Zeposia (ozanimod) is a new drug indicated for the treatment of adult patients with relapsing forms of multiple sclerosis, including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) in its active form.
Approval by the U.S. Food and Drug Administration (FDA) is granted to Bristol-Myers Squibb in March 2020.
The European Medicines Agency (EMA) has approved Zeposia in May 2020 for the treatment of adult patients with relapsing-remitting multiple sclerosis in the active form confirmed by clinical manifestations (relapses) or on MRI images of the brain (areas of active inflammation).
Zeposia is in the same class of oral disease-modifying therapy (DMT) of multiple sclerosis as Gilenya (fingolimod) and Mayzent (siponimod) by Novartis. Ozanimod and siponimod are appropriately positioned as improved versions of fingolimod in terms of safety profile with fewer adverse reactions. If we compare the efficacy of multiple sclerosis treatment, the results given by Gilenya, Mayzent, and Zeposia are generally identical.
Prescribing Zeposia does not require, as with Mayzent, mandatory pre-testing for cytochrome P450 2C9 (CYP2C9) genotype, whose gene, being extremely polymorphic, can lead to serious changes in this enzyme activity which is reflected by a restriction of any drug or adjustment of its dose.
Zeposia: Mechanism of Action of Ozanimod
One approach to therapy of relapsing forms of multiple sclerosis relies on targeting the ligand-receptor system of sphingosine-1-phosphate (S1P) to modulate autoimmune responses.
Sphingosine-1-phosphate is a lipid-signaling molecule that regulates a number of biological processes through its interaction with the G protein-coupled receptor (GPCR) family. Sphingosine-1-phosphate binds to five of them (S1PR1–5), each characterized, first, by a different expression in tissues and, second, by different physiological effects triggered when activated by the S1P ligand.
- Sphingosine-1-phosphate receptor 1 (S1PR1) is expressed on T and B cells, astrocytes and neurons, vascular endothelial cells, and cardiomyocytes. Sphingosine-1-phosphate receptor 5 (S1PR5) is expressed on natural killer (NK) cells, oligodendrocytes, and vascular endothelial cells.
Sphingosine-1-phosphate is responsible for the important signaling required for lymphocyte release from lymphoid organs into the systemic circulation. If appropriate modulation of the S1P signaling pathway is carried out, lymphocyte retention in lymph nodes can be achieved with the resultant attenuation of inflammatory processes.
The blood-brain barrier (BBB) prevents peripheral immune cells from entering the central nervous system (CNS). However, in multiple sclerosis (as well as many other neurodegenerative diseases), the integrity of the barrier is compromised. Therefore, these cells freely infiltrate the CNS; autoreactive CD8+ T cells infiltrate it and release pro-inflammatory cytokines and promote recruitment and activation of other immunocytes, including B cells, macrophages, microglia, astrocytes, and plasma cells. The increasing process of chronic CNS inflammation is mirrored by demyelination, axonal death, and neurodegeneration.
Since increased levels of sphingosine-1-phosphate are associated with inflammation, it makes sense to target its signaling pathway to block gradient-dependent (from low-gradient areas to high-gradient areas) chemotactic migration of lymphocytes in the CNS.
Ozanimod (RPC1063) is an oral low-molecular-weight selective agonist of sphingosine-1-phosphate receptors 1 and 5 (S1PR1 and S1PR5). The immunomodulatory mechanism of action of ozanimod is due to internalization of S1P receptors with their subsequent degradation (functional antagonism) in the ubiquitin-proteasome pathway. This leads to inhibition of migration of a certain subtype of activated lymphocytes (T helpers CD4+ CCR7+ and T killers CD8+ CCR7+) from the lymphoid tissue to the sites of inflammation. The integrity of the immunological surveillance of infections and tumors is preserved because S1P signaling does not affect a subset of lymphocytes that do not migrate through the lymphoid tissue.
Simply put, ozanimod sequesters (directs) lymphocytes to peripheral lymphoid organs eliminating them from the circulatory system and areas of chronic inflammation.
The therapeutic justification for the use of ozanimod in multiple sclerosis is due to the following. First, it binds to S1PR1 on lymphocytes and prevents their migration to the central nervous system, providing an anti-inflammatory effect. Second, ozanimod binds to S1PR1 and S1PR5 on astrocytes and oligodendrocytes, respectively; functional antagonism of astrocytic S1PR1 restrains astrogliosis and agonism of oligodendrocytic S1PR5 promotes cell survival and myelination. In other words, ozanimod modulates the destructive cellular activity and inhibits the deterioration of neurological functions associated with multiple sclerosis; by suppressing inflammatory cytokines and demyelination and axonal loss processes and by preserving GABAergic transmission.
Ozanimod has 27-fold selectivity for S1PR1 versus S1PR5 and more than 10,000-fold for S1PR2–4, which minimizes the risks of unsafe S1P3 activation on cardiomyocytes.
Zeposia: Efficacy and Safety of Multiple Sclerosis Treatment With Ozanimod
The regulatory decision regarding Zeposia was based on the results of SUNBEAM (NCT02294058) and RADIANCE (NCT02047734), two phase 3 clinical trials (randomized, double-blind, active comparison group, multicenter, international), that evaluated the safety and effectiveness of ozanimod. The comparison has been made with Avonex (interferon beta-1a) by Biogen.
Clinical trials lasting 1 and 2 years, respectively, included patients (n=895 and n=874) who had experienced at least one relapse of multiple sclerosis that had occurred before randomization either in the preceding year or in the past two years if there was confirmation of brain lesion on gadolinium-enhanced T1-weighted MRI images. The baseline Expanded Disability Status Scale (EDSS) score of the participants was 0.0–5.0. Patients with progressive forms of multiple sclerosis were excluded.
Subjects received daily oral ozanimod or weekly intramuscular interferon beta-1a. The primary end point was determined by a change in the annualized relapse rate (ARR) of multiple sclerosis. Relapse was defined as the occurrence of new or worsening multiple sclerosis-related symptoms that persisted for at least 24 hours and preceded a relatively stable or improved neurological condition of at least 30 days.
Administration of Zeposia resulted in a 48% and 38% (p<0.0001) reduction in ARR relative to the group treated with Avonex, in SUNBEAM and RADIANCE, respectively. At the same time, 78% and 76% of the subjects remained relapse-free for 1 and 2 years — versus 66% and 64%.
The number of new or increasing brain lesion areas on T2-weighted MRI images was 1.47 and 1.84 — vs. 2.84 and 3.18; the relative reduction in the number of lesions in the ozanimod group was 48% and 42% (p<0.0001).
The number of lesions on gadolinium-enhanced T1-weighted MRI images was 0.16 and 0.18 — vs. 0.43 and 0.37; the relative reduction in the ozanimod group was 63% (p<0.0001) and 53% (p=0.0006).
Zeposia was unable to delay the confirmed disability progression(CDP), stated by an EDSS gain of at least 1 point which persisted at 3 and 6 months. Thus, cumulatively in the ozanimod groups multiple sclerosis status worsened in 7.6% and 5.8% of patients — versus 7.8% and 4.0% in the Avonex groups.
Administration of ozanimod contributed to a more pronounced inhibition of processes leading to a decrease of brain, cortical gray matter, and thalamic volumes (p≤0.0133).
Among the most common adverse events to the administration of ozanimod: upper respiratory infections (in 26% of patients — versus 23% in the interferon beta-1a group), elevation of liver transaminases (10% vs. 5%), orthostatic hypotension (4% vs. 3%), urinary tract infections (4% vs. 3%), low back pain (4% vs. 3%), hypertension (4% vs. 2%), abdominal pain upper (2% vs. 1%).
In all cases, the administration of Zeposia should be done with a gradual increase in the daily dose (in the first week of treatment), monitoring the decrease in heart rate and the slowing of atrioventricular conduction. This is necessary to avoid adverse cardiac chronotropic effects.
Zeposia: Ozanimod and Market Competitors
Bristol-Myers Squibb took over Celgene’s entire drug portfolio, including ozanimod, after its $74 billion acquisition in November 2019.
Celgene had expected ozanimod, positioned as a safer alternative to Gilenya (fingolimod) by Novartis, to hit the market in late 2018, but was inexcusably negligent and careless in sending an incomplete New Drug Application (NDA) to the regulator. And so additional work had to be done to prepare an updated NDA, which was not sent to regulators until late March 2019.
- The regrettable misstep was that the NDA did not include all the data concerning CC112273, which is the major metabolite for ozanimod and which is responsible for approximately 90% of the beneficial mechanism of action of ozanimod in multiple sclerosis.
As a result, the competitive advantage was ruinously lost. Novartis was the first to offer Mayzent (siponimod) as a replacement for fingolimod and with a similar mechanism of action and spectrum of therapeutic indications.
Siponimod released by Novartis is an improved version of Gilenya.
The market picture is as follows. Firstly, in view of the imminent loss of patent protection for Gilenya in the United States, Novartis is pushing Mayzent with all its might and pedaling its identical therapeutic efficacy while eliminating key safety concerns.
Secondly, Zeposia will obviously have to play with the price in order to gain the favor of insurance providers, doctors, and patients.
- In fact, Bristol-Myers Squibb has not implemented any special price discounts. As a rough guide, if a one-month course of Gilenya and Mayzent in the United States is billed at $9,100 and $8,000, then treating multiple sclerosis with Zeposia for 30 days would cost $7,400.
Thirdly, all of these oral DMTs aren’t doing well in the face of the strength of Ocrevus (ocrelizumab), which is positioned as one of the most effective drugs and which earned $2.40 billion, $3.75 billion, and $4.60 billion for Roche in 2018, 2019, and 2020.
Meanwhile, the multi-year DAYBREAK (NCT02576717) and ENLIGHTEN (NCT04140305) phase 3 clinical trials continue. The first clarifies the safety profile of ozanimod, the second finds out how cognitive processing speed changes in patients, according to the Symbol Digit Modalities Test (SDMT).
Bristol-Myers Squibb understands that ozanimod’s entry into the heavily saturated DMTs market is unlikely to translate into adequate revenues. Therefore, ozanimod is being clinically tested in the treatment of other autoimmune diseases such as ulcerative colitis (UC) and Crohn’s disease. And it seems to be more than successful. No matter what, the FDA has already begun reviewing the ozanimod’s NDA against UC; a decision will be made by the end of May 2021.
Going into detail, Zeposia has not brought anything new to the multiple sclerosis treatment paradigm. Patients who are already on fingolimod or siponimod therapy have no good reason to switch to ozanimod. Zeposia may be to the liking of those who are moving away from injectable platform drugs intending to be treated with oral DMTs. But that was true until the coming of Ocrevus which has captured a leadership position on the efficacy of therapy for relapsing forms of multiple sclerosis.
To be fair, it should be clarified that S1P modulators are probably the most effective among oral DMTs. Although, however, they are only slightly ahead of Tecfidera (dimethyl fumarate) promoted by Biogen, which, by the way, has been reborn as Vumerity (diroximel fumarate) with improved gastrointestinal tolerance. Again, all S1P modulators come with a certain risk of progressive multifocal leukoencephalopathy (PML), infections, and macular edema. There is also a problem associated with not treating with S1P modulators when discontinuing therapy can lead to a dramatic deterioration of the course of multiple sclerosis, in some cases to an irreversible grade accompanied by permanent disability.
Gilenya (fingolimod), which debuted in September 2010, was the first to provide therapy for relapsing forms of multiple sclerosis by modulating the sphingosine-1-phosphate signaling pathway. In March 2018, Gilenya expanded the eligible patient population by becoming the first DMT approved for multiple sclerosis therapy in children and adolescents.
Fingolimod (FTY720) is a nonspecific modulator of sphingosine-1-phosphate because it binds with high affinity to its receptors 1, 3, 4, and 5 (S1PR1, S1PR3, S1PR4, and S1PR5). This lack of selectivity leads to side effects; there are risks of bradycardia and atrioventricular block.
In late 2019, the FDA approved three generic copies of Gilenya by China’s HEC Pharm and India’s Biocon and Sun Pharmaceutical Industries. In June of that year, however, a court ruled that no generics of fingolimod should be released on the U.S. market until all patent disputes, which Novartis is pursuing in an effort to delay the appearance of copies of its best-selling product (two dozen generics are scheduled), have been resolved. Moreover, in August 2020, Novartis defended its patent on the dosing scheme for fingolimod. Thus, Gilenya will continue to bring the Swiss pharma giant a lot of money for years to come.
In 2018 and 2019 Gilenya earned $3.34 billion and $3.22 billion for Novartis; the drug generated $3.00 billion in 2020.
In late March 2019, Novartis released Mayzent (siponimod), an oral DMT focused on relapsing-remitting forms of multiple sclerosis. For U.S. patients, the drug was the first to be officially approved against secondary progressive multiple sclerosis in its active form.
Siponimod (BAF312), being a modulator of sphingosine-1-phosphate, is much more selective than fingolimod because it targets S1PR1 and S1PR5. In contrast to ozanimod, siponimod, firstly, is characterized by the same affinity for S1PR1 and S1PR5 and, secondly, exhibits significantly greater affinity for S1PR4.
Siponimod’s selectivity endowed Mayzent with the status of a safer variant of fingolimod.
Novartis has also proven that Mayzent has the potential to delay by more than four years the time to the need for wheelchair use in patients with active secondary progressive multiple sclerosis. In other words, the siponimod will preserve independent mobility.
In March 2021, Janssen, part of Johnson & Johnson, received FDA approval for Ponvory (ponesimod) indicated to treat adult patients with relapsing-remitting forms of multiple sclerosis including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
Ponesimod is a new drug that changes the course of multiple sclerosis and is a direct competitor to Gilenya (fingolidoma), Mayzent (siponimod), and Zeposia (ozanimod).
Ponesimod (ACT-128800), which modulates sphingosine-1-phosphate, differs from fingolimod, siponimod, and ozanimod in its high selectivity to S1PR1.
Johnson & Johnson obtained ponesimod through its $30 billion purchase of Switzerland’s Actelion Pharmaceuticals.
Zeposia vs. Gilenya: Ozanimod or Fingolimod — Which Is Better
Since no clinical trials directly comparing ozanimod and fingolimod have been conducted, we can only draw lines of difference between the two, that is, with a certain bias.
Adjusted analysis of clinical outcomes after 1 and 2 years found no statistically significant differences between ozanimod and fingolimod on measures such as annualized relapse rate (ARR ratio 1.08 and 1.06; p=0.80 and p=0.78) and the proportion of patients who did not experience confirmed disability progression at 3 months (difference in proportions 1.1% and 5.2%; p=0.72 and p=0.12).
Ozanimod was indeed safer than fingolimod. Thus, according to cardiac monitoring after the first dose of drugs, the adjusted risk difference (RD) was −3.5% for conduction abnormalities, −3.0% for first-degree atrioventricular block, −8.3% for monitoring to be performed for more than 6 hours, −2.6% for monitoring on day 2 (all p=0.001).
Ozanimod resulted in a less pronounced drop in systolic blood pressure (2.2 mm Hg difference between averages) and diastolic blood pressure (5.0 mm Hg), compared with fingolimod after the first dose (p<0.001).
In year 1 of multiple sclerosis treatment with ozanimod, statistically significant differences were demonstrated compared with fingolimod therapy with respect to the risk of developing any side effect (RD −9.9%; p<0.05), a decrease in absolute lymphocyte count (difference between averages was 0.4×109/l; p<0.001), and the risk of ALT increases 3 or more times above the upper limit of normal (difference between patient proportions was −6.8%; p<0.001).
In year 2 of treatment of multiple sclerosis with ozanimod, statistically significant differences were demonstrated in comparison with fingolimod therapy with respect to the risk of developing any side effect (RD −22.7%; p<0.001), herpetic infection (RD −4.9%; p<0.05), basal cell carcinoma (RD −1.8%; p<0.001), bradycardia (RD −0.5%; p<0.05), ALT rise (−3.0%; p<0.05).
In January 2021, the U.K. National Institute for Health and Care Excellence (NICE) opposed approval of Zeposia for therapy of relapsing-remitting multiple sclerosis in the active stage as confirmed by clinical signs or on MRI images.
Yes, ozanimod undoubtedly helps to reduce relapse rates but it is still unclear whether it can limit the progression of disability at a level comparable to other already approved DMTs because no direct comparisons with those have been made. Therefore, the cost-effectiveness of introducing Zeposia into clinical practice cannot be properly assessed.
The decision to approve Zeposia, however, rests with the regulator.
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