TOLEDO Trial: Apomorphine Infusions Reduce 'Off' Time in Parkinson's Disease

Deborah Brauser

April 20, 2017

Treatment with subcutaneous infusion (SCI) of the dopamine agonist apomorphine (Britannia Pharmaceuticals) can decrease "off" time in advanced Parkinson's disease (PD), new research suggests.

In PD, "off" time refers to the wearing off of a medication's effects as the condition progresses, often leading to periods of immobility. The phase 3 TOLEDO trial is the first prospective and randomized study to assess the efficacy of apomorphine SCI vs placebo to fight this outcome in this patient population, note its investigators. 

TOLEDO showed that the participants who received the active treatment had significantly greater reduction in "off" time between baseline and week 12 than did those who received placebo saline infusions (the primary endpoint). These reductions were seen as early as the first week of treatment and were sustained during the entire 12-week period.

In addition, the apomorphine SCI group had greater "on" episodes without experiencing the treatment-associated adverse event of dyskinesia.

"The results were expected, based on clinical experience, and confirmed that apomorphine is a very efficacious treatment — comparable to deep-brain stimulation surgery and enteral levodopa therapy," coinvestigator Andrew J. Lees, FMedSci, FRCP, The National Hospital, London, United Kingdom, told Medscape Medical News.

Dr Andrew J. Lees

Professor Lees said their findings provide "incontrovertible evidence of apomorphine's efficacy in parkinsonian patients with refractory motor fluctuations."

The findings were released April 19 and will be presented at the upcoming American Academy of Neurology 2017 Annual Meeting (AAN).

Delayed Introduction?

Apomorphine was first produced in 1865, and its first use as a PD treatment in the United States was in 1950, according to an American Academy of Neurology press release. In the 1990s, European doctors started using SCI versions of the drug to treat these patients' mobility fluctuations not controlled by medication.

"Although apomorphine pumps are an established therapy for advanced Parkinson’s disease in many countries, the lack of a randomized controlled trial has delayed introduction of a highly efficacious treatment in the Americas," said Professor Lees.

TOLEDO included 106 patients (100% white) with advanced PD from seven Western European countries. Of these participants, 53 were randomly assigned to receive apomorphine SCI (64% men; mean age, 63.6 years) and 53 were assigned to placebo (60% men; mean age, 63 years).

The mean hourly infusion rate was 4.35 ± 1.39 mg (range, 1.8 - 7.6 mg) in the active-treatment group and 5.00 ± 1.59 mg (range, 1.5 - 7.7 mg) in the placebo group. Infusions were administered over 16 ± 2 hours during waking time.

From baseline to 12 weeks, the apomorphine group had a reduction in "off" time of 2.47 hours vs 0.58 hours for the placebo group (P = .0025).

Those receiving the active infusion also reported higher scores on the Patient Global Impression of Change at the 12-week mark than those receiving placebo (P < .001).

Also, 71% vs 18%, respectively, reported that they felt their symptoms had improved, while 19% vs 45% reported that they had worsened.

Finally, the active treatment "was generally well tolerated and no unexpected adverse events were observed," write the investigators.

"If a person with Parkinson's disease can reduce their off times, that can have a great impact on their everyday life," lead author Regina Katzenschlager, MD, Danube Hospital and the Medical University of Vienna, Austria, noted in the release.

"In some patients in the trial, the insecurity of unpredictable periods of incapacity was completely alleviated," said Dr Katzenschlager.

The investigators add that the findings fill "an important knowledge gap" about the medication.

FDA Approval Coming?

Rajesh Pahwa, MD, professor of neurology and director of the Parkinson's Disease and Movement Disorder Center at the University of Kansas Medical Center, Kansas City, noted to Medscape Medical News that apomorphine injections are currently available in the United States for rescue therapy.

Dr Rajesh Pahwa

"This study used the same medication but subcutaneously. And while this [version] has been available in Europe for several years, it isn't in the US because they have not had good controlled studies to get approval" from the US Food and Drug Administration (FDA), he said.

He added that he sees TOLEDO being more about getting FDA approval than about changing current clinical practice. "Even if I wanted to use it today, I couldn't."

That said, he thinks the study will go a long way toward getting that approval. "It was a controlled study that was positive."

A few limitations he mentioned, however, were the lack of detail about treatment-related adverse events, "which is always an issue as people want to know the safety parts of a study" and its being conducted only in Europe, with no patients from the United States.

"But I think this study is efficacious, and, I think, based on it, the FDA is very likely to approve this route of administration of this drug," said Dr Pahwa.

Old Drug, New Forms of Delivery

Although he wasn't involved with this research, Dr Pahwa published a study in 2007 that looked at subcutaneous apomorphine treatment of PD.

He is also working on the open-label dose-titration part of a phase 3 trial assessing sublingual apomorphine film (APL-130277, Sunovion Pharmaceuticals) for the treatment of off episodes in PD, which will be presented at the upcoming AAN meeting.

The analysis, which included 76 patients, showed that 83% achieved a full "on" with this version of the drug and that there was a 5- to 12-minute onset for clinical benefit. In patients who achieved "on" status, 38% reached this by 15 minutes after treatment and 78% by the 30-minute mark.

In addition, topline results were released last month from a phase 1 pilot study from another investigative team assessing the medication in a sublingual spray (Renown Pharmaceuticals).

Twelve healthy volunteers first received a 2.5-mg subcutaneous injection of apomorphine, followed by 10-, 15-, 20-, and 25-mg doses of the spray. The 25-mg dose "closely replicated the characteristics of the subcutaneous injectable with very fast absorption…and similar peak plasma concentrations," the manufacturer reported in a release.

On the basis of these data, the investigators estimate that time to "on" would be 5 to 10 minutes and the dose to treat "off" episodes would be between 15 and 25 mg "for the majority of patients."

"This was using the same drug in a different route of administration. The idea is that people don't like using injections, so using a spray or a strip would be another way to get the medicine," said Dr Pahwa.

He added that an intranasal spray version had been assessed before, "but because of some nasal problems, that was given up. So this is more of a sublingual spray, which bypasses some of those problems. But it's still a novel control."

Overall, "the idea is to provide rescue therapy for people who have episodes of 'off' times," said Dr Pahwa. "It's an old drug that we know works in Parkinson's, but now it's being used in different ways."

TOLEDO was supported by Britannia Pharmaceuticals; the sublingual film study was supported by Sunovion Pharmaceuticals and Cynapsus Therapeutics; and the sublingual spray study was supported by Renown Pharmaceuticals.

American Academy of Neurology 2017 Annual Meeting (AAN). Emerging Science abstract 9049, to be presented April 25, 2017; abstract 1348, to be presented via poster April 23, 2017.

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