Fingolimod
|
|
| Systematic (IUPAC) name |
| 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol |
| Clinical data |
| AHFS/Drugs.com |
monograph |
| Licence data |
US FDA:link |
| Pregnancy cat. |
C (US) |
| Legal status |
℞-only (US) |
| Routes |
Oral |
| Identifiers |
| CAS number |
162359-55-9 N |
| ATC code |
L04AA27 |
| PubChem |
CID 107970 |
| ChemSpider |
97087 Y |
| UNII |
3QN8BYN5QF Y |
| ChEBI |
CHEBI:63115 N |
| ChEMBL |
CHEMBL314854 Y |
| Chemical data |
| Formula |
C19H33NO2 |
| Mol. mass |
307.471 g/mol |
SMILES
- OCC(N)(CCc1ccc(cc1)CCCCCCCC)CO
|
InChI
-
InChI=1S/C19H33NO2/c1-2-3-4-5-6-7-8-17-9-11-18(12-10-17)13-14-19(20,15-21)16-22/h9-12,21-22H,2-8,13-16,20H2,1H3 Y
Key:KKGQTZUTZRNORY-UHFFFAOYSA-N Y
|
N (what is this?) (verify)
|
Fingolimod (rINN, trade name Gilenya, Novartis) is an immunomodulating drug, approved for treating multiple sclerosis. It has reduced the rate of relapses in relapsing-remitting multiple sclerosis by over half. Fingolimod is a sphingosine 1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction.
Contents
- 1 Structure and mechanism
- 2 Approvals and indications
- 3 Study related to heart failure and arrhythmia
- 4 History
- 5 Clinical trials
- 5.1 Organ transplant
- 5.2 Multiple sclerosis
- 6 Side effects
- 7 Chemical synthesis
- 8 See also
- 9 References
Structure and mechanism[edit]
It is derived from the myriocin (ISP-1) metabolite of the fungus Isaria sinclairii. It is a structural analogue of sphingosine and is phosphorylated by sphingosine kinases in the cell (most importantly sphingosine kinase 2).[1][2][3] The molecular biology of phosphofingolimod is thought to lie in its activity at one of the five sphingosine-1-phosphate receptors, S1PR1.[4] It can sequester lymphocytes in lymph nodes, preventing them from moving to the central nervous system for autoimmune responses in multiple sclerosis, and was originally proposed as an antirejection medication indicated after transplantation. It has been reported to stimulate the repair process of glial cells and precursor cells after injury.[5] Fingolimod has also been reported to be a cannabinoid receptor antagonist,[6] a cPLA2 inhibitor [7] and a ceramide synthase inhibitor.[8]
Approvals and indications[edit]
Multiple sclerosis[edit]
On September 22, 2010, fingolimod became the first oral disease-modifying drug approved by the Food and Drug Administration to reduce relapses and delay disability progression in patients with relapsing forms of multiple sclerosis.[9][10] Novartis announced on March 10, 2011 that it had received a notice of compliance from Health Canada and that the drug would be available April 1, 2011 at pharmacies.[11][12] On March 17, 2011, the European Medicines Agency approved the drug for use in the European Union.[13]
Study related to heart failure and arrhythmia[edit]
Fingolimod has recently been discovered as a candidate therapeutic drug for the treatment of heart failure and arrhythmias. Heart failure is a leading cause of hospitalization and death in many countries, and an ever-increasing health burden worldwide.[14][15][16] Pathogenic hypertrophy of the myocardium is a cardinal sign leading to heart failure and is associated with an increased risk of cardiac morbidity and mortality.[14][17] Cardiac arrhythmias are disturbances in cardiac rhythm that often arise as a lethal complication of heart failure. This occurs due to the progressive ischemic/reperfusion injury the heart faces.[18]
Many signaling pathways, including pathways involving P21-activated kinase-1 (Pak1), play a role in the pathogenesis of heart failure and arrhythmias.[17] The cardioprotective effects of fingolimod have been attributed to Pak1 activation.[14][19][20] Studies using animal models have shown promising results for fingolimod as a potential therapeutic drug for arrhythmias and prevention of hypertrophy and heart failure[14][19][20]
P21-activated kinases (Paks) are a family of serine/threonine protein kinases involved in the G-protein signaling pathway activated by Cdc42 and Rac1. Cdc42 and Rac1 are GTPases that upon activation by extracellular stimuli lead to activation of Pak.[21] Paks are widely expressed in mammalian tissue and at least three Pak isoforms exist in the heart, including Pak14. Pak1 has been shown to regulate many cellular functions in the heart including cell growth, survival, and motility.[14][22] Pak1 has also been implicated in the regulation of vital cardiac processes such as hypertrophy and contractility.[23]
Previous studies have shown that Pak1 activation contributes to the pathogenesis of cardiac hypertrophy through multiple mechanisms.[24][25][22][23][26][27] Contrary to this, a recent study has discovered Pak1 plays a cardioprotective role during the pathogenesis of cardiac hypertrophy and thus heart failure.[14] A knock-out mouse model and myocyte cell culture experiments have identified Pak1 as a key player in a signaling cascade relaying antihypertrophic signals within the heart. This effect is a result of a c-Jun N-terminal kinase (JNK)-dependent cascade directly downstream of Pak1 activation. Results of this study revealed fingolimod as a potential antihypertrophic cardiac treatment through its activation of Pak1 and the resultant antihypertrophic effects seen in animal models.[14]
A study using ex vivo rat hearts and myocyte cell culture has also identified fingolimod as a candidate drug for preventing cardiac arrhythmias resulting from ischemic/reperfusion injury.[19][20] Fingolimod prevents arrhythmias through the activation of Pak1 and its downstream effectors. These include upregulation of protein phosphatase 2 (PP2A) and subsequent dephosphorylation of troponin I (TnI,) and activation of the sphingosine-1-phosphate (S1P) signaling cascade.[20] The latter inhibits cardiac pacemaker rate by altering the activity of acetylcholine-regulated potassium channels (KACh).[28]
History[edit]
First synthesized in 1992 by Yoshitomi Pharmaceuticals, fingolimod was derived from an immunosuppressive natural product, myriocin (ISP-I) through chemical modification. Myriocin was isolated from the culture broth a type of entomopathogenic fungus (Isaria sinclairii) that was an eternal youth nostrum in traditional Chinese medicine.[29] Showing positive results in both in vitro (mixed lymphocyte reaction) and in vivo screening (prolonging rat skin graft survival time), myriocin was modified through a series of steps to yield fingolimod, code named at the time FTY720. [30]
Structure activity relationship (SAR) studies on myriocin homologs and partially synthetic derivatives showed that the configuration at the carbon bearing the 3-hydroxy group or the 14-ketone, the 6-double bond, and the 4-hydroxy group were not important for its activity and simplification of the structure of ISP-I was done in an attempt to reduce toxicity and improve drugability.[29]
Elimination of side chain functionalities and removal of chiral centers was part of the simplification process and an intermediate compound (ISP-I-28) with the carboxylic acid of myriocin transformed to a hydroxymethyl group was generated. ISP-I-28 was found to be less toxic and more effective at lengthening rat skin allograft time than ISP-1.
Clinical trials[edit]
Organ transplant[edit]
In a previous phase III clinical trial of kidney transplantation, fingolimod was found to be no better than the existing standard of care.[31][32] Fingolimod is studied in human models in vitro and in animal kidney transplantation.[32][33][34][34]
Multiple sclerosis[edit]
In two Phase III clinical trials, fingolimod reduced the rate of relapses in relapsing-remitting multiple sclerosis by over half compared both to placebo and to the active comparator interferon beta-1a.[35]
A double-blind randomized control trial comparing fingolimod to placebo[36] found the drug reduced the annualized frequency of relapses to 0.18 relapses per year at 0.5 mg/day or 0.16 relapses per year at 1.25 mg/day, compared to 0.40 relapses per year for those patients taking the placebo. The probability of disease progression at 24 month followup was lower in the fingolimod groups compared to placebo (hazard ratio 0.70 at 0.5 mg and 0.68 at 1.25 mg). Fingolimod patients also had better results according to MRI imaging of new or enlarged lesions at 24 month followup. Side effects leading to discontinuation of the study drug were more common in the higher dose group (14.2% of patients) than at the lower dose (7.5%) or placebo (7.7%). Serious adverse events in the fingolimod group included bradycardia, relapse, and basal-cell carcinoma. Seven episodes of bradycardia occurred during the monitoring period after administration of the first dose, and were asymptomatic in six of these cases. There was a higher rate of lower respiratory tract infections (including bronchitis and pneumonia) in the fingolimod groups (9.6% at 0.5 mg, 11.4% at 1.5 mg) than the placebo group (6.0%). Other adverse events reported on the study drug included macular edema, cancer, and laboratory abnormalities.[37]
Side effects[edit]
Fingolimod has been associated with potentially fatal infections, bradycardia and, recently, a case of hemorrhaging focal encephalitis, an inflammation of the brain with bleeding. Two subjects died: one due to brain herpes infection, and a second one due to zoster. It is unclear whether the drug was responsible for the events.[38]
The most common side effects of fingolimod have been head colds, headache, and fatigue, but a few cases of skin cancer have been reported, which has also been reported in patients taking natalizumab (Tysabri), an approved MS drug.[39]
Fingolimod has also been known to cause macular edema, resulting in decreased vision.[40][41]
European Medicines Agency is advising doctors to increase their level of monitoring of patients after the first dose of the medicine. This includes electrocardiogram (ECG) monitoring before treatment and then continuously for the first six hours after the first dose, and measurement of blood pressure and heart rate every hour.[42]
Chemical synthesis[edit]
Several studies have described the synthesis of fingolimod and analogs.[43][44]
See also[edit]
- Laquinimod, in clinical trials for MS
References[edit]
- ^ Paugh SW, Payne SG, Barbour SE, Milstien S, Spiegel S (2003). "The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2". FEBS Lett 554 (1–2): 189–93. doi:10.1016/S0014-5793(03)01168-2. PMID 14596938.
- ^ Billich A, Bornancin F, Dévay P, Mechtcheriakova D, Urtz N, Baumruker T (2003). "Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases". J Biol Chem 278 (48): 47408–15. doi:10.1074/jbc.M307687200. PMID 13129923. Free full text
- ^ Sanchez, T; Estrada-Hernandez, T; Paik, JH; Wu, MT; Venkataraman, K; Brinkmann, V; Claffey, K; Hla, T (2003). "Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability". The Journal of Biological Chemistry 278 (47): 47281–90. doi:10.1074/jbc.M306896200. PMID 12954648.
- ^ Hla T, Lee MJ, Ancellin N, Paik JH, Kluk MJ (2001). "Lysophospholipids--receptor revelations". Science 294 (5548): 1875–8. doi:10.1126/science.1065323. PMID 11729304.
- ^ FTY720 (Fingolimod) for Relapsing Multiple Sclerosis, Expert Review of Neurotherapeutics, Alejandro Horga; Xavier Montalban 06/04/2008; Expert Rev Neurother. 2008;8(5):699-714
- ^ Paugh SW, Cassidy MP, He H, Milstien S, Sim-Selley LJ, Spiegel S, Selley DE (2006). "Sphingosine and its analog, the immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, interact with the CB1 cannabinoid receptor". Mol Pharmacol. 70 (1): 41–50. doi:10.1124/mol.105.020552. PMID 16571654.
- ^ Payne SG, Oskeritzian CA, Griffiths R, Subramanian P, Barbour SE, Chalfant CE, Milstien S, Spiegel S. (2007). "The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors". Blood 109 (3): 1077–85. doi:10.1182/blood-2006-03-011437. PMC 1785128. PMID 17008548.
- ^ Berdyshev EV, Gorshkova I, Skobeleva A, Bittman R, Lu X, Dudek SM, Mirzapoiazova T, Garcia JG, Natarajan V. (2009). "FTY720 Inhibits Ceramide Synthases and Up-regulates Dihydrosphingosine 1-Phosphate Formation in Human Lung Endothelial Cells". Journal of Biological Chemistry 284 (9): 5467–77. doi:10.1074/jbc.M805186200. PMC 2645812. PMID 19119142.
- ^ "Gilenya Information from". Drugs.com. Retrieved 2013-09-30.
- ^ FDA press release on approval of Gilenya
- ^ First oral MS treatment approved for Canada http://www.vancouversun.com/health/First+oral+treatment+approved+Canada+says+drug+company/4420028/story.html
- ^ "Novartis new MS treatment receives Notice of Compliance in Canada". NewsMedical.net. 10 March 2011.
- ^ EMA approval information about Gilenya
- ^ a b c d e f g Liu, W., Zi, M., Naumann, R., Ulm, S., Jin, J., Taglieri, D.M., Prehar, S., Gui, J., Tsui, H., Xiao, R., Neyses, L., Solaro, R.J., Ke, Y., Cartwright. E.J., Lei, M., and Wang, X. Pak1 as a novel therapeutic target for antihypertrophic treatment in the heart. Circulation (2011) 124:2702-2715
- ^ Public Health Agency of Canada, Tracking Heart Disease and Stroke in Canada, 2009. Available at: http://www.phac-aspc.gc.ca/publicat/2009/cvd-avc/index-eng.php. Accessed March 12, 2012
- ^ Stewart, S., Jenkins, A., Buchan, S., McGuire, A., Capewell S., et al. The current cost of heart failure to the National Health Service in the UK. Eur J Heart Fail (2002) 4:361-71.
- ^ a b Hunter, J.J., and Chien, K.R. Signaling pathways for cardiac hypertrophy and failure. The New England Journal of Medicine (1999) 341.17:1276-1283
- ^ Corr, P.B., and Witkowski F.X. Potential electrophysiologic mechanisms responsible for dysrhythmias associated with reperfusion of ischemic myocardium. Circulation (1983) 68:I16–24
- ^ a b c Egom. E.E, Mohamed, T., Mamas, M., Shi, Y., Liu, W., Chirico, D., Stringer, S., Ke, Y., Shaheen, M., Wang, T., Chacko, S., Wang, X., Solaro, R.J., Fath-Ordoubadi, F., Cartwright. E., and Lei, M. Activation of Pak1/Akt/eNOS signaling following sphingosine-1-phosphate release as part of a mechanism protecting cardiomyocytes against ischemic cell injury. Am J Physiol Heart Circ Physiol (2011) 301:H1487-H1495
- ^ a b c d Egom, E.E., Ke, Y., Musa, H., Mohamed, T., Wang, T., Cartqright, E., Solaro, R.J., and Lei, M. FTY720 prevents ischemia/reperfusion injury-associated arrhythmias in an ex vivo rat heart model via activation of Pak1/Akt signaling. Journal of Molecular and Cellular Cardiology (2010) 48:406-414
- ^ Jaffe, A.B and Hall, A. Rho GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. (2005) 21:247-269
- ^ a b Mao, K., Kobayashi, S., Jaffer, Z.M., Huang, Y., Volden, P., Chernoff, J., and Liang, Q. Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes. Journal of Molecular and Cellular Cardiology (2008) 44:429–434
- ^ a b Ke, Y., Wang, L., Pyle, W.G., de Tombe, P.P., and Solaro, R. J. Intracellular localization and functional effects of P21-activated kinase-1 (Pak1) in cardiac myocytes. Circulation (2004) 94:194-200
- ^ Cheng, G., Kasiganesan, H., Baicu, C.F., Wallenborn, G., Kuppuswamy, D., and Cooper, G. Cytoskeletal role in protection of the failing heart by β-adrenergic blockade. Am J Physiol Heart Circ Physiol (2012) 302:H675-H687
- ^ Cheng, G., Takahashi, M., Shunmugavel, A., Wallenborn, G., DePaoli-Roach, A.A., Gergs, U., Neumann, J., Kuppuswamy, D., Menick, D.R., and Cooper, G. Basis for MAP4 dephosphorylation-related microtubule network densification in pressure overload cardiac hypertrophy. Journal of Biological Chemistry (2010) 285:38125-38140
- ^ Ke, Y., Lei, M., Collins, T.P., Rakovic, S., Mattick. P., Yamasaki, M., Brodie, M.S., Terrar, D.A., and Solaro, R. J. Regulation of L-type calcium channel and delayed rectifier potassium channel activity by P21-activated kinase-1 in Guinea Pig sinoatrial node pacemaker cells. Circulation (2007) 100:1317-1327
- ^ Sussman, M.A., Welch, S., Walker, A., Klevitsky, R., Hewett. T.E., Price, R.L., Schaefer, E., and Yager, K. Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1. J. Clin. Invest. (2000) 105:875-886
- ^ Guo, J., MacDonell, K.L., and Giles, W.R. Effects of sphingosine 1-phosphate on pacemaker activity in rabbit sino-atrial node cells. Pflugers Arch (1999) 438:642–648
- ^ a b Adachi, K; Chiba, K (2007). "FTY720 Story. Its Discovery and the Following Accelerated Development of Sphingosine 1-Phosphate Receptor Agonists as Immunomodulators Based on Reverse Pharmacology". Perspectives in medicinal chemistry 1: 11–23. PMC 2754916. PMID 19812733.
- ^ Fujita, T., Yoneta, M., Hirose, R., Sasaki, S., Inoue, K., Kiuchi, M., Hirase, S., Adachi, K., Arita, M. and Chiba, K. (1995). "Simple compounds, 2-alkyl-2-amino-1,3-propanediols have potent immunosuppressive activity". Bioorg. Med. Chem. Lett. 5 (8): 847–52. doi:10.1016/0960-894X(95)00126-E.
- ^ Saab G, Almony A, Blinder KJ, Schuessler R, Brennan DC (January 2008). "Reversible cystoid macular edema secondary to fingolimod in a renal transplant recipient". Arch. Ophthalmol. 126 (1): 140–1. doi:10.1001/archophthalmol.2007.23. PMID 18195237.
- ^ a b Westhoff TH, Schmidt S, Glander P, et al. (August 2007). "The impact of FTY720 (fingolimod) on vasodilatory function and arterial elasticity in renal transplant patients". Nephrol. Dial. Transplant. 22 (8): 2354–8. doi:10.1093/ndt/gfm313. PMID 17526535.
- ^ Zhou PJ, Wang H, Shi GH, Wang XH, Shen ZJ, Xu D (July 2009). "Immunomodulatory drug FTY720 induces regulatory CD4+CD25+ T cells in vitro". Clin. Exp. Immunol. 157 (1): 40–7. doi:10.1111/j.1365-2249.2009.03942.x. PMC 2710591. PMID 19659769.
- ^ a b Park SI, Felipe CR, Machado PG, et al. (May 2005). "Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients". Braz. J. Med. Biol. Res. 38 (5): 683–94. doi:10.1590/S0100-879X2005000500005. PMID 15917949.
- ^ Jeffrey A. Cohen, et al. (2010). "Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis". New England Journal of Medicine 362 (5): 402–15. doi:10.1056/NEJMoa0907839. PMID 20089954.
- ^ Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis. ClinicalTrials.gov
- ^ Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfield R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P for the FREEDOMS Study Group (2010). "A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis". New England Journal of Medicine 362 (5): 387–401. doi:10.1056/NEJMoa0909494. PMID 20089952.
- ^ http://www.msrc.co.uk/index.cfm/fuseaction/show/pageid/1309
- ^ "Good News for Oral MS Drug Fingolimod". Webmd.com. 2008-04-16. Retrieved 2013-09-30.
- ^ USA (2013-03-25). "Fingolimod-associated macular edema: incidence, de... [Neurology. 2012] - PubMed - NCBI". Ncbi.nlm.nih.gov. Retrieved 2013-09-30.
- ^ "Fingolimod-Associated Macular Edema". Aao.org. 2010-07-08. Retrieved 2013-09-30.
- ^ "European Medicines Agency - News and Events - European Medicines Agency starts review of Gilenya (fingolimod)". Ema.europa.eu. 2012-01-20. Retrieved 2013-09-30.
- ^ Kiuchi, M; Adachi, K; Kohara, T; Teshima, K; Masubuchi, Y; Mishina, T; Fujita, T (1998). "Synthesis and biological evaluation of 2,2-disubstituted 2-aminoethanols: analogues of FTY720". Bioorganic & Medicinal Chemistry Letters 8 (1): 101–6. doi:10.1016/S0960-894X(97)10188-3. PMID 9925439.
- ^ B.Sivaraman, A.Senthilmurugan, I.S.Aidhen (2007). "Weinreb Amide Based New Synthetic Equivalents for Convenient Access to Immunosuppressive Agent FTY720 and Analogues". Synlett 2841 (18): 2841. doi:10.1055/s-2007-990961.
|
Immunomodulators: Immunosuppressive drugs / Immunosuppressants (L04)
|
|
Intracellular
(initiation) |
|
Antimetabolites
|
- purine synthesis inhibitors: Azathioprine
- Mycophenolic acid
- pyrimidine synthesis inhibitors: Leflunomide
- Teriflunomide
antifolate: Methotrexate
|
|
|
Macrolides/
other IL-2 inhibitors
|
- FKBP/Cyclophilin/Calcineurin: Tacrolimus
- Ciclosporin
- Pimecrolimus
|
|
|
Other
|
- Lenalidomide
- Pomalidomide
- Thalidomide
|
|
|
Intracellular
(reception) |
|
IL-1 receptor antagonists
|
|
|
|
mTOR
|
- Sirolimus
- Everolimus
- Ridaforolimus
- Temsirolimus
- Umirolimus
- Zotarolimus
|
|
|
| Extracellular |
|
Antibodies
|
|
Monoclonal
|
|
Serum target
(noncellular)
|
- Complement component 5 (Eculizumab)
- TNF (Adalimumab
- Afelimomab
- Certolizumab pegol
- Golimumab
- Infliximab
- Nerelimomab)
- Interleukin 5 (Mepolizumab)
- Immunoglobulin E (Omalizumab)
- IL-12 and IL-23 (Lebrikizumab
- Ustekinumab)
|
|
|
Cellular target
|
- CD3 (Muromonab-CD3
- Otelixizumab
- Teplizumab
- Visilizumab)
- CD4 (Clenoliximab
- Keliximab
- Zanolimumab)
- CD11a (Efalizumab)
- CD18 (Erlizumab)
- CD20 (Obinutuzumab
- Rituximab
- Ocrelizumab
- Pascolizumab)
- CD23 (Gomiliximab
- Lumiliximab)
- CD40 (Teneliximab
- Toralizumab)
- CD62L/L-selectin (Aselizumab)
- CD80 (Galiximab)
- CD147/Basigin (Gavilimomab)
- CD154 (Ruplizumab)
- BLyS (Belimumab
- Blisibimod)
- CTLA-4 (Ipilimumab
- Tremelimumab)
- CAT (Bertilimumab
- Lerdelimumab
- Metelimumab)
- Integrin (Natalizumab)
- Interleukin-6 receptor (Tocilizumab)
- LFA-1 (Odulimomab)
- IL-2 receptor/CD25 (Basiliximab
- Daclizumab
- Inolimomab)
- T-lymphocyte (Zolimomab aritox)
|
|
|
Unsorted
|
- Atorolimumab
- Cedelizumab
- Fontolizumab
- Maslimomab
- Morolimumab
- Pexelizumab
- Reslizumab
- Rovelizumab
- Siplizumab
- Talizumab
- Telimomab aritox
- Vapaliximab
- Vepalimomab
|
|
|
|
Polyclonal
|
- Anti-thymocyte globulin
- Anti-lymphocyte globulin
|
|
|
|
-cept (Fusion)
|
- CTLA-4 (Abatacept
- Belatacept)
- TNF inhibitor (Etanercept
- Pegsunercept)
- Aflibercept
- Alefacept
- Rilonacept
|
|
|
|
|
cell/phys/auag/auab/comp, igrc
|
|
|
|
|
|