High Cost Therapy Pipeline News: December 2022

HIGH COST THERAPY PIPELINE NEWS

DECEMBER 2022

NEUROLOGY

Ublituximab Intravenous (IV)

TG Therapeutics

PROPOSED INDICATIONS

Multiple sclerosis, relapsing

FDA APPROVAL TIMELINE

December 28, 2022

 Standard Review

PLACE IN THERAPY

Ublituximab is an investigational glycoengineered (lacking certain sugar molecules) monoclonal antibody (mAb) that targets cluster of differentiate 20 (CD20), a cell surface antigen present on pre-B and mature B lymphocytes. Ublituximab induces potent antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity (CDC). When ublituximab binds to the B cell, it triggers a series of immunological reactions, which include antibodydependent cellular cytotoxicity (ADCC) and CDC, which leads to cell destruction.

• If approved, ublituximab will be the third anti-CD20 mAb to treat relapsing MS (RMS), following ocrelizumab (Ocrevus®) and ofatumumab (Kesimpta®). In non-comparison trials, efficacy of ublituximab appears to be similar to ofatumumab regarding relative reduction in annualized relapsed rates (ARR) reported with ofatumumab compared to teriflunomide (Aubagio®). Ublituximab’s uptake in the MS space may be hindered by ocrelizumab being a well-established therapy for MS. Additionally, ocrelizumab and ofatumumab are also approved for progressive MS and ublituximab has not been studied in progressive MS at this time.

• Ublituximab will be the first B-cell therapy for RMS that can be given as a 1-hour infusion every 6 months, following the initial dose (ocrelizumab is a 2-hour infusion every 6 months).

• In clinical trials, ublituximab demonstrated significantly lower ARR and fewer brain lesions on MRI compared to teriflunomide but did not significantly lower worsening of disability.

BUDGET IMPACT MODEL

ANTICIPATED ANNUAL COST MEMBERSHIP UPTAKE ASSUMPTION

$63,534 to $73,549

YEAR 1 YEAR 2 YEAR 3 YEAR 4

$54,197,043 $0.03 PMPM $170,721,454 $0.08 PMPM $298,764,464 $0.14 PMPM $439,181,673 $0.21 PMPM

Commercial 1% to 7%

$7,835,648 $0.01 PMPM $24,682,403 $0.05 PMPM $43,194,483 $0.08 PMPM $63,495,587 $0.12 PMPM Medicaid $3,265,012 $0.00 PMPM $10,284,835 $0.01 PMPM $17,998,577 $0.02 PMPM $26,457,782 $0.03 PMPM

Medicare

Total dollars are based off the total United States (US) population (standard commercial lives: 176 million; Medicaid: 64 million; Medicare: 44.8M); PMPM = Per Member Per Month

Key Assumptions: Patients with RMS ≥ 18 years of age were included. Uptake predictions (1% to 7% from year 1 to year 4) are based on sales forecasts and feedback from key opinion leaders specializing in neurology and treating patients with MS.

PAYER MANAGEMENT CONSIDERATIONS

Pharmacy Prior Authorization (PA) NA Medical Pharmacy PA 

Site of Service Optimization NA Dose Optimization NA Adherence Program NA

Prior Authorization Criteria Considerations:

• Patient is 18 years or older; AND

• Patient does not have an active infection and has been screened for latent hepatitis B virus (HBV) infection; AND

• Patient has a confirmed (e.g., MRI) diagnosis of multiple sclerosis; AND

• Must be used as a single agent; AND

• Patient has a relapsing form of disease

• Renewal Criteria: Disease response with treatment

UNDERSTANDING YOUR DATA

Ublituximab is a type 1 chimeric immunoglobulin G1 (IgG1) mAb that targets an epitope on CD20 which is distinct from other anti-CD20 targeted epitopes. Ublituximab is glycoengineered with a low fucose (a modified sugar) content in its fragment crystallizable (Fc) region. This enhances the affinity for all variants of FcγRIIIa (or CD16A) and activates natural killer (NK)-cell function. Glycoengineering has been shown to enhance the potency of ublituximab. There are several ongoing clinical trials assessing the efficacy and safety of ublituximab in patients with RMS, which include:

NCT03277261 ULTIMATE I: Phase 3, ublituximab in multiple sclerosis treatment effects

NCT03277248 ULTIMATE II: Phase 3, ublituximab in multiple sclerosis treatment effects

NCT04130997: An open label extension study of ublituximab in subjects with relapsing multiple sclerosis

NCT03381170: An open label extension of the TG1101-RMS201 trial, for subjects currently enrolled in TG1101RMS201 treated with ublituximab for relapsing forms of multiple sclerosis

Identification of patients would reflect the clinical trials criteria listed in the studies above as well as diagnosis codes identified from claims data requiring among others:

Common Measurable Inclusion Criteria:

• Age: 18 years and older

• Diagnosis: Multiple Sclerosis [ICD-10: G35]

CLNICAL DEEP DIVE Disease State Overview

Multiple sclerosis is a complex autoimmune-type inflammatory disease of the central nervous system. Although the etiology is predominantly unknown, MS is a potentially disabling disorder of the brain and spinal cord that occurs when the immune system attacks the protective sheath (myelin) that covers nerve fibers, resulting in communication problems between the brain and the rest of the body. The disorder can eventually cause permanent damage or deterioration of the nerves. Signs and symptoms of MS can vary depending on the amount of damage to the nerves and the nerves that are impacted. Symptoms often affect movement and include numbness or weakness in limbs or legs and trunk, electric-shock sensations occurring with certain neck movements, visual disturbances (e.g., loss of vision, prolonged double vision, blurred vision), slurred speech, fatigue, dizziness, and tingling sensations. While some patients may experience long periods of remission without any new symptoms, others may lose the ability to walk independently or at all. Although there is no cure for MS, there are treatments that help with recovery from attacks, modify the course of the disease, and manage symptoms.

There are core phenotypes of MS including relapsing-remitting (RRMS), which presents with clearly defined attacks (relapses, flares, or exacerbations with full or incomplete recovery), and progressive disease (primary and secondary), as well as clinically isolated syndrome, which often represents the first MS attack. Approximately 50% of patients with RRMS will eventually develop a steady progression of symptoms within 10 to 20 years from disease onset. Some patients will experience a gradual onset and steady progression of signs and symptoms without any relapses, which is considered as primary-progressive MS.

Epidemiology

The prevalence of MS is estimated in every 363 people per 100,000 persons, which equals roughly 1.2 million cases in the US. Women are three times more frequently affected than men and are diagnosed between the ages of 20 and 50 years. About 85% of patients have RRMS. Significant physical disability occurs in over 30% of patients within 20 to 25 years of onset and cognitive function affects 40 to 70% of patients.

Treatment

There is no cure for MS. Treatment typically focuses on preventing new MS attacks, improving physical function, recovery from attacks [e.g., corticosteroids, plasma exchange (plasmapheresis)], slowing the progression of the disease, and managing the symptoms. For RRMS, several disease-modifying therapies (DMTs) are available to modify the progression. Aggressive treatment with these medications as early as possible can lower the relapse rate, slow the formation of new lesions, and potentially reduce risk of brain atrophy and disability accumulation. Due to significant health risks of the DMTs, selecting the right therapy depends on many factors, including duration and severity of disease, effectiveness of previous MS treatments, other health issues, cost, and child-bearing status.

Injectable treatments for MS include glatiramer acetate, interferon beta medications, and ofatumumab. Oral agents include cladribine, dimethyl fumarate, diroximel fumarate, fingolimod, monomethyl fumarate, ozanimod, ponesimod, siponimod, and teriflunomide. Infusion treatments include alemtuzumab, natalizumab, and ocrelizumab. For primaryprogressive MS, ocrelizumab is the only FDA-approved DMT. Dalfampridine is used to slightly increase walking speed. Other medications are used to treat muscle symptoms and fatigue.

DRUG AND CLINICAL TRIAL OVERVIEW

Ublituximab was studied in ULTIMATE I and II, 96-week, phase 3, double-blind, randomized trials evaluating the efficacy and safety of ublituximab compared to teriflunomide in patients (n=1094) with RMS. Patients received ublituximab through IV infusion on day 1, given as 150 mg over four hours then 450 mg over one hour on day 15 then every 6 months thereafter up to 18 months plus oral placebo or oral teriflunomide (14 mg daily) plus IV placebo. Adult patients enrolled in ULTIMATE I had similar demographics to patients enrolled in ULTIMATE II. In addition, patient demographics in the ublituximab arm were comparable to patients in the teriflunomide arm and included a median age 36.2±8.2 years, 61.3% female, 97.4% White, 97.4% had RRMS, and had an average of 1.3±0.6 relapses in the previous 12 months or 1.8±1.0 in the previous 24 months.

The primary outcome was the ARR and ublituximab significantly reduced ARR by 59.4% (p<0.0001) and 49.1% (p=0.0022) relative to teriflunomide, in ULTIMATE I and II, respectively. In ULTIMATE I and ULTIMATE II, ublituximab reduced the mean total number of gadolinium-enhancing lesions by 96.7% and 96.5%, respectively, and new or enlarging T2 lesions by 92.4% and 90%, respectively, relative to teriflunomide (p<0.0001 for all). Pooled analysis of the 2 trials showed a significant increase in confirmed disability improvement (CDI) with ublituximab over teriflunomide at 12 and 24 weeks (116% [p=0.0003] and 103% [p=0.0026], respectively). However, there was no significant difference in confirmed disability progression (CDP) comparing ublituximab to teriflunomide.

Almost half of the patients in the ublituximab group reported having mild to moderate infusion-related reactions (47.7%) and more serious infections occurred in ublituximab group (5%) compared to teriflunomide group (2.9%) despite decrease in frequency of subsequent doses. However, no cases of progressive multifocal leukoencephalopathy (PML) were reported. Adverse events occurred at similar rates between the ublituximab and teriflunomide and the most frequently reported treatment related adverse events reported were infusion-related reactions, headache, nasopharyngitis, pyrexia, nausea, and lymphopenia. Three deaths occurred in the ublituximab group, 1 each due to encephalitis after measles, pneumonia, and salpingitis after an ectopic pregnancy. No deaths were reported with teriflunomide.

PIPELINE (LATE-STAGE DEVELOPMENT)

References:

• ClinicalTrials.gov. Study to assess the efficacy and safety of ublituximab in participants with relapsing forms of multiple sclerosis (RMS) (ULTIMATE I). Available at: https://clinicaltrials.gov/ct2/show/NCT03277261?term=NCT03277261&draw=2&rank=1. Accessed November 28, 2022.

• ClinicalTrials.gov. Study to assess the efficacy and safety of ublituximab in participants with relapsing forms of multiple sclerosis (RMS) (ULTIMATE II). Available at: https://clinicaltrials.gov/ct2/show/NCT03277248?term=NCT03277248&draw=2&rank=1. Accessed November 28, 2022.

• ClinicalTrials.gov. An open label extension of the TG1101-RMS201 trial, for subjects currently enrolled in TG1101RMS201 treated with ublituximab for relapsing forms of multiple sclerosis. Available at: https://clinicaltrials.gov/ct2/show/ NCT03381170?term=NCT03381170&draw=2&rank=1. Accessed November 28, 2022.

• ClinicalTrials.gov. An open label extension study of ublituximab in subjects with relapsing multiple sclerosis. Available at: https:// clinicaltrials.gov/ct2/show/NCT04130997?term=NCT04130997&draw=2&rank=1. Accessed November 28, 2022.

• Landmark study estimates nearly 1 million in the U.S. have multiple sclerosis. February 15, 2019. National MS Society. Available at: https:// www.nationalmssociety.org/About-the-Society/News/Landmark-Study-Estimates-Nearly%C2%A01-Million-in-the-U. Accessed November 28, 2022.

• Olek MJ, Howard J, Gonzalez-Scarano F, et al. Clinical presentation, course, and prognosis of multiple sclerosis in adults. UpToDate. Available at: https://www.uptodate.com/contents/clinical-presentation-course-and-prognosis-of-multiple-sclerosis-in-adults?search=multiple%20 sclerosis&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2. Accessed November 28, 2022.

• Overview: What is multiple sclerosis? Available at: https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/ syc-20350269. Accessed November 28, 2022.

• Steinman L, Fox E, Hartung HP, et al. Ublituximab versus teriflunomide in relapsing multiple sclerosis. N Engl J Med. 2022 Aug 25;387(8):704-714. DOI: 10.1056/NEJMoa2201904.

The information provided has been developed based on available information as of November 2022. This therapy is not yet FDA-approved, and content may change as more information becomes available. Caution should be used when developing formulary and utilization management strategies. The trademarked drug name is the property of its respective manufacturer.

By receipt of this report, each recipient agrees that the information contained herein will be kept confidential and that the information will not be photocopied, reproduced, or distributed to or disclosed to others at any time without the prior written consent of Magellan Rx Management. The information contained in this report is intended for educational purposes only and is not intended to define a standard of care or exclusive course of treatment, nor be a substitute for treatment.

2022 Magellan Rx Management, LLC. All rights reserved. MRX1373_1222

Download the full report at magellanrx.com/pipeline