November 9, 2015
Multiple Sclerosis (MS) is a degenerative, chronic immune-mediated disease of the central nervous system (CNS). Pathologic features of MS disease lesions include inflammation, demyelination, axonal degeneration, and neuronal loss. Although prevalence and incidence are not reliably tracked within the U.S., MS is the most common neurological non-traumatic cause of disability in the western world, with an estimated worldwide prevalence of 2.3 million individuals affected. In most patients, the disease initially presents as a relapse remitting condition (RRMS); over time, most RRMS patients eventually progress and develop secondary progressive MS (SPMS). See Figure 1 for an illustration of the typical MS disease course. Clinical symptoms of MS include motor and sensory deficits, partial or complete visual loss, diplopia, and impaired coordination. Diagnosis involves assessing CNS damage and inflammation via magnetic resonance imaging (MRI), visual evoked potentials, and cerebrospinal fluid analysis. The current landscape of disease-modifying therapies for MS is comprised of recombinant proteins, antibodies, and several emerging oral agents.
Shown below, we have devised a MS competitive landscape map, which separates approved, investigational, and discontinued therapies into two groups based on broadly defined treatment objectives. The first group includes all currently approved therapeutics, and comprises therapies aimed at modifying disease course through reducing autoimmune activation. The second group has fewer clinical assets, all of which are still in development, and are aimed at reversing nerve damage and promoting remyelination.
Leading first-line therapies
The mechanistic basis for currently approved disease-modifying MS therapies revolves around reducing aberrant immune activation and associated inflammation. Recombinant interferon-β1a was the first drug to be used widely in the first-line RRMS setting and has been demonstrated to decrease the annual relapse rate of RRMS by approximately 30% (see Figure 2 for cross-trial comparisons of annual relapse rate). For example, Rebif, which is administered as a subcutaneous injection, was approved following multicenter, double-blind, placebo-controlled phase III trials. Recombinant interferon-β1a is well tolerated and common side effects include flu like symptoms, increase in liver enzyme activities, and injection-site reactions. In 2014, Biogen received FDA approval for a pegylated version of interferon-β1a (Plegridy), which has better pharmacokinetic properties than previous interferon-β1a drugs like EMD Serono’s Rebif, allowing for less frequent dosing. Teva’s Capoxone (glatiramer acetate) is another first-line treatment for RRMS and consists of a four amino acid synthetic copolymer based on the composition of myelin basic protein. The myelin-based oligomer mixture acts as a myelin immune decoy and functions to divert autoreactive immune activity away from nerves in the CNS. Capoxone was approved after a single multicenter, randomized phase III trial using MRI activity as a primary outcome. Capoxone has an efficacy profile similar to that of Rebif, and similarly reduces the annualized relapse rate of RRMS by approximately 30%. Common side effects include injection site reactions in approximately 15% of patients. The value and market share of Capoxone is on the decline with recent 2015 FDA approval of Glatopa, a generic form of Capoxone, co-developed by Novartis and Momenta Therapeutics. Both interferon-β1a and glatiramer acetate require regular self-administered injections and are therefore complicated by issues of tolerance and adherence, which reduce the likelihood of durable efficacy.
Biogen’s Tecfidera (dimethyl fumarate) is the only oral agent currently used in first-line RRMS. Tecfidera is also commonly used in the second line in patients failing interferon-β1a treatment. Although the molecular mechanism of Tecfidera is unclear, it involves immunosuppression via activation of the NRF2 pathway. Tecfidera was approved on the basis of a 47% reduction in the annual relapse rate (see Figure 2 for cross-trial comparison). The ease of administration and tolerability profile of Tecfidera should enable it to continue gaining market share of older injectable interferon-based drugs.
Leading second-line therapies
Second-line treatments for RRMS have significantly improved efficacy profiles relative to first-line counterparts but are commonly associated with more serious side effects. However, if a patient is experiencing relapses and disability progression while on interferon-β1a, Capoxone, or Tecfidera a neurologist may decide to switch patients to more effective second-line therapies. The most effective option for progressing patients is Biogen’s Tysabri (natalizumab), a humanized monoclonal antibody against a4-integrin. Tysabri prevents immune-cell mediated inflammation by stopping leukocyte migration from the periphery into the CNS by disrupting vascular cell adhesion molecule (VCAM) interactions on endothelial surfaces. In a pivotal phase III trial, Tysabri, administered monthly as an intravenous infusion, reduced the relapse rate of RRMS by 68%, and produced a 92% reduction in Gd-enhancing lesions as detected by MRI. In approximately 3.4/100 patients Tysabri use is associated with the development of progressive multifocal leukoencephalopathy (PML), a potentially fatal complication. The presence of anti-JC virus antibodies and immunosuppressant exposure are risk factors used to stratify patients and mitigate the development of PML. Tysabri’s safety profile will likely limit its use to second-line RRMS.
Emerging clinical candidates poised for market success
Roche’s humanized anti-CD20 antibody, ocrelizumab, is an emerging competitor, and with an expected FDA filing to occur in mid-2016, it is poised to steal market share from Tysabri, and perhaps Tecfidera, in second-line RRMS. The anti-CD20 mechanism involves systemic depletion of CD20+ lymphocytes and thus reduces the pool of autoreactive immune cells capable of infiltrating and damaging the CNS. Recent phase III data of ocrelizumab demonstrated an absolute 80% reduction in the annual relapse rate, and a 95% reduction of Gd-positive lesions compared to Rebif in RRMS. In addition, ocrelizumab has demonstrated a 25% reduction in disability on progression in Primary Progressive MS (PPMS) – a smaller MS population with an aggressive disease progression that has few therapeutic options. Many analysts believe activity in PPMS may afford Roche an opportunity for accelerated approval. Although the long-term safety profile of ocrelizumab is unknown, a history of off-label Rituximab use (anti-CD20) provides some context for future expectations. The impressive efficacy profile of ocrelizumab should make a solid case for use in second-line RRMS patients.
By way of recently acquiring Receptos, Celgene is developing ozanimod (RPC1063), a next-generation, selective oral sphingosine-1-phosphate receptor-1 (S1PR) modulator currently in phase III. S1PR modulators act through functional S1PR1 antagonism, which results in the sequestration of lymphocytes in lymph nodes and prevents trafficking of autoreactive immune cells to the CNS. Gilyena, a S1PR modulator currently marketed by Novartis, is the incumbent in this space. However, Gilyena binds broadly to S1PRs and possess cardiovascular toxicity due to high affinity for S1PR3. Since onzanimod is highly selective for S1PR1, it should be significantly differentiated from Gilyena, potentially offering a better efficacy and safety profile. Novartis has received two reports of the development of PML with patients on Gilyena; however, both of these patients were previously on Tysabri; therefore, the risk of PML development may not be attributed to S1PR modulation. It is not yet clear if this potential PML liability could be mitigated with the better selectivity profile offered by ozanimod. Should ozanimod demonstrate a clean safety profile in phase III it will likely be used in first and second-line RRMS, primarily competing against Biogen’s Tecfidera. Ozanimod is currently projected to launch in 2018.
Repairing nerve damage by targeting demyelination
Although disease-modifying therapies that address inflammation have significantly advanced the treatment of MS, they fail to address persistent demyelination and subsequent axonal loss; thus, they fail to prevent the onset of disability in MS patients. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination may improve long-term outcomes through reversal of axonal injury. LINGO-1 is a leucine-rich repeat and Ig domain containing protein expressed exclusively in the CNS on both oligodendrocytes and neurons. In preclinical models, monoclonal antibodies against LINGO-1 have been shown to negatively regulate oligodendrocyte differentiation and myelination, neuronal survival, and axonal regeneration. Biogen is currently developing a monoclonal antibody against LINGO-1 (BIIB-033) for RRMS. Although BIIB-033 recently missed secondary endpoints in a phase II study of patients with acute optic neuritis, there was clinical evidence of activity with improved optic nerve conduction latency, indicative of a drug-mediated remyelination mechanism. A headline risk for the Biogen anti-LINGO-1 program is the limited CNS penetration of BIIB-033. Since LINGO-1 expression is restricted to the CNS, Biogen is attempting to make up for this liability by aiming to achieve high systemic concentrations of anti-LINGO-1. Still, it’s unclear whether they will be able to achieve adequate BIIB-033 CNS exposure and enough target engagement to elicit a biological effect in RRMS patients. The phase II study of BIIB-033 in RRMS will read out mid-2016. At its recent R&D day, Biogen mentioned the ongoing development of an oral remyelinating compound (BIIB-061; undisclosed mechanism of action), potentially with better BBB penetration and CNS exposure, to enter phase II in 2016.
The clinical armamentarium of effective agents used to modify the course of MS has grown substantially in recent years. Although guidelines on implementing novel disease-modifying therapies in MS have not yet been issued by NIH, expert commentary suggests that oral therapies, such as Tecfidera, are likely to supplant older interferon-based injectables due to ease of use and tolerability. More potent and less tolerable agents, such as antibodies acting against infiltrating immune cells, will most likely continue to be used in the second line for patients who have failed a prior line of therapy. A remaining challenge to the field involves an incomplete understanding of the molecular mechanisms of neurodegeneration. In our view, in order to unlock the next generation of therapies, the development of novel imaging techniques and relevant biomarker strategies will be critical. MS treatment decisions will continue to be driven by provider and patient preference based on a blend of cost, risk, and efficacy.
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Publicly traded companies mentioned: Acorda Therapeutics (ACOR), Biogen (BIIB), Celgene (CELG), Eli Lilly (LLY), Momenta Therapeutics (MNTA), Novartis (NVS), Roche (RHHBY), Sanofi (SNY)
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