Drugs that prevent S1P degradation could be particularly effective in treating schizophrenia

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Researchers at the RIKEN Center for Brian Science (CBS) in Japan have discovered a deficiency in the brains of people with schizophrenia that could lead to the development of new drug therapies.

A postmortem comparison published in Schizophrenia Bulletin revealed that schizophrenia was associated with lower than normal levels of S1P, a type of fatty molecule found in the white matter of the brain.

Preventing S1P degradation might therefore be a new direction for drug development in treating schizophrenia.

In recent years, drug therapy for schizophrenia has come to a stand-still. Most of the drugs available for schizophrenia are based on dopamine, but they are ineffective in about one out of every three patients.

“Because we don’t have another angle on what causes schizophrenia, many pharmaceutical companies are pulling out of schizophrenia-related drug development,” says Takeo Yoshikawa, team leader at RIKEN CBS. “Hopefully, our findings can provide the new angle with a new target for drug development.”

Although schizophrenia is a well-known mental disorder that affects the brain, how it does so remains somewhat of a mystery. Scientists have known for some time that the brains of people with schizophrenia have less white matter than normal brains.

White matter in the brain is made from oligodendrocytes, special cells that wrap around the parts of neurons that carry outgoing signals, which helps them communicate with each other.

Characteristic symptoms of schizophrenia include hallucinations and the inability to distinguish reality from fantasy, which might originate in white matter abnormalities that cause irregular communication between neurons.

Led by Takeo Yoshikawa, the team at RIKEN CBS investigated sphingolipids, a group of lipids known to have many functions, some related to white matter. Postmortem analysis of the large white matter tract that connects the left and right sides of the brain showed a severe deficiency in S1P, a sphingolipid necessary for oligodendrocyte production.

Further tests showed that although normal amounts of S1P had been produced, it was metabolized and degraded when it should not have been. “Drugs that prevent S1P degradation could be particularly effective in treating schizophrenia,” says first author and postdoctoral research scientist, Kayoko Esaki.

Although the experiment sounds simple, measuring S1P levels in postmortem brains was a big challenge and required interdisciplinary expertise in chemistry–specifically mass spectrometry–that was brought to the team by Esaki.

“This was the first psychiatric study of the postmortem brain to use mass spectroscopic analysis, and our discovery would not have been possible without our newly established comprehensive technique for screening sphingolipids,” says Yoshikawa.

After finding S1P sphingolipid deficiency in schizophrenia, the researchers examined postmortem brains of people with bipolar disorder or major depressive disorder. They found that S1P levels did not differ from what they found in normal brains, indicating that the problem is specific for schizophrenia, and not a common feature of mental disorders.

Before schizophrenia specific clinical trials can begin, studies in animals will be necessary. “The next important step,” says Yoshikawa, “is to determine precisely which S1P receptor-acting drugs are effective in experimental animals.

Although the new blockbuster drug fingolimod works at the S1P receptor and is effective at treating multiple sclerosis, we do not yet know how effective it would be for schizophrenia.”


Relapsing multiple sclerosis (RMS) and inflammatory bowel disease (IBD) are chronic immune-mediated inflammatory disorders that are often treated with immunosuppressants and immune system modulators, with the intent to dampen aberrant immune responses.1,2

RMS is characterized by inflammatory infiltration of the central nervous system, with resultant   edema,   demyelination,   and oligodendrocyte

and neuronal loss.3 IBD, including ulcerative colitis and Crohn’s disease, are chronic gastrointestinal in- flammatory disorders characterized by infiltration of lymphocytes, macrophages, and other immune cells.4 Both RMS and IBD have  a lifelong chronic course   of exacerbations and remissions, with impairment that accumulates over time.3,5,6

Currently approved medications for RMS and IBD have multiple limitations. Many drugs for RMS and IBD are administered by injection, presenting chal- lenges associated with injection-related adverse events, compliance, and convenience.7

Newer  oral  agents  for RMS are more efficacious but carry significant tolerability and/or safety concerns that affect patient quality of life and treatment adherence.1 With respect to IBD, conventional oral immunomodulators (eg, thiopurines, methotrexate) have limited efficacy and often a delay in the onset of action, whereas biologics (eg, anti–tumor necrosis factor antibodies) are associated with serious adverse reactions such as opportunistic infections and lymphoma.8

Thus, a substantial unmet medical need exists for oral treatments that are highly effective, safe, and well tolerated in patients with these immune-mediated diseases.

The sphingosine-1-phosphate receptor (S1P1R) is expressed by lymphocytes, dendritic cells, cardiomyocytes, and vascular endothelial cells and is involved in the regulation of chronic inflammation (via mediation of lymphocyte movement), heart rate,  smooth  muscle tone, and endothelial function.9,10

Because RMS and IBD are characterized by the recirculation and accumulation of autoreactive lymphocytes,11 modula- tion of the S1P1R is a rational target to ameliorate immunopathologic processes associated with these dis- eases. Fingolimod, a nonselective S1P receptor modulator, is approved for  the  treatment  of  RMS,  but  has a number of safety concerns including cardiovas- cular events (eg, bradycardia, conduction abnormali- ties, hypertension), macular edema, and elevated liver transaminases.12,13

Unlike the nonselective fingolimod, ozanimod is a selective and potent activator of only the S1P1R and S1P5R.14 The objectives of the current study were to characterize the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a range of single and multiple oral doses of ozanimod in healthy volunteers.

Discussion

Ozanimod is a selective S1P1R and S1P5R modulator being developed for the treatment of RMS and IBD. This was a first-in-human study evaluating the safety, PK, and PD of a range of single and multiple oral doses of ozanimod.

Ozanimod was well tolerated up  to the maximum dose of  3 mg as a single dose used  in this study. No severe or dose-limiting toxicities were observed, and most TEAEs were not considered related to the drug.

Target TEAEs of special interest were based on the safety profile of fingolimod. Potential dose-dependent safety findings in this study included

cardiovascular (eg, asymptomatic bradycardia, cardiac conduction abnormalities) and pulmonary events (eg, transient decline in FEV1 and FVC) that occurred at doses of 1.5 mg and higher. However, none of the observed events was considered of clinical concern. No significant changes or abnormalities in liver func- tion tests were observed. A dose-dependent negative chronotropic effect was observed after the first dose  of ozanimod, which was also observed with other S1P receptor modulators.15–17 The negative chronotropic effect of S1P receptor modulators may attenuate over time, secondary to S1P receptor desensitization on atrial myocytes.18 Because the negative chronotropic effect appears to occur with increasing exposure to ozanimod on day 1, the DE cohort demonstrated that gradual dose escalation of ozanimod (over several days) rather than starting with a high dose on day 1 appears to mitigate larger reductions in heart rate. Because gradual escalation may represent a safer approach to dosing agents in this class, it has been carried forward into

completed phase 2 and ongoing phase 3 clinical trials of ozanimod.19,20

Ozanimod exhibited linear PK, with dose- proportional increases in exposure and low to moderate intersubject variability. The  desirable  PK  properties of ozanimod include high steady-state volume of distribution, moderate apparent oral clearance,  and  an elimination half-life of approximately 20 hours, supporting the use of once-daily oral therapy.

Ozanimod high steady-state volume of distribution likely reflects extensive distribution of ozanimod into tissues, which is also consistent with high tissue-to- blood ratios in rat (data on file). Once-daily dosing regimens resulted in a steady-state peak-to-trough concentration ratio and a drug accumulation ratio of approximately 2. Renal clearance is not an important excretion pathway for ozanimod.

S1P1R modulators limit lymphocyte egress from peripheral lymphoid organs, resulting in reductions in ALCs.21 Because this effect is likely an important driver

Figure 4. Mean percent change in absolute lymphocyte count ± SEM in subjects receiving fixed doses of ozanimod 0.3, 1, or 1.5 mg/d for 28 days (A) or after dose escalation of ozanimod (0.3 mg/d on days 1–3; 0.6 mg/d on days 4 and 5; 1 mg/d on days 6 and 7; and 3 mg/d on days 8–10) or placebo (B). Baseline for all trough samples is defined as the day 0, -24-hour ALC values. Baseline for all nontrough samples collected after dosing is defined as the sample collected on day 0 at the same time. ALC, absolute lymphocyte count; SEM, standard error of the mean.

of the efficacy observed in clinical trials with other S1P modulators,13 lymphocyte counts were included in this study as a PD marker. Robust dose-dependent reductions in ALC were observed at all ozanimod doses studied, and lymphocyte counts normalized within 3 days after cessation of dosing.

After 28 days of dosing, lymphocyte count reductions were 65% and 68% for the 1- and 1.5-mg doses, respectively, suggesting a plateau effect at 1 mg. When a dose-escalation regimen was used, lymphocyte counts continued to decrease throughout the 10-day dosing  period. 

The  decrease in lymphocyte counts observed with ozanimod was similar to those observed with other S1P receptor agonists; decreases ranged from 34% to 68% in the current study and from 35% to 76% in studies with other drugs.18,22–24 However, recovery of lymphocyte counts to the normal range occurred more rapidly in the present study (within 2–3 days of drug cessation) than in a study of the 0.5-mg dose of fingolimod (6 weeks),25 which is a likely consequence of the shorter t1/2 of ozanimod.

The PD effects of ozanimod showed selectivity for lymphocyte subtypes, with greater effects on CD4+ CCR7+ and CD8+ CCR7+ T cells, and a lesser effect on effector memory cells than central memory cells.

This might indicate that ozanimod can enable maintenance of protective immunity while targeting the T cells believed to be part of the immunopathologic process in RMS and IBD. Lymphocyte subset selectivity also has been reported for other drugs that target S1P receptors,18,22 but further investigation of this apparent selectivity will be required to assess whether differences exist between agents or diseases and whether the differ- ences are of clinical significance.


Source:
RIKEN

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