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What is the significance of targeting CD20? Hear MS experts review the role of B cells in RMS pathogenesis and KESIMPTA MOA
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This educational video is sponsored by Novartis Pharmaceuticals Corporation. The speakers in this program have been compensated by Novartis to conduct this presentation.
KESIMPTA offers power, precision, and flexibility for your adult RMS patients.
Please see full Prescribing Information, including Medication Guide, accompanying this video and additional Important Safety Information on the adjacent panel of this video.
Dr Nicholas
Tonight we're going to talk about why KESIMPTA may be a good option for some of your patients with relapsing forms of multiple sclerosis
So, as you know, KESIMPTA is indicated for the treatment of relapsing forms of MS, and this includes clinically isolated syndrome, relapsing-remitting disease, as well as active secondary progressive disease in adults
Now prior to starting KESIMPTA, we want to make sure that we rule out active hepatitis B virus infection in our patients, because that would be a contraindication of starting
And it is administered via Sensoready® Pen. There are loading doses, and then it's given once monthly by self-administration via sub Q injection
Dr West
The CD20 evidence that has come out over the years has been fairly overwhelming, and what's interesting about it is that it seems like the anti-CD20, we know that it is a specific marker found on B cells and so you're really targeting B cells
The B cells in multiple sclerosis pathophysiology seem to function like an antigen-presenting cell to the T cells, which activate the T cells and therefore cause a cascade of events that lead to demyelination
So the idea is to go a little bit upstream from the effector T cells and deplete the B cells that might be functioning as a means of triggering those T cells to attack
So, in a weird way, we are having a T-cell immunity effect, even though we're actually going after the B cells.
Dr Williams
And I would just add to that, I think one of the wonderful things about seeing the evolution of treatment choices and therapy options in the field of MS is that we now have different targets. So, as you said, we were very, very focused on T cells and cytokines, and adjusting cytokines, Th1 and Th2, and so now we have a variety of different ways to try to attack or target MS so that we can have a variety of options for our patients
Dr Nicholas
Absolutely, and it's pretty amazing what we learn about the immune system and MS
Dr Williams
So just a little bit about the mechanism of action. So, we know that it's an anti-CD20 monoclonal antibody. Of course, the precise mechanism of action of any of our DMTs is not fully known, but it's presumed that ofatumumab binds to CD20, and it binds to both the small and large extracellular loops of CD20
It leads to basically cell lysis, and it primarily affects mature B lymphocytes as well as pre-B cells
So we know that CD20 is expressed on a variety of B cells, including the pre-B-stage, as well as mature lymphocytes
Essentially, when ofatumumab binds to CD20, it leads to cell lysis by two pathways by both the antibody-dependent pathway, as well as the complement-mediated pathway, which leads to cell lysis
Dr Nicholas
So, Dr Williams, can you tell us why it's thought that, if we are giving KESIMPTA in the sub Q delivery, that we're providing a precise way of targeting B cells?
Dr Williams
Also, an excellent question
It's thought that or it's presumed that when, you know, this therapy is delivered subcutaneously, it leads to preferential depletion of the B cells in the lymph nodes. And, of course, we know that profound depletion of CD20 cells could lower the host defenses against infection.
So this is extremely important, and based on some of the preclinical data, it is thought that by depleting the CD20 cells and in the lymph nodes, KESIMPTA may actually spare the marginal zone B cells, which are essential for immune defense against bloodborne pathogens.
So basically we will be able to deplete the ones in the lymph nodes but spare those that would help fight infection
Dr Nicholas
Thanks and Dr Williams, how long does it take to deplete B cell counts, when a patient starts taking KESIMPTA?
Dr Williams
Yeah. So essentially a reduction in the CD19 cells below the lower limit of normal were seen in about 95% of the patients, about 2 weeks after treatment discontinuation, so it occurs fairly rapidly
We can see from the graphic here that we see a significant decrease at 1 week but definitely by 2 weeks, definitely by 4 weeks there's a pretty profound depletion of the cells
From weeks 12 through 120 while on treatment, over 90% of patients in both trials had B-cell counts that will remain below the lower limit of normal, so we can see that effect continued once it occurred while patients remained on treatment out through 120 weeks
Important Safety Information
Infections
Delay KESIMPTA administration in patients with an active infection until the infection is resolved. Vaccination with live-attenuated or live vaccines is not recommended during treatment with KESIMPTA and after discontinuation, until B-cell repletion
Injection-Related Reactions
Management for injection-related reactions depends on the type and severity of the reaction
Reduction in Immunoglobulins
Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with KESIMPTA until B-cell repletion. Consider discontinuing KESIMPTA if a patient develops a serious opportunistic infection or recurrent infections if immunoglobulin levels indicate immune compromise
Fetal Risk
May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for at least 6 months after the last dose
KESIMPTA Important Safety Information | Click here for full Prescribing Information, including Medication Guide.
KESIMPTA Important Safety Information | Click here for full Prescribing Information, including Medication Guide. ▾
IMPORTANT SAFETY INFORMATION
Contraindications: KESIMPTA is contraindicated in patients with active hepatitis B virus (HBV) infection, or history of hypersensitivity to ofatumumab, or life-threatening injection-related reaction to KESIMPTA. Hypersensitivity reactions have included anaphylaxis and angioedema.
WARNINGS AND PRECAUTIONS
Infections: Serious, including life-threatening or fatal, bacterial, fungal, and new or reactivated viral infections have been observed during and following completion of treatment with anti-CD20 B-cell depleting therapies.
INDICATION
KESIMPTA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Indication
KESIMPTA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Important Safety Information
Contraindications: KESIMPTA is contraindicated in patients with active hepatitis B virus (HBV) infection, or history of hypersensitivity to ofatumumab, or life-threatening injection-related reaction to KESIMPTA. Hypersensitivity reactions have included anaphylaxis and angioedema.
Warnings and Precautions
Infections: Serious, including life-threatening or fatal, bacterial, fungal, and new or reactivated viral infections have been observed during and following completion of treatment with anti-CD20 B-cell depleting therapies. The overall rate of infections and serious infections in KESIMPTA-treated patients was similar to teriflunomide-treated patients (51.6% vs 52.7%, and 2.5% vs 1.8%, respectively). The most common infections reported by KESIMPTA-treated patients in relapsing MS (RMS) trials included upper respiratory tract infection (39%) and urinary tract infection (10%). Delay KESIMPTA administration in patients with an active infection until resolved.
Consider the potential increased immunosuppressive effects when initiating KESIMPTA after an immunosuppressive therapy or initiating an immunosuppressive therapy after KESIMPTA.
Hepatitis B Virus: Reactivation: No reports of HBV reactivation in patients with MS treated with KESIMPTA. However, HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ofatumumab at higher intravenous doses for chronic lymphocytic leukemia (CLL) than the recommended dose in MS and in patients treated with other anti-CD20 antibodies.
Infection: KESIMPTA is contraindicated in patients with active hepatitis B disease. Fatal infections caused by HBV in patients who have not been previously infected have occurred in patients treated with ofatumumab at higher intravenous doses for CLL than the recommended dose in MS. Perform HBV screening in all patients before initiation of KESIMPTA. Patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], should consult liver disease experts before starting and during KESIMPTA treatment.
Progressive Multifocal Leukoencephalopathy: No cases of progressive multifocal leukoencephalopathy (PML) have been reported for KESIMPTA in RMS clinical studies; however, PML resulting in death has occurred in patients being treated with ofatumumab at higher intravenous doses for CLL than the recommended dose in MS. In addition, JC virus infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies. If PML is suspected, withhold KESIMPTA and perform an appropriate diagnostic evaluation. If PML is confirmed, KESIMPTA should be discontinued.
Vaccinations: Administer all immunizations according to immunization guidelines: for live or live-attenuated vaccines at least 4 weeks and, whenever possible at least 2 weeks prior to starting KESIMPTA for inactivated vaccines. The safety of immunization 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.
Vaccination of Infants Born to Mothers Treated with KESIMPTA During Pregnancy. For infants whose mother was treated with KESIMPTA during pregnancy, assess B-cell counts prior to administration of live or live-attenuated vaccines. If the B-cell count has not recovered in the infant, do not administer the vaccine as having depleted B-cells may pose an increased risk in these infants.
Injection-Related Reactions and Hypersensitivity Reactions: KESIMPTA can result in systemic injection-related reactions and hypersensitivity reactions, which may be serious or life-threatening. Injection-related reactions with systemic symptoms occurred most commonly within 24 hours of the first injection, but were also observed with later injections. There were no life-threatening injection reactions in RMS clinical studies.
In the post-marketing setting, additional systemic injection-related reactions and hypersensitivity reactions have been reported, including anaphylaxis, angioedema, pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, dizziness, nausea, and tachycardia. Most cases were not serious and occurred with the first injection. Symptoms of systemic injection-related reactions may be clinically indistinguishable from acute hypersensitivity reactions.
The first injection of KESIMPTA should be performed under the guidance of an appropriately trained health care professional. If systemic injection-related reactions occur, initiate appropriate therapy. Patients who experience symptoms of systemic injection-related reactions or hypersensitivity reactions with KESIMPTA should be instructed to seek immediate medical attention. If local injection-related reactions occur, symptomatic treatment is recommended.
Reduction in Immunoglobulins: As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed. Monitor the levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections and after discontinuation of therapy until B-cell repletion. Consider discontinuing KESIMPTA therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.
Liver Injury: Clinically significant liver injury, without findings of viral hepatitis, has been reported in the post-marketing setting. Signs of liver injury have occurred weeks to months after administration. Patients treated with KESIMPTA found to have an alanine aminotransferase or aspartate aminotransferase greater than 3 times the upper limit of normal (ULN) with serum total bilirubin greater than 2 times the ULN are potentially at risk for severe drug-induced liver injury.
Obtain liver function tests prior to initiating treatment. Monitor for signs and symptoms of hepatic injury during treatment, including new or worsening fatigue, anorexia, nausea, vomiting, right upper abdominal discomfort, dark urine, or jaundice. If symptoms of liver injury are reported, measure serum aminotransferases, alkaline phosphatase, and bilirubin levels. Discontinue KESIMPTA if liver injury is present and an alternative etiology is not identified.
Fetal Risk: Based on animal data, KESIMPTA can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to KESIMPTA in utero. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 B-cell depleting antibodies during pregnancy. Advise females of reproductive potential to use effective contraception while receiving KESIMPTA and for at least 6 months after the last dose.
Most common adverse reactions: Most common adverse reactions (>10%) are upper respiratory tract infection, headache, injection-related reactions, and local injection-site reactions.
Please see full Prescribing Information, including Medication Guide.
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