Multiple Sclerosis (MS)

Ponvory

Ponvory™ (ponesimod) is an oral immunomodulatory drug approved for use in adults with relapsing forms of multiple sclerosis (MS), including relapsing-remitting multiple sclerosis (RRMS), active secondary-progressive multiple sclerosis (SPMS), and clinically isolated syndrome (CIS).1

Ponvory was approved by the US Food and Drug Administration in March 20212 to be taken as a 20-mg, once-daily, oral tablet (after an initial 15-day dose titration regiment).1 The European Medicines Agency Committee for Medicinal Products for Human Use  recommended granting approval of Ponvory for adults with relapsing forms of MS in March 2021, with marketing authorization being granted in May 2021.3

Development of Ponvory was initially undertaken by Actelion Pharmaceuticals, Ltd. before being acquired by Janssen Pharmaceuticals, Inc., a subsidiary of Johnson & Johnson Pharmaceutical Research & Development, LLC.

Ponesimod, experimental anti-inflammatory drug molecule.

Ponvory’s Mechanism of Action

Multiple sclerosis is caused by the progressive demyelination of nerve cells because of autoimmune attacks. Central nervous system (CNS) infiltration of T-cells and B-cell autoantibodies lead to neural inflammation, demyelination, and ultimately neurodegeneration4. 

The exact mechanism of action for Ponvory is not fully known. Ponvory is a sphingosine-1-phosphate receptor 1 (S1P1R) modulator similar to several other MS therapies, including Gilenya® (fingolimod), Mayzent® (siponimod), and Zeposia® (ozanimod). The S1P1R is critical to the process of lymphocyte egress from the thymus and lymphoid organs.5 Ponvory and the other listed medications bind to the S1P1R with high affinity, causing the receptor to internalize and making the cell desensitized to the S1P ligand. Cell desensitization results in the lymphocytes’ inability to exit secondary lymphoid organs, leading to a reduction in peripheral blood levels of lymphocytes.1 With limited levels of lymphocytes circulating in the blood, fewer are available to infiltrate and cause inflammation in the CNS.

Get detailed prescribing information on the Ponvory monograph page on MPR.

Ponvory is selective for S1P1Rs, and research indicates that its activity can be rapidly reversed in patients if needed.4

Warnings, Precautions, and Adverse Reactions

Patients with existing heart conditions, including sinus bradycardia, first- or second-degree atrioventricular block, or a history of myocardial infarction or heart failure, should receive 4-hour monitoring after their first dose, as Ponvoy can lead to bradycardia.6

Before treatment initiation, all patients should receive additional screening, such as complete blood count, including lymphocyte levels; an electrocardiogram to detect conduction problems; liver function tests for transaminase and bilirubin levels; ophthalmic evaluation of the fundus; a review of medications being taken with immunomodulatory effects; and tests for antibodies to varicella-zoster virus.6

As Ponvory has immunosuppressive effects, it can increase patients’ risk of developing infections, including herpes virus and cryptococcal meningitis. Treatment with Ponvory may also lead to reduced respiratory function, liver injury, hypertension, macular edema, skin malignancies, and posterior reversible encephalopathy syndrome.6 Results in animal studies also indicate Ponvory may lead to fetal harm, and women of childbearing age should use contraception while being treated and for at least 1 week afterward.

The most common adverse effects of Ponvory, occurring in at least 10% of patients in clinical trials, were upper respiratory tract infection, elevation of hepatic transaminase levels, and hypertension.6

Efficacy in Trials and Trial Results

Ponesimod was studied in several clinical trials leading up to its approval. An initial double-blind, placebo-controlled phase 2b study (NCT01006265) recruited 464 patients with RRMS between the ages of 18 and 55 years. Patients were randomly assigned to receive 10-, 20-, or 40-mg doses of Ponvory or a placebo once daily for 24 weeks.7 The results showed a significant and dose-dependent reduction in gadolinium-enhancing lesions detected on T1-weighted magnetic resonance imaging scans between weeks 12 and 24 compared with placebo.7 The study also showed reductions in annualized relapse rate (ARR) of 37%, 21%, and 52% for the 10-, 20-, and 40-mg doses, respectively, when compared with the placebo group. The study size was only large enough to reach statistical significance in the 40-mg dose level, however.

Patients from the phase 2b trial could continue in an extension study (NCT01093326). The 40-mg dose was discontinued during the first trial period of the extension study, and the 10-mg dose was discontinued after the second trial period.8 This resulted in all patients receiving either the 10- or 20-mg doses in trial period 2 and only the 20-mg dose in trial period 3. Results reported as of March 2019 showed a total of 214 patients were still receiving Ponvory, and the 20-mg dose group had a median exposure of 8.02 years. This group had an ARR of 0.154 (95% CI, 0.111-0.214) with 64.1% of patients free of confirmed relapses.8

A pivotal phase 3 trial, called OPTIMUM (NCT02425644), recruited 1133 adult patients with RRMS or active SPMS. Patients were randomly assigned 1:1 to receive either 20 mg of Ponvory or 14 mg of Aubagio® (teriflunomide) for 108 weeks. Results showed a significant 30.5% reduction in ARR between patients receiving Ponvory (0.202) and patients receiving Aubagio (0.29).9 The study also showed statistically significant differences in the Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis (FSIQ–RMS)10 scores and brain volume loss between the two treatments in favor of Ponvory.9 Adverse events were similar between both treatment groups. After reaching these findings, Ponvory was approved for use in the US and the EU.

Patients participating in the OPTIMUM study were given the opportunity to continue in the long-term extension, OPTIMUM-LT (NCT03232073), where they will be monitored for ARR, time to relapse, and a number of different disease markers and disability measurements. The extension trial is scheduled to continue until February 2024.

Ponvory was also tested in combination with Tecfidera® (dimethyl fumarate) in a phase 3 clinical trial called POINT (NCT02907177). Patients received either Tecfidera in combination with Ponvory or a placebo. The study was terminated because of slow enrollment, however. Studies in animals indicated that the combination of treatments could improve disease control,11 but the early termination resulted in too few patients to show a statistical difference in endpoints.12

References

  1. Ponvory™ (ponesimod). Package insert. Janssen Pharmaceuticals, Inc.; 2021.
  2. FDA approves oral Ponvory™ (ponesimod) for relapsing forms of MS. National Multiple Sclerosis Society; March 19, 2021. Updated March 30, 2021. Accessed June 22, 2021.
  3. Ponvory® (ponesimod). European Medicines Agency (EMA). Published June 2, 2021. Updated June 2, 2021. Accessed June 22, 2021.
  4. Musella A, Gentile A, Guadalupi L, et al. Central modulation of selective sphingosine-1-phosphate receptor 1 ameliorates experimental multiple sclerosis. Cells. 2020;9(5):1290. doi:10.3390/cells9051290
  5. D’Ambrosio D, Freedman MS, Prinz J. Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases. Ther Adv Chronic Dis. 2016;7(1):18-33. doi:10.1177/2040622315617354
  6. Initiation of Ponvory. Ponvory healthcare professionals website. Published January 7, 2021. Last updated May 2021. Accessed June 17, 2021. 
  7. Olsson T, Boster A, Fernández Ó, et al. Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry. 2014;85(11):1198-1208. doi:10.1136/jnnp-2013-307282
  8. Freedman MS, Pozzilli C, Havrdova EK, et al. Long-term efficacy and safety of ponesimod, an oral S1P1 receptor modulator: results from randomized phase II core and extension studies in relapsing-remitting multiple sclerosis (1752). Neurology. 2020;94(15 Supplement):1752. Accessed April 28, 2021. 
  9. Kappos L, Fox RJ, Burcklen M, et al. Ponesimod compared with teriflunomide in patients with relapsing multiple sclerosis in the active-comparator phase 3 OPTIMUM study: a randomized clinical trial: a randomized clinical trial. JAMA Neurol. 2021;78(5):558-567. doi:10.1001/jamaneurol.2021.0405 
  10. Hudgens S, Schüler R, Stokes J, Eremenco S, Hunsche E, Leist TP. Development and validation of the FSIQ-RMS: a new patient-reported questionnaire to assess symptoms and impacts of fatigue in relapsing multiple sclerosis. Value Health. 2019;22(4):453-466. doi:10.1016/j.jval.2018.11.007
  11. Pouzol L, Piali L, Bernard CC, Martinic MM, Steiner B, Clozel M. Therapeutic potential of ponesimod alone and in combination with dimethyl fumarate in experimental models of multiple sclerosis. Innov Clin Neurosci. 2019;16(3-4):22-30. 
  12. Clinical study to compare the efficacy and safety of ponesimod to placebo in subjects with active relapsing multiple sclerosis who are treated with dimethyl fumarate (Tecfidera®) (POINT). ClinicalTrials.gov. September 20, 2016. Updated May 18, 2021. Accessed June 17, 2021.

Reviewed by Kyle Habet, MD, on 7/1/2021.

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