Medicines

• Efficacy: KESIMPTA has demonstrated efficacy in ASCLEPIOS I and II (2-year core studies), two Phase III randomised, double-blind, double-dummy, active comparator-controlled, parallel-group, multicentre pivotal trials, comparing a range of outcomes to active comparator teriflunomide in 1882 patients with RMS, following patients for up to 7 years (including the 5-year extension phase, the ALITHIOS study).^1,2,4,5 ALITHIOS is an ongoing, open-label, single-arm, umbrella-extension, Phase IIIb study assessing the risk–benefit profile of KESIMPTA (20 mg subcutaneously every 4 weeks) and its tolerability in patients with RMS. The study enrolled 1703  patients with RMS from the APLIOS, APOLITOS and ASCLEPIOS I/II trials who continued KESIMPTA treatment.^4,6 The primary endpoint, annualised relapse rate (ARR), was defined as the number of confirmed relapses of MS per year, according to pre-specified criteria. Secondary endpoints included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualised rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at Month 3, and change in brain volume⁵

  • KESIMPTA met the primary endpoint in ASCLEPIOS I/II, with up to 58% reduction in ARR vs teriflunomide (ASCLEPIOS I: 51% [0.11 vs 0.22]; rate ratio (RR): 0.49 [95% CI: 0.37–0.65]; ASCLEPIOS II: 58% [0.10 vs 0.25]; RR: 0.42 [95% CI: 0.31–0.56]; both p<0.001)^1,5

• Efficacy at Year 7: Of 1882 patients included in the efficacy population, 1367 entered ALITHIOS, including 465 who were recently diagnosed (≤3 years) and treatment-naïve. Continuous group refers to patients randomised to KESIMPTA in the core study; switch group refers to the patients who were randomised to teriflunomide in the core study and switched to KESIMPTA during the extension phase²

• At Year 7, 77.31% of continuous KESIMPTA patients (n=64) vs 73.8% of switch group patients (n=52) were free from 6m CDW (secondary endpoint). Differences in 6m CDW between continuous and switch group were not statistically significant in the 7-year analysis (p=0.069)^†2

• At Year 7, 83.7% of continuous KESIMPTA patients (n=70) vs 82.3% of switch group patients (n=56) were free from 6m progression independent of relapse activity (PIRA) (exploratory endpoint). Differences in 6m PIRA between continuous and switch group were not statistically significant in the 7-year analysis (p=0.426; exploratory endpoint)^‡2

• Safety profile: Across the pooled analysis of ASCLEPIOS clinical trials, ofatumumab exhibited a comparable safety profile to teriflunomide.^1,5 In the ALITHIOS open-label extension, KESIMPTA’s safety profile remained generally consistent over 7 years and no unexpected safety signals were observed. Safety population analysis included participants receiving ≥1 dose of KESIMPTA in ASCLEPIOS I/II, APOLITOS, APLIOS or the umbrella extension study ALITHIOS (N=1969).² Please refer to the KESIMPTA safety profile for more information

  • The most important and frequently reported adverse reactions are upper respiratory tract infections (39.4%), systemic injection-related reactions (20.6%), injection-site reactions (10.9%) and urinary tract infections (11.9%)¹

  • Symptoms most frequently observed in RMS clinical studies include fever, headache, myalgia, chills, fatigue, nausea and vomiting and were predominantly (99.8%) mild to moderate in severity. There were no life-threatening systemic injection-related reactions (SIRRs) reported in RMS clinical studies¹

• Self-administration: Following the initial dosing period, KESIMPTA offers 1 minute-a-month self-administration (after preparation), at home or on the go, giving patients the independence to administer their treatment in an appropriate environment of their choice.^§1,7  KESIMPTA is intended for self-administration, with initial guidance from an appropriately trained healthcare professional (HCP).¹ The flexibility to self-administer without the need for HCP involvement means dosing can occur at home or elsewhere appropriate outside the hospital setting. ‘1 minute a month’ refers to the time it takes for a patient to inject a full dose of KESIMPTA; based on stability data⁷

  • Patients must take the pen out of the refrigerator about 15 to 30 minutes before self-administration to allow it to reach room temperature. Additional time is required to prepare the pen and clean the administration site. First injection should be performed under the guidance of a HCP^1,3

Contraindications¹

• Hypersensitivity to the active substance or to any of the excipients listed in the KESIMPTA SmPC

• Patients in a severely immunocompromised state 

• Severe active infection until resolution

• Known active malignancy

Special warnings and precautions for use¹

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Injection-related reactions

Patients should be informed that systemic injection-related reactions (SIRRs) could occur, generally within 24 hours and predominantly following the first injection. Symptoms most frequently observed in RMS clinical studies include fever, headache, myalgia, chills, fatigue, nausea and vomiting and were predominantly (99.8%) mild to moderate in severity. There were no life-threatening SIRRs reported in RMS clinical studies.

Additional SIRRs reported in the post-marketing setting include rash, urticaria, dyspnoea and angioedema (e.g., tongue, pharyngeal or laryngeal swelling), and rare cases which were reported as anaphylaxis. While there were some cases which were serious and resulted in discontinuation of KESIMPTA treatment, there were also serious cases where patients were able to continue KESIMPTA treatment without further incidents.

Some SIRR symptoms may be clinically indistinguishable from Type 1 acute hypersensitivity reactions (IgE-mediated). A hypersensitivity reaction may present during any injection, although typically would not present with the first injection. For subsequent injections, more severe symptoms than previously experienced, or new severe symptoms, should prompt consideration of a potential hypersensitivity reaction. Patients with known IgE-mediated hypersensitivity to KESIMPTA must not be treated with KESIMPTA.

Only limited benefit of premedication with steroids was seen in RMS clinical studies. Injection-related reactions can be managed with symptomatic treatment, should they occur. Therefore, use of premedication is not required. 

The first injection should be performed under the guidance of an appropriately trained healthcare professional. 

Local injection-site reaction symptoms observed in clinical studies included erythema, swelling, itching and pain.

Infections

It is recommended to evaluate the patient’s immune status prior to initiating therapy. Based on its mode of action and available clinical experience, KESIMPTA has the potential for an increased risk of infections. 

Administration should be delayed in patients with an active infection until the infection is resolved.

KESIMPTA must not be given to patients in a severely immunocompromised state (e.g. significant neutropenia or lymphopenia).

Progressive multifocal leukoencephalopathy (PML)

Since John Cunningham virus infection resulting in PML has been observed in patients treated with anti-CD20 antibodies, other MS therapies, and KESIMPTA at substantially higher doses in oncology indications, physicians should be vigilant for medical history of PML and for any clinical symptoms or MRI findings that may be suggestive of PML. If PML is suspected, treatment with KESIMPTA should be suspended until PML has been excluded.

Hepatitis B virus reactivation

Hepatitis B reactivation has occurred in patients treated with anti-CD20 antibodies, which in some cases resulted in fulminant hepatitis, hepatic failure and death.

Patients with active hepatitis B disease should not be treated with KESIMPTA. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment. As a minimum, screening should include hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) testing. These can be complemented with other appropriate markers as per local guidelines. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult a liver disease expert before the start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Treatment of severely immunocompromised patients

Patients in a severely immunocompromised state must not be treated until the condition resolves.

It is not recommended to use other immunosuppressants concomitantly with KESIMPTA except corticosteroids for symptomatic treatment of relapses.

Vaccinations

All immunisations should be administered according to immunisation guidelines at least 4 weeks prior to initiation of KESIMPTA for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of KESIMPTA for inactivated vaccines.

KESIMPTA may interfere with the effectiveness of inactivated vaccines.

The safety of immunisation with live or live-attenuated vaccines following KESIMPTA therapy has not been studied. Vaccination with live or live-attenuated vaccines is not recommended during treatment and after discontinuation until B-cell repletion. The median time to B-cell recovery to the lower limit of normal (LLN, defined as 40 cells/µL) or baseline value is 24.6 weeks post treatment discontinuation based on data from Phase III studies.

Vaccinations of infants born to mothers treated with KESIMPTA during pregnancy

In infants of mothers treated with KESIMPTA during pregnancy, live or live-attenuated vaccines should not be administered before the recovery of B-cell counts has been confirmed. Depletion of B cells in these infants may increase the risks from live or live-attenuated vaccines.

Inactivated vaccines may be administered as indicated prior to recovery from B-cell depletion; however, assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted.

Excipients with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’. This medicinal product contains 0.08 mg of polysorbate 80 per dose. Polysorbates may cause allergic reactions.

Women of childbearing potential

Women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) while receiving KESIMPTA and for 2 months after the last administration of KESIMPTA.

Pregnancy

There is a limited amount of data from the use of KESIMPTA in pregnant women. KESIMPTA may cross the placenta and cause foetal B-cell depletion, based on findings from animal studies.

Treatment with KESIMPTA should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus. To help determine the effects of KESIMPTA in pregnant women, healthcare professionals are encouraged to report all pregnancy cases and complications that happen during treatment or within 2 months after the last dose of KESIMPTA to the local representative of the marketing authorisation holder, in order to allow monitoring of these patients through the PRegnancy outcomes Intensive Monitoring (PRIM) programme. In addition, all adverse pregnancy events should be reported via HPRA Pharmacovigilence website: www.hpra.ie.

Lactation

There are limited data on the use of KESIMPTA in women during lactation. There are no data on the effects of KESIMPTA on milk production. In humans, excretion of IgG antibodies in milk occurs during the first few days after birth, which is decreasing to low concentrations soon afterwards. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts.

An observational study reported that concentration of KESIMPTA in breast milk was generally low, with C_avg and C_max of less than 0.02 μg/ml in the breast milk of treated lactating women.

In the same observational study, five infants with available B cells had normal levels. Eight infants received live vaccines during/after exposure during breast-feeding with no complications. Infants (up to 24 months of age) did not show abnormalities in infections, antibiotic use, hospitalisations or developmental delays. 

Consequently, a risk to the breastfed child cannot be excluded during this short period. Afterwards, KESIMPTA could be used during breastfeeding if clinically needed. However, if the patient was treated with KESIMPTA up to the last few months of pregnancy, breastfeeding can be started immediately after birth.

Undesirable effects

Very common (≥10%): upper respiratory tract infections, urinary tract infections, injection-site reactions (local), injection-related reactions (systemic). 

Common (≥1 to <10%): oral herpes, blood immunoglobulin M decreased, nausea, vomiting, hepatic enzymes increased.

This is not an exhaustive list of warnings and precautions.

Please refer to KESIMPTA Prescribing Information and SmPC for further information.