Ponvory: Another Drug for Multiple Sclerosis

Highlights

Ponvory (ponesimod) 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 the active form (that is still relapsing).

Ponvory was approved by the U.S. Food and Drug Administration (FDA) in March 2021. Authorization is granted by Janssen of Johnson & Johnson (Johnson & Johnson).

Ponvory is in the same class of disease-modifying therapy (DMT) for multiple sclerosis as Gilenya (fingolimod) and Mayzent/Kiendra (siponimod) by Novartis and Zeposia (ozanimod) by Bristol-Myers Squibb.

 

Ponvory: Ponesimod’s Efficacy in Multiple Sclerosis

The OPTIMUM (NCT02425644) phase 3 clinical trial (randomized, double-blind, with comparison drug group, multicenter, international) enrolled adult (18–55 years) patients (n=1133) with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis with superimposed relapses.

Among the main inclusion criteria for the trial:

• or at least one relapse between 1–12 months prior randomization, or at least two relapses between 1–24 months prior randomization, or at least one brain lesion on gadolinium-enhanced T1-weighted MRI images within 6 months prior randomization
• a baseline score of 0.0–5.5 on the Expanded Disability Status Scale (EDSS)
• participants may not have previously been treated for multiple sclerosis or may already be on DMT.

For 108 weeks, subjects received daily oral ponesimod or Aubagio (teriflunomide) which is marketed by Sanofi.

The ponesimod group statistically significantly outperformed the teriflunomide group in the task of reaching the primary endpoint, stated annualized relapse rate (ARR) of multiple sclerosis: 0.202 versus 0.290. Ponvory reduced the risk of relapse by a relative 30.5% (p=0.0003).

Over the entire follow-up period, 70.7% of patients treated with ponosimod and 60.6% with teriflunomide remained relapse-free.

Ponvory did not succeed in delaying confirmed disability progression (CDP) claimed by an EDSS gain of at least 1 point which persisted for 3 months. Thus, 10.8% of participants in the ponesimod group experienced CDP — vs. 13.2% of subjects in the teriflunomide group (p=0.29).

Treatment of multiple sclerosis with Ponvory benefited other secondary points:

• a relative 55.7% reduction in the new or increasing number of brain lesions on T2-weighted MRI images (these are indicative of demyelination) was recorded: an average of 1.40 per year — versus 3.16 (p<0.0001)

• demonstrated relative 58.5% elimination of brain lesions on gadolinium-enhanced T1-weighted MRI images (they reflect the presence of an active inflammatory process): an average number of 0.18 — vs. 0.43 (p<0.0001).

Ponesimod continues to be tested in the OPTIMUM-LT (NCT03232073) phase 3 clinical trial which evaluates its safety and efficacy with long-term use (up to 7 years).

Ponesimod was in the POINT (NCT02907177) phase 3 clinical trial which examined its use over Biogen’s Tecfidera (dimethyl fumarate) in active relapsing-remitting multiple sclerosis. The study was discontinued in December 2019 due to insufficient enrollment.

 

Ponvory: Mechanism of Action of Ponesimod for Multiple Sclerosis

Ponesimod (ACT-128800, R-3477, RG 3477), a class of drugs that change the course of multiple sclerosis, works by modulating the sphingosine-1-phosphate (S1P) signaling pathway which is responsible for the process of lymphocytes leaving lymphoid organs and entering the systemic stream. Simply put, ponesimod sequesters (directs) lymphocytes to the lymph nodes: the number of freely circulating lymphocytes decreased and this reduces the pool of T-cells that can enter the central nervous system where they aggravate inflammatory processes with damage to myelin sheaths.

Ponesimod is an oral low-molecular-weight selective agonist of the sphingosine-1-phosphate receptor subtype 1 (S1PR₁). The immunomodulatory mechanism of action of ponesimod is due to internalization of S1P-receptors with their subsequent degradation (functional antagonism) in the ubiquitin-proteasome metabolic 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 immunological surveillance of infections and tumors is preserved since S1P signaling does not affect a subset of lymphocytes that do not migrate through the lymphoid tissue.

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BioPharma Media talked in depth about the mechanism of action of S1P modulator DMTs in Zeposia: New Drug to Treat Relapsing Multiple Sclerosis.

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Johnson & Johnson got ponesimod as a result of its $30 billion acquisition of Actelion Pharmaceuticals (Switzerland) in 2018. Under the terms of the deal, 8% of the drug sales will go to Idorsia Pharmaceuticals organized by the former owners of Actelion.

 

Multiple Sclerosis Treatment: Fingolimod, Siponimod, Ozanimod, and Ponesimod — What’s the Difference

Ponesimod is not the first representative of sphingosine-1-phosphate modulators aimed at treating multiple sclerosis.

It started with the drug Gilenya (fingolimod) which, when it appeared in September 2010, became an instant blockbuster and has already earned Novartis a whopping $27 billion. By the way, in May 2018, Gilenia became the first DMT to be prescribed to children and adolescents.

In March 2019, Novartis released Mayzent/Kiendra (siponimod) as a replacement for fingolimod which has been declining in revenue due to the advent of less expensive generic copies.

In March 2020, Zeposia (ozanimod) promoted by Bristol-Myers Squibb, which took it over after taking over Celgene, saw the light of day.

The key difference between all four of these DMTs lies in their selectivity for the sphingosine-1-phosphate receptor subtypes; this is reflected by the specific spectrum of adverse events and the resulting route of administration.

Thus, fingolimod, being a non-specific S1P modulator of the first generation, binds to its receptors of subtypes 1, 3, 4, and 5 (S1PR₁, S1PR₃, S1PR₄, and S1PR₅). Such non-selectivity is associated with a risk of bradyarrhythmia and atrioventricular block, and therefore initiation of therapy with fingolimod requires careful monitoring of heart rate decrease and atrioventricular conduction delays — in the first day. Within a month of continuous treatment with fingolimod, the heart rate returns to normal.

Siponimod and ozanimod, which exhibit specificity to sphingosine-1-phosphate receptor subtypes 1 and 5, are similarly characterized by risks of bradyarrhythmia and atrioventricular block and are therefore prescribed with a gradual increase in the daily dose. Siponimod requires a 5-day preparatory period for its chronic use; ozanimod requires a 7-day preparatory period.

In addition, therapy of multiple sclerosis with siponimod is preceded by mandatory testing to identify the cytochrome P450 2C9 (CYP2C9) genotype whose gene, being extremely polymorphic, may lead to serious changes in the activity of this enzyme which is reflected by a ban on the use of any drug or adjustment of its dose. In the case of the *1/*3 or *2/*3 genotype, siponimod is used in a halved dose.

Ozanimod is not recommended when consuming food high in tyramine (more than 150 mg) because the drug interacts with it, preventing it from breaking down. Tyramine, being an exogenous amine, can cause severe hypertension (including hypertensive crisis) by releasing norepinephrine. Aged, fermented, dried, smoked, and pickled foods (e.g., aged cheese, soy sauce, salami, pickled herring, unpasteurized beer) come with high levels of tyramine.

Ponesimod, acting for the most part as a selective S1PR₁ modulator, addresses a much longer period of increasing the daily dose which would have to be followed for 2 weeks at a time.

When it comes to the frequency of bradycardia in the first day after administration of fingolimod, siponimod, ozanimod, or ponesimod, based on data collected in clinical trials, 6%, 4.4%, 0.6%, and 5.8% of patients experienced bradycardia, respectively. Grade 1 atrioventricular block was reported in 4.7%, 5.1%, 0.0%, and 3.4% of subjects; more severe block was reported in 4.0%, 1.7%, 0.0%, and 0.0%.

Currently, scientific and clinical data support the view that S1P₁/S1P₅ modulation has predominantly beneficial effects and that S1P₃/S1P₄ modulation carries negative effects. Thus, S1P₁ agonism may be more associated with the effect of inducing acute bradycardia at the initial point of treatment when compared with the chronotropic and dromotropic effects mediated by S1P₃ agonism in their chronic application to cardiac rhythm and conduction. In other words, the selectivity of S1P modulators and the slow build-up of the therapeutic dose are decisive in terms of cardiac adverse reactions.

When it comes to the efficacy of treating relapsing forms of multiple sclerosis, fingolimod, siponimod, ozanimod, and posenimod provide reductions in recurrence rates per year of 0.18; 0.07; 0.17–0.18, and 0.20, respectively. In other words, the therapeutic efficacy of S1P modulators is generally the same.

According to a network meta-analysis, carried out in the absence of direct clinical comparisons of S1P modulators, the maximum effectiveness of multiple sclerosis therapy should be expected from the still experimental amiselimod (MT-1303) [in a dose of 0.4 mg], behind the development of which is Mitsubishi Tanabe Pharma (Japan). Next up (in descending order of efficacy) are:

• ponesimod (40 mg)
• fingolimod (1.25 mg)
• fingolimod (0.5 mg — recommended maintenance dose [RMD])
• ozanimod (1.0 mg — RMD)
• ponesimod (10 mg)
• ozanimod (0.5 mg)
• ponesimod (20 mg — RMD)
• siponimod (2 mg — RMD)
• amiselimod (0.2 mg)
• laquinimod (0.6 mg — RMD): Teva Pharmaceutical Industries has stopped sales of Nerventra (laquinimod) due to lack of efficacy and safety concerns
• amiselimod (0.1 mg).

In terms of safety profile, represented by patients’ withdrawal from treatment due to severe adverse events, the ranking of S1P modulators is as follows (in order of deterioration):

• ozanimod (1.0 mg — RMD)
• ozanimod (0.5 mg)
• amiselimod (0.2 mg)
• laquinimod (0.6 mg — RMD)
• amiselimod (0.1 mg)
• fingolimod (0.5 mg — RMD)
• amiselimod (0.4 mg)
• siponimod (2 mg — RMD)
• fingolimod (1.25 mg)
• ponesimod (20 mg — RMD)
• ponesimod (10 mg)
• ponesimod (40 mg).

As for the issue of forced discontinuation of therapy with S1P-modulators — for example, when there is a need to vaccinate or cure an infection — it is appropriate to outline the period of time that it will take to fully restore the lymphocyte pool after stopping these DMTs. So, in the case of fingolimod it will take 30–60 days, siponimod 1–5 days, ozanimod 2–3 days, and ponesimod 7 days.

It is important to note that discontinuing treatment of multiple sclerosis with S1P modulators, namely fingolimod, can dramatically worsen the course of the disease, and to an irreversible level which, as a result, will probably lead to permanent severe disability. For instance, some patients who were able to walk independently before the withdrawal of Gilenya have progressed to the point where they require a wheelchair or are completely confined to bed.

 

Extras

Ponvory (ponesimod). Prescribing information. U.S. [PDF]

Ponvory (ponesimod). FDA CDER. Clinical review. [PDF]

Efficacy and acceptability of the S1P receptor in the treatment of multiple sclerosis: a meta-analysis. Neurol Sci. 2021 Feb 1. [source]

Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: differential downstream receptor signalling and clinical profile effects. Drugs. 2021 Feb;81(2):207-231. [source]

Ponesimod for the treatment of relapsing multiple sclerosis. Expert Opin Pharmacother. 2020 Nov;21(16):1955-1964. [source]

Sphingosine-1-phosphate: its pharmacological regulation and the treatment of multiple sclerosis: a review article. Biomedicines. 2020 Jul 18;8(7):227. [source]