July 26, 2022

The drug ecopipam shows promise for bringing relief to RLS patients who develop augmentation, a common side effect of dopamine medications.

Stefan Clemens, PhD, HdR, a professor of physiology at East Carolina University, is a member of the RLS Foundation’s Scientific and Medical Advisory Board, and chair of the Foundation’s Research Grant Committee. Regarding the worsening of RLS symptoms known as augmentation, Clemens developed the hypothesis, “Augmentation may be a consequence of increased D1-receptor activation in the nervous system” and that “identifying a new pharmacological target that specifically tackles the long-term side effects of standard dopaminergic treatments in RLS may keep the treatments effective for a longer time or avoid augmentation altogether.”

In other words, a dopamine-1 (D1)-receptor antagonist medication might be a new way to treat RLS and the symptoms of augmentation.

This new concept was first presented by Clemens and his group at the 2015 meeting of the International Restless Legs Syndrome Study Group. In 2016, a small pilot study funded by the RLS Foundation and performed by William Ondo, MD, suggested a positive clinical outcome when patients with RLS augmentation took ecopipam, a D1- receptor antagonist drug.

Clemens obtained a US patent for ecopipam to treat RLS augmentation, and East Carolina University has entered into a licensing agreement with Emalex Biosciences to study this first-in-class medication.

Many regular readers of NightWalkers know the basic facts about RLS treatments and the risks of augmentation, but a bit of history is useful to understand the importance of the new approach. For the 7% to 8% of the adult US population affected by RLS, some 3% need regular daily medication to control their symptoms. The Food and Drug Administration (FDA) has approved three dopaminergic drugs (pramipexole, ropinirole and rotigotine patch) for the treatment of RLS, and for decades these medications were considered first-line therapies for RLS.

Unfortunately, recent research has shown that of the patients on dopaminergic drugs, 7-8% per year develop augmentation so that by 10 years, almost 80% will be augmented and will experience a worsening of their symptoms caused by the drugs themselves. Augmentation typically includes an earlier onset of symptoms, an increase in intensity, a shorter period of rest or inactivity before symptoms start, and the involvement of other body parts (arms, torso or face). There are no FDA-approved medications for the treatment of RLS augmentation.

New clinical guidelines published in 2021 in the Mayo Clinic Proceedings no longer recommend dopaminergic drugs, but rather name iron and alpha-2 delta-ligands, such as gabapentin, first–line treatments for RLS. When a patient’s RLS becomes unresponsive to first- or second–line therapies due to augmentation or other side effects, it is considered refractory (resistant to treatment), and a low-total-daily-dose opioid therapy is the only option currently available. That is why new approaches and new drug therapies are urgently needed.

According to Clemens, ecopipam works by selectively blocking the dopamine D1-receptor subtype, whereas other dopaminergic medications that are used to treat RLS activate other dopamine receptor classes, in particular D3 and D2 subtypes. D3 and D2 receptors mediate inhibitory actions in the nervous system, meaning that they reduce excitability and thus reduce RLS symptoms. Over time, however, those effects wane and the nervous system responds with an upregulation of the D1-receptor subtype, the target of this new drug. In contrast to D3 and D2 receptor-mediated actions, the D1- receptor subtype mediates excitatory action in the nervous system, thus increasing its excitability and increasing the severity of the symptoms. The new drug, ecopipam, is thought to reduce the activation of the D1 receptor and in turn decrease the severity of augmentation symptoms.

The RLS Foundation’s executive director, Karla Dzienkowski says, “RLS augmentation is an untoward side effect of dopaminergic therapy. The potential for a new treatment for this side effect gives hope for the future for those living with the daily impacts of RLS augmentation. It could be a game changer.”