Close on the heels of the approval last year of the first oral disease-modifying drug for multiple sclerosis (MS), Novartis’s fingolimod, six more late-stage contenders — including novel oral agents and monoclonal antibodies (mAbs) — are next up. As a result, the landscape for immunomodulatory agents is becoming increasingly crowded.
The latest clinical trial results for these relapsing–remitting MS (RRMS) treatment contenders were presented in October at the joint ECTRIMS–ACTRIMS meeting in Amsterdam. A highlight was data for Biogen Idec’s BG-12 (dimethyl fumarate), an orally available small molecule (with a relative molecular
mass of <150) that is thought to act in part by modulating the activity of the transcription factors nuclear factor-κB and NRF2, which have important roles in inflammation. Results from the Phase III DEFINE trial of the drug showed that the drug met its primary end point, significantly reducing the proportion of patients who relapsed at 2 years. Top-line data from the CONFIRM trial — which included Teva’s injectable immunomodulator glatiramer acetate as an active comparator — were reported days after the meeting and provided similarly positive results.
BG-12 so far appears to have a clean safety profile, with flushing and diarrhoea as the main side effects. It also reduced disease progression significantly in the DEFINE trial,
although not in the CONFIRM trial. Based on these data, Biogen Idec says it plans to file the drug for regulatory approval next year. The efficacy and safety findings, combined with the ease of use of the oral agent, have led some analysts to propose that BG-12 could be set to become the best of the oral immunomodulators.
Another promising immuno - modulatory agent, administered by injection rather than orally, is Genzyme/Sanofi’s alemtuzumab, which has already been approved for chronic lymphocytic leukaemia. The CD52-specific mAb — which was one of the first mAbs to be created in the laboratory of Nobel prize winner César Milstein — depletes both T and B lymphocytes, temporarily reducing key inflammatory players ▶
Success of immunomodulators in MS shifts discovery focus to neuroprotectionWith six immunomodulatory agents in late-stage development for relapsing–remitting multiple sclerosis, this area of the therapeutic space has become highly competitive. Could remyelination therapies that provide neuroprotection be the next frontier?
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and potentially leading to the reconstitution of cell populations that are less prone to engage in autoimmune attack. In CARE-MS I, a Phase III trial in treatment-naive patients, the mAb met its primary end point, significantly improving the annualized relapse rate compared with the active comparator, Merck Serono’s subcutaneous interferon-β1a.
The CARE-MS II trial, which tested the mAb in a treatment-experienced patient setting, also recently reported positive data, potentially paving the way for a filing early next year.
The other Phase III candidates include Sanofi’s oral dihydroorotate dehydrogenase inhibitor teriflunomide, Roche/Biogen Idec’s injectable CD20-specific mAb ocrelizumab and Biogen Idec’s injectable interleukin-2-specific mAb daclizumab. Teva’s Phase III immunomodulator laquinimod failed to meet the primary end point in a first pivotal trial, and the company now says it may delay plans to file early next year and could instead initiate another pivotal trial.
Promisingly, all the different approved and experimental therapies offer patients considerable options. Each exerts its effect via a different mechanism of action — in the periphery, at the blood–brain barrier or in the brain — providing a unique safety–efficacy profile and the possibility of personalization if ongoing biomarker efforts prove fruitful. Yet, despite these advances, the successes are also united by a common theme that highlights an outstanding unmet need in MS: they act by modulating the immune aspects of MS, but do not induce the repair of damaged tissue. “We’ve pretty much sorted the inflammatory phase of MS, with whatever drug,” says Alasdair Coles, a neurologist at Cambridge University, UK, and investigator on the CARE-MS I trial. “The big challenge now is neuroprotection.”
The remyelination challengeIn the early stages of RRMS, it is thought that demyelination of axons through autoimmune processes compromises neuronal conduction, resulting in the early neurological deficits. Although endogenous remyelination pathways work to repair axonal damage, this process seems to slow down as the disease progresses. In the more progressive stages of disease, the hallmarks of inflammation fade away even as the rate of neurodegeneration increases. How then can neurodegeneration be delayed?
“The most fruitful avenue for preventing axonal degeneration in MS, most of us would agree, is to induce remyelination itself,” says Timothy Vartanian, a neurologist at Weill Cornell Medical College, New York, USA.
Although there has been some work to protect oligodendrocyte precursors — which generate the cells that are responsible for laying down the myelin sheaths — accumulating evidence suggests that a shortage of these is not typically the problem, he adds.
And so efforts are underway to enhance the efficacy of the endogenous remyelination process. One of the lead remyelination candidates is Biogen Idec’s BIIB033 (also known as anti-LINGO1) — a monoclonal antibody that targets LINGO1, a negative regulator of oligodendrocyte differentiation and myelination. In 2007 Biogen Idec and collaborators showed that gene knockout and antibody antagonism of LINGO1 activity aided the recovery of mice with experimental autoimmune encephalomyelitis, a widely accepted inflammatory model of disease that, despite limitations, has given rise to both glatiramer acetate and Biogen Idec’s natalizumab (Nature Med. 13, 1228–1233; 2007). The same study also suggested that inhibition of LINGO1 activity improved axonal integrity. The mAb is now in Phase I trials.
Another potential remyelination approach that is in the clinic is GlaxoSmithKline’s mAb GSK1223249, which targets Nogo-A, a neurite growth inhibitor. Although the candidate is in Phase I trials for amyotrophic lateral sclerosis, it has been proposed by some as a potential remyelination therapeutic for MS as well.
Yet, although there are few candidates in the clinic, advances in the understanding of the basic biology underpinning remyelination may provide new fodder for translational research. “The field has rumbled along the ground for many years, but in the past 5 years it has really taken off,” says Robin Franklin, a neuroscientist at the University of Cambridge. “I think a lot of companies are dipping their toes in the water here,” he adds.
Industry experts agree. “I’ve noticed that people are starting to take the remyelination approach up,” says Alfred Sandrock, Senior Vice President of Research and Development at Biogen Idec. Mike Panzara, Therapeutic Area Head for Multiple Sclerosis at Genzyme, moreover notes that Genzyme
has a “very active business development and internal efforts to bolster neurorepair and remyelination efforts”.
Neither Biogen Idec nor Genzyme would comment on which targets or pathways they are prioritizing for preclinical research, but several avenues of exploration have recently emerged. Franklin and his colleagues published a paper on the retinoid X receptor-γ (RXRγ) signalling pathway earlier this year, for example (Nature Neurosci. 14, 45–53; 2011). Knockdown or inhibition of the pathway blocked oligodendrocyte differentiation, and administration of RXRγ agonists increased axon remyelination in an aged rat model of demyelination. “We are now pursuing strategies to develop isoform-specific agonists that can target RXRγ,” says Franklin. Other pathways that are getting attention include the WNT pathway, chemokine receptor pathways, the Notch pathway and growth factors for oligodendrocytes (FEBS Lett. doi:10.1016/j.febslet.2011.08.017).
Sandrock points out that recent advances in genetics are providing hints for new pathways too. A recent paper in Nature identified 29 new susceptibility loci for MS and replicated many of the previously identified associations (Nature 476, 214–219; 2011). “We now have more than 50 polymorphisms that increase the risk of MS,” says Sandrock. “Many of these are in the immune pathways, but many are not. These could provide clues as to how to prevent neurodegeneration.”
While drug discoverers search for suitable targets — and work towards developing animal models that better replicate the neurodegenerative aspects of disease — drug developers have their hands full with the clinical challenges of testing remyelination therapies. Two key questions plague the space: which patients are most likely to respond, and how can you measure remyelination?
On the patient population front, explains Vartanian, there are a couple of difficult questions. If you enrol patients with RRMS who are at an early stage of the disease and look for remyelination either specifically within lesions or across the whole brain, then there may not be a large enough signal-to-noise ratio to detect an effect if endogenous remyelination processes are active in these patients. However, if you take patients with more progressive disease — who will have the most marked demyelination and are in most need of new treatments — then the extensive glial scarring and modification of the extracellular matrix around damaged axons may not be conducive to remyelination. “I think in reality you are probably going to want to test both types of patients,” he suggests.
The field has rumbled along the ground for many years, but in the past 5 years it has really taken off.
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In regard to an end point for success in these trials, as yet there are no non-invasive surrogate markers for quantifying myelin in the human brain and/or spinal chord. But, says Vartanian, progress is being made. In particular, he points to the advances in positron emission tomography scanning and magnetic resonance imaging tools — including the myelin water fraction, the magnetization transfer ratio and DESPOT post-processing approach — as leading possibilities. “I think we
are very close to the place where we can come up with a quantitative measure,” he says.
And so despite the hurdles, the view that remyelination therapies are the way forward is becoming increasingly widespread. “The MS treatment of the future is a drug to treat inflammation and stop relapses, plus another drug to provide neuroprotection,” says Coles. And although the immunomodulatory space is increasingly crowded, the remyelination approach remains wide open.
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