Biotin for use in treating X-linked adrenoleukodystrophy

Abstract

The invention relates to the use of biotin for treating X-linked adrenoleukodistrophy, in particular adrenomyeloneuropathy.

Claims

1. A method for treating adrenomyeloneuropathy, comprising administering to a patient in need thereof a composition comprising biotin and a pharmaceutically acceptable excipient, wherein the daily amount of biotin administered to the patient is at least 250 mg.

2. The method according to claim 1, wherein the daily amount of biotin administered to the patient is at least 300 mg.

3. The method according to claim 1, wherein the composition is in a form suitable for oral administration.

4. The method according to claim 1, wherein the composition is in the form of gel capsules, tablets, lozenges or pills.

5. The method according to claim 1, wherein biotin is the sole active ingredient.

6. The method according to claim 1, wherein the excipient is chosen from the group consisting of talc, microcrystalline cellulose, lactose and mannose.

7. The method according to claim 1, wherein the composition is in a form suitable for injectable administration.

8. The method according to claim 1, wherein the composition is in the form of a slow release composition.

9. The method according to claim 1, wherein the composition further comprises another drug against adrenomyeloneuropathy for simultaneous, separate or sequential use in the treatment of adrenomyeloneuropathy.

10. The method according to claim 9, wherein said other drug is Lorenzo's oil or Fampridine.

11. The method according to claim 4, wherein the tablets are film-coated.

12. The method according to claim 9, wherein the sequential use is spread out over time.

13. The method according to claim 1, wherein the daily amount of biotin administered to the patient is about 300 mg.

Description

EXAMPLES

(1) One patient suffering from AMN was treated for 5 month with high doses of biotin (100 to 300 mg/day) and showed marked clinical improvement after a delay of 3 months (see below). Treatment was then arrested for 1½ month resulting in worsening with return to baseline. After reintroduction, the patient improved again. This case report is detailed below. The fact that this patient responded to biotin suggests that high doses of biotin are efficacious in modifying evolution of AMN and/or alleviating the symptoms of the disease. These results shall later be confirmed in a placebo randomized clinical trial.

(2) Clinical Case

(3) This 44 year-old patient born in 1969 was diagnosed with adrenomyeloneuropathy in 2012. The diagnosis was confirmed genetically with a pathogenic mutation (c.584A>G) in the ABCD1 gene. He had a 15 years history of progressive spastic paraparesis with urinary problems (urinary urgencies). Treatment with biotin was started in early February 2013 at 100 mg/day. At that time, the patient was able to walk independently with no limitation of his walking distance. However, he exhibited marked spasticity in lower limbs together with urinary problems: he had to wake up several times during the night because of urinary urgencies. He used a urethral catheter before sleep and once at night to empty his bladder. The best time to walk 15 meters (corridor length) was 17 seconds. Treatment with biotin was started for three months. After this period, no significant change was noticed: the best time to walk 15 meters was 15 seconds with an improvement of 11.7% compared to baseline which was considered as non significant. No change in urinary problems was noticed. During this period, the patient was followed by a physical therapist two times a week with no noticeable improvement at different tests (Table 1).

(4) TABLE-US-00001 TABLE 1 Follow-up with physical therapy two times a week. Exercice 3 Leg Exercice 1 Exercice 2 scissors on Exercice 4 Knees up on Leg trampoline Leg trampoline scissors on with elastic scissors on Week (1 min) trampoline resistance the floor 1 78 43 24 in 30″ 20 78 51 in 58″ .sup.  28 in 30″ 28 in 27″ 2 83 50 in 53″ .sup.  30 in 31″ 16 in 15″ 93 62 in 1′05″ 40 in 45″ 20 in 19″ 3 98 66 in 1′07″  .sup. 60 in 1′05″ 22 in 21″ 92 60 in 1′03″ 52 in 56″ 26 in 26″ 4 99 70 in 1′17″ 41 in 43″ 22 in 22″ 95 80 in 1′27   .sup. 60 in 1′05″ 30 in 29″ 5 NA NA NA NA 99 62 in 1′08″ 49 in 57″ 20 in 19″ 6 100  76 in 1′22″  .sup. 68 in 1′13″ 24 in 23″ NA NA NA NA 7 101  82 in 1′28″  90 in 1′40 35 in 33″ 101  97 in 1′40″  93 in 1′42 33 in 33″ 8 NA NA NA NA NA NA NA NA 9 NA NA NA NA NA NA NA NA 10 90 62 in 1′09″  70 in 1′16 22 in 22″ 100  69 in 1′18″  .sup. 54 in 1′01″ 34 in 33″ 11 97 67 in 1′13″  .sup. 88 in 1′38″ 19 in 18″ 97 71 in 1′20″  .sup. 55 in 1′01″ 31 in 32″ 12 97 72 in 1′23″ 48 in 56″ 38 in 37″ 103  63 in 1′12″  .sup. 88 in 1′38″ 39 in 39″ Mean +/− 94.5 +/− 7.6 66.8 +/− 12.6 57.7 +/− 21.7 26.6 +/− 7 SD NA: non available. Column 1: weeks of examinations, column 2: maximum number of   knees up   on a trampoline in less than 1 minute, column 3: maximum number of leg scissor movements on a trampoline, column 4: same as column 3 but with an elastic around his legs, column 5: same as column 3 but on the floor. Between early February (treatment start), and end of April (3 months of treatment), numbers were comparable.

(5) After 3 months (May 2013), the dosage was increased to 300 mg/day. One month later (June 2013) the patient noticed improvement of spasticity and urinary problems. The best time to walk 15 meters was 14.3 seconds (−15.9% compared to the pre-treatment value which can be considered as clinically meaningful). In the mean while, the patient noticed marked improvement of urinary problems. Urinary urgencies had markedly decreased during the night and the patient was not obliged to use a urethral catheter during the night. The dosage (300 mg/day) was pursued for one month more. At Month 5 (July 2013), the best time to walk 15 meters was 13.7 seconds (−19.4% compared to the pre-treatment value). Urinary urgencies remained improved to the same level than at 4 months. Physical therapy follow-up between the first of May and end of June 2013 (M4 to M5) showed a marked improvement of all parameters including maximum number of knees up on a trampoline in less than 1 minute (+31.9%), maximum number of leg scissor movements on a trampoline (+67.7%), maximum number of leg scissor movements on a trampoline with elastic resistance (+103%), maximum number of leg scissor movements on the floor (+43.2%, tables 2 and 3).

(6) TABLE-US-00002 TABLE 2 Physical therapy follow-up two times a week during the M4 to M5 period. Exercice 3 Leg Exercice 1 Exercice 2 scissors on Exercice 4 Knees up on Leg trampoline Leg trampoline scissors on with elastic scissors on Week (1 min) trampoline resistance the floor 13 108 80 in 1′30 109 in 2′03  30 in 31″ 14 106 104 in 1′53  125 in 2′16″ 35 in 35″ 133 120 in 2′12  100 in 1′54″ 40 in 41″ 15 NA NA NA NA NA NA NA NA 16 NA NA NA NA 126  73 in 1′22″  57 in 1′05″ 35 in 36″ 17 120 130 in 2′19  129 in 1′14″ 46 in 46″ 133 148 in 2′40″ 152 in 2′42″ 48 in 48″ 18 127  84 in 1′30″  88 in 1′38″ 41 in 41″ NA NA NA NA 19 131 140 in 2′34″ 134 in 2′37″ 39 in 38″ NA NA NA NA 20 130 110 in 2′00″ 133 in 2′26″ 31 in 31″   1. 21 133 132 in 2′24″ 147 in 2′36″ 36 in 25″ Mean +/− 124.7 +/− 10.2 112 +/− 26.4 117.4 +/− 29.2 38.1 +/− 5.9 SD NA: not available. Column 1: dates of examinations, column 2: maximum number of knees up on a trampoline in less than 1 minute, column 3: maximum number of leg scissors on a trampoline, column 4: same as column 3 but with an elastic around his legs, column 5: same as column 3 but on the floor. Compared with table 1 all numbers in creased (see TABLE 3).

(7) TABLE-US-00003 TABLE 3 comparisons of different physical therapy exercises between the M0-M3 period (week 0 to week 12) and the M4-M5 period (week 13 to week 21). Mean +/− SD Mean +/− SD % Type of Week 0 to Week 13 to improve- P exercise Week 12 Week 21 ment value* Knees up on 94.5 +/− 7.6  124.7 +/− 10.2 +31.9 <0.0001 trampoline (1 min) Leg scissors 66.8 +/− 12.6 .sup. 112 +/− 26.4 +67.7 0.0003 on trampoline Leg scissors 57.7 +/− 21.7 117.4 +/− 29.2 +103 <0.0001 on trampoline with elastic resistance Leg scissors 26.6 +/− 7   38.1 +/− 5.9 +43.2 0.00012 on the floor *bilateral student's t test for unpaired data comparing M0-M3 values to M4-M5 values.

(8) At Month 5, a brain MRI with brain NMR spectroscopy (NMRS) was performed in the brain white matter. This showed some improvement of the N-acetyl aspartate (NAA)/creatine (Cr) ratio compared to baseline (table 4).

(9) TABLE-US-00004 TABLE 4 Changes in NMR spectroscopy parameters between 2013 Jan. 26 (before treatment) and 2013 Jun. 25 (after treatment). Note an increase in the NAA/Cr ratio from 1.67 to 1.81. M0: 2013 Jan. 26 M5: 2013 Jun. 25 NAA 20.00 29.00 Cr 12.00 16.00 Ch 18.00 25.00 NAA/Cr 1.67 1.81 Ch/Cr 1.50 1.56 Ch/NAA 0.90 0.86

(10) Treatment with biotin was then stopped in July 2013 (at M5). After 10 days of treatment arrest, the patient noticed some worsening of walking and of urinary problems. When he was seen at the end of August 2013 (after 1½ month of treatment arrest), the best time to walk 15 meters had returned to 17.2 seconds (+1.2% compared to baseline value). The patient was using a urethral catheter again during the night.

(11) Treatment was then reintroduced at 300 mg/day. After a week, the patient noticed some improvement of urinary urgencies. When he was seen one month after reintroduction of the treatment, the best time to walk 15 meters was 14.6 seconds (−14.1% compared to baseline).

(12) TABLE-US-00005 TABLE 5 Evolution of the best time to walk 15 meters at different time points (see text) Best time % change from Patient (one go) baseline M0 (before treatment) .sup. 17 sec M3 (after 3 months) .sup. 15 sec −11.7% M4 14.3 sec −15.9% M5 13.7 sec −19.4% 1.5 month after arrest 17.2 sec +1.2% 1 month after reintroduction 14.6 sec −14.1%
Discussion

(13) Overall, this observation indicates a benefit of treatment with high doses of biotin in patients with AMN. The demonstration of treatment's efficacy relies on several observations in the same patient. 1) Clinical tests including the best time to walk 15 meters as well as physical therapy measures clearly showed an improvement while on treatment. 2) Improvement of clinical symptoms such as urinary urgencies and ability to avoid urethral catheter at night are reminiscent of drug's efficacy. 3) Improvement of the NAA/Cr ratio is usually considered as a robust marker of neuronal health. An increase in this ratio after treatment suggests some neuronal recovery after 5 months of treatment. 4) Worsening of the clinical status after drug withdrawal and re-improvement after drug re-introduction strongly suggests that improvement has been caused by the drug and is not linked to spontaneous evolution or to physical therapy training. 5) The fact that the patient improved after increasing the dosage from 100 to 300 mg strongly suggests a dose-effect. 6) The fact that the patient improved after at least 3 months of treatment and that improvement was sustained during months 4 and 5 is against a placebo effect which usually appears shortly after drug introduction.

(14) These results thus support treatment efficacy of high doses of biotin in AMN, and shall be confirmed in a placebo-controlled-double blind-randomized clinical trial.

REFERENCES

(15) Fourcade S et al, Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy. Hum Mol Genet. 2008 Jun. 15; 17(12):1762-73. Epub 2008 Mar. 14 Powers J M et al, Adreno-leukodystrophy: oxidative stress of mice and men. J Neuropathol Exp Neurol. 2005 Dec.; 64(12):1067-79.