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QUANTIFYING THE RELATIVE RISK OF DISEASE MODIFYING

THERAPIES

Donna Graves, MD

Assistant Professor

University of Texas Southwestern

Disclosures

• Dr. Graves serves as a consultant and has received honoraria from Teva Neuroscience, Bayer, Novartis, EMD Serono and Pfizer.

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Objectives

• Recognize potential adverse events associated with DMTs

• Understand challenges in defining all risks associated DMTs

• Understand proper risk assessment involves consideration of disease characteristics as well as risk mitigation strategies

• Gain insight to patient perception of risk associated with DMTs and how to effectively communicate risks with patients

The changing landscape of MS therapies

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The changing landscape of MS therapies

Betaseron

AvonexCopaxone

RebifTysabri

Novantrone Gilenya

TecfideraAubagioExtavia

1995 2000 2005 2010

Considerations in risk assessment

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Considerations in risk assessment

Considerations of disease characteristics• Approximately 50% of patients will enter SPMS after 10 years.

• One-third of patients will require assistive device for ambulation after 10 years

• Weinshenker, et al. Brain. 1989;112:133-146.

• Studies have shown relapses can lead to worsening long term disability. • 42% of patients had worsening of at least 0.5 points on EDSS and

28% had worsening of 1 point or more on EDSS • Lublin, et al. Neurology. 2003;61:1528-1532.

• While long term efficacy data is scarce, there is clear data to support benefit of DMT in short and medium term outcomes.

• Observational studies have shown benefit with early initiation of DMT.

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• Decision to treat should be shared decision between patient and doctor

• Communication regarding risks/benefits should be objective and understandable and comprehensively documented

• Patients should be updated as new information regarding safety comes available

• Physicians and patients should report adverse events to regulators.

• Safety profile should take into account a risk mitigation plan

Natalizumab

• Hypersensitivity/anaphylaxis < 1%

• Antibody formation – 6%

• Headache, fatigue, arthralgia

• Immunosuppression/Infection• UTI

• Upper respiratory infection or influenza

• Post marketing reports found increased risk of HSV or VZV meningitis/encephalitis

• Hepatotoxicity

• Other lab abnormalities – leukocytosis or anemia

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Risk Stratification for PML with NTZ

Anti-JCV Antibody Status

Negative

Prior IS Use?

YesNo

1:6,239Overall Risk

1:17,693Overall Risk

Positive

Prior IS Use?

No Yes

1:1,288< 24 months

1:241> 24 months

1:454< 24 months

1:85> 24 months

Fox and Rudick. Neurology. 2012; 78:436-437.

• Study of 69 patients and 66 neurologists regarding comfort level with risk of PML and use of NTZ

• 49% of physicians but only 17% of patients said they would discontinue NTZ if risk of PML was 1 in 5000 or worse

• Patients had a worse perception of MS as a malignant disease

Heesen C, et al. Mult Scler. 2010;16:1507-12.

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NatalizumabRecommendations for risk assessment and risk mitigation

of PML:Consider individual’s risk factors:

o JCV Ab status

o Prior use of immunosuppressants

o Duration of therapy

Repeat JCV Ab testing every 6 months

MRI repeated every 6 months after treatment duration of 24 months

Several reports have documented reactivation of MS after discontinuation of NTZ (should be considered upon initiation of treatment)

Lugaresi A, et al. Neuropsychiatr Dis Treat. 2013;9:893-914

Fingolimod• Reduced lymphocyte count

• 3-4% with lymphopenia

• Infection • Lower respiratory tract, bronchitis, herpes zoster

• FDO associated AR:• Bradycardia• 1st or 2nd degree AV block

• Hypertension• Macular edema – 0.5%• Elevated transaminases

• 8% elevated 3x ULN• 2% elevated 5x ULN

• Malignancy – basal cell carcinoma?• Mild reduction in mean FEV1

Kappos, et al. NEJM 2010;362:387-401. Cohen, et al. NEJM 2010;362:402-415

Cohen, et al. Abstract presented at ECTRIMS 2012

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Fingolimod

• EMA began review in January 2012 after releasing statement of 11 deaths in patients receiving fingolimod.• One US death occurred within 24 hours of FDO

• 10 deaths reported by EMA• 6 of unknown cause

• 3 from myocardial infarction

• 1 from arrhythmia

Revised Recommendations for use of Fingolimod

Contraindications for Fingolimod

MI, Stroke, TIA, unstable angina, decompensated heart failure within the last 6 months

Concominant use of class 1a or III anti‐arrythmics

Corrected QT interval > 500ms

Mobitz type II second degree or third degree heart block or sick sinus syndrome (unless with pacemaker) 

INDICATIONS FOR PROLONGED CARDIAC MONITORING WITH FINGOLIMOD

First Dose Observations

> Observe all patients with hourly heart rate and blood pressure monitoring

> EKG before FDO and at end of 6 hour observation

> Patients with symptomatic bradycardia should begin continuous telemetry monitoring

Indications for Prolonged Monitoring

Pre‐existing conditions that may increase risk of bradycardia 

* Ischemic heart disease

* History of myocardial infaraction

* Congestive heart failure

* History of cardiac arrest

* History of recurrent syncoope

* Atrioventricular block

* Sinoatrial heart block 

* Symptomatic bradycaria

* Uncontrolled hypertension

* Cerebrovascular disease

* Severe untreated sleep apnea

Indications identified during FDO

* Heart rate < 45 bpm at end of 6 hour observation

* Heart rate at lowest post dose value at end of 6 hour observation

* Second degree or higher AV block

* QT prolongation before or during 6 hour observation

* Concominant use of medications that cause prolonged QT with known risk of torsades de pointes (citalopram, chlorpromazine, haloperidol, methadone or erythromycin)

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FIRST study

• 2400 RRMS patients • Targeted patients that would have previously been excluded in

phase III study

• Open label, 16 week safety study

• Overall incidence of AEs similar in high-risk and low-risk group

• Of note:• Macular edema seen in 5% of patients > 55 years

• number of patients with DM in the study was low but only 1 patients with DM developed ME

• Cardiac adverse events were seen in 4.7% of patients with cardiac disease history versus 3.9% of those without history of cardiac disease

Gold, et al. abstract presented at ECTRIMS. 2012.

PML cases in patients treated with Fingolimod• Total of 3 cases reported

• 2 cases were in patients previously treated with natalizumab (NTZ)• Each of these were treated for only short time with fingolimod (1 week; 6

weeks) and fingolimod was started in close proximity to discontinuation of NTZ

• Felt to be related to NTZ use

• 1 case (July 2013) – atypical case (now suspected NMOSD)• Treated with fingolimod for 8 months

• Complicating factors:• received 1 month azathioprine prior to fingolimod and repeated courses of

steroids during fingolimod treatment

• Review of MRI prior to start showed atypical lesions; can not rule out PML

Information from Novartis Medical Information as of April 2014

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Pregnancy issues with fingolimodPregnancy category C66 pregnancies occurred during clinical trials28 live births

o 26 healthy babieso 1 congenital bowing of tibiao 1 acrania; delivered prematurely; died at 2 days

9 spontaneous abortions24 elective abortions

• 1 with tetratalogy of Fallot• Ectopic pregnancy• Intrauterine death• Pregnancy not developing

4 ongoing pregnancies (at time of report)1 lost to follow up

Karlsson G, et al. Neurology 2014;82:674-680

Teriflunomide

• Hepatoxicity ~ 15%

• Peripheral neuropathy ~ 2%

• Immunosuppression potential

• Infections

• Renal toxicity ~ 1%

• Hyperkalemia ~ 1%

• Increased blood pressure

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Teriflonomide• Remember drug interactions

• Warfarin – causes decrease in INR• Inhibitor of CYP2C8

• Several DM medications (rosiglitazone, pioglitazone, repaglinide)• Paclitaxel

• Inducer of CYP1A2 • Tizanidine• Duloxetine• Naproxen• Cyclobenzaprine• Several psychiatric meds

• Vaccinations: live, attenuated vaccinations are not recommended while on teriflunomide

Teriflunomide

• Pregnancy category X• Teratogenic effects (skeletal deformities) and increased risk of fetal

death noted in animal studies

• Teriflunomide is detected in semen

• Accelerated elimination procedure• Goal to reduce plasma concentration to < 0.02 mg/L

• Takes average of 8 months (up to 2 years) without elimination procedure

• Cholestyramine 8 grams every 8 hours for 11 days

-or-

• 50 grams of activated charcoal powder every 12 hours for 11 days.

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Dimethyl fumarate/BG 12

• Tolerability issues• Flushing – 35%

• GI side effects – 36%

• Leukopenia/lymphopenia ~ 5%

• Elevated transaminases ~ 5%

• Proteinuria ~ 10% (similar to PBO group)

Case

• 32 yo M with RRMS diagnosed in 2011 though symptoms dated back to 2003. He was initially started on GA daily.

• He tolerated injections well and his disease remained stable both clinically and radiographically after beginning GA. However, he expressed interest in starting an oral medication and was eager to begin DMF upon its FDA approval.

• He started DMF on April 15, 2013.

• A few days after starting the 240mg BID dosing, he developed fever, rash, chest and abdominal pain and diarrhea

• He was admitted to our hospital

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Case (cont)

• He was noted to have diffuse erythematous rash (thin papules coalescing into plaques), lymphadenopathy, abdominal tenderness

• Labs:• Peak ALT 587; AST 179

• Relative eosinophilia

• Diagnosed with DRESS syndrome

• Discontinued DMF and treated with topical steroids

• Symptoms resolved and lab abnormalities resolved completely.

Mitoxantrone• Dosing: 12mg/m2 IV every 3 months (maximum cumulative dose

120mg/m2)

• Adverse effects:• Nausea/emesis• Alopecia• Immunosuppression – anemia, thrombocytopenia• Amenorrhea or infertility• Elevated transaminases• Leukemia ~ 2-3% (at 5 year follow up)• Cardiotoxicity

• 12% risk of decreased systolic function• 0.4% risk of CHF

• Recommended to evaluate LVEF after each infusion

• Patients should be monitored for cardiotoxicity and leukemia for 5 years after discontinuation of medication

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EMERGING THERAPIES

Alemtuzumab

• Infusion related reactions

• Infections (URI, UTI, influenza, herpes viral infections)

• Thyroid disease – 30%

• Immune thrombocytopenia – 1%

• Goodpasture disease – 1 case

• Thyroid cancer- 3 cases

Cohen, et al. Lancet 2012;380:1819-28Coles, et al. Lancet 2012;380:1829-39

Coles, et al. Neurology 2012;78:1069-78

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DaclizumabPooled data from phase 2 studies• Infections – overall risk is similar among groups but serious

infections more frequent in daclizumab group

• Elevated transaminases - ~4% 5x ULN

• Cutaneous events – atopic dermatitis, allergic dermatitis, erythema nodusum, exfoliative dermatitis

• Malignancies – total 4 cases • Cervical cancer (1 in PBO; 1 in daclizumab)• Melanoma – 2 cases in daclizumab• Breast cancer – 1 case• Pseudomyxoma peritonei – 1 case (recurrence of pre-existing

condition)

Gold, et al. Lancet 2013;381:2167-75Wynn, et al. Lancet 2010;9:381-90

MONITORING OF DMT

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Interferons

Screening

• None specified

• CBC, LFTs, TSH prior to start

Follow-up monitoring

• CBC and LFTs at 1, 3 and 6 months during titration and then periodically thereafter

• TSH as indicated (if history of thyroid disease)

• Routine surveillance for nAbs is controversial.

• CBC, LFTs at 1, 3, 6 months and every 6 months thereafter.

• TSH every 6-12 months as indicated

Glatiramer acetate

Screening Follow-Up monitoring

• Screen for site reactions

• Immediate post-injection reactions

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Natalizumab

Screening

• CBC and LFTs (within 6 months)

• JCV Ab titer

Follow-up monitoring

• CBC and LFTs every 6 months

• JCV Ab titer every 6 months• Readdress risk of PML

• Tysabri antibodies after 4-6 months

Fingolimod

Screening

• Screen for contraindications

• CBC and LFTs

• Baseline EKG

• VZV titer

• Baseline ophthalmologic exam

Follow-up monitoring

• FDO (must be repeated if off DMT for 2 weeks)

• Ophthalmologic examination at 3 months

• CBC, LFTs and ophthalmologic examination at 3, 6 and every 6 months

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Teriflunomide

Screening

• Exclude pregnancy

• CBC, LFTs and bilirubin (within last 6 months)

• TB skin test or quantiferongold

Follow-up monitoring

• Monthly ALT for 6 months• CBC, renal function and

potassium as indicated• Monitor blood pressure

periodically• Readdress family

planning education

• In addition, CBC and CMP every 6 months

Dimethyl fumarate/BG12

Screening

• CBC (within last 6 months)

• Also recommend LFTs

Follow-up monitoring

• CBC yearly

• Recommend CBC and LFTs at 1, 3, 6 months and every 6 months.

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Closing remarks• Risk-benefit evaluation should include a clear

understanding of safety concerns with medications, as well as how patient’s comorbid conditions or concomitant medications may impact safety.

• Risk mitigation strategies should be considered as part of risk profile

• Safety concerns must be balanced by understanding and acknowledgement of risk of disability from MS

• Patient should be involved in decision as patient perceptions may vary

• Risks should be communicated clearly and patients should be updated about risks as new information becomes available