Erica Slaughter

A recently published study shows that modulation of the integrated stress response (ISR) may be an effective neuroprotective therapy for 

 patients with Sephin1 treatment. Sephin1 was shown to protect oligodendrocytes, axons, and myelin, which is correlated with a prolonged ISR, as well as reduced central nervous system (CNS) inflammation, in MS mouse models with chronic experimental autoimmune encephalomyelitis (EAE).

The pathological hallmarks of MS are the destruction of oligodendrocytes, the myelin-producing cells of the CNS, with resultant demyelination and axonal degeneration. The ISR, a cellular protective response that is activated by a variety of cytotoxic insults, has been shown to be triggered in oligodendrocytes by CNS inflammation.

The findings, from investigators at the University of Chicago, further demonstrate that Sephin1 treatment of chronic EAE mice significantly delays disease onset and reduces the number of inflammatory CD3+ T cells and inflammatory cytokine production within the CNS, without affecting the peripheral immune response. The team hypothesized that Sephin1 could lead to better clinical outcomes in MS patients as a safe, neuroprotective drug.

When used in combination with interferon beta-1a (IFN-b), the decrease in clinical disease development in chronic EAE mice was even more pronounced, and may produce better therapeutic outcomes than with either Sephin1 or IFN-b alone. Investigators found that onset of disease was significantly delayed with combination therapy compared to IFN-b treatment alone, which did not affect the onset of disease.

Combination treatment also seemed to affect disease course, as chronic EAE mice treated with both Sephin1 and IFN-b reached the peak of disease much later than those treated with IFN-b alone. Brian Popko, PhD, Jack Miller Professor of Neurological Disorders, and Director, The University of Chicago Center for Peripheral Neuropathy, speculated to 

that Sephin1’s benefits would be complementary to current immunomodulatory therapies, as it acts on the distinct ISR pathway, and with oligodendrocyte protection.

“This is supported by the studies presented in our manuscript that showed that Sephin1 and interferon beta provided additive therapeutic benefit to a mouse model inflammatory demyelination,” Popko explained.

Similar in mechanism of action to Sephin1, Guanabenz was investigated in a clinical trial for its safety and tolerability in patients with MS (NCT02423083). The trial has since been terminated due to side effects. The anti-hypertensive drug had previously been shown to successfully delay disease onset and attenuate clinical symptoms in chronic EAE mice. Guanabenz, an alpha-2 adrenergic receptor agonist, is characterized by its lowering of blood pressure, Popko said, as well as its propensity to create drowsiness, lethargy, and additional adverse effects in patients.

“Sephin1 does not display these adrenergic effects, such that it should be much more tolerable,” he said. “Nevertheless, it will, of course, need to go through safety testing before being introduced to MS patients.”

Popko and colleagues are presently investigating the potential of Sephin1 to provide protection to remyelinating oligodendrocytes against inflammation in EAE mice.

“We are hopeful that Sephin1, which prolongs the integrated stress response, will provide protection to remyelinating oligodendrocytes in the presence of an inflammatory environment,” Popko said. “We are testing this in mouse models of demyelination that display an inflammatory environment during CNS remyelination.”

Such results should be available to the team by this summer.

Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis

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Articles

Sephin1 found to protect oligodendrocytes, axons, and myelin, as well as reduce central nervous system inflammation in multiple sclerosis.

Sephin1 Therapy Could Be Effective Therapy for Multiple Sclerosis

A phase 3 multi-center, randomized, double-blind, parallel group, active-controlled superiority study assessing oral ponesimod versus teriflunomide (Aubagio) in relapsing 

 (OPTIMUM) is nearing its estimated primary completion date of April 17, 2019.

The 1100-patient study, which kicked off in June 2015, is a comparison of the efficacy and safety of once-daily 20 mg ponesimod and 14 mg teriflunomide. The primary outcome measure is annualized relapse rate (ARR) with secondary outcome measures of time to 12-week confirmed disability accumulation (CDA), percent change in brain volume (PCBV), time to first confirmed relapse, cumulative number of combined unique active lesions (CUAL), and change from baseline to week 108 in fatigue-related symptoms.

Ponesimod is an orally active, selective sphingosine-1-phosphate receptor 1 (S1P

) immunomodulator which prevents lymphocytes from leaving lymph nodes, thus rapidly reducing circulating blood lymphocyte counts and preventing infiltration of lymphocytes into target tissues. 

In a double-blind, placebo-controlled, dose-finding phase 2b study evaluating ponesimod

, study author Tomas Olsson, MD, PhD, and colleagues found that ponesimod 10, 20, or 40 mg was well-tolerated and significantly reduced the number of new T1 Gd+ lesions at weeks 12-24 of the 24-week trial.

 revealed that ponesimod has a favorable safety profile that allows for maximizing its ability to inhibit circulating lymphocytes in a given dosing regimen. It can be sustained with continued dosing, and with its short half-life, is rapidly eliminated upon discontinuation.

"Our clinical development program for ponesimod in multiple sclerosis was already innovative when we decided to move into phase 3,” Guy Braunstein, MD and Head of Global Clinical Development at Actelion Ltd, said in a statement. “OPTIMUM is the first study in MS to target superiority over a commercialized oral therapy. It also includes a number of patient-oriented outcome assessments."

Actelion is also sponsoring a second phase 3 trial with ponesimod, the multicenter, randomized, double-blind, parallel-group, add-on, superiority study (POINT). An ongoing trial with an estimated completion date of March 2020, POINT compares the efficacy, safety, and tolerability of therapy with 20 mg ponesimod vs placebo, in an estimated enrollment of 600 subjects with active RMS who are treated with twice-daily dimethyl fumarate (Tecfidera).

"I have always believed that combination therapy is the future for the treatment of relapsing multiple sclerosis,” Jean-Paul Clozel, MD and Chief Executive Officer of Actelion, said in a statement. “The properties of ponesimod, supported by our preclinical knowledge and clinical results, all point towards ponesimod being ideally suited for use in combination.”

The primary outcome measure of POINT is the confirmed relapses per subject-year as compared to placebo. Secondary outcome measures include CDA, time to first confirmed relapse, CUALs per post-baseline scan, longitudinal change over time in fatigue-related symptoms as measured by the symptoms domain of the FSIQ-RMS, and longitudinal percent change from baseline over time in brain volume. Treatment adverse events (AE) and serious AEs will also be recorded.

“With POINT, the first trial in active RMS adding one oral drug to another, we will assess the clinical utility of combination therapy with ponesimod, to offer patients better control of their disease,” said Braunstein.

Details and updates to the trial, “Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM),” can be found 

Trial comparing oral ponesimod versus teriflunomide (Aubagio) in relapsing multiple sclerosis will evaluate annualized relapse rate as well as other disease activity measures.