Ultra-high dose methylcobalamin and other emerging therapies for amyotrophic lateral sclerosis.

Recent development in understanding the pathophysiology of amyotrophic lateral sclerosis (ALS) has led to increasing number of promising test drugs in the pipeline along with the existing ones. We will review these agents focusing on ultra-high dose methylcobalamin, which is pending approval in Japan. Clinical trial design best suited for ALS will also be discussed. The most recent phase 3 trial (JETALS) of ultra-high dose methylcobalamin demonstrated significant slowing of ALSFRSR changes (0.5/month), with marked reduction of serum homocysteine levels in the initial double-blind period. The post hoc analysis of the previous phase 2/3 study (E761 trial; Eisai) showed that it prolonged survival of ALS patients, if started within 1 year of onset, but the previous studies suggested its efficacy even in later stages, depending upon the rate of progression. Phase 3 trial of AMX0035 or Relyvrio on the other hand showed negative results despite the promising phase 2 data. The latter did not adjust the disease progression rate before entry. Ultra-high dose methylcobalamin is not a vitamin supplement but a novel disease-modifying therapy for ALS, and it emphasizes homocysteine as a key factor in the disease process. Clinical trial design must include entering patients early and with similar rates of progression using pretrial observation periods for meaningful results, since ALS is a chronologically heterogenous condition with similar phenotypes.

Kaji R ，Izumi Y ，Oki R 《-》

[JETALS: The Japanese Early-stage Trial of high dose methylcobalamin for ALS].

Izumi Y ，Oki R ，Kuwabara S ，Kaji R ... -  《-》

Neuroprotective effect of ultra-high dose methylcobalamin in wobbler mouse model of amyotrophic lateral sclerosis.

High-dose of methylcobalamin promotes nerve regeneration in rats with acrylamide neuropathy. A double-blind controlled trial suggested that high-dose methylcobalamin could increase compound muscle action potentials in patients with amyotrophic lateral sclerosis (ALS). A large-scale extended period human trial is now on-going in ALS (Clinicaltrial.govNCT00444613). We attempted to study whether high-dose methylcobalamin can improve symptoms or retard progression of motor dysfunction in the wobbler mouse model of ALS. After initial diagnosis of the disease at the postnatal age of 3-4 weeks, wobbler mice received methylcobalamin (3 or 30 mg/kg, n=10/group) or vehicle (n=10), daily for 4 weeks by intraperitoneal administration in a blinded fashion. We compared clinical symptoms and pathological changes among all groups. Vitamin B12 concentrations were measured in the serum, the skeletal muscle and the spinal cord of three groups (n=5/group). In comparison with vehicle, mice treated with ultra-high dose (30 mg/kg) of methylcobalamin significantly inhibited muscle weakness and contracture in the forelimb, and increased the weight of the bicep muscles and the number of musculocutaneous nerves. Methylcobalamin-treated mice significantly elevated vitamin B12 concentrations of the serum, the bicep muscle and the spinal cord compared to vehicle. Our results suggest that treatment with methylcobalamin could delay progression of motor symptoms and neuropathological changes in wobbler mouse motor neuron disease if very high doses are used.

Ikeda K ，Iwasaki Y ，Kaji R 《-》

Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Oki R ，Izumi Y ，Fujita K ，Miyamoto R ，Nodera H ，Sato Y ，Sakaguchi S ，Nokihara H ，Kanai K ，Tsunemi T ，Hattori N ，Hatanaka Y ，Sonoo M ，Atsuta N ，Sobue G ，Shimizu T ，Shibuya K ，Ikeda K ，Kano O ，Nishinaka K ，Kojima Y ，Oda M ，Komai K ，Kikuchi H ，Kohara N ，Urushitani M ，Nakayama Y ，Ito H ，Nagai M ，Nishiyama K ，Kuzume D ，Shimohama S ，Shimohata T ，Abe K ，Ishihara T ，Onodera O ，Isose S ，Araki N ，Morita M ，Noda K ，Toda T ，Maruyama H ，Furuya H ，Teramukai S ，Kagimura T ，Noma K ，Yanagawa H ，Kuwabara S ，Kaji R ，Japan Early-Stage Trial of Ultrahigh-Dose Methylcobalamin for ALS (JETALS) Collaborators ... -  《-》

Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study.

To evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS). 373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration ≤36 months) were randomly assigned to placebo, 25 mg or 50 mg of methylcobalamin groups. The primary endpoints were the time interval to primary events (death or full ventilation support) and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to week 182. Efficacy was also evaluated using post-hoc analyses in patients diagnosed early (entered ≤12 months after symptom onset). No significant differences were detected in either primary endpoint (minimal p value=0.087). However, post-hoc analyses of methylcobalamin-treated patients diagnosed and entered early (≤12 months' duration) showed longer time intervals to the primary event (p<0.025) and less decreases in the ALSFRS-R score (p<0.025) than the placebo group. The incidence of treatment-related adverse events was similar and low in all groups. Although ultra-high-dose methylcobalamin did not show significant efficacy in the whole cohort, this treatment may prolong survival and retard symptomatic progression without major side effects if started early. NCT00444613.

Kaji R ，Imai T ，Iwasaki Y ，Okamoto K ，Nakagawa M ，Ohashi Y ，Takase T ，Hanada T ，Shimizu H ，Tashiro K ，Kuzuhara S ... -  《-》