Disease indication
Why the animal models predict symptom relief — and almost nothing else
Disease-modifying: Slow or halt the nigrostriatal degeneration itself. Every model put to this test has so far failed to predict the clinic: strong preclinical neuroprotection, then a null result in patients — ten times over.
No therapy has ever been shown to slow the progression of Parkinson's disease.
Every disease-modifying programme below with a completed readout. Unlike the symptomatic count, this one has a real denominator — the entries were not selected on their outcome. One further programme is still running.
A delayed-start or withdrawal design is required to separate symptom masking from true modification — the single largest cost driver.
Larger and longer than symptomatic trials because the effect being measured is a change in slope.
The quietest reason this disease is hard. Toggle between the two goals and watch the standing column: symptom relief has measures everyone accepts, and disease modification has none.
No endpoint is accepted as establishing disease-modifying benefit in Parkinson's Disease. Every measure below is either contested or exploratory. A trial can therefore succeed on its own terms and still not support the claim.
| Endpoint | Type | Read at | Standing |
|---|---|---|---|
| MDS-UPDRS progression slope | Composite | 2-5 years | None accepted |
| Delayed-start design | Trial design | 2-5 years | Contested |
| DaTscan dopamine transporter imaging | Imaging | 2-4 years | Contested |
| Alpha-synuclein seed amplification assay | Laboratory | Baseline | Exploratory |
Three standard axes. Toggle the therapeutic goal above and watch only the third column change — that asymmetry is the whole story.
| Model | FaceDoes it look like the disease? | ConstructDoes it arise the same way? | PredictiveSlow progression |
|---|---|---|---|
Every programme below cleared its animal model. None has yet changed the course of the disease in a patient.
| Intervention | Rested on | Primary endpoint | Reached | Outcome |
|---|---|---|---|---|
Exenatide UCL / NIHR · GLP-1 receptor agonist | 6-OHDAMPTP mouse | MDS-UPDRS Part III off medication at 96 weeks | Phase 3 Exenatide-PD3 · 2025 | Failed |
BIIB122 / DNL151 Denali / Biogen · LRRK2 kinase inhibition | LRRK2 G2019S | Change in MDS-UPDRS Parts II and III (ongoing) | Phase 2b LUMA · 2025 | Ongoing |
Prasinezumab (PRX002) Roche / Prothena · Anti-alpha-synuclein monoclonal antibody | α-syn PFFAAV α-syn | PASADENA: MDS-UPDRS total change at 52 weeks. PADOVA: time to confirmed motor progression | Phase 2b PASADENA / PADOVA · 2024 | Missed primary |
Cinpanemab (BIIB054) Biogen · Anti-alpha-synuclein monoclonal antibody | α-syn PFF | Change in MDS-UPDRS total score | Phase 2 SPARK · 2021 | Failed |
Inosine NINDS / Parkinson Study Group · Urate elevation / antioxidant | 6-OHDAMPTP mouse | Rate of change in MDS-UPDRS total over 2 years | Phase 3 SURE-PD3 · 2021 | Failed |
Nilotinib Georgetown University · c-Abl inhibition promoting alpha-synuclein clearance | AAV α-synα-syn PFF | Safety and tolerability, with MDS-UPDRS and CSF measures as secondary | Phase 2 NILO-PD · 2021 | Failed |
Isradipine NINDS / Parkinson Study Group · Cav1.3 calcium-channel blocker | MPTP mouse6-OHDA | Change in MDS-UPDRS total (on medication) over 36 months | Phase 3 STEADY-PD III · 2020 | Failed |
Creatine NINDS / NET-PD · Mitochondrial bioenergetic buffering | MPTP mouse | Global statistical test across five clinical outcomes over 5 years | Phase 3 NET-PD LS-1 · 2015 | Failed |
Coenzyme Q10 NINDS · Mitochondrial complex-I support / antioxidant | MPTP mouse | Change in MDS-UPDRS total to end of study | Phase 3 QE3 · 2014 | Failed |
CERE-120 (AAV2-neurturin) Ceregene · Neurotrophic factor gene therapy | 6-OHDAMPTP primate | UPDRS motor score off medication at 12 months | Phase 2b CERE-120 Phase 2b · 2013 | Failed |
GDNF (intraputaminal) Amgen · GDNF/RET neurotrophic signalling | 6-OHDAMPTP primate | UPDRS motor score at 6 months | Phase 2 Intraputaminal GDNF · 2006 | Failed |
Rate of change in total score across motor and non-motor domains
The central problem on this page. Any drug with a symptomatic effect improves this score without touching progression, so a difference cannot be read as disease modification. No trial using it has been accepted as establishing the claim.
No per-trial cost figure specific to Parkinson's exists. Rather than quote one that doesn't, this computes cost from cited trial designs and a single labelled assumption — and shows the arithmetic.
The endpoint is a change in the slope of progression, which cannot be seen quickly and cannot be distinguished from symptom masking without a delayed-start or withdrawal design. Both facts inflate exposure enormously.
6,685 patient-years against 515 for a symptomatic programme. Cost grows more slowly than exposure because the fixed enrolment cost of each participant — screening, baseline imaging — is paid once however long they are then followed. The goal, not the molecule, still sets the budget.
Citedenrolment, duration and study counts, from named trials.Assumptionthe two cost parameters below.Computedeverything else.
| Phase | Design | N × studies | Duration | Patient-years | Modelled cost |
|---|---|---|---|---|---|
| Phase 1 | SAD / MAD, healthy volunteers Reads: Safety, tolerability and pharmacokinetics Identical in kind to the symptomatic programme. Nothing has diverged yet. Conventional first-in-human designmoderate confidence | 60 | 9 mo | 45 | $1.6M–$2.7M |
| Phase 2 | Parallel-group with delayed-start extension Reads: MDS-UPDRS change, with imaging and fluid biomarkers Sized and timed after PASADENA (n=316) and SPARK (n=357), both of which ran a one-year blinded period followed by an extension. PASADENA (Pagano et al., NEJM 2022); SPARK (Lang et al., NEJM 2022)high confidence | 320 | 2 yr | 640 | $17M–$28M |
| Phase 3 | Delayed-start or long-term parallel-group Reads: MDS-UPDRS progression slope under a delayed-start design Between STEADY-PD III (n=336 over 36 months) and NET-PD LS-1 (n=1,741 over 5 years). A registrational modification claim needs both the scale and the years — this is the single largest driver of the gap. STEADY-PD III (Ann Intern Med 2020); NET-PD LS-1 (JAMA 2015)moderate confidence | 1,000 × 2 | 3 yr | 6,000 | $144M–$246M |
| Total | 5.8 yr of clinical development, treating phases as sequential | 6,685 | $162M–$277M |
Model assumptions, not citations — the only free parameters here. The fixed component covers screening, baseline imaging and randomisation, incurred once per participant; the running component covers visits, monitoring and site fees for each year on study. Splitting them matters: a single rate per patient-year would price short symptomatic trials far below what pivotal trials actually cost.
Calibration: priced this way a single pivotal trial in this programme comes to $9.0M–$14M, against published pivotal trial costs of $12–33M (median $19M) across all indications. A 20-week motor-scale study belongs toward the bottom of that spread, against multi-year outcome trials — which is where it lands. Moore et al., JAMA Internal Medicine 2018.
Programme cost divided by a 6% likelihood of approval from Phase 1 in neurology — what one success costs once the failures are paid for. BIO / Informa / QLS, Clinical Development Success Rates — neurology is among the lowest of any therapeutic area.
Read this one carefully: That rate is area-level and does not separate symptomatic from disease-modifying — the very distinction this page is about. Applied unchanged to both, it flatters disease modification, where the observed record is 0 of 10.
These are portfolio figures spanning all of R&D and already carry the cost of failure, so they are not comparable with the per-programme clinical costs above — they are the order of magnitude those costs roll up into.
The predictive-validity problem is being attacked at its root — by defining the disease biologically rather than clinically.
Seed amplification assays detect misfolded alpha-synuclein in cerebrospinal fluid with roughly 88% sensitivity in sporadic PD. For the first time, trials can enrol biologically confirmed patients rather than clinically defined ones — plausibly the reason earlier disease-modifying trials were doomed before they began.
Siderowf et al., Lancet Neurology 2023 (PPMI)
The Neuronal Alpha-Synuclein Disease Integrated Staging System proposes staging from biomarkers instead of motor signs, opening a route to intervening years before the motor threshold — by which point most nigral neurons are already lost.
Simuni et al., Lancet Neurology 2024
LRRK2 and GBA1 programmes derive from human genetics rather than from a toxin model, sidestepping the predictive-validity problem at its root. The trade-off is that the corresponding mice barely degenerate, so efficacy rests on biomarkers until a pivotal trial reads out.
LUMA (BIIB122) programme disclosures