From an idea to an approved medicine

Animal models

Experimental autoimmune encephalomyelitis (EAE) is an animal model of inflammation in the brain and spinal cord, often induced using myelin antigens. Early work in 1933 used repeated injections of brain extracts in monkeys. Later EAE models became important in developing MS medicines. Natalizumab came straight from this work. In 1992 researchers showed that an antibody against a molecule called alpha-4 integrin prevented EAE, and the antibody that became natalizumab was approved for MS twelve years later.[1][2]

EAE resembles the inflammation of relapsing MS far better than the slow worsening of progressive MS, which is one reason medicines that look promising in animals so often fail in progressive disease.[3]

Three phases

Phase 1 trials test safety and dose in a small number of people. Phase 2 trials, often with a few hundred participants, look for an early sign that the medicine works, which in relapsing MS is usually fewer new lesions on MRI. Phase 3 trials, often with hundreds or thousands of participants, followed for a period that depends on the trial design, test whether the medicine changes what matters to patients: relapses or disability.[4]

What a trial compares against

Early MS trials compared a medicine with placebo. Once effective medicines existed, giving placebo for two years to people with relapsing MS became harder to justify, and most new medicines are now compared with an existing one, often interferon beta or teriflunomide. Such trials need more participants to show a difference, and they answer a different question: not whether the medicine works, but whether it works better than another. In progressive MS, where few medicines work, placebo-controlled trials are still usual.[5][6]

Early signals that may not hold

In relapsing MS, a medicine's effect on new MRI lesions predicts its effect on relapses well enough for MRI to guide early trials. Progressive MS has no measure like this yet. The early signals used in its phase 2 trials, such as the rate of brain shrinkage, have often failed to predict the phase 3 result. High-dose simvastatin slowed brain shrinkage in phase 2 and did not slow disability in phase 3.[4][7][8]

Regulators and labels

In Europe the European Medicines Agency recommends whether a medicine should be authorised, and in the United States the Food and Drug Administration decides. They read the same trials but can approve a medicine for different groups of people, so the approved use written on a medicine's label often differs between the two. Ocrelizumab in primary progressive MS is an example.[10][11]

After approval

Rare side effects often appear only when many thousands of people have taken a medicine for years. Natalizumab was withdrawn in 2005, a year after its approval, when cases of progressive multifocal leukoencephalopathy (PML), a serious brain infection, were reported. It returned in 2006 with restrictions, and later studies showed which people are at highest risk.[9][12]

Old medicines, new uses

Some medicines tested in MS were developed for other diseases: simvastatin for cholesterol, metformin for diabetes and clemastine for allergies. They are cheap, their safety is well known and they can move quickly into trials. Because these medicines are often inexpensive or off-patent, commercial incentives may be limited. These trials are often run by universities and funded by charities and public bodies. The Trial Bank shows the sponsor of every trial.[1][2]