BTK Inhibitors in Multiple Sclerosis Treatment - Triumph or Tragedy?
BTK… no my fellow true crime junkies, we are not here to talk about Dennis Rader. BTK inhibitors are a class of drugs that target Bruton’s tyrosine kinase (BTK), an enzyme involved in the activation of B cells. BTK inhibitors have primarily been used in the treatment of certain types of B-cell malignancies, such as Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma. There is great interest in BTK inhibitors as a Disease Modifying Therapy (DMT) for Multiple Sclerosis. This is far from the first time that a cancer treatment has been repurposed to treat MS. For example, the DMT that I take, Kesimpta, is the same drug, ofatumumab, as Arzerra, which is used to treat certain types of cancer, including CLL.
BTK inhibitors have the MS community excited for a couple of reasons. First, the DMTs that are currently available, while effective in preventing relapses and relapse-associated worsening of disability, kind of suck when it comes to preventing progression independent of relapse activity (PIRA). You may have heard this referred to as “smouldering MS”. Researchers have found that, even during periods of remission, there are areas of the Central Nervous System (CNS) of people living with MS that remain in an inflammatory process. Accumulation of disability in people living with MS can occur independent of relapse activity. Additionally, while there have been significant advances in MS treatment over the past couple of decades, little progress has been made for the treatment of Primary Progressive and Secondary Progressive MS. The DMTs currently on the market modulate the peripheral immune response in order to prevent peripheral immune cells crossing the blood-brain barrier and driving the formation of demyelinating plaques, but they aren’t particularly effective in addressing CNS-compartmentalized inflammation. BTK is an intracellular signaling molecule that is involved in the maturation, survival, migration, and activation of B cells and microglia. BTK inhibitors can penetrate the CNS. MS researchers think that BTK inhibitors may be effective against both relapses and PIRA, as they may target B cells and microglia on both sides of the blood-brain barrier. Second, unlike many of the DMTs currently on the market, BTK inhibitors work by modulating B cells rather than killing them. While the selective killing of B cells has proven an effective way to prevent MS attacks (this is the mechanism of action for Rituximab, Ocrevus, Kesimpta, and Briumvi, four of the best DMTs available today), this leaves those of us taking them immunocompromised and therefore more susceptible to viruses, bacteria, and fungi. The DMTs currently on the market may suppress the immune system too much, impacting the patient’s ability to fight infections. If we could find a DMT as effective as these B cell killers, without the downside of immune suppression, all the better.
Several different BTK inhibitors, which vary in selectivity, strength of inhibition, binding mechanisms, and the ability to modulate immune cells within the CNS are currently being investigated in phase 3 clinical trials for MS. The MS Community has been all abuzz about the promise of BTK inhibitors as the future of MS treatment. Many members of Big Pharma have entered a horse in this race, with Merck, Sanofi, Biogen, Novartis, and Roche each heavily investing in their chosen BTK inhibitor. Unfortunately, BTK inhibitors were dealt a blow this week. Merck’s BTK inhibitor, Evobrutinib, flunked it’s trials against Aubagio (Teriflunomide). Aubagio is a recent favourite drug for controlled trials of new DMTs, because it’s effective, but not that effective. Drug companies don’t want to use the most effective DMTs on the market when testing proposed new DMTs, because this would increase the likelihood of the new DMT failing against the control DMT. The Asclepios I and II trials that led to Kesimpta’s approval pitted Kesimpta against Aubagio. Likewise, the Ultimate I and II trials that led to Briumvi’s approval pitted Briumvi against Aubagio. Kesimpta and Briumvi each blew Aubagio out of the water. Aubagio is known to reduce the average relapse rate to approximately one relapse every three years. The annualized relapse rates were near identical between recipients of Evobrutinib and Aubagio in the Evolution trials, equivalent to approximately one relapse every ten years. Surprisingly, Aubagio performed better than expected in the trial, with a lower annualized relapse rate than has been typical in other trials. This may have contributed to Evobrutinib’s failure. Whatever the cause of this underperformance, the results sent shockwaves through the MS community. Several BTK inhibitors have recently been placed on a partial clinical hold by the FDA after patients developed signs of liver injury. We don’t yet know whether BTK inhibitors will be the future of MS treatment, but this week’s news certainly threw a wet blanket on the high hopes that many of us have been holding for these up-and-coming DMTs.
