A core unmet need in Parkinson’s disease (PD) is a new way to address “off” time, a term that refers to the return of motor symptoms when a dose of levodopa (the standard of care in PD) wears off prematurely or doesn’t provide full therapeutic benefit. DRG’s epidemiologists estimate that as many as 40% of PD patients experience wearing “off” in a given year, and nearly all PD patients eventually develop wearing “off” over the course of the disease. In early stages of PD, “off” periods can be addressed by taking levodopa more frequently and adding supplemental medications, but in more-advanced stages, today’s chronic medications are not always sufficient to prevent wearing “off”.
APO-go PEN/Apokyn, a subcutaneous injection of apomorphine, is approved for the acute (rescue) treatment of “off” episodes in advanced PD across the G7. There is no doubt that Apokyn is effective: 90% of patients who use it convert from “off” to full “on” within 20 minutes, and the motor improvement is considerable.1 But injections require the help of a caregiver, and interviewed KOLs report that patients feel a stigma associated with injecting themselves in public. Moreover, it causes several unpleasant side effects and patients must be pretreated with an antiemetic to prevent vomiting. Finally, it’s a costly medication in a cost-sensitive population. As a result, it’s no surprise that few patients use it (we estimate <0.5% drug-treated patients in the G7 markets), and those that do use it do so only occasionally.
In the race to seize upon the clear opportunity for alternatives, two new acute rescue therapies have completed Phase III development in the United States and Europe: Acorda Therapeutics’ Inbrija, an inhalable formulation of levodopa, and Sunovion/Sumitomo Dainippon Pharma’s APL-130277, a sublingual film formulation of apomorphine. KOLs I’ve interviewed have been awaiting these rescues with enthusiasm – and frankly, so have I. The Phase III data are now available for both products and both achieved success in a placebo-controlled Phase III trial. Admittedly, however, the data are somewhat disappointing upon closer inspection and – for APL-130277 especially – they fall short of my (high) expectations.
In the plus column, both products are much easier to use than Apokyn in the “off” state and both are well tolerated, though patients taking APL-130277 were still pretreated with an antiemetic in the clinical trials. These features alone will drive demand and grow the market for rescue therapies well beyond its current value. However, while 90% of patients treated with Apokyn reported full “on”, only 58% of Inbrija-treated and 35% of APL-130277-treated patients did.1-3 Moreover, the placebo-adjusted motor improvement (as measured by UPDRS Part III) was markedly higher for Apokyn than the newer rescues: a 19-point improvement for Apokyn versus 4- and 8-point improvements for Inbrija and APL-130277, respectively. All three had a similar time to onset (~10 minutes) and duration of effect (~60-90 minutes), though Apokyn appears to have a slightly faster onset time and shorter duration. But APL-130277 seemed to have more-promising efficacy in the open-label titration phase of the Phase III trial: 83% of patients converted to full “on” on one of the six doses tested, and the average motor improvement more closely resembled Apokyn’s non-placebo-adjusted improvement.4 So what happened between the open-label and randomization phases? With the limited data released so far, we can only speculate.
I remain confident that physicians will find Inbrija and APL-130277 to have a positive impact on PD patients’ lives. KOLs I interviewed last year about the Inbrija data were surprised at the relatively low conversion rate and small motor improvement, but remained optimistic. They pointed out that patients recruited for the Inbrija trial were less advanced than those in the Apokyn trial and that the definition of “full ‘on’” is patient reported and subjective. Moreover, they emphasized that even a partial “on” can have a big impact: it can afford the patient some level of independence until the next dose of levodopa takes effect. One U.K. PD expert explains, “The idea of these medications isn’t really to treat the ‘off’ period, but to ‘top up’ the dose of levodopa in order to reach the next full dose. So, it’s possible that the dose isn’t enough to give a full ‘on’ but is still useful for the patient.”
With similar efficacy profiles between Inbrija and APL-130277 (at least compared to Apokyn), our challenge is to determine which rescue product physicians are likely to reach for first. (We’ll be assessing this, among many other things, in an upcoming “Special Topics” report we’re writing on new/emerging therapies in PD this year.) When pressed in interviews last year, KOLs admit to having a preference for Inbrija over APL-130277 based on the favorable tolerability and familiarity of levodopa over apomorphine; however, they state that APL-130277’s oral film will likely be easier for patients to use while “off”, and report that each therapy will have an advantage depending on the patient. For example, one KOL indicated that patient comorbidities (e.g., asthma, mouth ulcers) will dictate rescue choice, and another suggested that APL-130277 would be the best choice for morning “off” while Inbrija would be ideal for “off” periods during the day. Apokyn will also likely still have a role to play in PD; although its delivery mechanism severely limits its use, it will likely remain the best choice for severe PD patients thanks to its outstanding efficacy.
DRG’s forecast favored Inbrija (known then as CVT-301) when I took over our PD research in 2015. In 2017, I projected a different scenario in which neurologists ultimately would favor APL-130277 based on the positive tolerability profile and excellent open-label efficacy data–at the time, I assumed a placebo response consistent with the Inbrija/Apokyn trials.4-5 But now that APL-130277’s efficacy doesn’t appear much better than Inbrija (based on cross-trial comparison), I anticipate reverting to a forecast that will favor Inbrija again, though perhaps not as much as before. Regardless, I still expect that both drugs will significantly expand the number of patients receiving a rescue therapy and earn ex-manufacturer sales of more than $500 million combined in the U.S. market in 2026.
Side note: There are more data still to come. A European Phase III trial comparing APL-130277 with the APO-go PEN is expected to complete in May 2019. APL-130277 will probably be inferior on most efficacy endpoints (e.g., percentage of patients reporting full “on”, MDS-UPDRS Part III score improvement), but the primary endpoint is overall patient preference. If APL-130277 wins on that endpoint, how much weight will it carry in HTAs?
- Apokyn [package insert on the internet]. Louisville, KY: US WorldMeds, 2004 [cited February 5, 2018]. Available from: https://www.apokyn.com/sites/all/themes/apokyn/content/resources/Apokyn_PI.pdf
- LeWitt PA, et al. Inhaled levodopa (CVT-301, 84-mg dose) significantly improves motor function during OFF periods in Parkinson’s disease subjects: A Phase 3 study [SPAN-PD]. Poster presented at the annual Movement Disorder Society Congress, 2017. Vancouver, BC, Canada.
- Sunovion announces positive topline results from pivotal study of apomorphine sublingual film (APL-130277) in patients with Parkinson’s disease [press release]. January 29, 2018.
- Hauser RA, et al. Efficacy of sublingual apomorphine film (APL-130277) for the treatment of OFF episodes in patients with Parkinson’s disease: preliminary results from the Phase 3 study dose titration phase. Poster presented at the annual Movement Disorder Society Congress, 2017. Vancouver, BC, Canada.
- Isaacson S, et al. Safety of sublingual apomorphine film (APL-130277) for the treatment of OFF episodes in patients with Parkinson’s disease: preliminary results from the Phase 3 study dose titration phase. Poster presented at the annual Movement Disorder Society Congress, 2017. Vancouver, BC, Canada.
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Bethany Christmann, Ph.D., has been with DRG since 2015, and is a Senior Business Insights Analyst with the Central Nervous System/Ophthalmology team. In this role, she covers the neurology space, specializing in Parkinson’s disease and epilepsy; she provides expert insight and authors primary market research and forecasting content focused on these and other neurology indications. Prior to joining DRG, Bethany earned her Ph.D. in neuroscience from Brandeis University, where she studied the cellular interactions involved in memory consolidation and their link to sleep behavior.