During the virtual 2021 American Academy of Neurology (AAN) Conference on April 17–22, Sunovion Pharmaceuticals discussed the debate over the earlier introduction of on-demand therapies for Parkinson’s disease (PD) patients who are experiencing off-episodes.
In the symposium “Navigating the Treatment Options for Off-Episodes in Parkinson’s Disease: The Role of On-Demand Treatments”, a panel of expert neurologists showcased the best approach to help manage the burden of off-episodes by using on-demand therapies. Traditional Parkinson’s treatment left a major unmet need, with up to 50% of patients having off-episodes after a few years of taking oral levodopa, which is currently the standard care. Some drugs have recently been approved to treat acute off-episodes, as on-demand options are easier to use and more effective. As a result, there is likely to be a shift towards incorporating on-demand therapies early at the onset of off-episodes.
Off-episodes are periods when patients experience worsening and fluctuating symptoms despite being on medication. This occurs because of the short half-life of levodopa and the limitations of the gastrointestinal (GI) tract, which become increasingly affected as patients continue to use levodopa and their disease progresses. Typically, physicians start adjusting the levodopa dosing frequency and prescribe oral adjunctive therapies to lower the frequency of these episodes. These include adding dopamine agonists, catechol-o-methyl transferase inhibitors, or monoamine oxidase type B inhibitors, all of which offer a reduction of only 0.6–2.2 hours per day against 5.4–7.0 hours per day of baseline daily off-time.
Physicians sometimes offer patients an additional on-demand treatment, also called rescue medication, for the acute intermittent treatment of off-episodes. They start their action within 10 minutes and bypass the GI tract so they are not affected by dietary considerations, unlike levodopa.
Until 2018, the only on-demand drug that was approved for off-episodes was Supernus’ Apokyn (apomorphine), which is a subcutaneous injectable pen that can be given up to five times daily. Acorda’s Inbrija (levodopa inhalation powder) was approved in the US in 2018 for the same indication, creating another option for patients who had difficulties using the injections. However, some patients experienced difficulties when using Inbrija as it requires manual loading of the capsules into the inhaler device, which can be difficult for advanced-stage patients, in addition to the risk of cough and upper respiratory tract infections.
In 2020, Sunovion’s Kynmobi (apomorphine sublingual film) was approved by the FDA. Compared with Apokyn and Inbrija, Kynmobi is the simplest and easiest to use, but the three options appear to be equally efficacious in managing off-episodes. This has led some to argue the potential benefits of adding these on-demand treatments early following the onset of off-episodes, as opposed to keeping them as the final resort after other adjunctive therapies become less effective. The data that support the early use of on-demand therapies shows that oral adjunctive therapies may worsen other dopaminergic side effects, such as dyskinesia and psychotic behavior. Additionally, increasing the dosing frequency of levodopa requires delaying meals and restricting dietary protein, leading to unintended weight loss and a complex treatment regimen resulting in an increased risk of nonadherence.
The recent launch of Kynmobi, with its favorable oral administration, is expected to drive the uptake of on-demand medications and encourage physicians to prescribe these treatments on a larger scale. GlobalData estimates that Kynmobi will have total sales of $361M by 2029 in the US, versus $180M for Inbrija and $102M for Apokyn.
The treatment of PD patients is associated with many complications, so it is highly individualized according to each patient’s needs. This means most effective treatment approach is ultimately targeting the patient’s most bothersome complications and tailoring the dosing regimen of different add-on medications according to the patient’s lifestyle requirements.