Therapies

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5 Sep 2026

EU approves Hopledo for motor fluctuations

Marco Hamburger
5 Sep 2026
EU approves Hopledo

In August 2026, the European Commission approved Hopledo (manufacturer: Zambon) — a new oral levodopa/carbidopa formulation with dual drug release. It will be available from October 2026. Hopledo is aimed at people with Parkinson’s disease whose oral levodopa therapy no longer adequately controls motor fluctuations.

This article places Hopledo within the landscape of all current levodopa preparations — based on the published trial data (RISE-PD Phase III plus 9-month open-label extension). If you would first like an overview of the disease itself, you’ll find it in our Parkinson’s Disease Basics.

Why a new levodopa formulation is needed in the first place

Levodopa has been the gold standard in Parkinson’s therapy for more than 50 years. The problem is not the active substance itself but its short half-life of roughly 60 to 90 minutes.

As long as the brain’s own dopaminergic neurons still act as a buffer, this goes unnoticed. Once those neurons continue to die off, the levodopa level in the blood becomes the direct pacemaker for mobility.

Motor fluctuations: the clinical reality after a few years

After an average of five to ten years, the consequence is motor fluctuations. More than 80 percent of all people with Parkinson’s experience them within the first ten years after disease onset.

In practical terms, this means:

  • Wearing-off: the effect of a dose fades before the next intake.
  • ON phases: time windows with good mobility.
  • OFF phases: stiffness, tremor, slowed movement, often accompanied by anxiety and pain.
  • Dyskinesias: involuntary, excessive movements when levodopa levels are too high.

The goal of every modern formulation is to keep the active-substance level as constant as possible — neither too low (OFF) nor too high (dyskinesias). This is exactly where the new generation of preparations comes in.

What exactly is Hopledo (IPX203)?

Hopledo — known in clinical trials and in the U.S. under the development name IPX203 and the brand name Crexont — is a hard capsule that combines two components.

  • Immediate-release granules (IR): contain 100% of the carbidopa and 25% of the levodopa — for a fast onset of action.
  • Extended-release pellets (ER): contain the remaining 75% of the levodopa. They are coated with a combination of sustained-release, mucoadhesive and enteric layers to maximize absorption in the proximal small intestine — the only relevant site of absorption for levodopa.

This dual architecture is the central difference from standard IR preparations such as Madopar or Sinemet.

Approval history

Several milestones preceded Hopledo’s European launch:

  • USA: FDA approval in August 2024 as Crexont (Amneal Pharmaceuticals).
  • EU: approval in August 2026 as Hopledo (Zambon), market launch October 2026.
  • Zambon took over the exclusive license for the EU, UK and Switzerland from Amneal in 2024.

The evidence: RISE-PD in detail

The approval of Hopledo is based on the RISE-PD trial — a 20-week, randomized, double-blind, double-dummy Phase III study conducted at 105 centers in the U.S. and Europe (November 2018 to June 2021). The results were published in JAMA Neurology in 2023.

Study design

The key facts of the study at a glance:

  • 630 patients with Parkinson’s, average age 66.5 years.
  • Inclusion criteria: at least 400 mg levodopa daily, at least 2.5 hours of OFF time per day.
  • After an optimization phase on IR carbidopa/levodopa and a 4-week conversion to IPX203, 506 participants were randomized 1:1: IPX203 (n = 256) vs. IR carbidopa/levodopa (n = 250) over 13 weeks of double-blind treatment.
  • Primary endpoint: change in daily “good ON time” (ON time without troublesome dyskinesias).

Results

The central findings of the randomized phase:

  • +0.53 hours of good ON time per day on Hopledo vs. IR (95% CI 0.09–0.97; p = 0.02).
  • Significantly longer duration of action per dose — levodopa plasma concentrations were maintained above 50% of the peak for approximately 4.6–4.7 hours, compared with only 1.5–1.9 hours for IR levodopa/carbidopa and 3.9 hours for Rytary (Numient/IPX066).
  • Substantially lower dosing frequency compared with the IR standard.
  • Safety profile: comparable to IR. The most common adverse events on Hopledo were nausea (4.3% vs. 0.8%) and anxiety symptoms (2.7% vs. 0%).

Original source: Hauser RA, LeWitt PA, Waters CH et al. IPX203 vs Immediate-Release Carbidopa-Levodopa for the Treatment of Motor Fluctuations in Parkinson Disease: The RISE-PD Randomized Clinical Trial. JAMA Neurology, 2023. ScienceDirect reference

Long-term data: the RISE-PD open-label extension

Because short trials say little about everyday viability in Parkinson’s therapy, the randomized phase was extended by a 9-month open-label extension (Espay AJ et al., published in Movement Disorders, February 2024).

The central findings:

  • The benefit from the randomized phase remained stable over nine months.
  • Improvements were consistently measured in MDS-UPDRS scores (a motor rating scale) as well as in patient and clinical global impression assessments.
  • The safety profile showed no new or unexpected signals over the longer observation period.

This is the point that matters most for patients in everyday practice: the effect lasts, and tolerability remains manageable.

Original source: Espay AJ, Hauser RA, Dhall R et al. Safety and Efficacy of IPX203 in Parkinson’s Disease: The RISE-PD Open-Label Extension Study. Mov Disord. 2024;39(2):428–432. Movement Disorders (Wiley)

The big levodopa comparison

Here is an overview of all relevant levodopa preparations — arranged by mode of administration and stage of use. For a broader classification of further Parkinson’s therapies and medications, see our category page.

1. Oral standard preparations (immediate release, IR)

This class includes the classic combinations of levodopa with a decarboxylase inhibitor, such as Madopar (levodopa/benserazide) and Sinemet (levodopa/carbidopa).

  • Onset of action: approx. 30 minutes.
  • Duration of action: 2–4 hours; peak plasma concentration only about 1.5–1.9 hours above 50% of the maximum.
  • Use: standard in the early phase.
  • Limitations: short duration of action, pronounced peak-trough curve, the most important trigger for fluctuations and dyskinesias in the late phase.

2. Classic sustained-release preparations

Preparations such as Madopar HBS, Sinemet CR and Nacom retard extend the effect of standard levodopa but are less finely controllable.

  • Duration of action: 4–6 hours.
  • Downside: irregular absorption, delayed and less predictable onset of action.
  • Common use: at night, against morning akinesia.
  • Limitation: in the mid to late phase, no longer sufficiently fine-tunable.

3. Dual release — the modern class

This class includes Hopledo — and, alongside it, a predecessor that is considerably less established in the German-speaking market than its data would suggest: Rytary / Numient (IPX066, levodopa/carbidopa ER capsule).

  • Approved in the EU since 2015 (as Numient).
  • Combination of fast- and slow-releasing beads.
  • Levodopa level above 50% peak: approx. 3.9 hours.
  • Reduces OFF time compared with IR.
  • Available in Germany but underprescribed relative to its data.

And the current newcomer in this class: Hopledo / Crexont (IPX203).

  • EU approval 2026, market launch October 2026.
  • Levodopa level above 50% peak: approx. 4.6–4.7 hours.
  • In RISE-PD significantly superior to IR; in direct pharmacokinetic comparisons also longer-acting than Rytary/Numient.
  • Positioning: next-generation product within the dual-release segment.

4. Inhaled levodopa

For sudden OFF phases where every minute counts, there is Inbrija (levodopa inhalation powder) — not a baseline therapy but a rescue option.

  • Approved in the EU since 2019.
  • Onset of action: approx. 10 minutes.
  • Use: rescue medication for sudden OFF phases.
  • Does not replace baseline therapy — it complements it.

5. Continuous intestinal infusion

When oral therapies are no longer sufficient, more invasive options come into play. The established one is Duodopa / Duopa (levodopa/carbidopa gel via PEG-J tube).

  • Approved since 2004.
  • Continuous 16-hour infusion (during the day) directly into the small intestine.
  • Highly effective in advanced disease.
  • Downsides: surgical procedure to place the tube, maintenance effort, infection risks.

Lecigon is a further development that adds entacapone (a COMT inhibitor), further extending the levodopa effect.

6. Continuous subcutaneous infusion — the newest class

The most elegant current option for stable 24-hour levels without a PEG-J tube is Produodopa / Vyalev (foslevodopa/foscarbidopa).

  • EU approval 2024.
  • Subcutaneous 24-hour pump; no tube required.
  • Prodrug approach: better solubility enables continuous subcutaneous administration.
  • Downsides: skin reactions at the injection site, daily cannula changes.

Where does Hopledo fit into this landscape?

Hopledo fills a very specific gap: the phase in which oral standard therapy is no longer sufficient but pump therapy (Duodopa, Produodopa) or deep brain stimulation is not yet indicated or wanted.

Many patients live in this window for years — often taking five, six, seven levodopa doses a day and yet with unstable control. Anyone who is also dealing at this stage with accompanying symptoms such as freezing or fatigue knows the interplay of too little and too much active substance all too well.

What the RISE-PD data actually suggest

In summary, the data support four practically relevant benefits:

  • Dose reduction: fewer intakes per day, with at least equally good symptom control.
  • Extension of good ON time: roughly half an hour more per day (statistically significant, clinically noticeable for some patients).
  • Smoother peaks: potentially fewer dyskinesia-triggering spikes.
  • Long-term stability: confirmed over 9 months of extension follow-up.

Rytary/Numient offers something conceptually similar but never became the standard in the German-speaking region. With Zambon, Hopledo has a marketer with a clear neurology presence in Europe — that could make the difference.

Further therapeutic approaches beyond levodopa

If you’re interested in new avenues beyond classical dopaminergic therapy, our articles on gold nanocrystals in Parkinson’s therapy and on N-acetyl-DL-leucine (ADLL) offer further current perspectives — both focused on potential disease-modifying effects rather than just symptom control. We continue to cover current studies and basic research in our Research & Studies category.

Personal note

I am not writing this article purely for the overview. I am in exactly this phase myself: my ON times are getting shorter, my dyskinesias on levodopa are pronounced, and my OFF phases are clearly noticeable.

This is the everyday reality for many patients after a few years with Parkinson’s — and one of the reasons why, at Kill Parkinson, we work so intensively to bring therapy information together and to build a global patient registry. So that decisions about the next stage of therapy rest on better data — and not on chance, place of residence, or the timing of the next specialist appointment.

I note the approval of Hopledo with cautious optimism. I will discuss it with my treating neurologist — and I recommend that everyone in the same transitional phase do the same. New options are good. What ultimately fits is an individual decision.

Conclusion

The levodopa landscape has diversified considerably over the past ten years. From classic Madopar to Rytary and Inbrija through to Duodopa and Produodopa, there is now a suitable form of administration for practically every stage of the disease.

Hopledo strengthens the middle segment — the decisive phase between stable oral therapy and pump therapy — and brings with it the currently most robust study data among oral sustained-release formulations. For many patients, it could be a valuable intermediate step before more invasive options become necessary.

Frequently asked questions (FAQ)

When will Hopledo be available in Germany?

From October 2026, following EU approval in August 2026.

What is the difference between Hopledo and Rytary/Numient?

Both are dual levodopa/carbidopa formulations with IR and ER components. In direct pharmacokinetic comparisons, Hopledo (IPX203) keeps the levodopa level in the therapeutic range for about 4.6–4.7 hours — compared with 3.9 hours for Rytary/Numient. The Phase III RISE-PD trial showed significantly more good ON time per dose compared with standard IR levodopa.

Who is Hopledo suitable for?

For adult Parkinson’s patients with moderate to severe motor fluctuations who are no longer adequately stabilized on standard oral levodopa therapy.

Does Hopledo replace pump therapies such as Duodopa or Produodopa?

No. Hopledo is an oral option for the phase before continuous infusion therapy becomes necessary.

How long does the effect of Hopledo last?

The 9-month open-label extension of the RISE-PD trial (Espay et al., Mov Disord 2024) showed sustained efficacy over the entire observation period, with no new safety signals.

Important notice — not medical advice

This article is an informational overview from Kill Parkinson gUG (KiPa). It does not replace medical diagnosis, treatment recommendations or advice. Decisions about Parkinson’s therapy — in particular a switch or an addition to levodopa preparations — belong exclusively in the hands of your treating neurologist.

All information provided to the best of our knowledge, with reference to the original sources cited in the text. Our team uses AI to work faster, but every article is reviewed by a human expert.

Sources

  1. Hauser RA, LeWitt PA, Waters CH et al. IPX203 vs Immediate-Release Carbidopa-Levodopa for the Treatment of Motor Fluctuations in Parkinson Disease: The RISE-PD Randomized Clinical Trial. JAMA Neurology. 2023. sciencedirect.com/science/article/pii/S1353802024012513
  2. Espay AJ, Hauser RA, Dhall R et al. Safety and Efficacy of IPX203 in Parkinson’s Disease: The RISE-PD Open-Label Extension Study. Mov Disord. 2024;39(2):428–432. movementdisorders.onlinelibrary.wiley.com/doi/full/10.1002/mds.29685
  3. European Commission, Hopledo marketing authorisation, August 2026.
  4. Zambon SpA, press release on the EU approval (August 2026).
  5. Apotheke Adhoc, coverage of the EU approval of Hopledo.

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