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Detailed Pharmacology Review of Neuroprotective agents for ALS TABLE OF CONTENTS Page 1. AEOL10150 ..2 2. Arimoclomol ..7 3. Ceftriaxone 10 4. Celastrol 14 5. CGP3446 18 6. Copaxone 21 7. Coenzyme Q10 25 8. Insulin Growth Factor-1 - AAV 31 9. Insulin Growth Factor-1 34 10. Memantine 38 11. Minocycline 41 12. NAALADase Inhibitors 47 13. NBQX 50 14. Nimesulide 53 15. Nimodipine 56 16. ONO2506 60 17. Sodium Phenylbutyrate 63 18. Riluzole 68 19. Scriptaid 73 20. Talampanel 76 21. Tamoxifen 79 22. Thalidomide 83 23. Trehalose 86 24. Vitamin E 89 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. AEOL 10150 PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Catalytic antioxidant Manufacturer Incara Pharmaceuticals, Inc. RTP, NC (Aeolus Pharmaceuticals) Regulatory Approval Status Investigational Mechanism of Antioxidant – downstream reduction in protein nitration and oxidation Action CASE FOR USE IN ALS Rationale Ongoing oxidative stress may be involved in the pathogenesis of ALS. Clinical Data None Animal Data Kiael M, 2004 (Abstract Only): AEOL 10150 (2.5 mg/kg/day, i.p.) was administered to G93A transgenic mice from the time of symptom onset, which was determined by a combination of tests (i.e., Rotarod performance at 15 rpm, appearance of tremor of the hind legs, and gait abnormalities). AEOL 10150 treatments attenuated weight loss, enhanced motor performance and increased the survival interval (time from symptom onset to death) by 38% in G93A mice. AEOL 10150 treatments also extended the survival in these mice by 14%. Crow JP, 2004 (presented at AAN): In four separate studies in two academic medical centers, 2 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. AEOL 10150 was compared to control in a transgenic mouse model of ALS. The drug was initiated at symptom onset at 2.5 mg/kg/day IP. The treated mice experienced a survival interval ratio of 2.98, p<0.01 (they lived 3 times longer). Also, when added to an already proven effective combination of rofecoxib and creatine, AEOL 10150 resulted in a further doubling of survival time. In Vitro Data None HUMAN USE PROFILE Examined ALS Indications Safety/Tolerability Aeolus Pharmaceuticals, Inc Press Release (www.focusonals.com): Currently being studied in a Phase I dose-ranging, PK study in ALS patients. PK/Drug Pharmacokinetics: Interactions Unknown in humans Sheng H, 2004: In a spinal cord injury model in mice, only when the drug was given intrathecally (compared to IV) was it effective in improving performance and reducing injury. The IV dose in this study was 0.5 mg/kg bolus followed by 1 mg/kg/h x 24 h. However, in the Crow study, IP administration of 2.5 mg/kg daily was effective in improving 3 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. survival in ALS. Drug Interactions Unknown 4 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. RELEVANT PRECLINICAL DATA Sheng H, 2004: Intrathecal AEOL 10150, administered 5 minutes after spinal cord injury in mice, improved outcome. Bowler RP, 2002: IV AEOL 10150, administered 5 minutes after reperfusion in a model of cerebral ischemia (MCAO for 60 minutes), reduced the expression of inflammatory genes. MISCELLANEOUS SUMMARY: Needed prior to development as a treatment in ALS: 1. Pharmacokinetics and BBB penetration in humans 2. Therapeutic concentrations in animal model 3. Human safety REFERENCES www.focusonals.com www.aeoluspharma.com Bowler RP, Sheng H, Enghild JJ, Pearlstein RD, Warner DS, Crapo JD. A catalytic antioxidant (AEOL 10150) attenuates expression of inflammatory genes in stroke. Free Rad Biol Med 2002; 33(8):1141-1152. Kiael M, Kipiani K, Petri S, Chen J, et al. A novel catalytic antioxidant, manganese (AEOL 10150) slows disease progression and extends lifespan in transgenic mouse model. ALS/MND 2004; 5(suppl 2):91. (Abstract Only). Sheng H, Spaspjevic I, Warner DS, Batinic-Haberle I. Mouse spinal cord compression injury is ameliorated by 5 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. intrathecal cationic manganese (III) porphyrin catalytic antioxidant therapy. Neurosci Lett 2004; 366:220-225. 6 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. ARIMOCLOMOL PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Heat shock protein inducer; may have as neurotrophic factor Manufacturer Cytrx Regulatory Approval Status Investigational (maybe preclinical only) Mechanism of Lindquist S, 1986: Interacts with, and amplifies the heat shock protein response, which has Action been shown to be a powerful cytoprotective mechanism. CASE FOR USE IN ALS Rationale Kieran D, 2004: Heat shock proteins (HSPs) are upregulated in ALS, but in motor neurons, there is evidence that they have reduced availability. Increasing HSP levels may protect motor neurons from apoptosis in ALS. Clinical Data None Animal Data Kieran D, 2004: Arimoclomol (10 mg/kg IP daily), starting at 35 days or 70 days (after symptoms emerged) in SOD mutant mice, resulted in a 22% increase in lifespan and improved hindlimb muscle function. The animals receiving the treatment also had significantly preserved body weight compared to controls. Delay of treatment until after the emergence of symptoms (70 days) did not impair the efficacy of the intervention! 7 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. In Vitro Data None HUMAN USE PROFILE Examined None Indications Safety/Tolerability Unknown PK/Drug Unknown Interactions 8 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. RELEVANT PRECLINICAL DATA Kalmar B, 2002: BRX-220 (is this arimoclomol??) pretreatment, improved the survival of motor neurons at 14 days after sciatic crush injury in rat pups BIMOCLOMOL (advanced Phase II in 1997 – Vigh, 1997) – close relative, also developed by Biorex R&D Biro k, 1997: ameliorates peripheral neuropathy in rats Erdo F, 1998: reduces vascular consequences of SAH in rats Biro K, 1998: improves early signs of retinopathy in diabetic rats Jednakovits A, 2000: prevents vascular changes in SHRs Lubbers NL, 2002: pretreatment decreased infarct size in a rat model of coronary ischemia and reperfusion MISCELLANEOUS SUMMARY: Needed prior to development as a treatment in ALS: 1. Pharmacokinetics and BBB penetration in humans 2. Therapeutic concentration in animal model 3. BBB penetration in mouse 4. Human Safety REFERENCES Kieran D, Kalmar B, Dick JRT, Riddoch-Contreras J, et al. Treatment with arimoclomol, a coninducer of heat shock proteins, delays disease progression in ALS mice. Nature Medicine. 2004 Apr. 10(4):402-405. 9 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. CEFTRIAXONE PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Antibacterial; cephalosporin Manufacturer Roche - Rocephin Regulatory Approval Status Approved Mechanism of Action Rothstein, 2005: Antiexcitatory and antioxidant (discovered through the NDSC program of 1040 compounds, of which 16 were cephalosporins). The cephalosporins seem to be antiglutamatergic by increasing astrocytic uptake of glutamate by the EAAT2 transporter (increased activity of the transporter). CASE FOR USE IN ALS Rationale Rothstein, 2005: NINDS in vitro assays of EAAT2 transporter and motor neurons demonstrated potential activity of the cephalosporins. Ceftriaxone was chosen for further study because of its superior penetration into the CNS and its long t ½. Clinical Data None 10 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. Animal Data Rothstein, 2005: G93A SOD1 mice were treated daily with 200 mg/kg IP, starting at 12 weeks of age and survival was prolonged 10 days (8%) over saline treated animals (122 days) (p>0.006). When the treatment was initiated at 6 weeks of age, the survival was similarly increased (10%- 122 vs 135 days). Treated animals also demonstrated improved body weight retention and grip strength. Rats given 200 mg/kg IP x 5 days had a 3-fold increase in GLT1 protein (glutamate transporter). In Vitro Data Rothstein, 2005: Increases EAAT2 activity and enhances synaptic glutamate clearance. - increased EAAT2 promoter in astroglial cell lines - lower concentrations (1 µM) required to increase EAAT2 than to protect motor neurons from toxicity in culture (100 µM) HUMAN USE PROFILE Examined Indications MD consult, 2004: Bacterial infections including meningitis, septicemia, etc Safety/Tolerability MD consult, 2004: Generally well-tolerated; side effects similar to other cephalosporins: superinfections, diarrhea (up to 50%), skin and blood dyscrasias. No serious adverse events when 4 g/day (maximum approved dose) was administered x 10-14 days. 11 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. Guglielmo, 2000: In 21 patients receiving 2 g q24 of ceftriaxone for 6-7 weeks for the treatment of osteomyelitis, no adverse effects were documented (no diarrhea or biliary symptoms). PK/Drug Pharmacokinetics: Interactions Patel, 1981: t ½ =4-6 hours in serum and is linear. Nau, 1993: t ½ = up to 18 hours in CSF. Chandrasekar, 1983: In humans with uninflamed meninges, 2 gm IV resulted in average peak concentrations in plasma of 262.4 mg/L and the peak in the CSF was 2.12 mg/L (about 1%), which occurred 3-4 hours post dose MD consult, 2004: t ½ increased to 12-15 hours in renal impairment; no dosage adjustment needed in hepatic dysfunction.

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