Ponesimod in the Treatment of Relapsing Forms of Multiple Sclerosis: An Update on the Emerging Clinical Data

Figures & data

Table 1 Location, Function and Cellular Expression of Sphingosine 1-Phosphate Receptor Subtypes

Location	Function	Cellular Expression	Receptors
			S1P1	S1P2	S1P3	S1P4	S1P5
Immune system	Immune cell trafficking (migration, chemokinesis) Lymphoid tissue expression	B cells	X	X	X	X
		T cells	X			X
		Natural killer cells	X				X
		Monocyte/macrophages	X	X	X	X
		Dendritic cells	X		X	X
Endothelium	Permeability Vascular tone regulation	Endothelial cells	X	X	X	X
Conduction system	Heart rate control	Atrial myocytes	X
		Smooth muscle cells	X	X	X
Central nervous system	Neuron migration Oligodendrocyte function	Neurons	X	X	X		X
		Astrocytes	X	X	X		X
		Microglia	X	X	X		X
		Oligodendrocytes	X		X		X

Table 2 Comparison of Sphingosine 1-Phosphate Receptor Modulators Currently Available for Treating Multiple Sclerosis

	Fingolimod	Ozanimod	Siponimod	Ponesimod
Target S1P receptor	S1P1, S1P2, S1P3, S1P5	S1P1, S1P5	S1P1, S1P5	S1P1
Oral dose	0.5 mg	0.92 mg after titration	1 or 2 mg after titration*	20 mg after titration
Pro-drug (require phosphorylation)	Yes	No	No	No
Active Metabolites	Yes	Yes	No	No
T max	12–16 hours	~10 hours	3–5 hours	2–5 hours
Half-life	6–9 days	19–22 hours	~30 hours	22–33 hours
Steady state	8 weeks	7 weeks	6 days	5 days
Relative lymphocyte reduction	–70–80%	–55%	–70–80%	–60–70%
Absolute lymphocyte count nadir	~500/µL	~800/µL	~560/µL	~650/µL
Time to lymphocyte recovery	1–2 months	~1 months	3–4 weeks	~1 weeks
Effect on relapse rate	–48–55% versus placebo –52% versus IFNB	–38–48% versus IFNB-1a	–45% versus placebo**	–30% versus teriflunomide

Notes: *The final dose differs according to the cytochrome CYP2C9 genotype; **Secondary endpoint.

Figure 1 Chemical structure of ponesimod (C23H25ClN2O4S).

Table 3 Main Findings of the Oral Ponesimod versus Teriflunomide in Relapsing Multiple Sclerosis (OPTIMUM)

	Relative Risk* Ponesimod versus Teriflunomide
Primary endpoint
Annualised relapse rate per year	–30%
Secondary endpoints
12-week confirmed disability accumulation	–17%**
Cumulative no. of combined unique active lesions	–55%
Change in FSIQ score	–3.6 point (between-arm difference)
Exploratory endpoints
24-week confirmed disability accumulation	–16%**
Cumulative no. of gadolinium-enhancing lesions	–58%
Change in whole brain volume	0.34% (between-arm difference)
NEDA-3	+70%
NEDA-4	+85%

Notes: *Unless indicated otherwise; **Not statistically significant.

Abbreviations: FSIQ, Fatigue Symptom and Impact Questionnaire; NEDA, no evidence of disease activity.

Table 4 Up-Titration Scheme of Ponesimod to Mitigate the First-Dose Effect on Heart Rate

Day 1 and 2	2 mg
Day 3 and 4	3 mg
Day 5 and 6	4 mg
Day 7	5 mg
Day 8	6 mg
Day 9	7 mg
Day 10	8 mg
Day 11	9 mg
Day 12, 13 and 14	10 mg
From day 15	20 mg

Note: In case of interruption during dose titration or maintenance period resume treatment with either the first missed dose (if less than 4 consecutive doses missed) or with day 1 (2 mg) of the titration (if 4 or more consecutive doses missed).