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| Primary information |
|---|
| ID | 13388 |
| Therapeutic ID | Th1399 |
| Protein Name | Ravulizumab |
| Sequence | >Th1399_Ravulizumab
DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
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| Molecular Weight | NA |
| Chemical Formula | NA |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | The mean (SD) terminal elimination half-life of ravulizumab in patients with PNH was recorded as 49.7 (8.9) days [FDA Label]. |
| Description | Ravulizumab is considered a long-acting complement 5 (C5) inhibitor that has been undergoing clinical trials for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) as of 4 February, 2016. A drug similar to ravulizumab (ALXN1210), called eculizumab, is currently approved for the treatment of PNH in 46 countries under the brand name Soliris®. Ravulizumab is considered by Alexion Pharmaceuticals Inc. to be a "next-generation" eculizumab molecule. Ravulizumab was subsequently approved by the US FDA in December of 2018 for a variety of beneficial characteristics that make it an advanced, next-generation agent in comparison to eculizumab [F2473]. In particular, ravulizumab is currently the first and only long-acting C5 complement inhibitor that can be administered every eight weeks for the treatment of adult patients with PNH whereas eculizumab is a bi-weekly treatment [F2473, FDA Label]. Moreover, virtually all of the phase 3 trial results for ravulizumab have demonstrated the equivalent efficacy and safety established by eculizumab and that patients transition safely and effectively from using eculizumab to ravulizumab [F2473]. Subsequently, whereas PNH patients may have needed to previously plan their lives rather strictly around the bi-weekly infusion administrations of eculizumab, with ravulizumab such patients can find a more relaxed dosing schedule of only six or seven infusions over an entire year [F2473, FDA Label]. Just as the US FDA permitted a timely and expedited approval of ravulizumab ahead of the Prescription Drug User Fee Act (PDUFA) date of February 18, 2019 following the use of a rare disease priority review voucher by Ultomiris (ravulizumab) developer Alexion for many of the aforementioned beneficial treatment reasons, regulatory authorities in the European Union (EU) and Japan have currently accepted and are reviewing applications for the approval of Ultomiris (ravulizumab) as a treatment for adults with PNH as well [F2473]. |
| Indication/Disease | Ravulizumab is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) [FDA Label]. |
| Pharmacodynamics | Immediate and complete inhibition of serum-free complement protein C5 (concentration of less than 0.5 mcg/mL) was observed by the end of the first ravulizumab infusion and sustained throughout the entire 26-week treatment period in all patients, both complement-inhibitor naïve and previously treated with eculizumab [FDA Label]. The extent and duration of the pharmacodynamic response in patients with PNH were exposure dependent for ravulizumab [FDA Label]. Free C5 levels of <0.5 mcg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition [FDA Label]. Complete terminal complement inhibition following initiation of ravulizumab treatment led to normalization of serum LDH by week 4 in complement-inhibitor naïve patients and maintained LDH normalization in patients previously treated with eculizumab [FDA Label]. |
| Mechanism of Action | Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, debilitating and life-threatening ultra-rare blood disorder characterized by hemolysis (destruction of red blood cells) that is mediated by the uncontrolled activation of the complement system, a component of the body’s immune system [L4900]. Ravulizumab is subsequently a terminal complement inhibitor that specifically binds to the particular complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex [C5b-9]) and preventing the generation of the terminal complement complex C5b9 [FDA Label]. Ravulizumab inhibits terminal complement-mediated intravascular hemolysis in patients with PNH [FDA Label]. |
| Toxicity | Although PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes like fetal death and premature delivery, there are no available data on ravulizumab use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes [FDA Label]. Although there are currently no human reproductive studies, human immunoglobulins like ravulizumab are known to cross the human placental barrier, and thus may potentially cause terminal complement inhibition in the fetal circulation [FDA Label]. There are no data on the presence of ravulizumab in human milk, the effect on the breastfed child, or the effect on milk production [FDA Label]. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in a nursing child, breastfeeding should be discontinued during treatment and for 8 months after the final dose [FDA Label]. The safety and efficacy of ravulizumab in pediatric patients and geriatric use have not yet been established [FDA Label]. Genotoxicity studies have not been conducted with ravulizumab [FDA Label]. Effects of ravulizumab upon fertility have not been studied in animals [FDA Label]. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ravulizumab had no adverse effects on mating or fertility [FDA Label]. |
| Metabolism | Monoclonal antibody agents like ravulizumab are not expected to generate toxic metabolites as they generally undergo proteolysis to their constituent amino acids [F94]. |
| Absorption | It has been demonstrated that mean ravulizumab Cmax and AUC8 increase in a dose-proportional manner and that a single 400 mg intravenous dose of ravulizumab administered to subjects reach or exceed the threshold level of 100 µg/mL [L4915]. |
| The mean (SD) volume of distribution at steady state was 5.34 (0.92) L [FDA Label]. |
| Clearance | The mean (SD) clearance of ravulizumab in patients with PNH was recorded as being 0.08 (0.022) L/day respectively [FDA Label]. |
| Categories | Immunosuppressive Agents |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Complement C5 |
| Brand Name | NA |
| Company | NA |
| Brand Description | NA |
| Prescribed For | NA |
| Chemical Name | NA |
| Formulation | NA |
| Physical Appearance | NA |
| Route of Administration | NA |
| Recommended Dosage | NA |
| Contraindication | NA |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | NA |
| Remarks | NA |