1. Ukraine Prof. Elena Grechanina, Kharkov Genetic & Neonatal Screening Centre Russia Prof. Peter Novikov, Moscow Central Genetic Center Denmark Flemming Güttler, M.D., PhD., Glostrup, J. F. Kennedy Genetic Institute USA Reuben Matalon, M.D., Ph.D., Kim Matalon, the University of Texas Medical Branch

2. Denmark LNAA STUDY 1 tablet/kg/day Blood Samples PKU 20 PKU 39 PKU 93 PKU 105 PKU 128 Avg 1143616811697159716271608 02126216911591148016021525 04 04116416431526141414071431 1 week 184-58220184268160

3. Denmark LNAA STUDY 2 tablets/kg/day Blood Samples PKU 20 PKU 39 PKU 93 PKU 105 PKU 128 Avg 08125217391477141313591448 09114615371370123313731332 11111915561389117913131311 15119916501349122213351351 2 week 23731348375292257

4. 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

5. 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

6. 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

7. 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

8. 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

9. µmol/l 1260 870 960 474 762 426 780

10. µmol/l 1200 828 765 624

11. 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

12. 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

13. NeoPhe 0.5 g/kg in PKU Subjects 13 subjects 13 subjects Mean age 26.6 years Mean age 26.6 years 7 males, 6 females 7 males, 6 females Mean decrease in blood Phe after one week 243 µmol/L Mean decrease in blood Phe after one week 243 µmol/L Average decrease in blood Phe 22 %. Average decrease in blood Phe 22 %.

14. NeoPhe 1.0 g/kg in PKU Subjects 7 subjects 7 subjects Mean age 25.2 years Mean age 25.2 years 5 males, 2 females 5 males, 2 females Mean decrease in blood Phe after one week 377 µmol/L Mean decrease in blood Phe after one week 377 µmol/L Average decrease in blood Phe 25 %. Average decrease in blood Phe 25 %.

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

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

17. CONCLUSIONS: For the first time mixture of LNAA can lower blood phenylalanine For the first time mixture of LNAA can lower blood phenylalanine Using NeoPhe avoids lysine deficiency and negative nitrogen balance Using NeoPhe avoids lysine deficiency and negative nitrogen balance NeoPhe offers new options to treat PKU NeoPhe offers new options to treat PKU Diet can be more liberal with NeoPhe Diet can be more liberal with NeoPhe Still blood phe- levels need to be controlled Still blood phe- levels need to be controlled