The Basic Mediators of Edema in the Hereditary Angioedema - Article Example

Name of the student Professor’s name Name of class 18th August 2013 Part I: ICATIBANT (FIRAZYR) Description: Icatibant is a high selective bradykinin inhibitor. They are manmade bradykinin B2 receptor antagonists. It is basically similar to bradykinin and its performance is by selectively and competitively antagonizing the bradykinin B2 receptor. Bradykinin acts as the basic mediators of edema in the Hereditary Angioedema (HAE). Icatibants are prepared as isotonic, sterilized, acetate buffered solutions. It is supplied as 10 mg/ml in the 3 ml pre-filled syringes. It is approved to be used while treating severe attacks of the HAE patients aging from 18 years old or older. (“The New England Journal of Medicine”) Chemistry: Icatibants are man-made decapeptides which have 5 non-proteinogenic amino acids.  Chemical formula: C59H89N19O13S Chemically known as: D-Arginyl-L-arginyl-L-prolyl-L[(4R)-4-hydroxyprolyl]-glycyl-L[3-(2-thienyl)alanyl]-Lseryl-D-(1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)-L[(3aS,7aS)-octahydroindol-2-ylcarbonyl]-Larginine, acetate salt. (Firazyr) Its mechanism: Icitibants are competitive antagonistic selectives for bradykinin B2 receptors. Bradykinin are vasodilators believed to be accountable for the distinctive hereditary angioedema signs of restricted swellings, inflammations and pain. Icitibants inhibit bradykinins not to bind the B2 receptors thus treating the clinical signs of any severe, intermittent attacks of the hereditary angioedema. (Firazyr) Side effects: Side effects include but not limited to: (“The New England Journal of Medicine”) Injection site reaction.(the most common) Transaminase increase. Pyrexia. Rash. Dizziness. Additional information: Icatibant is supplied as a solution for subcutaneous administration. The commended dosage is 30 mg managed through the use of subcutaneous injections in the patient’s abdominal areas. Supplementary doses might be overseen at interims of no less than six hours whenever the responses aren’t sufficient or whenever the symptoms persist. Less than three doses might be administered in a 24 hours’ time-frame. It can be self-administered through injections in the abdominal parts; patients can treat themselves whenever the HAE attacks are recognized. Icatibants aren’t meant to be used like prophylactic agents. Icatibant’s specific indication for use: Icatibants are meant for treating any hereditary angioedema (HAE) severe attacks of the. Icatibant’s patient population: Icatibant is intended and investigated for use in only adults who are at least 18 years old. Non clinical development: B2 receptor antagonism was demonstrated in vitro and vivo studies. The affinity to the B2 receptor was found to be similar to the affinity of bradykinin to B2 receptor. In vitro human mast cell; study demonstrates that icatibant is responsible for histamine release in high concentrations. These concentrations expected to occur in the site of injection leading to site of injection reaction, which also seen in almost every subject participating in the clinical studies. Single and repeated dose studies for embryo-fetal toxicity studies in rats and rabbets with subcutaneous administration were conducted. Studies were conducted in animals and bacteria to provide data on safety and toxicity. Icitibant didn’t test positive for genotoxicity in the in-vitro Ames bacterial reverse mutation tests. Also, it tested negative in the vitro Chinese hamster bone marrow chromosome aberration assays. It didn’t test positive in the vivo mouse micronucleus tests. Also a decreased in the development of the ovarian follicles, uterine atrophy and the mammary gland masculinization happened. When administered on non-daily basis; harmfulness to the ovaries, uterus, testes, mammary glands and prostates didn’t occur in any dog which was treated twice in every week for a period of nine months. Bradykinin and antagonists of these receptors might possibly have adverse cardiovascular implications in the reperfusion after severe ischemia. In isolated guinea pig heart; icitibants reduced the flowing of the coronary blood. In the secluded rat hearts; Icatibant worsened the time of post-ischemic reperfusion arrhythmias. In an anesthetized myocardial infarction in dogs; intracoronary infusion of icatibant enlarged mortality rates twice as compared to the saline ischemia. (Firazyr) Clinical development: Phase I and Phase II trials: A summarized clinical progress program for the icatibants is represented in Table 1. (Firazyr) Table1: clinical development program for icatibant. Study Design Dose(s) Study population Phase I studies JE049-1001 Open single dose single blinded safety and tolerance 0.8 mg/kg IV infusion /4-h 0.15 mg/kg IV infusion/ 24-h 26 normal healthy volunteers JE049-1101 Double blinded, placebo controlled safety and tolerance 0.4mg/kg/1 h 0.5mg/kg/0.5 h 10 normal healthy volunteers JE049-1102 Double blinded, placebo controlled Ascending SC dose. Starts: 0.05 ml (40mg/ml) Ends: 0.4 ml (20mg/ml) 16 normal healthy volunteers JE049-1103 Double blinded, placebo controlled safety and tolerance SC 30mg; 3doses/day1 and single dose days 8&15 32 normal healthy volunteers JE049-2001 Double blinded, placebo controlled, randomized 2way crossover. safety and tolerance 0.15/mg/kg per day continuous infusion over 3 days 8 normal healthy volunteers 8 patients with hepatic insufficiency JE049-2002 Double blinded, placebo controlled, Ascending dose 0.15,0.3,0.6 or 1.2/mg/kg/day continuous infusion over 5 days 41 patients with hepatic insufficiency HGT-FIR-061 Double blinded, placebo controlled, randomized Effect of single dose on QT prolongation. 30mg single dose/SC 71 normal healthy volunteers HGT-FIR-061 Open label, uncontrolled safety and tolerance 30mg multiple doses/SC at 6-h interval. 21 normal healthy volunteers Phase II study JE049-2101 Proof of concept, dose ranging 0.4mg/kg IV over 30 min 0.8mg/kg IV over 30 min 0.4mg/kg IV over hours 30 mg SC icatibant 45 mg SC icatibant 21 Patients with HAE Phase III trials: 3 double blinded, randomized, controlled phase III studies (FAST-1, FAST-2 and FAST-3) have been conducted in patient with type I or type II HAE. (Lumry WR, et al) The FAST studies were similar in design. FAST-1 and FAST-3 were placebo-controlled; FAST-2 used tranexamic acid as comparator. (Details in Table 2) Total of 1055 HAE attacks has been treated throughout the studies. Endpoints: (Lumry WR, et al. & Firazyr ) The fundamental endpoints in the 3 researches were that the “Time to onset of the symptom relief of the primary symptom (TOSR-P)" the basic symptoms were recognized on the basis of the nature of attacks (cutaneous or abdominal). (Lumry WR, et al) Later it was noted that the usage of single primary symptoms lacks the capability to capture the full clinical picture of the disease during the acute attack; a composite endpoint was developed. The new endpoint (TOSR) conceders 3 more components (cutaneous pain, cutaneous swelling and abdominal pain) Secondary endpoints were assessed across the controlled Phase III studies. 4 secondary endpoints are used for assessing the effect of icatibant on the broad spectrum of symptoms; for efficacy and resolution of attack: Change from baseline in composite visual analogue scale (VAS). Time from treatment administration to subject- and investigator-assessed Initial symptom Improvement (TISI). Time from treatment administration to almost complete symptoms relief (TACSR). Use of rescue therapy. Table 2: Phase III Clinical trials conducted in HAE patients for icatibant Study [year] Study type Dose Primary Endpoint Phase III efficacy and safety trials (FAST-2) 2006 Efficacy and safety 30 mg SC icatibant Tranexamic acid (3 x 1g for 2 days) time to onset of symptom relief (single symptom VAS) Open-label extension (FAST-1) 2006 Efficacy and safety 30 mg SC icatibant Placebo time to onset of symptom relief (single symptom VAS) Open-label extension (FAST-3) 2010 Efficacy and safety 30 mg SC icatibant Placebo time to onset of symptom relief (3-symptom composite VAS) Open-label extension Additional Phase III studies 2007 Observational patient reported outcome validation study No intervention Correlation of VDS to VAS to calculate MCSD (EASSI) 2010 Open-label self-administration trial 30 mg SC icatibant Safety Results: The major endpoint was attained in 21/2 hourswith the icitibants against 4.6 hours with placebo in the FAST-1 trials and in 2 hours with icitibants against 12 hours with the tranexamic acids in the FAST-2 trials. In the FAST-1 studies, 3 individuals who received icitibants and 13 others who received the placebo required being treated with rescue treatment. The median duration to the first progress of any symptom, as evaluated by patients and investigators, was considerably lesser than for the icitibants in both trials. No icitibant-connected severe adverse happenings were reported. In a patient who has hereditary angioedema having serious attacks, there is a major benefit of icitibant as compared to tranexamic acid in one trial. Table-2 above illustrates all of the clinical trials conducted for icitibants as compared to the placeboand tranexamic acid with regard to the primary endpoint. (Lumry WR, et al. & Firazyr ) Orphan drug designation: Icatibants did receive Orphan drug label status on 25th November 2003. (Drugs @ FDA Food) Fast track approval: The development program for Icatibant was granted fast track status on 15 June 2004. (Drugs @ FDA Food) Part II: Newest Drugs for Treating the HAE Before developing an investigational plan for newest drugs for treating the HAE; studying and analyzing currently approved drugs is essential for developing suitable and applicable plan to obtain the most reliable and optimum data. Approved drugs for HAE: 1- Icatibant (Firazyr) (The New England Journal of Medicine, Drugs @ FDA Food & Cicardi M, et al): Company: Shire. Approval Status: Approved August 2011. Treatment Area: Severe attacking of the hereditary angioedema  Class: Bradykinin Receptor Antagonists. 2- (Cinryze): (Craig T et al & Cinryze) Company: Lev Pharmaceuticals, Inc. Approval Status: Approved January 2012. Treatment Area: prophylaxis of hereditary angioedema. Class: C1-Inhibitor concentrates. 3- (Berinert): (FDA & Berinert) Company: CSL Behring GmbH. Approval Status: Approved October 2009. Treatment Area: facial attacking o the hereditary angioedema (HAE)  Class: C1-Inhibitor (human). 4- Ecallantide (Kalbitor): (FDA) Company: Dyax Approval Status: Approved November 2009. Treatment Area: Severe attacks of the hereditary angioedema.  Class: Kallikrein Inhibitor. Non clinical development for the new drug: The new drug is intended for sublingual administration. Therefore, we assume that this drug is not a plasma derivative and its molecular weight is relatively low. The first step on non-clinical assessment should be whether or not this drug is suitable for sublingual administration. Mucosal absorption rate should be determined. Mucosal cells testing should be performed. In addition, the drug formulation should be water soluble. The drug is for sublingual route; we assume that it is in tablet form. The tablet should disintegrate and dissolve very easily and rapidly. Disintegration and dissolution tests must be performed. Animal testing is challenge because we cannot administer the drug sublingually to any animal model. Therefore, the drug should be administered intravenously and we take the difference in time to achieve the required plasma-drug concentration into consideration when analyzing the data obtained. Pharmacology testing should be in vitro and in vivo to determine the effects of the drug besides also for safety pharmacology (Cardiovascular, Respiratory, CNS). Measurement, data of Absorption, distribution, Metabolism and Excretion. (Pharmacokinetics) should be assessed. Toxicity should be assessed with Single dose - 2 species (1 rodent 1 nonrodent) with continuous monitoring of clinical signs, body weight, pathology, and histopathology Repeat dose should also be administered to plan the dosing to be used in clinical studies. Schedule, duration and the duration should cover the length of the studies proposed. Clinical Development: Table 3: Summary of Phase III clinical trial conducted on the approved drugs meant to treat the severe attack of the HAE.  Drug Origin No. of clinical trials conducted in Phase III Primary Endpoint Secondary Endpoint(s) Icatibant [12] Synthetic 3 FAST studies + 2 additional studies Time to onset of symptom relief of the primary symptom (TOSR-P) -Change from baseline in composite visual analogue scale (VAS). -Time from treatment administration to subject- and investigator-assessed Initial symptom Improvement (TISI). -Time from treatment administration to almost complete symptoms relief (TACSR). -Use of rescue therapy. Berinert [8] Plasma Derivative 4 Time from initiation of treatment to onset of symptom relief Time to complete HAE symptom resolution Percent of patients with worsened HAE symptoms between 2 and 4 hours after treatment initiation vs. baseline for at least 1 baseline HAE symptom Number of vomiting episodes within 4 hours of treatment initiation Ecallantide [11] Plasma Derivative 3 The primary endpoint was the TOS at 4 hours The change from baseline in MSCS at 4 hours Clinical improvement strategy for these new drugs: The Clinical improvement strategies for these new drugs have to be built on the clinical development plans of other approved drugs. Because the drug is intended for sublingual administration; the primary endpoint should be “Time from initiation of treatment to onset of symptom relief” and secondary endpoint should be “Time from treatment administration to almost complete symptoms relief” In phase I clinical trials; 2 clinical trials should be conducted on is open single dose single blinded to assess safety and tolerance the other is double blinded, placebo controlled dose ascending also to determine safety and tolerance and maximum tolerated dose. The subjects should be normal healthy volunteers. In phase II clinical trials; 1 trail is required to determine the optimum dose of the drug. Subjects should be patients with HAE. Phase III trials should be 2 double blinded, placebo controlled with patient with HAE and additional open label trial for patients self-administration. And also a QT prolongation study should be performed. Orphan designation: The drug is intended for serious and life threatening disease and the prevalence of this disease is 1:10,000 to 1:50,000 (The New England Journal of Medicine) which is less than 200,000 per year. Therefore, the drug is eligible for orphan status. Fast track eligibility: Fast track designation is granted for drugs that are meant for the treatment of severe or life threatening disease. The drug must demonstrate the potentiality to address medical need for the condition which no other medication available for the same medical need. (Drugs @ FDA Food) The new drug is intended for serious and life threatening disease which is HAE. However, the drug has no promise to address unmet medical need, because there are several drugs for the treatment of the condition. Although, the drug is intended for sublingual administration and have lifestyle and convenience benefit over existing drugs. But this will not be seen as medical benefit. Therefore, the drug will not be eligible for fast track approval. Further assessment should be done after early evidence of efficacy. The drug might become eligible for fast track approval if the data obtained demonstrate medical benefit over existing treatments. Work Cited 1- -Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. The New England Journal of Medicine. (2010): 363(6):532-41. Print. 2- Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. (2009): 15(2):69-78. Print. 3- Craig T, Riedl M, Dykewicz MS, Gower RG, Baker J, Edelman FJ, et al. When is prophylaxis for hereditary angioedema necessary?Ann Allergy Asthma Immunol. (2009): 102(5):366-72. Print. 4- US Food and Drug Administration advisory committee meeting briefing (Firazyr) 2013. Web. 18th November. 5- Drugs @ FDA Food and Drug Adminstration 2013. Web.18th November. 6- Cinryze. (C1 inhibitor [human]) prescribing information. New York, NY:Lev Pharmaceuticals, Inc.(2008): print. 7- Berinert. [C1 Esterase inhibitor (human)] prescribing information. Kankakee, IL:CSL Behring LLC.(2009): Print. 8- US Food and Drug Administration (FDA). FDA Approves Berinert to Treat Abdominal Attacks, Facial Swelling Associated With Hereditary Angioedema. Available from: FDA Web site. 9- US Food and Drug Administration. Advisory Committee Briefing Document:Kalbitor (ecallantide)For Acute Attacks of Hereditary Angioedema 2013. Web. 18th November. 10- Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. (2010): 363(6):523-31. Print. 11- Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. (2010): 363(6):532-41. Print. 12- Lumry WR, et al. Results from FAST-3: A phase III randomized, double-blind, placebo-controlled, multicenter study of subcutaneous icatibant in patients with acute hereditary angioedema (HAE) attacks. American Academy of Allergy, Asthma, & Immunology Meeting. March 22, 2011. Read More