AAN 2019: New MS meds in development
New MS drug research continues to be a very active field and many novel therapies are currently being investigated. Some are knock-offs of existing drugs, some are medications used for other diseases that can be retooled for MS, and some are exploring entirely new approaches to controlling the inflammation and damage caused by MS. Here’s a wrap-up of new drug research presented at the American Academy of Neurology’s (AAN) annual meeting, held in Philadelphia in May 2019.
Evobrutinib: Some MS medications (e.g. Ocrevus, Rituxan) work by specifically killing off B cells, a type of immune cell that causes inflammation and damage in the brain. However, B cells can also promote healing, so other ways of targeting B cells have been investigated. One result is evobrutinib. Rather than kill B cells, the drug acts like a thermostat to dial down the B cell’s ability to cause inflammation. Perhaps more importantly, evobrutinib appears to have effects on other immune cells such as macrophages, which directly cause damage to myelin and nerve fibres (Beguem and colleagues. AAN 2019; abstract P2.2.077). A phase II study in people with relapsing MS reported that evobrutinib significantly reduced the number of inflammatory lesions in the brain compared to placebo over 48 weeks of treatment (Montalban and colleagues. AAN 2019; abstract S56.004). The drug has some effects on the liver, so this potential safety issue will need to be examined further. Phase III studies involving more people will be needed to determine if this new treatment is effective in MS.
Vumerity: Tecfidera (dimethyl fumarate) is well-established as an MS treatment, but some people find it hard to tolerate because of stomach upset. So the molecule was tweaked to produce diroximel fumarate (tentatively branded as Vumerity), which may be easier on the stomach. The drug has been submitted for approval by the FDA based on two ongoing trials that haven’t been published yet. According to the interim results from the EVOLVE-MS-1 trial, Vumerity reduced the rate of relapses by 79% from baseline (no comparator group was used) after 48 weeks of treatment, and 87% of people were relapse-free (Arnold and colleagues. AAN 2019; abstract P3.2.060). However, the real test will be the EVOLVE-MS-2 study, which will directly compare Vumerity with Tecfidera to see if it’s easier on the stomach.
Elezanumab: Monoclonal antibodies (such as Tysabri, Ocrevus and Lemtrada) are engineered to target specific proteins involved in disease processes. A new potential target is a protein called RGMa (for repulsive guidance molecule A), a signalling molecule that coordinates the cross-talk between the immune system and the nervous system (Korner and colleagues. Nat Commun 2019;10:633). Laboratory studies have shown that RGMa inhibits nerve regrowth after damage, and that blocking this molecule may promote recovery of nerve function (Tanabe and colleagues. Cell Death Dis 2018;9:1061). A phase I safety study has reported that monthly infusions of elezanumab, which blocks RGMa, appeared to be safe (Ziemann and colleagues. AAN 2019; abstract S56.001). The most common side effect was headache. Larger studies will be needed to determine if elezanumab is effective in preventing or reversing nerve damage in MS.
Thyroid hormone: It’s long been known that people with MS often have abnormal thyroid function (Kiessling and colleagues. Acta Neurol Scand 1980;62:255-258), although the reasons aren’t clear. Subsequent studies in animals found that treatment with one type of thyroid hormone (called T3, or triiodothyronine) appeared to promote remyelination in the brain (D’Intino and colleagues. J Neuroendocrinol 2011;23:778-790). A small study has now examined liothyronine, a synthetic thyroid T3 supplement, in 20 people with MS (Newsome and colleagues. AAN 2019; abstract S56003). The preliminary results indicated that treatment was safe and tolerated well – the necessary first step in drug development – but larger studies will be needed to determine if it improves nerve function.
Ibudilast: This anti-inflammatory drug was developed in the early 1980s and is used in some countries to treat asthma and stroke. Laboratory studies a decade ago found that the drug also inhibited inflammation in the brain and prevented the death of nerve cells (Mizuno and colleagues. Neuropharmacology 2004;46:404-411). A phase II trial subsequently showed that ibudilast slowed brain tissue loss in people with progressive MS, although the effects were very small (Fox and colleagues. N Engl J Med 2018;379:846-855). Side effects included stomach upset, headache and depression. A new analysis of markers of tissue damage in the brain found that ibudilast had no effect (Fox and colleagues. AAN 2019; abstract P3.2.033) – a disappointing result. This suggests that use of ibudilast (if development continues) may be limited to add-on therapy with other medications in people with progressive MS.
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