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Host:

On behalf of Alexion, welcome to our podcast featuring a case that illustrates the transition of a patient with atypical hemolytic uremic syndrome, or atypical-HUS, from eculizumab to ULTOMIRIS (ravulizumab-cwvz).

INDICATION

ULTOMIRIS is indicated for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).

Limitation of Use:

ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

SELECT IMPORTANT SAFETY INFORMATION ULTOMIRIS^® (ravulizumab-cwvz) injection for intravenous use, 300 mg per 3 mL vial

WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

Life-threatening meningococcal infections/sepsis have occurred in patients treated with ULTOMIRIS. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

• Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
• Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing a meningococcal infection. See Warnings and Precautions for additional guidance on the management of the risk of meningococcal infection.
• Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.

Because of the risk of serious meningococcal infections, ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called ULTOMIRIS REMS.

Host:

ULTOMIRIS is the first and only long-acting medication for the treatment of atypical hemolytic uremic syndrome, or atypical-HUS, in adult and pediatric patients one month of age and older.¹

As we talk about transitioning, it’s important to keep in mind how ULTOMIRIS differs from eculizumab.

Like eculizumab, ULTOMIRIS binds to C5 in the bloodstream, although ULTOMIRIS binds to FcRn with greater affinity.^1-3

For eculizumab, binding to C5 inhibits FcRn-mediated recycling, which means that eculizumab is destroyed when C5 is destroyed.³

ULTOMIRIS uses FcRn to recycle back to the bloodstream, leaving C5 to be degraded by lysosomes.³

Through these modifications, ULTOMIRIS has a half-life of 51.8 days, approximately 4x that of eculizumab, so ULTOMIRIS provides immediate, complete, and sustained inhibition of C5 for up to 8 weeks, compared to 2 weeks with eculizumab.^1-3

This increased time between infusions can provide patients with additional freedom to enjoy the things they love.^1-3

Host:

We are fortunate to be joined today by Dr Edward George.

Co-founder and former leader of Virginia Oncology Associates, Dr George is a board-certified hematology specialist who has treated or been consulted on many patients diagnosed with atypical-HUS.

Dr George is a paid consultant for Alexion and has been compensated for his time.

Host:

Welcome, Dr George.

Let’s discuss a patient who received a diagnosis and care from a colleague in your practice.

This case certainly illustrates challenges faced by patients with atypical-HUS and their transition from eculizumab to ULTOMIRIS.

This case is based on an actual patient, but the name has been changed to protect the patient’s privacy.

Dr George, tell us about this patient’s history.

Dr George:

Well, thanks for letting me share this illustrative case.

Andrew’s history included significant issues, beginning early in his adult life.

He was diagnosed with acute end-stage renal disease at age 25, he also suffered a stroke, which caused permanent left visual field cut.

He went on dialysis until he was able to receive a kidney.

Unfortunately, the transplant had to be removed due to immunologic acute humoral rejection, and so Andrew went back on dialysis.

In the process of dialysis, he had 3 arteriovenous fistulas, or AVFs, all of which thrombosed.

At age 34, he received his second kidney transplant but experienced graft-related pain, renal graft failure, and edema.

The pathology of the graft indicated a thrombotic microangiopathy, or a TMA.

Following that, he was misdiagnosed with thrombotic thrombocytopenic purpura, or TTP, underwent plasmapheresis and, subsequently, had the second kidney transplant removed because it failed.

Host:

Wow, what an experience this patient had. This really emphasizes the severity of this condition. What happened next?

Dr George:

Andrew is an articulate and persistent advocate for his own health.

After being in contact with other patients in the transplant community, he came to us, asking for a new opinion.

Our diagnosis went through the process of elimination.

His blood tests showed ADAMTS13 activity of 100%, which essentially ruled out a TTP.^4-6

He also received a negative stool test for Shiga toxin–producing E coli, or STEC.⁶

These, combined with a reassessment of his lab values and the exclusion of other causes of TMA, indicated the patient had atypical-HUS, and Andrew was started on eculizumab.⁶ He was immunized with meningococcal vaccines two weeks prior to the administration of his first dose.¹

The decision considered the failure of both of his transplants, even with immunosuppression. And considering his 3 AVFs and his stroke, we sought complement inhibition before considering a third transplant.

He subsequently underwent a third renal transplant and has been able to maintain it to the present.

Host:

It would be understandable that many patients and physicians would consider this a noteworthy resolution.

How did the idea of conversion to ULTOMIRIS emerge?

Dr George:

After almost 7 years of being treated with eculizumab, Andrew came to see us for a follow-up visit, and this was about the same time that our practice became aware of the impending approval of ULTOMIRIS.

With ULTOMIRIS for adult patients, infusions are administered once every 8 weeks vs every 2 weeks with eculizumab.^1,2

That’s a difference of 6 to 7 times per year vs 26 times per year.

Andrew was briefed on ULTOMIRIS by my colleague, who viewed the possibility of 8 weeks between infusions as an effective alternative to eculizumab.

Then, it all started to come together when ULTOMIRIS was approved.

When Andrew heard of its approval, he requested a thorough discussion of the data, efficacy, safety, and risks.

Host:

Often, a caregiver or loved one is also involved in such a significant decision. Was that the case here?

Dr George:

Yes.

Andrew had a lengthy discussion with his wife, and jointly they concluded that transitioning to this new medication, with its proven efficacy data and well-understood safety and tolerability profile, would be a good choice.¹

He also believed that ULTOMIRIS would open up his schedule and create a more convenient, less obligated lifestyle. In his words, it offered him additional freedoms in his life.¹

Host:

So, Andrew was then transitioned to ULTOMIRIS.² Tell us more about that.

Dr George:

His transition to ULTOMIRIS went smoothly, other than early transient headache with the first infusion and tiredness on the day of administration.

His impression of ULTOMIRIS remains positive. And it allows him to get back to doing the things he loves.

Host:

As you reflect on this patient and the transition, what are the lessons learned?

Dr George:

ULTOMIRIS is FDA approved and has an established safety and efficacy profile.¹

In our practice, we have successfully transitioned many patients to ULTOMIRIS.

We feel all atypical-HUS patients on eculizumab should be considered for a transition to ULTOMIRIS.

Don’t be surprised when patients say that the ULTOMIRIS 8-week infusion interval for adult atypical-HUS patients, vs 2 weeks with eculizumab, gives them a chance to enjoy more freedoms in life and have more time for their families and favorite activities.^1,2

Host:

Thank you, Dr George.

I’d like to remind our listeners of the basic steps in conversion of atypical-HUS patients from eculizumab to ULTOMIRIS.

Evaluate your patient before transitioning.

Educate them about the safety and efficacy of ULTOMIRIS.

Ensure ULTOMIRIS is available and covered by the patient’s insurance.

Confirm the appropriate ULTOMIRIS dose and schedule based on weight.¹

Vaccinate for meningococcal disease according to Advisory Committee on Immunization Practices, or ACIP, guidelines.¹

Set an appointment at the time of the patient's next scheduled eculizumab dose to begin the first dose of ULTOMIRIS.¹

Provide 2 weeks of antibacterial drug prophylaxis to patients if ULTOMIRIS must be initiated immediately or vaccines are to be administered less than 2 weeks before starting ULTOMIRIS therapy.¹

Thank you for listening.

We invite you to learn more about ULTOMIRIS at UltomirisHCP.com/aHUS or contact your local ULTOMIRIS sales representative.

If you are unsure who your local sales representative is, you can reach out to Alexion Connect by phone at 833-551-2539 or email AlexionConnectTeam@alexion.com.

Host:

SELECT IMPORTANT SAFETY INFORMATION (CONTINUED)

CONTRAINDICATIONS

• Patients with unresolved Neisseria meningitidis infection.
• Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing a meningococcal infection.

WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections

Life-threatening meningococcal infections have occurred in patients treated with ULTOMIRIS. The use of ULTOMIRIS increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis). Meningococcal disease due to any serogroup may occur.

Vaccinate or revaccinate for meningococcal disease according to the most current ACIP recommendations for patients with complement deficiencies. Immunize patients without history of meningococcal vaccination at least 2 weeks prior to the first dose of ULTOMIRIS. Patients who initiate ULTOMIRIS treatment less than 2 weeks after receiving meningococcal vaccine(s) must receive appropriate prophylactic antibiotics until 2 weeks after vaccination.

The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving ULTOMIRIS have not been established. Consider discontinuation of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection.

ULTOMIRIS REMS
Due to the risk of meningococcal infections, ULTOMIRIS is available only through a restricted program under a REMS called ULTOMIRIS REMS.

Under the ULTOMIRIS REMS, prescribers must enroll in the program. Prescribers must counsel patients about the risk of meningococcal infection/sepsis, provide the patients with the REMS educational materials, and ensure patients are vaccinated with meningococcal vaccines.

Additional information on the REMS requirements is available at www.ultomirisrems.com or 1-888-765-4747.

Other Infections
Patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP guidelines. If ULTOMIRIS is administered to patients with active systemic infections, monitor closely for worsening infection.

Monitoring Disease Manifestations after ULTOMIRIS Discontinuation
ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months. Due to heterogeneous nature of aHUS events and patient-specific risk factors, treatment duration beyond the initial 6 months should be individualized. There are no specific data on ULTOMIRIS discontinuation. After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months.

TMA complications post-discontinuation can be identified if any of the following is observed: Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure. In addition, at least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment. If TMA complications occur after discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.

Thromboembolic Event Management
The effect of withdrawal of anticoagulant therapy during treatment with ULTOMIRIS has not been established. Treatment should not alter anticoagulant management.

Infusion-Related Reactions
Intravenous or subcutaneous administration of ULTOMIRIS may result in systemic infusion-related reactions, including anaphylaxis and hypersensitivity reactions. In clinical trials, infusion-related reactions occurred in approximately 1% of patients treated with ULTOMIRIS. These events included lower back pain, drop in blood pressure, elevation in blood pressure, limb discomfort, drug hypersensitivity (allergic reaction), dysgeusia (bad taste), and drowsiness. These reactions did not require discontinuation of ULTOMIRIS. If signs of cardiovascular instability or respiratory compromise occur, interrupt ULTOMIRIS infusion and institute appropriate supportive measures.

Injection Site Reactions-Subcutaneous administration
27% (23/84) of patients treated with subcutaneous administration of ULTOMIRIS experienced injection site reactions which included application site rash, device allergy, infusion site pain, infusion site reaction, injection site bruising, injection site erythema, injection site hematoma, injection site induration, injection site inflammation, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, injection site urticaria, medical device site bruise, medical device site erythema, medical device site hematoma, medical device site induration, medical device site pruritus, medical device site rash, and medical device site reaction.

Allergies to Acrylic Adhesives
The on-body injector of ULTOMIRIS uses acrylic adhesive. For patients with a known allergy to acrylic adhesive, use of this product may result in an allergic reaction. Premedication can be considered, and supportive measures should be instituted if signs of allergy appear.

ADVERSE REACTIONS
Most common adverse reactions in patients with aHUS (incidence ≥20%) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension and pyrexia. Serious adverse reactions were reported in 42 (57%) patients with aHUS receiving ULTOMIRIS. The most frequent serious adverse reactions reported in more than 2 patients (2.7%) treated with ULTOMIRIS were hypertension, pneumonia and abdominal pain. In clinical studies, clinically relevant adverse reactions in <10% of patients include viral tonsillitis in adults and viral infection in pediatric patients and in 3% of adult patients include infusion-related reactions.

Adverse Reactions for Subcutaneous Administration of ULTOMIRIS

Most common adverse reactions (≥10%) with ULTOMIRIS subcutaneous administration via On Body Injector in adult patients with PNH were local injection site reactions, diarrhea, and headache.

DRUG INTERACTIONS
Plasma Exchange, Plasmapheresis, and Intravenous Immunoglobulins
Concomitant use of ULTOMIRIS with plasma exchange (PE), plasmapheresis (PP), or intravenous immunoglobulin (IVIg) treatment can reduce serum ravulizumab concentrations and requires a supplemental dose of ULTOMIRIS.

Neonatal Fc Receptor Blockers

Concomitant use of ULTOMIRIS with neonatal Fc receptor (FcRn) blockers (e.g., efgartigimod) may lower systemic exposures and reduce effectiveness of ULTOMIRIS. Closely monitor for reduced effectiveness of ULTOMIRIS.

Please see full Prescribing Information (bit.ly/UltomirisPI) for ULTOMIRIS, including Boxed WARNING regarding serious and life-threatening meningococcal infections/sepsis.

References

1. ULTOMIRIS. Prescribing information. Alexion Pharmaceuticals, Inc.
2. SOLIRIS. Prescribing information. Alexion Pharmaceuticals, Inc.
3. Sheridan D, et al. PLoS One. 2018;13(4):e0195909.
4. Berger B. Clin Kidney J. 2018;12(3):338-347.
5. Asif A, et al. J Nephrol. 2017;30(3):347-362.
6. Laurence J, et al. Clin Adv Hematol Oncol. 2016;14(11)(suppl 11):2-15.

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