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ICIEM 2006 Double Blind Placebo Control Trial in PKU with NeoPhe Reuben Matalon 1, Kimberlee Michals-Matalon 1, Alberto Burlina 2, Alesandro Burlina.

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Presentation on theme: "ICIEM 2006 Double Blind Placebo Control Trial in PKU with NeoPhe Reuben Matalon 1, Kimberlee Michals-Matalon 1, Alberto Burlina 2, Alesandro Burlina."— Presentation transcript:

1

2 ICIEM 2006

3 Double Blind Placebo Control Trial in PKU with NeoPhe Reuben Matalon 1, Kimberlee Michals-Matalon 1, Alberto Burlina 2, Alesandro Burlina 2, Marcello Giovannini 3, Laura Fiori 3, Elena Grechanina 4, Peter Novikov 5, James Grady 1, Stephen Tyring 6, Flemming Guttler 7 1 University of Texas Medical Branch, 2 University of Padova, 3 University of Milan, 4 University of Kharkiv, 5 University of Moscow, 6 University of Texas, 7 Kennedy Institute

4 Large Neutral Amino Acids (LNAA) Phenylalanine (Phe) Phenylalanine (Phe) Leucine Leucine Tyrosine Tyrosine Tryptophan Tryptophan Methionine Methionine Histidine Histidine Isoleucine Isoleucine Valine Valine Threonine Threonine

5 Transport of LNAA to the Brain Phenylalanine (Phe) 0.12 0.45 Phenylalanine (Phe) 0.12 0.45 Leucine0.150.53 Leucine0.150.53 Tyrosine0.160.58 Tyrosine0.160.58 Tryptophan0.190.71 Tryptophan0.190.71 Methionine0.190.77 Methionine0.190.77 Histidine0.281.10 Histidine0.281.10 Isoleucine0.331.30 Isoleucine0.331.30 Valine0.632.50 Valine0.632.50 Threonine 0.733.00 Threonine 0.733.00 K m mmol/L K m app Pardridge, Inborn Errors of Metabolism in Humans. MTP Press, 1980.

6 Andersen AE, Avins L LNAA injected to rat pups LNAA injected to rat pups Phenylalanine hydroxylase was ihibited by parachlorophenylalanine Phenylalanine hydroxylase was ihibited by parachlorophenylalanine Brain phenylalanine decreased Brain phenylalanine decreased 1976 Arch Neurology 33:684

7 Tyrosine in The Treatment of PKU Lou et al used Tyr 160 mg/kg in treated patients with PKU Increased attention span Increased attention span Increased dopamine synthesis Increased dopamine synthesis 1987 Acta Paediatr Scand 76:560

8 Tyrosine in Treatment of PKU Pietz et al. used high dose tyrosine in adults with PKU and high blood Phe Pietz et al. used high dose tyrosine in adults with PKU and high blood Phe No difference in treated group vs placebo No difference in treated group vs placebo 1995 J Pediatr 127:936

9 Tryptophan in Treated PKU Nielsen et al used tryptophan 4.5 gm/day to treated PKU for 3 weeks Nielsen et al used tryptophan 4.5 gm/day to treated PKU for 3 weeks Showed a 3 fold increase in 5-HIAA in CSF despite high blood Phe Showed a 3 fold increase in 5-HIAA in CSF despite high blood Phe 1988 Dietary Phenylalanine and Brain Function. Birkhauser

10 LNAA Supplementation in PKU Dotremont et al. used LNAA and a low protein diet 0.6 gm/kg on 4 patients with PKU Dotremont et al. used LNAA and a low protein diet 0.6 gm/kg on 4 patients with PKU After 1 month subjects found with negative nitrogen balance After 1 month subjects found with negative nitrogen balance Lysine was limiting amino acid Lysine was limiting amino acid 1995 J Inherit Metab Dis 18:127

11 Km (app) – Km (1 + ∑[aa]/Km] This predicts that, if the plasma level of an LNAA is much less than its value of Km, then that amino acid will not compete effectively for the carrier protein This predicts that, if the plasma level of an LNAA is much less than its value of Km, then that amino acid will not compete effectively for the carrier protein

12 Absolute and apparent Km values of neutral amino acids for the neutral amino acid transporter in the BBB (Partridge, 1980)0 Amino acid Typical plasma level (mM) Km(mM) App Km (mM) LNAA’s Phe0.050.120.45 Leu0.100.150.53 Tyr0.090.160.58 Trp0.100.160.71 Met0.040.190.77 Isoleu0.070.331.3 Val0.140.632.5 Thr0.190.733.0

13 Absolute and apparent Km values of neutral amino acids for the neutral amino acid transporter in the BBB (Partridge, 1980) Amino acid Typical plasma level (mM) Km(mM) App Km (mM) Basic aa’s His0.050.281.1 Arg0.100.090.40 Lys0.300.100.25

14 LNAA Transport in Intestinal Mucosa K m mmol/L Phenylalanine1.0 Phenylalanine1.0 Leucine2.0 Leucine2.0 Valine3.0 Valine3.0 Methionine5.0 Methionine5.0 Histidine6.0 Histidine6.0 Competition effect is not likely to occur in tissue other than brain unless high concentration of amino acids is used Competition effect is not likely to occur in tissue other than brain unless high concentration of amino acids is used Pardridge, Inborn Errors of Metabolism in Humans. MTP Press, 1980.

15 Amino acid inhibition of Phe transport in Caco-2- cells – 10uM Phe in buffer applied to monolayers in presence of 1 mM concentration of each amino acid Inhibitor % inhibition LNAA’s Leu55% Tyr45% Trp36% Basis Aa’s Lys50% His33% Hidalgo Biochem Biophys. Acta 1008: 5-30a (1990)

16 78-80-83-86-159-162- F 577 23.821.419.424.91811 F 579 23.725.128.433.18.314.8 F 582 28.821.922.220.910.38.3 F 584 23.83025.330.77.812.4 PKU Mice on NeoPhe phe mg/dl Mice Control NeoPhe

17 78-80-83-86-159-162- F 585 20.621.724.419.88.512.3 F 586 23.225.721.221.913.511.3 F 588 21.621.724.224.410.910.9 Avg each time pt 23.623.923.625.11111.6 Avg all Pre-LNAA 24.1 Avg all Post-LNAA 11.3 PKU Mice on NeoPhe phe mg/dl Mice Control NeoPhe

18

19 Time Phe PheTyr KAµmol/lmg/dlµmol/lmg/dl 0’718.811.9853.90.98 3 days 668.411.1491.31.66 523.28.72103.41.88 376.26.27108.31.97 Russia LNAA STUDY

20 Time Time Phe PheTyr KNµmol/lmg/dlµmol/lmg/dl0’707.411.7942.90.78 3 days 607.210.12126.52.30 572.49.54159.52.91 585.69.7683.61.52 Russia LNAA STUDY

21 Russia LNAA Study TimePheTyr KHµmol/lmg/dlµmol/lmg/dl 0’635.410.5933.00.60 3 days 554.49.24242.04.40 322.25.3794.61.72 136.22.27110.02.00 102.61.7194.01.71

22 µmol/l 1260 870 960 474 762 426 780

23 µmol/l 1200 828 765 624

24 USA LNAA STUDY Time Phe PheTyr GDLµmol/lmg/dlµmol/lmg/dl 0’1290.621.5169.81.27 2 days 1198.219.9773.71.34 4 days 115.81.93140.252.55 KM0’1540.225.6730.80.56 8 days 883.814.3753.80.98 0’1978.232.9768.71.25 2 days 1608.626.81207.353.77

25 USA LNAA STUDY Time Phe PheTry ESµmol/lmg/dlµmol/lmg/dl 0’1375.822.9331.90.58 4-7 days 767.412.79121.52.12 RC0’965.416.0958.81.07 2 days 828.613.81156.22.84

26 US Blood Phe and Tyr NeoPhe Patient K 1 Week µmol/L (mg) ControlNeoPhe phetyrphetyr µmol/L (mg) µmol/L (mg) 1978.1(32.97)1.25 1356.0 (22.6) 5.0 1139.6 (25.66) 0.62 1308 (21.8) 4.1 1456.2 (24.27) 0.62 1146 (19.1) 3.82 24% reduction

27 US Blood Phe and Tyr NeoPhe Patient G 1 Week µmol/L (mg) ControlNeoPhe phetyrphetyr mg/dl mg/dl 1560 (26.0) 0.92 953 (15.89) 4.35 1764 (29.4) 1.9 505 (8.43) 3.32 56% reduction

28 US Blood Phe and Tyr NeoPhe Patient K 1 Week µmol/L (mg) ControlNeoPhe phetyrphetyr µmol/L (mg) µmol/L (mg) 1978.1(32.97)1.25 1356.0 (22.6) 5.0 1139.6 (25.66) 0.62 1308 (21.8) 4.1 1456.2 (24.27) 0.62 1146 (19.1) 3.82 24% reduction

29 US Blood Phe and Tyr NeoPhe Patient G 1 Week µmol/L (mg) ControlNeoPhe phetyrphetyr mg/dl mg/dl 1560 (26.0) 0.92 953 (15.89) 4.35 1764 (29.4) 1.9 505 (8.43) 3.32 56% reduction

30 Figure 1. Blood Phe Response to 0.5g/kg NeoPhe in Patients with PKU Paired t-test: p=0.001

31 Figure 2. Blood Phe Response to 1.0 g/kg NeoPhe in Patients with PKU Paired t-test: p=0.006

32 Double-Blind Placebo Control on patients in the US Patients were genotyped Patients were genotyped Baseline Phenylalanine was determined 3 times Baseline Phenylalanine was determined 3 times Placebo or Neophe was administered for one week, 1tablet/kg/day Placebo or Neophe was administered for one week, 1tablet/kg/day Blood Phe was determined 3 times Blood Phe was determined 3 times

33 E280K/E280K mg/dl  mol/L Before Neophezero 126.11566 zero 229.361761 zero 327.21632 Neophe24 hrs16.04962 72 hrs16960 96 hrs8.4504 1 week8.8528 Placebo 24 hrs 72 hrs 96 hrs 1 week 21.2 24.1 23.6 22.5 1272 1446 1416 1350

34 299C/IVS12 nt1 g>a mg/dl  mol/L Before Neophezero 125.61536 zero 232.91974 zero 326.81608 Neophe24 hrs14.3858 72 hrs16.81008 96 hrs18.11086 1 week12.2732 Placebo24 hrs 72 hrs 96 hrs 1 week 19.2 20.6 24.8 23.7 1152 1236 1488 1422

35 F299C/- mg/dl  mol/L Before Neophezero 116.09965.4 zero 218.11086 zero 317.21032 NeoPhe24 hrs12720 72 hrs14.1846 96 hrs10.1606 1 week11.4684 Placebo 24 hrs 72 hrs 96 hrs 1 week 16.2 18.2 17.1 16.12 972 1092 1026 967.2

36 I65T/R408W mg/dl  mol/L Before Neophezero 124.11446 zero 223.01380 zero 321.11266 Neophe24 hrs12.8768 72 hrs11.2672 96 hrs12.9774 1 week13.5810 Placebo24 hrs 72 hrs 96 hrs 1 week 18.2 22.2 19.1 22.3 1092 1332 1146 1339

37 Zero µmol/l NeoPhe µmol/l Placebo µmol/l E280K/E280K 1653738.51350 F299C/IVS12ntgl>a 17069211422 F299C/- 1027.8712967.2 I65T/R408W 13647521339.2 Summary of Average Blood Phe

38 Summary of Double Blind Study

39 Conclusion LNAA can reduce blood Phe levels when given with meals LNAA can reduce blood Phe levels when given with meals Longer term double-blind placebo control studies are needed Longer term double-blind placebo control studies are needed Establishing the efficacy and safety of LNAA can improve treatment of PKU Establishing the efficacy and safety of LNAA can improve treatment of PKU

40 Acknowledgement This study was supported in part by grants from Mid-Atlantic Connection for PKU and Allied Diseases (MACPAD) & South Texas Association for PKU and Allied Disease (STAPAD) This study was supported in part by grants from Mid-Atlantic Connection for PKU and Allied Diseases (MACPAD) & South Texas Association for PKU and Allied Disease (STAPAD) Generous supply of NeoPhe was given by PreKulab, Denmark Generous supply of NeoPhe was given by PreKulab, Denmark


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