If the FDA approves Sunovion’s APL-130277 come January, Parkinson’s patients will have a first oral treatment — and a first new treatment in more than a decade — for off episodes, those times of difficulties with movement despite taking treatments that stimulate dopamine receptors, like levodopa.
“We think that for the first time, we may have a product that can be used in a manner that is really effective, accessible, and helpful for patients who suffer from off episodes,” Antony Loebel, MD, Sunovion’s chief medical officer, told Parkinson’s News Today. The U.S. Food and Drug Administration accepted the company’s request to approve APL-130277 in June, and set Jan. 29 as a decision date.
Off episodes, or motor fluctuations, can come in a variety of forms. All affect a Parkinson’s disease patient’s ability to move voluntarily or cause unwanted movement (dyskinesia).
Some involve waking “up early in the morning and be frozen and not able to get out of bed until their morning dose kicks in, which can be in an hour. There are off episodes as the dose wears off,” said David Blum, MD, global head of neurology clinical research at Sunovion. “And there are more unpredictable off episodes that happen because of the internal bizarre nature of dopamine agonists like levodopa for Parkinson’s — erratic off episodes [and] delayed-on, where a patient takes a drug but it doesn’t act for a long time.”
About 40 to 50 percent of all patients experience off episodes, which generally become more severe and less predictable as the disease advances.
Parkinson’s is caused by the progressive loss of neurons that release a neurotransmitter, called dopamine, in the substantia nigra, a part of the brain that controls movement. Levodopa, an oral medication that is absorbed through a patient’s gastrointestinal tract and transported to the brain — where it is converted into dopamine — is considered the gold standard of Parkinson’s treatment.
Levodopa (combined with benserazide or carbidopa in a capsule or tablet) doesn’t stop or slow neuronal death. But it treats some of the disease’s most common symptoms, such as tremors and stiffness, by temporarily making more dopamine available.
Over time and with longer use, a patient’s response to levodopa diminishes and off periods become more frequent.
APL-130277 (apomorphine sublingual film) is not the only treatment targeting these episodes, but it may be more convenient and effective than Apokyn (apomorphine hydrochloride, US WorldMeds), approved in 2004.
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Most off periods last 60 to 90 minutes, so any treatment needs to be fast-acting. Apomorphine — the active ingredient in both Apokyn and APL-130277 — can penetrate the brain quickly and stimulate dopamine receptors to provide short-term, levodopa-like relief. But it’s not easily absorbed when taken orally.
“If you deliver it in a way that bypasses oral absorption,” Blum said, “you can get a rapid rise in apomorphine levels … which kicks the patient from the off state to the on-state.”
Apokyn needs to be assembled and injected under the skin. Blum notes this can be a challenge for patients with movement disorders and their caregivers.
APL-130277 is a quick-acting sublingual treatment. Patients place the two-layer film under the tongue, and the medication is absorbed and transported to the brain. One layer contains apomorphine. The other contains buffers, including an acid neutralizer thought to improve absorption and reduce oral irritation, and a vitamin.
The new formulation may also reduce side effects associated with apomorphine, including nausea, which can be severe due to the treatment’s ability to stimulate a brain area that controls vomiting.
Patients using Apokyn are required to pretreat with Tigan (trimethobenzamide), an antiemetic in that it works to stop apomorphine from triggering this area.
In some APL-130277 trials, including the pivotal Phase 3 trial (NCT02469090), patients also took Tigan, largely because that medication was required in those using Apokyn.
But other studies, like a Phase 2 cardiac safety study (NCT03187301) that opened after the Phase 3 trial was underway did not pretreat with Tigan. Still others left the antiemetic optional. “We found that patients seem to be able to dose without the use of the antiemetic, and we will submit that data to FDA,” Blum said.
He added APL-130277 may be less likely to induce nausea because it is absorbed and processed more gradually than Apokyn.
“We also think there’s a clinical advantage — the pharmacokinetics look a little different … The Apokyn curve [a measure of the amount of the treatment in the body over time] climbs up to a very high peak, then falls off very rapidly. The APL curve has a broader, blunter peak,” Blum said. “We think that lowers the total amount of nausea for APL as compared to the subcutaneous program [Apokyn].”
Data from the completed Phase 3 trial in 109 Parkinson’s patients showed those treated during its 12 weeks improved by a significant 7.6 points — compared to placebo — on the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III. The measure was taken prior to and 30 minutes after APL-130277 treatment at week 12. Part III addresses a patient’s motor skills and function, attributing one point for each type of disability found, such as rigidity. A difference of 4 or 5 points is considered clinically meaningful — and improvement is marked by lower scores.
The treatment’s effectiveness was seen to last for at least 90 minutes, when a final post-dose measure was made.
According to Blum, patients can take APL-130277 as-needed up to five times a day, and most test a range of doses before settling on one that best manages their symptoms with minimal side effects. Most used the treatment two or three times each day.
Sunovion is asking that six doses, ranging from 10 mg to 35 mg, be approved in its FDA request, because “a range of doses allows the patient to fine-tune the doses to get exactly what’s best for them,” Blum said.
Meanwhile, the company is sponsoring a 24-week, open-label extension study (NCT02542696) at sites in the U.S., Canada, and the U.K. Good numbers from the earlier Phase 3 study rolled into this extension, with U.S. sites only continuing to enroll new patients (information can be found here). A total of 226 people are expected to use APL-130277 at one or more of six doses, with outcomes focused on the safety and tolerability of longer-term use, including patient response without Tigan pre-treatment.
Data will also help to support a request for approval in Europe.
APL-130277’s “key benefit,” Blum said, “is the patients turn ‘on’ when they take the product.”
In the pivotal 12-week study, daily use was evident even though no minimum dose was required of participants. Enrolled “patients voted with their feet,” staying with that study and then continuing in the open-label extension that followed, Blum said, taking “an average of two or three doses a day.
“So that indicates they’re getting a benefit and … it’s not given on a prescribed schedule — they chose to use it two or three times a day.”