P.059 Results From the Randomized and Open-Label Periods of the CENTAUR Trial of Sodium Phenylbutyrate and Ursodoxicoltaurine in Amyotrophic Lateral Sclerosis (ALS)

Background: An oral, fixed-dose sodium phenylbutyrate-ursodoxicoltaurine (PB-TURSO) coformulation was evaluated in a multicenter ALS trial (CENTAUR). Methods: Adults with definite ALS, ≤18 months from symptom onset, (N=137) were randomized 2:1 to PB-TURSO or placebo for 6 months. Completing participants were eligible to receive PB-TURSO in the open-label extension (OLE) (≤30 months). The primary efficacy endpoint in both periods was rate of ALS Functional Rating Scale–Revised (ALSFRS-R) total score decline. All-cause survival was analyzed July 2020 (longest follow-up, 35 months). Safety was assessed in both periods. Results: Over 6-month randomized treatment, mean ALSFRS-R total score decline was slower with PB-TURSO vs placebo (difference, 0.42 points/month; P=0.03). Participants receiving PB-TURSO in the OLE (continued or crossover from placebo) maintained or initiated functional benefit beyond 6 months of therapy. Mean hazard of death was 44% lower (P=0.02) in the original PB-TURSO group. Overall adverse event (AE) incidence was similar, though early (week ≤3) gastrointestinal AEs were more frequent during initial exposure to PB-TURSO (randomized period or OLE). Conclusions: PB-TURSO resulted in superior retention of function in the randomized period. Long-term OLE results support functional benefits of early vs delayed therapy and of sustained treatment. Survival was longer in the original PB-TURSO group after nearly 3 years.

Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NFκB to promote axonal regeneration and remyelination

Background Epigenetic regulation by histone deacetylases (HDACs) in Schwann cells (SCs) after injury facilitates them to undergo de- and redifferentiation processes necessary to support various stages of nerve repair. Although de-differentiation activates the synthesis and secretion of inflammatory cytokines by SCs to initiate an immune response during nerve repair, changes in either the timing or duration of prolonged inflammation mediated by SCs can affect later processes associated with repair and regeneration. Limited studies have investigated the regulatory processes through which HDACs in SCs control inflammatory cytokines to provide a favorable environment for peripheral nerve regeneration. Methods We employed the HDAC inhibitor (HDACi) sodium phenylbutyrate (PBA) to address this question in an in vitro RT4 SC inflammation model and an in vivo sciatic nerve transection injury model to examine the effects of HDAC inhibition on the expression of pro-inflammatory cytokines. Furthermore, we assessed the outcomes of suppression of extended inflammation on the regenerative potential of nerves by assessing axonal regeneration, remyelination, and reinnervation. Results Significant reductions in lipopolysaccharide (LPS)-induced pro-inflammatory cytokine (tumor necrosis factor-α [TNFα]) expression and secretion were observed in vitro following PBA treatment. PBA treatment also affected the transient changes in nuclear factor κB (NFκB)-p65 phosphorylation and translocation in response to LPS induction in RT4 SCs. Similarly, PBA mediated long-term suppressive effects on HDAC3 expression and activity. PBA administration resulted in marked inhibition of pro-inflammatory cytokine secretion at the site of transection injury when compared with that in the hydrogel control group at 6-week post-injury. A conducive microenvironment for axonal regrowth and remyelination was generated by increasing expression levels of protein gene product 9.5 (PGP9.5) and myelin basic protein (MBP) in regenerating nerve tissues. PBA administration increased the relative gastrocnemius muscle weight percentage and maintained the intactness of muscle bundles when compared with those in the hydrogel control group. Conclusions Suppressing the lengthened state of inflammation using PBA treatment favors axonal regrowth and remyelination following nerve transection injury. PBA treatment also regulates pro-inflammatory cytokine expression by inhibiting the transcriptional activation of NFκB-p65 and HDAC3 in SCs in vitro.

Oral sodium phenylbutyrate for hyperammonemia associated with congenital portosystemic shunt: a case report

ObjectivesThe efficacy of sodium phenylbutyrate (SPB) for hyperammonemia associated with congenital portosystemic shunt (CPSS) remains unknown. We show the effectiveness of oral SPB.Case presentationOur patient had CPSS with severe hypoplasia of extrahepatic portal veins. At 9 months of age, to assess the efficacy of oral SPB, we evaluated the 24 h fluctuations of venous ammonia levels. In the first two days without SPB, ammonia levels were above 80 μmol/L for half a day. On the third and fourth days, administration of oral SPB three times a day decreased ammonia to acceptable levels, except at midnight. On the fifth day, another oral SPB administration at 8 pm decreased ammonia at midnight. Low levels of branched-chain amino acids, as well as coagulation disturbances, were observed without apparent symptoms. At 12 months of age, he showed normal psychomotor development.ConclusionsOral SPB may be effective for hyperammonemia associated with CPSS.