General description for public users. This is the public user homepage for the Multiple Sclerosis (MS) Therapeutic Area. The MS area is undergoing exciting change as new compounds are entering the marketplace. The next 5 years holds promise for dramatic paradigm shifts in the management of MS patients.
The STEPh REPORT for Multiple Sclerosis reviews compounds and development programs currently under study from preclinical through NDA submission. Information is reviewed in multiple formats:
- mechanism of action
- phase of development
- projected year of approval
In addition, each compound has its own monograph that expands on the clinical efficacy and safety information reported during clinical trials. Where available, links are provided to abstracts of relevant information such as published literature, SEC filings, and press releases. The Multiple Sclerosis STEPh REPORT is kept current as new information becomes available (e.g., new reports are uploaded every other month). After downloading the STEPh REPORT, you can select the bookmark function from the PDF file for easy maneurverability through the document.
The Multiple Sclerosis homepage also includes links to relevant resources, daily and archived MS news of interest, mini-reviews of Hot Topics, and a continuously updated Pipeline Table.
Access to the full Multiple Sclerosis STEPh REPORT as well as the other information in this section of the web site is available by subscription. Please feel free to contact us for more information about becoming an active subscriber to this and other services offered by STEPh Inc.
Table of Contents
TABLE OF CONTENTS
OVERVIEW OF ORAL AGENTS
Table 1. Comparative Properties of Late Stage Oral Compounds
Table 2. Earlier Phase Oral Agents
Table 3. Oral Agents in Development for MS
Table 4. Earliest Possible Approval Dates for Oral Agents
OVERVIEW OF MONOCLONAL ANTIBODIES
Table 1. Monoclonal Antibodies in Development
OVERVIEW OF S1P AGONISTS
Table 1. Comparative Pharmacology Data for Some S1P Agonists
Table 2. S1P Modulators in Development for MS
Table 3. Earliest Possible Approval Dates for S1P Modulators in Development
OVERVIEW OF VACCINES AND INTERFERONS IN DEVELOPMENT
Table 1. Vaccines in Development for MS
Table 2. Interferons in Development for MS
Table 3. Earliest Possible Approval Dates for Interferons and Vaccines in Development
OVERVIEW OF AGENTS IN DEVELOPMENT as PART of COMBINATION or vs. ACTIVE COMPARATOR
Table 1. Agents Currently Under Study as Part of a Combination Treatment Regimen
Table 2. Agents Currently Under Study vs. an Active Comparator
OVERVIEW OF AGENTS IN DEVELOPMENT FOR CIS, PPMS, and SPMS
Table 1. Agents in Development for CIS, PPMS, and SPMS
OVERVIEW OF GENERIC COPAXONE AND ALTERNATIVE FORMULATIONS OF GLATIRAMER
OVERVIEW OF AGENTS UNDER STUDY FOR NEUROMYELITIS OPTICA (NMO)
Table 1. Currrent Treatment Approaches Studied for NMO
OVERVIEW OF COMPOUNDS AVAILABLE FOR LICENSING
Table 1. Compounds Available for Licensing
COMPANIES INVOLVED IN MULTIPLE SCLEROSIS RESEARCH
Table 1. Companies Involved in Multiple Sclerosis Research
Table 2. Earliest Possible Year Respective Companies Will Introduce New MS Products
INDIVIDUAL DRUG MONOGRAPHS
Table 1. Phase of Development for MS Compounds
Table 2. Earliest Possible Approval Date for MS Compounds in Development
Alphabetical Listing of Individual Drug Monographs
The mainstay of treatment for MS has historically consisted of a relatively small group of injectable drugs that includes interferons, glatiramer acetate (Copaxone), and natalizumab (Tysabri). The recent approvals of fingolimod (Gilenya), teriflunomide (Aubagio), and BG-12 (Tecfidera) has signaled a change in treatment paradigm to early use of a more convenient orally administered drug.
Drug Development Pipeline
There are ~65 agents currently in development (i.e., preclinical to NDA submission) for treatment of MS. The categories of agents that have drawn the most research interest include orally administered compounds, modulators of sphingosine phosphate, monoclonal antibodies, and improved/longer-acting versions of interferon. Stem cells have drawn recent interest and at least two programs are currently in progress.
Oral Agents and Sphingosine Phosphate (S1P) Modulators
To date, three oral agents (i.e., Gilenya, Aubagio, Tecfidera) have been approved for licensing in the US. Although cladribine was approved in a handful of foreign countries, it was subsequently withdrawn from all markets in 2011 after it was formally rejected for approval by FDA (2011).
- There are several oral agents currently in late phase development (i.e., laquinimod, BAF312). Results of pivotal registration studies suggest that BG-12/Tecfidera and Gilenya hold the most commercial promise while the effectiveness of laquinimod was numerically inferior to interferon. A third phase III trial (termed CONCERTO) for laquinimod has been deemed necessary by FDA before this compound can be approved in the US; the trial began 1Q2013. A phase III trial for BAF312/siponimod in SPMS began December 2012.
- The NDA for teriflunomide was accepted for filing by FDA in October 2011 and Aubagio was approved September 2012. The NDA for BG-12/Tecfidera was submitted February 28, 2012, accepted for filing in the US and Europe, and was approved by FDA in March 2013. The NDA for laquinimod has been delayed following poor results of late-stage trials. The drug failed in one trial and yielded disappointing results in a second. A third phase III trial is underway (CONCERTO) according to a Special Protocol Assessment and includes 2 dose levels (0.6 mg, 1.2 mg) administered to ~1800 patients over 24 months.
- Although BG-12/Tecfidera is generally well tolerated, initial trials were conducted with BID and TID regimens of two capsules per dose. Tecfidera was approved as a BID therapy.
- Given the initial commercial success of Tecfidera, development of similar fumarate Nrf2 activators (XP23929 phase I; FP187 phase II) will be closely watched. It remains to be determined if the newer fumarate drugs formulations will offer tolerability and/or dosing advantages over Tecfidera.
- There are approximately 20 oral drugs (of which the majority is S1P modulators) in various stages of development but most of these are not expected to be approved for several years.
- S1P receptors are located throughout the body. Preclinical data suggest there may be differences among S1P modulators with respect to specificity for individual receptor subtypes. However, results of animal studies may not be totally predictive of potential effects in humans. In this regard, fingolimod was the subject of US and European regulatory review for its effects on the heart, with subsequent changes made to official labeling in the US and Europe. Clinical trial data indicate that effects on the heart may be seen with all members of this class of drug and sheds further light that preclinical data in animal models are not totally predictive of pharmacodynamic effects in humans.
Monoclonal antibodies affect the autoimmune process by influencing a specific target cell (B-cell, lymphocytes in general) or receptor (VLA-4, or IL2), thereby reducing inflammation and the incidence of disease relapse. They all share favorable dosing schedules, are costly, have powerful immunosuppressant effects, and may be associated with risks for opportunistic infections. Immune responses to the antibodies are common, and hypersensitivity reactions as well as anti-idiotypic antibodies can occur.
- Given very favorable preliminary efficacy data for this class and their convenient dosing schedules, they should impact future use of Tysabri.
- There are more than one dozen monoclonal antibodies currently under study with 3 in phase III development or already submitted for approval (i.e., alemtuzumab, daclizumab, ocrelizumab). Long-term data (out to 5 years) has been generated for alemtuzumab and this agent is likely to be approved (late-2013) prior to the others [alemtuzumab was approved by European Commission in September 2013 for the treatment of adult RRMS patients with active disease defined by clinical or imaging features in a dosage of 12 mg IV infusion on 5 consecutive days followed by a second course on 3 consecutive days at 12 months later]. Alemtuzumab may find utility as a 1st- and 2nd-line agent.
- Clinical data from phase III trials show similar efficacy between alemtuzumab and daclizumab. Although alemtuzumab has a more acceptable dosing schedule than daclizumab, it is associated with a relatively high incidence of autoimmune side effects. In the phase III trials, 16%-20% of patients developed an autoimmune thyroid-related adverse event and ~1% developed immune thrombocytopenia. Regarding daclizumab, some investigators question its safety with respect to autoimmune-related side effects on the kidney and liver as well as cutaneous effects.
- Initial phase II data for ocrelizumab were very promising (80% reduction in ARR at 98 weeks) and phase III trials for RRMS and PPMS are ongoing.
There are several interferons in various stages of development with a PEGylated version of Avonex (i.e.,BLA) being the furthest along in the clinical trials process.
- The major advantage of the newer interferons is a reduced dosing frequency. It is hoped that future interferon products may be administered once every 2-4 weeks.
There has been some new recent development information on vaccines for MS. Tcelna is currently being studied (initiated fall 2012) in a phase IIb trial for SPMS and this agent holds promise in this class. A phase IIb trial for NeuroVax™ was initially projected to begin end-2012 but a start date of end-2013 is more likely. An early phase II trial with MyeloXen™ is underway in Russia.
Future Treatment Paradigm
With the coming arrival of additional oral agents, the notable clinical efficacy observed for monoclonal antibodies, the improved dosing schedule for next-generation/long-acting interferons, availability of a JCV assay for potential Tysabri users, and potential availability of several generic versions of Copaxone, clinicians will soon have many more options with respect to treatment of RRMS patients.
- Oral agents with demonstrated improved efficacy over interferon, and long-acting interferons will likely supplant currently available interferons as initial therapy for many patients.
- Combination therapy trials are in progress and initial results for several drug combinations have been encouraging. Although currently unknown, use of drug combinations may delay the need for more aggressive therapies. However, combination therapy is extremely costly and may only find utility when other treatment approaches fail. Future availability of generic interferons will make combination therapy more attractive.
- Monoclonal antibodies may provide a suitable alternative to Tysabri.
Several agents are undergoing study for more progressive forms of MS (including fingolimod, BAF312, Tcelna, ocrelizumab, masitinib, anti-LINGO, MIS416, idebenone, ibudilast) but none are expected to receive approval for some time. If trial results are positive, clinicians will have treatment options for a segment of MS patients that are not currently adequately served by available agents.
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