With the recently approved ozanimod, another potent compound for the treatment of adults with relapsing-remitting multiple sclerosis (RRMS) is entering the Swiss market. The oral sphingosine-1-phosphate (S1P) receptor modulator demonstrated good efficacy and a safety profile comparable to interferon β1a in two randomized multicenter phase 3 trials with a total of over 2600 participants [1,2]. A large follow-up study that included nearly 85% of patients continues to provide consistent results [3].
Like fingolimod, which is already widely used in MS therapy, the new active ingredient ozanimod acts on the sphingosine-1 receptor of lymphocytes and prevents the cells from leaving the lymph nodes. This leads to lower lymphocyte counts in the blood and thus to an attenuation of autoimmunit.t. There are 5 known S1P receptor subtypes, each with characteristic distribution and different physiological effects (Fig. 1). For lymphocyte migration into the blood circulation and thus the primary mechanism of action of S1P receptor modulators, the type 1 receptors are of particular importance. In contrast to previously used S1P receptor modulators, ozanimod binds with high affinity selectively to S1P receptor subtypes 1 and 5. While the role of S1P receptor subtype 1 is well understood, that of subtype 5 is less clear. It is mainly expressed in the brain and may be an important factor for the survival of oligodendrocytes and thus myelin sheath formation in the central nervous system [1].
Two completed Phase III studies
Two parallel controlled-randomized, multicenter studies were conducted to examine the efficacy and safety of ozanimod. W.hile the SUNBEAM study [1] was conducted over at least 12 months at 152 centers in 20 countries and had 1346 participants, 1313 patients participated in the RADIANCE study [2] (Table 1). This took place over 24 months at 147 sites in 21 countries. Patients with relapsing-remitting MS between 18 and 55 years of age were included. Both research groups compared the efficacy of ozanimod at two doses, 1 mg and 0.5 mg t.glich, with that of intramuscular interferon β1a and concluded that patients experienced significantly fewer relapses during therapy with ozanimod (1 mg ozanimod hydrochloride is equivalent to the approved dose of 0.92 mg). The primary endpoint was the frequency of relapses, measured as annualised relapse rate (ARR). However, other variables such as new T2 l.sions or brain volume depletion were also studied, which also showed better outcome with ozanimod treatment. The drug was more effective at the higher dosage in both studies. For the first time in a phase III trial in multiple sclerosis, both research groups independently demonstrated a slowing of brain volume decline with drug therapy [1,2]. This may be due to the ability of ozanimod to significantly affect structural changes caused by multiple sclerosis. These structural changes are closely linked to the progression of the disease and the decline in cognitive abilities. In addition to reducing the frequency of relapses, a positive influence on cognition and thus on the quality of life of patients with RRMS has been shown [3,6]. Regarding adverse effects, the SUNBEAM and RADIANCE studies paint a consistent picture. Ozanimod was well tolerated and, compared with interferon β1a, the incidence of treatment-emergent adverse events (TAEs) leading to treatment discontinuation was lower with the new agent. The most common adverse events were nasopharyngitis, headache, upper respiratory tract infection, elevated ALT, and hypertension. Concerns that the known cardiac effects of S1P receptor modulator therapies might be more pronounced under the new drug were refuted by both research teams [1,2]. Thus, there were no cases of high-grade AV block or clinically relevant bradycardia. Infections were about equally frequent in all patient groups, and no serious opportunistic infections occurred.
Comparison with other S1P receptor modulators.
A direct comparison with alternative drugs of the same drug class is pending, however, Elyse Swallow et al. published an indirect comparison with the S1P receptor modulator fingolimod in the Journal of Comparative Effectiveness Research [4]*. Especially in the area of adverse effects, ozanimod was superior to the other drug of the same substance class.
* No direct comparisons of the active ingredients exist.
The risk of cardiac side effects, as well as other adverse effects such as liver enzyme elevations, appeared to be lower with ozanimod therapy. In terms of relapse frequency, the authors found no difference between the two treatments. A clinical trial to directly compare different S1P receptor modulators remains to be seen. If the beneficial risk profile of the new agent can be demonstrated, this would be a significant step in the care of patients with RRMS.
Music of the future: The future is now
Even after approval, research into the new active ingredient is not the end of the story. To collect long-term data on efficacy and safety, the follow-up study DAYBREAK [3] is currently ongoing (Fig. 2). Of the original more than 2600 participants in the SUNBEAM and RADIANCE studies, 2257 patients were included. Exclusion criteria for the open-label study were specific cardiac problems such as recent myocardial infarction or prolonged QT time, type 1 diabetes, uncontrolled type 2 diabetes, and a resting heart rate below 55/minute. Under therapy with Ozanimod 1 mg daily, information is continuously collected and analyzed. For example, it was shown that relapse frequency decreased significantly after switching from interferon β1a treatment to ozanimod and that clinical success persisted after discontinuation of the initial SUNBEAM and RADIANCE protocols. Nasopharyngitis remained the most common side effect, and there have been no cases of higher-grade AV blocks or clinically relevant bradycardia after initial administration to date. According to the current data, this new compound raises hope for the future of MS therapy. Refining known targets and thus specifying existing treatments could contribute to a better understanding of the pathophysiology of this widespread disease and in particular the role of the S1P receptor.
Literature:
