH in transgenic rabbits in its own facilities. Rhucin is marketed in the U.S. and North Amercica by Santarus, Inc.
In Feb. 2005, Pharming concluded a manufacturing agreement with Diosynth B.V. (Diosynth Biotechnology), now Fuji Diosynth, for manufacture of clinical and commercial supplies of rhC1INH. Diosynth will primarily handle purification of rhC1INH supplied by Pharming. The availability of commercial supplies of rhC1INH enabled Pharming to pursue a preapproval compassionate use program for Rhucin in Europe.
In Sept. 2010, Santarus, Inc. exclusively licensed all North American marketing rights for Rhucin. Santarus paid Pharming a $15 million upfront fee and an additional $5 million milestone upon FDA acceptance of Pharming's BLA for Rhucin. Santarus may also pay Pharming additional success-based clinical and commercial milestones, including upon achievement of certain aggregate net sales levels of Rhucin. Santarus also purchases its commercial supply of RHUCIN from Pharming at a tiered supply price, based on a percentage of net sales of Rhucin.
Pharming has licensed marketing rights in Spain, Portugal and Greece to Esteve Group. Presumably, Pharming plans to market the product (or license marketing rights in the U.S., other European territories, and other countries worldwide.
In Aug. 2011, Swedish Orphan Biovitrum (SOBI) extended its agreement with Pharming, obtaining marketing rights in the Balkans, North Africa and the Middle East.
Manufacture: Recombinant human C1 inhibitor is obtained from transgenic rabbits. A special health monitoring system ensures that the rabbit population is specified pathogen free (SPF). Rabbits showing any abnormality are excluded from the colony. The raw milk is analyzed for compliance with internal criteria, prior to release for down stream processing. This ensures product safety and allows for a much higher degree of control over the raw materials used for purification compared to Rhucin’s competitor which is derived from pooled donor blood.
For high-value and small volume products, Pharming asserts transgenic rabbits represent an excellent production platform. Transgenic rabbits provide short development timeline. Rabbits are efficient breeders and produce milk containing the desired protein within one-year time after the start of a project. Pharming’s rabbits are specified pathogen free, and no zoonoses are known in rabbits, making the system extremely safe to produce therapeutic proteins. A rabbit can yield 100 mL milk per day with a protein content of about 14%. Rabbits can each produce up to 10 liters of milk a year, and expression levels of the transgenic protein can be as high as 20 grams per liter. For small and medium sized indications: (such as orphan diseases), the rabbit system is ideal to produce up to 50 kg of protein per year. Transgenic bovines (cows; cattle) are preferred for recombiant protein manufacture on a larger scale.
Transgenic rabbits are generated through microinjection. The procedure starts with the collection of fertilized oocytes (egg cells), after which the DNA construct (vector) encoding the protein of choice and a strong expression promoter sequence is injected directly into the nucleus of oocytes by microinjection. Transplanted oocytes are cultured to develop into embryos which are subsequently implanted in the oviducts of pseudopregnant female animals, resulting in birth of transgenic offspring (i.e., the injected embryos are transferred to foster mothers, where they develop into healthy rabbits). The first batches of milk containing the protein are available after six months, when the female transgenic rabbits start lactating. Sperm of the male transgenic rabbits is used for the rapid generation of a transgenic production colony. Secondary expression of C1 inhibitor proteins in tissues other than the mammary gland does not occur to an extent sufficient to cause deleterious effects in the rabbits. Human C1 inhibitor protein is secreted from the mammary gland with sufficient efficiency that no problem is presented by deposits clogging the secretory apparatus. Of course, only the female members of a species are useful for producing milk. Transgenic males are of value for breeding female descendants. The sperm from transgenic males can be stored frozen for subsequent in vitro fertilization and generation of female offspring.
In the construction of transgenic rabbits expressing rhC1NH, transgenes are designed to target expression of a recombinant C1 inhibitor to the mammary gland of a the transgenic mammal harboring the transgene. The basic approach entails operably linking an exogenous DNA segment encoding rhC1NH protein with a signal sequence, and a regulatory (promoter) sequence effective to promote (induce) expression of the exogenous DNA segment. Typically, the regulatory sequence includes a promoter and enhancer, and is from a gene that is exclusively or at least preferentially expressed in the mammary gland (i.e., a mammmary-gland specific gene). Preferred genes as a source of promoter and enhancer include alpha-S1-casein. A preferred transgene for expressing C1 inhibitor protein from genomic sequences comprises a genomic C1 inhibitor sequence encoding the entire coding sequence and a signal peptide, a 3’-UTR and a 3’-flanking sequence, operably linked to a 5’-alpha-S1 casein fragment containing regulatory sequence(s) sufficient to direct expression of the C1 inhibitor protein.
A typical rabbit, for instance, can produce an average of 120 milliliters of milk a day. In the modified rabbits, each liter contains 12 grams of human C1 inhibitor, according to Pharming
Upon European Union (EU) approval, Pharming planned to start milking a herd of about 1,000 rabbits. The rabbits are milked using mini pumping machines that attach to the female rabbits' teats. The method can roughly be compared to cow milking. After purification, due to strict laws governing transgenic products, the rest of the rabbit milk has to be destroyed.
As described in U.S. patent 7,067,713, purification of bulk rhC1INH involves loading the milk onto a cationic exchange column under conditions in which the human C1 inhibitor binds to the column; eluting the human C1 inhibitor from the cationic exchange column; loading the eluate on an anionic exchange column under conditions in which the human C1 inhibitor binds to the column; eluting the human C1 inhibitor from the anionic exchange column; loading the eluate onto a metal ion exchange column under conditions in which residual contaminating proteins bind to the column; and collecting eluate containing the human C1 inhibitor from the metal ion exchange column. The resulting purified rhC1INH has a ratio of human to rabbit C1 inhibitor of at least 500:1.
Example 7 of this patent describes purification of rhC1INH at 10 Liter milk scale. Presumably, Diosynth performs much this same process for commercial manufacture. Frozen milk, 11 kg, was stored frozen, thawed and pooled. An equal amount of 20 mM sodium citrate pH 5.5 was added. The diluted milk was filtered over 25 µm and skimmed (fat removed) by continues centrifugation at room temperature. The skimmed milk was applied with a flow of 60 cm/h on a SP Sepharose big bead (Pharmacia) column (450/15) equilibrated in 20 mM sodium citrate pH 7.0+0.02 M sodium chloride. The column was washed with 5 column volumes of 20 mM sodium citrate pH 7.0+0.02 M sodium chloride, and bound rH-C1INH was eluted with a step of 20 mM sodium citrate pH 7.0+0.2 M sodium chloride. The eluted rhC1INH was filtered through 0.2 pm and incubated for 6 hours at 25˚C. in the presence of 1% polysorbate 80 (Tween 80) and 0.3% tri-n-butyl phosphate (TNBP) to inactivate enveloped viruses. The pool was 3-fold diluted in 20 mM sodium phosphate pH 7.0, filtered over 0.2 µm and applied with a flow of 60 cm/hr on a Q Sepharose high performance (Pharmacia) column (450/15) that was equilibrated in 20 mM sodium phosphate pH 7.0+0.05 M sodium chloride. Q Sepharose FF is a preferred anion exchange column, because this material is relatively inexpensive compared with other anion-exchange columns and has a relatively large bead size suitable for large scale purification. Under specified conditions, C1INH can be eluted from Q Sepharose FF without eluting rabbit C1 inhibitor or other proteins found in rabbit milk. After washing of the column with 5 column volumes of 20 mM sodium phosphate pH 7.0+0.05 M sodium chloride, bound rH-C1INH was eluted with a step of 20 mM sodium phosphate pH 7.0+0.22 M sodium chloride. The eluate was 2-fold diluted in 20 mM sodium phosphate pH 7.0, 0.2 µm filtered, and applied with a flow of 30 cm/h on a zinc-charged Chelating Sepharose fast flow (Pharmacia) column (450/15) equilibrated in 20 mM sodium phosphate pH 7.0+0.1 M sodium chloride. After loading, the column was washed with 20 mM sodium phosphate pH 7.0+0.1 M NaCl and the protein fraction that had not been absorbed by the column was collected. This protein fraction was filtered over 0.2 µm followed by filtration over a Vira/Gard 500 membrane (AG/T) for removal of possible viral contaminants. In a later experiments and for commercial manufacture a Planova 15N (nanometer) filter from Asahi replaced the Vira/Gard membrane. After this viral filtration, the rhC1INH was concentrated and buffer exchanged to 20 mM sodium citrate pH 7.0 using a Biomax-10 membrane (Millipore). The concentrated rH-C1INH was filtered through 0.1 .µm, vialed and stored at –20˚C. In a later experiment, 6.5% sucrose was added to the concentrated rH-C1INH, which was subsequently filtered through 0.1 µm, vialed and freeze-dried. The recovery of this process was 37% using a specific ELISA for rhC1INH. The activity of rhC1INH throughout the purification was preserved as determined by the inhibition of C1 esterase. The purity was determined above 99% by size exclusion chromatography and above 99.999% using a specific ELISA that detects host proteins present in rabbit milk. The amount of endogenous rabbit C1INH was quantitated below 1 ppm.
Status: In July 2006, Pharming submitted a MAA for European Union approval of rhC1INH for the treatment of acute attacks of hereditary angioedema (HAE). It was accepted for filing on Aug. 17, 2006. Approval was expected in later 2007. The EU has granted orphan designation for prophylactic and acute treatment of HAE.
rhC1INH has received orphan designation in the U.S. and European Union for HAE, where it is marketed by Swedish Orphan Biovitrum (SOBI). FDA granted orphan designation for both prophylaxis and acute treatment of both hereditary and acquired angioedema. FDA has also granted designations prevention and/or the treatment of delayed graft function (DGF) after solid organ transplantation and the treatment of capillary leakage syndrome (CLS).
In July 2007, Pharming Group NV reported that its facilities for the manufacture of Rhucin had passed all inspections conducted by EMEA/EU for GMP manufacture
On Dec. 13. 2007, the Committee for Medicinal Products for Human Use (CHMP), EMEA/EU, issued a negative opinion regarding approval of Rhucin for the treatment of acute attacks of angioedema in patients with congenital C1 inhibitor activity deficiency. The CHMP was concerned that there was insufficient evidence to show the benefits and risks of Rhucin, with the available studies (prior to fall 2008 completion of a U.S. Phase III trial) were too small to show how effective Rhucin is in treating more severe forms of the disease, such as swelling in the larynx, or how safe and effective the medicine is when given to a patient more than once. There was also insufficient information over the likelihood of patients developing antibodies following repeated doses of Rhucin. The CHMP was also concerned over the possible presence of impurities in Rhucin from the rabbit milk which could affect safety. Pharming had not demonstrated that the levels of the impurities or the antibodies could be measured in a reliable manner. Pharming filed an appeal.
In March 2008, the CHMP again adopted a negative opinion on the MAA for Rhucin for acute HAE. The CHMP did not have a specific concern on the safety and efficacy data submitted in the MAA and accepted all the non-clinical and quality aspects of the product. However, it is not reassured that there is sufficient evidence to confirm the clinical benefits of Rhucin in repeat use, particularly the potential for immune responses following repeated administration. The re-examination procedure by EMEA included a review by an independent scientific advisory group composed of European recognized experts in the field of HAE. There was consensus among the experts, recognizing that the available clinical data were limited, that there was no evidence to indicate the development of neutralising antibodies to C1-inhibitor with repeat administration of Rhucin. Pharming will re-submit its MAA with additional data from completed its North American clinical study. As part of the re-submisson, Pharming will request an expedited review which is an assessment period of 150 days. In the meantime the Company continues to pursue registration in markets outside the European Union
Pharming had expected to file a BLA filing with FDA in late 2008.
On Dec. 30, 2008, Pharming reported that "the BLA file was recently transferred from the CDER to the CBER division of the FDA. The file is also reaching its final stage of readiness and dialogue with the CBER division is planned for 1Q 2009."
On Dec. 30, 2008, regarding its EMEA/EU (re)application, Pharming reported "pre-filing dialogue with EMEA has started with a regulatory dossier in final stages of readiness that contains well in excess of 300 treatments, including significant evidence on efficacy and safety in repeated use and absence of immunogenicity. A formal filing with the EMEA will be done as soon as practically possible, pending the response of the recently installed CHMP Paediatric Committee on the Rhucin Paediatric Investigation Plan. Currently the filing is expected mid 2009."
On June 24, 2010, European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion on Ruconest (Rhucin) for the treatment of acute angioedema attacks in patients with Hereditary Angioedema (HAE). It was also concluded that the name Rhucin may lead to confusion with a similarly sounding product marketed in some EU countries. Rhucin to be marketed in the EU was renamed as Ruconest.
In Aug. 2010, to further strengthen Rhucin's competitive profile, Pharming was preparing to initiate a Phase IIIB/IV global multicenter randomized placebo-controlled study, focusing on "time to onset of relief" of HAE symptoms, with 50 patients either receiving 50U/kg Rhucin or placebo.
On October 28, 2010, the European Union approved Ruconest for marketing by Swedish Orphan Biovitrum.
On Dec. 28, 2010, Pharming finally filed the BLA for Rhucin.
In Aug. 2011, Santarus and Pharming announced a Special Protocol Assessment (SPA) agreement with FDA for a Rhucin Phase III clinical study intended to support the submission of its BLA. Following discussions with the FDA and implementation of the Agency’s recommended changes to the study protocol, the FDA has confirmed that Pharming’s proposed trial design, clinical endpoints and statistical analyses were acceptable. As a result of the discussions with the FDA, the changes to the study design included a modification to the way the primary endpoint would be assessed and an increase in the number of patients from 50 to approximately 75. The protocol will also be changed to allow the introduction of open-label doses of Rhucin as a rescue medication. The study is expected to be completed by the third quarter of 2012
In Feb. 2012, Pharming received a “refusal to file” (rejection) letter from FDA that indicated that the BLA was not sufficiently complete to enable a critical medical review. FDA noted that the BLA did not provide data for a sufficient number of subjects to support the proposed dose of 50 U/kg and lacked prospective validation of the visual analog scale used in measuring the clinical effects of Rhucin. The BLA had included nine clinical studies covering 714 administrations in 190 subjects, but Pharming and Santarus believed it makes sense to do another trial to support the BLA.
In Feb. 2012, Pharming initiated another U.S. clinical trial to further support FDA approval. (covered by the SPA. The Phase IIIb trial will enroll 50 patients and take 12-18 months (less than cited in the SPA).
In April 2013, Pharming refiled its BLA seeking approval for RUCONEST for the treatment of acute angioedema attacks in patients with hereditary angioedema (HAE). In June 2013, the refiling was accepted for review.
Tech. transfer: Pharming has received patents covering aspects of rhC1INH manufacture in transgenic animals including U.S. 7,067,713, “C1 Inhibitor produced in the milk of transgenic non-human mammals,” expiring Jan 31, 2021, assigned to Dyax. Claims cover the production of rhC1INH in milk of transgenic mammals, the treatment of patients suffering from or susceptible to C1 inhibitor deficiency, and the purification of the protein yielding extremely pure and functional rhC1INH. In June 2006, when this patent was issued in the U.S., Pharming reported allowance of equivalent patent applications by the European and Australian patent offices. The exemplary claim (no. 1) of 7,067,713 is “A nonhuman mammal whose genome comprises a DNA segment encoding a C1 inhibitor heterologous to the mammal operably linked to at least one expression regulatory sequence from a gene that is preferentially expressed in mammary gland cells and a DNA segment encoding a signal peptide functional in mammary gland cells; wherein the DNA segment encoding the C1 inhibitor can be expressed in the mammary gland cells to produce C1 inhibitor in the milk of an adult form of said mammal or a female descendant thereof.”
U.S. 7,235,530, "Kallikrein inhibitors and anti-thrombolytic agents and uses thereof," expiring Sep 27, 2024, assigned to Dyax, includes claims for use of DX-88 in combination with anti-thrombolytic agents for preventing or reducing blood loss in patients undergoing invasive surgical procedures, especially procedures requiring cardiopulmonary bypass. With this patent, Dyax has eight issued U.S. patents covering DX-88 as well as other related kallikrein inhibitors, and their uses.
EP1812049, "KALLIKREIN INHIBITORS AND USES THEREOF," assigned to Dyax, expires in 2025.
As a pioneer in the development of transgenic animals for recombinant protein manufacture, Pharming has developed strong and broad portfolio of enabling technologies, including 36 patents on different aspects of transgenic technology and products derived from milk of transgenic animals, either through own patent filings or in-licensing. Pharming’s patent portfolio on transgenic technology includes milk specific expression in transgenic animals and associated promoters (e.g., U.S. 4,873,316 and 5,994,616); transgenic animals with very large trans-genes (i.e., .>50kb; e.g., U.S. 5,612,205 and 5,721,367); and purification of biopharmaceuticals from milk (e.g., U.S. 5,919,913). Pharming holds licenses on various aspects of transgenic antibody production, nuclear transfer, artificial mammalian chromosomes, and transgenesis by pronuclear microinjection.
In March 2008, Pharming further consolidated its patent position concerning nuclear transfer for generation of transgenic cattle by taking an exclusive license from Advanced Cell Technology (ACT). Pharming already had non-exclusive rights to these patents through prior agreements with Infigen, a former competitor to Advanced Cell Technology whose intellectual property assets relating to somatic cell nuclear transfer, parthenogenesis and associated technologies were acquired by ACT in Feb. 2007.
Disease: See the entry for Kallikrein inhibitor, rDNA (DX-88) also used for treatment of hereditary angioedema (HAE).
Hereditary angioedema (HAE) is a rare hereditary (genetic) disorder caused by a an inherited lack or insufficient functional C1 inhibitor activity. The genetic defect results in production of either inadequate or nonfunctioning C1-INH protein. Both males and females can be affected. HAE is caused by a defective gene for C1-INH, and this defect is passed on on by the parents. A child has a 50% chance of inheriting this disease if one parent is affected. The absence of family history, however, does not rule out HAE diagnosis, and as many as 20% of HAE cases involve patients who appear to have had a spontaneous mutation of the C1INH gene at conception.
The disease is characterized by acute attacks of painful and in some cases fatal swelling of several soft tissues (edema) in the extremeties (hands and feet), face, gastrointestinal tract and airway passages, which usually last up to five days when untreated. The course of the disease is diverse and unpredictable, even within a single patient over his lifetime. Swelling caused by HAE usually lasts for 24-72 hours, but the length of an attack can range from four hours to four days. On average, patients experience about one attack per month, but the frequency is highly variable. As many as five to 10% of patients are severely affected, experiencing attacks one to three times per week. The majority of patients experience periods of severe abdominal pain, nausea and vomiting caused by swelling in the intestinal wall. The disease can even be lethal if attacks in the throat area lead to asphyxiation. The mortality rate from untreated airway obstruction is over 30%.
In the Western world, the prevalence for HAE is about 1 in 30,000, meaning about 22,000 patients in the Western world, with patients having an average of seven acute attacks per year. There are thought to be 6,000 or more people with HAE in the U.S.
A patient having a genetic or other deficiency resulting in an insufficiency of functional C1 inhibitor can be treated by administering exogenous C1 inhibitor, e.g., Rhucin, to the patient. Patients in need of such treatment can be identified from non-pitting subepithelial edema resulting from a local increase in vasopermeability. The three sites primarily involved are: subcutaneous tissue (extremities, face, genitals, buttocks), abdominal organs and the upper airway (larynx). Swelling of the mucosa of the abdominal can be very painful and laryngeal edema is a life-threatening situation.
Intravenous administration of human plasma-derived C1INH is currently the preferred treatment for severe abdominal, facial and laryngeal HAE attacks. See the C1-esterase inhibitor (Cetor) entry (#714), However, this product has limited availability for reasons relating to its origin, supply and cost. Androgens can help to prevent attacks of HAE but may cause serious side effects, e.g., excessive hair growth in women, menstrual disorders, infertility, hepatitis and in rare cases hepatoma (liver cancer). Attacks are also treated with anti-fibrinolytics or plasma C1 inhibitor. Anti-fibrinolytics show side effects like nausea, abdominal pain, diarrhoea and even thrombosis.
Delayed Graft Function (DGF) is a common complication affecting all solid organs in the post-transplant period. DGF results in significant morbidity and mortality from early graft dysfunction and from decreased long- term graft survival. The condition also prolongs hospitalization and requires substitute therapies for these patients, such as dialysis or ventilatory support. Over 25,000 solid organs were transplanted in the U.S. in 2005, including kidney, liver, lung and heart transplants. DGF remains a critical unmet medical need, despite improvements in immunosuppression, organ preservation, and surgical technique. C1INH has been shown in numerous models of organ transplantation to improve early graft function.
Capillary Leakage Syndrome (CLS) is a complication of various disease states, including bone marrow/stem cell transplantation, IL-2 therapy, sepsis, and neonatal cardiac surgery. CLS affects over 100,000 patients in the U.S. annually. It is a severe life-threatening condition characterized by excessive fluid loss into the tissue space, which can result in hemodynamic instability, pulmonary edema, ascites, and death. Current therapies for patients with CLS are limited to supportive care and treatment of the underlying condition. Previous clinical work has shown that C1INH may be an effective anti-inflammatory that can control the mechanisms contributing to CLS.
Trials: The BLA and MAA filings for rhC1INH are based on clinical studies in which all HAE patients treated with rhC1INH demonstrated a rapid time to beginning of relief (typically less than 2 hrs) and time to minimal symptoms (typically less than 12 hrs). The data from preclinical and clinical studies reinforce rhC1INH’s safety and effectiveness with rapid and sustained relief for patients with acute attacks of HAE.
In Aug. 2007, results were reported from the pivotal Phase III trial. for HAE. The primary endpoint, time to start of symptom relief, achieved statistical significance (p = 0.0009). Among the first 28 patients randomized to Rhucin or placebo, those receiving Rhucin reported first relief at a median time of 60 minutes vs. 8.5 hours for the placebo, achieving a secondary endpont (p = 0.0038). 100% of Rhucin patients responded and all experienced sustained relief without a relapse. The trial's monitoring board recommended halting placebo/randomized treatment (i.e., ending the trial due to obvious efficacy).
In July 2008, positive results were reported from the treatment of 123 acute HAE attacks in 64 patients with different doses of Rhucin in the ongoing European and North American open-label studies. Rhucin has been consistently safe and effective in patients receiving up to nine treatments with no evidence of decreased response to Rhucin. All seven serious laryngeal attacks treated in these studies responded rapidly to Rhucin. The open-label data are consistent with findings from Pharming's two randomized, double-blind, placebo-controlled studies, with a median time to onset of relief of one hour and a median time to minimal symptoms of four hours. No clinically relevant adverse reactions were reported. These results are expected to support planned regulatory filings.
In Aug. 2007, positive results were reported from a European randomized placebo-controlled Phase III trial of Rhucin for the acute treatment of HAE in patients who presented with different sites of acute HAE attacks. Data were analyzed from the first 28 patients randomized to either Rhucin or placebo. Patients receiving Rhucin reported first relief at a median time of 60 minutes compared to 8.5 hours for those patients who received placebo. The primary endpoint, time to beginning of symptom relief, achieved statistical significance with a p-value of 0.0009 (log-rank test). The result achieved at the primary endpoint was also clinically relevant. There were no drug-related adverse events reported during this study.
In Dec. 2008, Pharming reported, "in addition to the investigation into efficacy and safety of rhC1INH in the treatment of antibody-mediated rejection in kidney transplants, preparations to initiate clinical investigations into reperfusion injury related rejection of kidney transplants are under way. In addition, initially pre-clinical, investigations into other reperfusion injury related indications: such as myocardial infarction and additional indications:, such as macular degeneration, an ophthalmological disease leading to blindness, are now also planned."
In April 2013, Pharming reported, "The safety and efficacy of RUCONEST for the treatment of HAE attacks had been evaluated in a clinical program that included a Phase III randomized placebo-controlled study conducted under a Special Protocol Assessment agreement with the FDA. The pivotal Phase III clinical study showed statistically significant and clinically relevant improvement in the primary endpoint of time to beginning of relief of symptoms for RUCONEST compared with placebo. The RUCONEST clinical program also included two additional randomized placebo-controlled studies and four open label treatment studies. In total, the BLA dossier includes ten clinical studies covering 940 administrations in 236 subjects."
Market: Pharming has developed a registry of HAE patients, which it expects will assist with product launch. The only other approved product for the treatment of HAE attacks is plasma derived human C1 inhibitor, Cetor (see related entry), which is available in a limited number of European countries.
Competition: Besides DX-88 from Dyax and plasma-derived C1-INH from Leva and Sanquin (see related entries), other companies developing treatments for HAE include Jerini (Germany), whose icatibant is in Phase III testing and was recently licensed to Kos Pharmaceuticals in the U.S., as well as Lev Pharmaceuticals’ C1INH (in Phase III) and Dyax Corp’s DX-88 (in Phase II).
Companies involvement:
Full monograph
113 C1-esterase inhibitor, rDNA
Nomenclature:
C1-esterase inhibitor, rDNA [BIO]
Rhucin [TR]
Ruconest [TR EU]
conestat alfa [INN]
80295-38-1 [RN for the human C1NH]
C1 esterase inhibitor [SY]
complement C1 esterase inhibitor, recombinant, transgenic rabbits [SY]
rhC1INH [SY]
FDA Class: Biologic BLA
Annual sales (2010, $millions) = $48
Biosimilars/biobetters Data
(Caution: Determining relevant patents, exclusivities and their expirations can be very complex and subjective!
Confirmatory studies are recommended before making business decisions based on these data.
U.S.A.
European Union (EU)
Biosimilars/biobetters-related U.S. Patents: 2024, based on 7,235,530 use patent; not approved, no biosimilars possible
U.S. Patent Expiration Year:
U.S. Biosimilars Data Exclusivity Expiration:
U.S. Biosimilars Orphan Exclusivity Expiration:
U.S. Biosimilars Launchability Year:
U.S. Biobetters Launchability Year: 2024
Biosimilars/biobetters-related EU Patents: 2025, based on EP1812049 use patent
EU Patent Expiration Year: 2025
EU Biosimilars Data Exclusivity Expiration: 2020
EU Biosimilars Orphan Exclusivity Expiration: 2020
EU Biosimilars Launchability Year: 2025
EU Biobetters Launchability Year: 2025
Exclusivity add-ons from pediatric and new indication approvals have not been
taken into account. U.S. patent extensions, based on time in clinical trials, have been included, but not those in Europe (where SPCs are individually
issued by each country).
Single year data are presented, but the situation is rarely that simple. This includes determining the relevance of
patents, presuming these have been retrieved, which cna be highly subjective. The first 2 fields for the US and EU are text fields, often
including diverse patent information, including citing other sources' published dates for patent expirations.
Orphan exclusivity is simply 7 years in the U.S. and 10 years in the EU after initial approval, with it left to the user to check monographs for
actual approvals with orphan status. Similarly, data exclusivity expiration in the U.S. is 12 years and in the EU is 10 years after initial reference product
approval, when biosimilar applications can be approved.
 Biosimilars launchability is the latest date of either patent, orphan or data
exclusivity, with any of these blocking approval and/or market entry. Biobetters, by definition products (bio)similar but different enough
to receive full, not biosimilar, approvals, have launchability dates the same as the patent expiration date, with these new/different products
not subject to reference product's orphan or data exclusivity.
Exclusive licensing of patents and other potential factors discussed in the full monographs that could, just as effectively as
patents held by the manufacturer, prevent or confound market entry were included in consideration of patent expiration.
Index Terms:
BHK-21 (C-13)
exempt from CBER lot release requirements
exempt from CBER lot release requirements
RA 27/3 Wistar Inst. strain, rubella virus
recombinant DNA
alpha granules
RA 27/3 Wistar Inst. strain, rubella virus
transgenic goats
BHK-21 (C-13)
bovine adenoside deaminase
Challenge Virus Standard (CVS; rabies virus)
Namalva cells
plague prophylaxis
PYinsl yeast cells
Sepharose
sodium carboxymethylcellulose
sodium cholate
sodium periodate
stroma
trehalose dihydrate
vesicular stomatitis virus (VSV)
viral inactivation, acid (low pH)
apheresis (hemapheresis)
apheresis (hemapheresis)
North American coral snake
North American coral snake
octoxynol (Triton X-100)
Sp2/0 murine hybridoma/myeloma cells
EU200 Currently Approved in EU
UM999 Not Available/Not Marketed in US
US002 FDA application pending
US01 FDA application withdrawn or rejected
EM001 Marketed Product in EU
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