MS Therapeutics Claudiu Diaconu Neuroimmunology Fellow 2018 withdrawn

MS Therapeutics Claudiu Diaconu Neuroimmunology Fellow

2018: withdrawn, due to autoimmune hepatitis and liver failure leading to deaths 2016: Zinbryta ® daclizumab 2017: Ocrevus ® ocrelizumab

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 Tecfidera & Copaxone – nodes Immunomodulation of Th 1 (proinflam) to Th 2 (anti-inflam) Lemtrada– Anti-CD 52, found on all lymphocytes (T cells, NK Cells, B cells) Rituximab and Ocrevus – Anti-CD 20, 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) Fingolimod (Gilenya) - Binds S 1 P to block egression of T-cells from lymph nodes • T-cells become activated towards myelin Interferon beta (Avonex, Rebif) - Dec antigen presentation (Aubagio) - Shift to antiinflam environtment • Activated T-cells then infiltrate CNS 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 Th 2 profile (immunosuppressive) Natalizumab (Tysabri) - Monoclonal Ab binds to integrins to prevent adhesion of activated T-cell to endothelial cell of BBB • CNS T-cells attack and damage myelin Dimethyl fumarate / BG 12 (Tecfidera) - Activates oxidative stress protective pathways in neurons and microglia - Immunomodulatory (shift from Th 1 [cell-mediated envir] to Th 2 [humoral-based])

Interferon Beta (IFNB) drugs: IFN-beta 1 a & 1 b Both are interferon beta 1 a. Avonex is IM q. Wk; 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 1 a & 1 b VS ? No trials compared these Both are interferon beta 1 a. Avonex is IM q. Wk; 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. Also interferon beta 1 a, that is pegylated with a polyethylene glycol (PEG) group to increase half-life and improve tolerance. Given SC q 2 wk. 2017: Ocrevus ® ocrelizumab

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

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

Copaxone (Glatiramer Acetate): safest, best tolerated Copaxone VS IFNB 1 b: - Similar efficacy - Copaxone better tolerated - PMID: 11997066 Copaxone: - 20 mg QD or 40 mg TIW - SE: GI sxs, N/V, abm pain (usu improve with time); flu-like sxs less common Copaxone is most often the medication of choice for initial therapy for non-severe MS, and if patient is okay with injection Generic Copaxone 2017: Ocrevus ® ocrelizumab

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

Oral DMD’s Efficacy: Gilenya (~Tysabri) > Tecfidera [fingolimod] Gilenya (1 st 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 [dimethyl fumarate, BG-12] = Aubagio [teriflunomide] Gilenya VS Tysabri - meta-analysis of placebo-controlled RTCs & observational studies - Tysabri decreased # of relapses more than Gilenya at 2 yrs - No diff btwn relapsefree 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 [fingolimod] Aubagio (Once daily) - Better than Placebo (TEMSO, TOWER trials) - SE: GI sxs (N/V, pain, etc), hepatoxicity, hair-thinning - Teratogen (also in semen, remains x 2 yrs after stopping, so needs charcoal tx prior to pregnancy) [dimethyl fumarate, BG-12] = Aubagio [teriflunomide] 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 - Aubagio & Tecfidera are safer than Gilenya and probably slightly less efficacious PMID’s: 27645339, 27919491, 27733070 2017: Ocrevus ® ocrelizumab

INFUSIONS: Novantrone , Tysabri, Lemtrada, Ocrevus [mitoxantrone] 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 [natalizumab] [alemtuzumab] [ocrelizumab] Lemtrada (for RRMS; anti-CD 52, 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 Rituximab Replaced with Lemtrada used for MS refractory to Tysabri or Ritux/Ocrevus (since Lemtrada is broader in terms of target cells) 2017: Ocrevus ® ocrelizumab

Ocrevus® [ocrelizumab] infusion • Anti-CD 20 (anti B cells, like Ritux, but binds to different site on CD 20) • 300 mg IV infusion x 2 (2 wks apart), then 600 mg IV q 6 months • Approved in 3/2017 for RRMS and PPMS • OPERA I & II Identical Trials – compared to IFNB-1 a, 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 T 2 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 Rituximab Replaced with 2017: Ocrevus ® ocrelizumab

SUMMARY – 2 nd Line Drugs – 1 st 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) Rituximab Replaced with 2017: Ocrevus ® ocrelizumab

SUMMARY – 3 rd 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 Rituximab Replaced with 2017: Ocrevus ® ocrelizumab

Drug Monitoring • Interferon Beta – check q 6 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 q 6 mo/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): JCV Ab status Prior Immunosuppressant Duration of Tysabri RISK of PML – – any <1: 10, 000 + – 0 -2 yrs 1: 1375 + – 2 -4 yrs 1: 128 + + 0 -2 yrs 1: 330 + + 2 -4 yrs 1: 31 • If no prior immunosuppressant use, a JCV Ab index <0. 9 = low risk of PML • In All. Scripts/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 6 months with MRI q 12 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)

Mc. Donald 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 • 32 M, 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 x 2 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 • 65 M 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? T 2 FLAIR post-Gad T 1 • JCV Ab is neg. After 5 days, IVMP, symptoms improve but persist for 3 wks • What would you treat with? 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 • 32 W, with RRMS x 5 years, presents 2 nd 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 • 28 W 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? FLAIR post-Gad T 1 • 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

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-Youand-Your-Practice/Resources-and-Tools#section-4