Claudiu Diaconu Neuroimmunology Fellow MS Therapeutics Claudiu Diaconu Neuroimmunology Fellow

2017: Ocrevus ® ocrelizumab 2016: Zinbryta ® daclizumab 2017: Ocrevus ® ocrelizumab 2018: withdrawn, due to autoimmune hepatitis and liver failure leading to deaths

Pathogenesis of multiple sclerosis     Changsheng et. al., (2012). Cell Research 22:1108–1128

Tysabri – Binds to integrins to prevent adhesion of activated T-cell to BBB Interferon beta & Aubagio – Decrease antigen presentation     Copaxone – Mimics MBP, competes w/ other antigens Gilenya – Blocks egression of T-cells From lymph nodes Tecfidera & Copaxone – Immunomodulation of Th1 (proinflam) to Th2 (anti-inflam) Lemtrada– Anti-CD52, found on all lymphocytes (T cells, NK Cells, B cells) Rituximab and Ocrevus – Anti-CD20, target B-cells; B-cells also act as APC’s; give OCBs

T-cell mediated injury in MS 4 major steps: T-cells increase in peripheral blood (egress from lymph nodes) T-cells become activated towards myelin Activated T-cells then infiltrate CNS CNS T-cells attack and damage myelin Fingolimod (Gilenya) Binds S1P to block egression of T-cells from lymph nodes Interferon beta (Avonex, Rebif) Dec antigen presentation (Aubagio) Shift to antiinflam environtment Gatiramer acetate (Copaxone) 4 amino acids that mimic MBP structure Competes with other MS putative antigens (e.g. MBP) for binding to T-cell receptors Induces Th2 profile (immunosuppressive) Natalizumab (Tysabri) Monoclonal Ab binds to integrins to prevent adhesion of activated T-cell to endothelial cell of BBB Dimethyl fumarate / BG12 (Tecfidera) Activates oxidative stress protective pathways in neurons and microglia Immunomodulatory (shift from Th1 [cell-mediated envir] to Th2 [humoral-based])

Interferon Beta (IFNB) drugs: IFN-beta 1a & 1b Both are interferon beta 1a. Avonex is IM qWk; Rebif is SC QOD. Rebif shown to be more effective and had less flu-like sxs than Avonex. However, Rebif had more neutralizing Ab’s. 2017: Ocrevus ® ocrelizumab

Interferon Beta (IFNB) drugs: IFN-beta 1a & 1b VS ? No trials compared these Also interferon beta 1a, that is pegylated with a polyethylene glycol (PEG) group to increase half-life and improve tolerance. Given SC q2wk. Both are interferon beta 1a. Avonex is IM qWk; Rebif is SC QOD. Rebif shown to be more effective and had less flu-like sxs than Avonex. However, Rebif had more neutralizing Ab’s. 2017: Ocrevus ® ocrelizumab

Interferon Beta (IFNB) drugs: IFN-beta 1a & 1b *biologicals can’t have generics, so FDA approved a new brand Both are interferon beta 1b. Formulations are identical. Extavia approved by FDA based on Betaseron trials. No trial compared Extavia vs Betaseron (since same formulation). Extavia comes with 27G needle; Betaseron with 30G. 2017: Ocrevus ® ocrelizumab

Interferon Beta (IFNB) drugs: IFN-beta 1a & 1b IFNB-1a VS 1b ? 1 trial showed IFNB-1b to be superior (PMID 11988242) 1 larger trial showed they are similar in efficacy (PMID 16510769) 2017: Ocrevus ® ocrelizumab Interferons chosen based on route/dosing or side effect tolerability. Not used very often anymore 2/2 flu-like SEs.

Copaxone (Glatiramer Acetate): safest, best tolerated Copaxone VS IFNB1b: Similar efficacy Copaxone better tolerated PMID: 11997066 Copaxone: 20mg QD or 40mg TIW SE: GI sxs, N/V, abm pain (usu improve with time); flu-like sxs less common Generic Copaxone 2017: Ocrevus ® ocrelizumab Copaxone is most often the medication of choice for initial therapy for non-severe MS, and if patient is okay with injection

Tysabri (natalizumab) – one of the most effective for RRMS, improves fatigue, risk of PML 1 infusion, Monthly Monitor for JCV Ab SE: infusion related (HA, flushing, dizziness), infections [UTI’s, URI’s] Tysabri VS IFNB’s & Copaxone Tysabri is about twice as effective at preventing relapses in RRMS PMID: 11997066 2017: Ocrevus ® ocrelizumab Tysabri is 1st line for severe MS, especially if fatigue is a sx. Tysabri is 2nd line for when patients fail IFNB’s, Copaxone or oral meds

Oral DMD’s Efficacy: Gilenya (~Tysabri) > Tecfidera = Aubagio [fingolimod] [dimethyl fumarate, BG-12] [teriflunomide] Gilenya (1st oral drug, Once daily) Better than Placebo (FREEDOMS trial) Better than IFN, more serious SEs w/ Gilenya (TRANSFROMS trial) SE: infection (HSV, VZV, crypto), AV block (pts need EKG), macular edema (pts need eye exam by ophtho), basal cell carcinoma (skin exam), tumefactive MS (upon starting or discontinuing tx), few PML cases now reported Gilenya VS Tysabri meta-analysis of placebo-controlled RTCs & observational studies Tysabri decreased # of relapses more than Gilenya at 2 yrs No diff btwn relapse-free pts or disability progression Switching to Tysabri better than to Fingolimod PMIDs: 27684943, 25546031 2017: Ocrevus ® ocrelizumab Gilenya has the advantage of being orally administered and almost as effective as Tysabri. However, it also has a SE profile similar to Tysabri; Reserve it for moderate-severe MS.

Oral DMD’s Efficacy: Gilenya (~Tysabri) > Tecfidera = Aubagio [fingolimod] [dimethyl fumarate, BG-12] [teriflunomide] Aubagio (Once daily) Better than Placebo (TEMSO, TOWER trials) SE: GI sxs (N/V, pain, etc), hepatoxicity, hair-thinning Teratogen (also in semen, remains x2 yrs after stopping, so needs charcoal tx prior to pregnancy) Tecfidera (BID dosing) Better than Placebo & slightly better than Copaxone (CONFIRM trial) SE: flushing, GI sxs, elev LFTs – similar to Copaxone; take w/ food Case reports of PML; less safety data than Copaxone Gilenya VS Aubagio VS Tecfidera VS Tysabri No direct comparison trials Indirect meta-analyses initially suggested Gilenya > Tecfidera > Aubagio More recently, studies suggest similar efficacy of all 3 Studies agree Tysabri is more efficacious than all 3 oral drugs PMID’s: 27645339, 27919491, 27733070 2017: Ocrevus ® ocrelizumab Aubagio & Tecfidera are safer than Gilenya and probably slightly less efficacious

INFUSIONS: Novantrone , Tysabri, Lemtrada, Ocrevus [mitoxantrone] [natalizumab] [alemtuzumab] [ocrelizumab] Novantrone (intercalates DNA) Only med to work in SPMS at time of approval (limited evidence) Hardly used bc of cardiac toxicity, risk for leukemia, and max lifetime dose limit Lemtrada (for RRMS; anti-CD52, found on T-cells, B-cells, NK-cells) More effective than IFNB (CARE-MS I) Effective after failure of IFNB or Copaxone (CARE-MS II) Metanalyses (indirect) More effective than Tysabri at preventing relapses (2018, PMID 29317954) Less effective than Tysabri at preventing relapses (2018, PMID 29465579) More frequent SE’s than Tysabri SE: ITP, autoimmune thyroiditis, HSV infection, bone marrow suppression 2017: Ocrevus ® ocrelizumab Replaced with Rituximab Lemtrada used for MS refractory to Tysabri or Ritux/Ocrevus (since Lemtrada is broader in terms of target cells)

Ocrevus® [ocrelizumab] infusion Anti-CD20 (anti B cells, like Ritux, but binds to different site on CD20) 300mg IV infusion x2 (2 wks apart), then 600mg IV q6months Approved in 3/2017 for RRMS and PPMS OPERA I & II Identical Trials – compared to IFNB-1a, significantly reduced relapse rates and enhancing MRI lesions (more than Tysabri did in other trials, but no direct comparisons available) ORATORIO trial – 732 adults, mean 45 y.o., PPMS assigned to Ocrevus vs placebo for at least 2 years Reduced disability progression (by 6%) Slowed worsening of Timed 25-ft walk at 2 years by 16% Less MRI T2 lesions, higher brain volume at 2 years SPMS not studied Rituximab failed similar study in the past First Drug to ever show positive results in PPMS SE’s: Infusion rxns (34%) >> infections (mainly URI’s, 1% serious) >> neoplasms (0.5-2%) PML not thought to be a risk, based on Ritux data True incidence of neoplasms or PML not known since only ~3 yrs median f/u Ocrevus is chosen for moderate-severe MS, unless Tysabri would be a better option (i.e. pt has fatigue and is not JCV Ab +)

SUMMARY – First Line Drugs – Mild/Moderate MS: IFNB – mainly used in the past Copaxone – safest, Categ B preg., best choice if pt tolerates injections Aubagio – oral, SE’s: hair thinning; teratogen (both genders) Tecfidera – oral, SE’s similar to Copaxone but more freq; a/w PML 2017: Ocrevus ® ocrelizumab Replaced with Rituximab

SUMMARY – 2nd Line Drugs – 1st line failure or Moderate/Severe MS Tysabri – if RRMS, fatigue is an issue, if JCV Ab neg Ocrevus – best option if fatigue not an issue; okay if JCV Ab+; also works in PPMS and suspected to work in SPMS Gilenya – if patient prefers oral (usually as first line for moderate RRMS) 2017: Ocrevus ® ocrelizumab Replaced with Rituximab

SUMMARY – 3rd Line Drugs – Refractory MS (failed 2 or drug classes) Lemtrada – used as a more broad-spectrum agent (blocks B-cells, T-cells, NK-cells) for refractory RRMS Novantrone – if SPMS or PPMS (rarely used; possibly if Ocrevus fails) Other Empiric Tx for Primary MS: - Monthly steroids or IVIG, Cytoxan, methotrexate, stem cell transplant Which of these are FDA-approved for NMO? -> none 2017: Ocrevus ® ocrelizumab Replaced with Rituximab

Drug Monitoring Interferon Beta – check q6 months, then yearly: LFTs monthly for first 6 months (asymptomatic elevation expected; rarely, liver failure) CBC (rare: anemia, leukopenia; very rare: thrombotic microangiopathy) TFTs Neutralizing Ab’s [3-35% of pts] – some suggest testing, others recommend just switching tx Copaxone – LFTs (yearly); Neutralizing Ab’s Oral Drugs Tecfidera – CBC q6mo/yearly (leukopenia), LFTs, JCV Ab Aubagio – LFTs, pregnancy testing as indicated Gilenya – prior to starting tx: Ophtho referral, EKG, VZV Ab (vaccinate if needed), pregnancy testing as indicated; monitor CBC, LFTs, JCV Ab Rituximab/Ocrevus Prior to dosing: HCVAb, HBV panel, Quantiferon Gold, CBC w/ diff, T cell panel for baseline. Optional: HIV, VZV, LFTs, BMP Monitor: CBC, B-cell count (at NYP called T cell panel) Tysabri (available only via the TOUCH prescribing program) JCV Ab / calculate PML risk LFTs Neutralizing Ab’s (up to 9% of pts) – occus usu. w/in 6 months; test if MS activity continues despite treatment

Calculating/Monitoring PML Risk with Tysabri Incidence of PML: 4 in 1000 3 factors (PMID 28228564, 2017 update): If no prior immunosuppressant use, a JCV Ab index <0.9 = low risk of PML In AllScripts/Crown, order as “Stratify JCV Antibody (with Index)” not as JCV Ab or JCV PCR (unless checking for actual PML) Check JCV Ab prior to starting Tysabri, and at 1 yr after, then q 6months with MRI q12 months (PML often seen on MRI prior to sxs) If JCV Ab positive, do risk/benefit analysis PML on avg occurs after 48 doses (or 2 yrs) of Tysabri [range 8-136] E.g. if no prior immunosuppressants, Ab index >0.9, limit to 24 doses of Tysabri (use TOUCH program for # doses) JCV Ab status Prior Immunosuppressant Duration of Tysabri – any + 0-2 yrs 2-4 yrs <1:10,000 1:1375 1:128 RISK of PML 1:330 1:31

McDonald Criteria of MS, 2017: New compared to 2015: CSF Oligoclonal bands Can prove Dissemination in time (e.g. in CIS patients) Must be unique to CSF (send gold top with CSF tubes) Asymptomatic and now symptomatic lesions Can prove dissemination in time/space Cortical lesions Also count as MS lesions (not only juxtacortical lesions) Usu needs high resolution research MRIs

Case #1 32M, previously healthy, presents 2 weeks after an episode of R arm weakness that resolved with 5 days of IVMP. MRI is shown. What would you do next? LP shows 8 Oligoclonal bands not seen in serum. Would you treat, and with what? Aubagio oral pill – if no concern for further hair-thinning, and no babies x2 yrs Tecfidera oral pill – more freq GI side effects than Copaxone and a/w PML though rare Copaxone – TIW, if patient is ok with injectable

Case #2 65M p/w numbness in legs for 2 weeks and worsening R leg numbness/weakness for past 5 days. Recalls no prior similar episodes, but reports feeling tired for the past month. MRI is shown. What would you do next? JCV Ab is neg. After 5 days, IVMP, symptoms improve but persist for 3 wks What would you treat with? T2 FLAIR post-Gad T1 Fingolimod oral pill – not a good choice with heart problems Tysabri monthly infusion – good choice for moderate-severe MS, esp in pts w/ fatigue Ocrevus twice yearly infusions – good, safer choice if fatigue is not MS-related

Case #3 32W, with RRMS x5 years, presents 2nd relapse in 3 months. She has been on Copaxone since diagnosis 5 years ago. She is tired of injecting herself but she has been compliant with all her doses. She wants on oral medication. What drug would you change her to? After explaining that switching to Tysabri rather than Fingolimod is more efficacious, she agrees to Tysabri monthly infusions. She is JCV Ab neg and never took an immunosuppressant in the past. 3 months after initiating Tysabri, she has another relapse. What would you do next? Neutralizing Ab’s return positive, so her MS is not necessarily ‘refractory’ to Tysabri. She is switched to Ocrevus, which has a good chance of controlling her disease. 1 month after starting Ocrevus, she has another relapse. What would you do next? It takes 2-3 months for B cell count to decrease and for Ritux/Ocrelizumab to start having efficacy. So you continue medication. 4 months later, patient has another relapse. What would you do next? 2 options left: Lemtrada (safer, more effective) and Novantrone (not used 2/2 side effects, initially FDA approved for SPMS)

Case #4 28W presents to the office after being referred by her ENT doctor for abnormal lesions seen on MRI. She obtained a nose/face MRI for assessment of intranasal warts, and the following findings were seen. She does not report any vision/eye problems, numbness/weakness, or fatigue. Does not ever recall such episodes. Would you treat? She has Radiologically Isolated Syndrome (RIS) and no indication for treatment. However, no data exists on whether to treat or not. Most patients choose to be treated. Clinicians often treat if oligoclonal bands are present, based on extrapolation from CIS data. FLAIR post-Gad T1

For Reference about MS info (provider or patient) National MS Society https://www.nationalmssociety.org/ Templates for Prior-Auth or Denial Letters for MS drugs: https://www.nationalmssociety.org/For-Professionals/Clinical-Care/Resources-for-You- and-Your-Practice/Resources-and-Tools#section-4