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| Figure/Metric | Value | Source | Significance |
|---|---|---|---|
| RADIANT Median Reduction | 54% - 56.3% | Praxis 2025 AES Update | Baseline active-arm efficacy for vormatrigine (non-controlled). |
| Cenobamate Ph3 Adjusted Reduction | 31.0% | ClinicalTrials.gov | Gold standard benchmark for potent sodium channel blockers. |
| Historical Placebo Median | 15% - 25% | ClinicalTrials.gov | Typical range for the control arm in FOS clinical trials. |
| POWER1 Enrollment | ~230 Participants | Praxis SEC Filings | Sample size for the Phase 2/3 registrational study. |
| Management Meaningfulness Target | ~30% | Q1 2026 Earnings Call | The threshold Praxis believes will ensure commercial success. |
| RADIANT Seizure Freedom (28-day) | ~33% | Praxis 2025 AES Update | Indicates high potency and potential for strong median outcomes. |
Historical data for focal onset seizure (FOS) treatments provides a clear baseline for performance. Cenobamate (Xcopri), a potent sodium channel modulator, set a high bar in its Phase 2 and Phase 3 trials (NCT01397968 and NCT01866111), achieving placebo-adjusted median reductions of 34.5 and 31.0 percentage points, respectively. Older generation drugs or those with less selective mechanisms often show lower adjusted reductions, typically in the 15-25% range. For instance, lacosamide (Vimpat) and other common anti-seizure medications (ASMs) generally fall within this lower band. Placebo performance in these registries is remarkably consistent, usually hovering between 15% and 23%. Praxis’s own open-label RADIANT study (2025) for vormatrigine reported a 54-56% median reduction, though without a control group. The company’s EMBRAVE study for a different candidate (elsunersen) achieved a 77% placebo-adjusted reduction, demonstrating the potential for high efficacy within their pipeline, albeit in a different epilepsy indication.
My prediction is primarily driven by the strong signal observed in Praxis’s Phase 2a RADIANT study, where vormatrigine achieved a median seizure reduction of 54% to 56%. While open-label results are typically inflated due to patient and investigator bias, the magnitude of this reduction suggests a highly potent effect on sodium channel hyperexcitability. To translate this into a placebo-adjusted value for the POWER1 trial, I analyzed historical placebo responses in focal onset seizure (FOS) trials. Data from ClinicalTrials.gov and historical benchmarks for drugs like cenobamate (Xcopri) and lacosamide (Vimpat) show that placebo median reductions consistently fall between 15% and 25%. If vormatrigine maintains an active-arm reduction between 50% and 55% in a double-blind setting, the resulting placebo-adjusted reduction would land in the 30% to 35% range.
This range aligns closely with management’s stated “clinically meaningful” threshold of 30%. In my modeling, I weighted the ‘Success’ scenario at roughly 65-70%. This scenario assumes the 30 mg dose utilized in POWER1 (which is higher than some doses in RADIANT) successfully overcomes the lack of blinding from the earlier study. I also considered the precedent set by cenobamate, which achieved placebo-adjusted reductions of 31.0% and 34.5% in its pivotal trials. Vormatrigine’s “unprecedented potency” in preclinical models and early clinical signs of seizure freedom for roughly one-third of RADIANT patients support a forecast at or slightly above these benchmarks.
However, I have incorporated a downward adjustment for the ‘Moderate/Underperformance’ scenario (25% weight). Historically, FOS trials often suffer from high placebo responses or regression to the mean when moving from small open-label cohorts to larger, multi-center trials (N=230 in POWER1). If the placebo response spikes to 28-30%—not uncommon in modern trials—the adjusted reduction would fall into the low 20s even if the drug is effective. Finally, a small 5-10% probability is reserved for trial failure, where the adjusted reduction falls below 15% due to high discontinuation rates or lack of dose-response, though blinded safety data mentioned by the CEO suggests competitive tolerability. The resulting median prediction of 32.25 percentage points reflects a high-performing drug that meets clinical expectations.
The question asks what POWER1’s primary readout will show for the placebo‑adjusted median percent reduction in focal seizure frequency for vormatrigine 20→30 mg QD versus placebo; no public POWER1 topline has been released and Praxis has only guided a Q2 2026 readout. Forecasters anchor on RADIANT’s uncontrolled open‑label 30 mg result (~54–56% median reduction) as evidence the drug can deliver substantial active‑arm effects, but all teams substantially discount that for open‑label bias/regression to the mean and subtract an expected placebo median change (likely mid‑teens to low‑20s). External RCT benchmarks split between modern high‑efficacy trials (XEN1101, cenobamate) implying placebo‑adjusted gaps ~30–43 points and older sodium‑channel adjunctive trials or the failed NaV1.6 program implying much smaller gaps, creating a material left‑tail failure risk. Forecasters therefore place central mass in the high‑20s to low‑30s percentage‑point placebo‑adjusted reduction, with meaningful probability (~10%–20%) below ~10 points and a thinner right tail for a standout XEN/cenobamate‑like result. Remaining uncertainties include the exact POWER1 dose effect (20→30 mg vs potentially higher optimal doses), actual placebo response in this trial, and how Praxis will report the topline (median percent change, arm‑level medians, p‑values, or responder rates).
Forecast: Probability distribution:
All forecasters agree Praxis has not yet publicly disclosed POWER1 topline efficacy as of 2026-05-23, with company guidance pointing to a Q2 2026 readout, so the main uncertainty is simply the (imminent) trial result rather than time-to-resolution.
On effect size: the most relevant anchor is the open-label RADIANT signal (~54–56% median reduction from baseline in focal-onset seizure patients), which is encouraging but likely overstates the placebo-adjusted separation expected in a blinded, randomized adjunctive trial. In POWER1, (1) placebo arms in focal seizure RCTs often show meaningful median reductions (commonly ~15–25%), and (2) open-label estimates can be inflated by regression-to-mean/expectancy and by differences in population and analysis window; additionally POWER1 includes 6 weeks at 20 mg then 6 weeks at 30 mg, which could modestly reduce the treatment-period median versus a fixed higher-dose open-label cohort.
Given typical focal-seizure add-on RCT base rates, I expect a successful but not “outlier” separation most likely in the mid-to-high 20s to low 30s percentage points. I discount Forecaster 2’s much higher center (median ~41) because it appears to rely on unusually large comparator separations and could be mixing endpoints/summary measures across trials; the other three forecasts cluster around a median ~24–29 with upper tails into the 40s, which better matches historical distributions for median placebo-adjusted seizure-frequency reductions.
I therefore set a median of 28 percentage points, with a meaningful left tail for a weak/failed readout (near zero or low teens) and a right tail for a clearly best-in-class result (40s, with small probability above that but still well below the open upper bound).
An amateur forecast would likely anchor on the ~54–56% open-label RADIANT median reduction and either (a) treat it as placebo-adjusted, or (b) subtract a simplistic placebo value without accounting for regression-to-mean/open-label inflation and POWER1’s 20 mg→30 mg schedule. My forecast instead centers on placebo-adjusted medians typical for blinded focal-seizure RCTs, downweights an outlying optimistic analyst distribution, and keeps non-trivial probability on both weak efficacy and strong upside. Confidence in improvement is moderate: the key drivers (placebo response and open-label-to-RCT shrinkage) are robust, but the true placebo-adjusted median can still vary substantially by enrolled population and analysis details.
Forecast rationale (numeric):
— Iteration 1 — Across the forecasts, the core reasoning is broadly aligned:
Overall, the forecasts converge on a view that POWER1 is likely to show a meaningful placebo-adjusted seizure reduction, but with enough uncertainty that the result could land anywhere from barely positive to strongly positive.
— Iteration 2 — Across the forecasts, the reasoning is broadly consistent:
Primary anchor: Phase 2 efficacy signal. All models rely heavily on Praxis’s Phase 2 RADIANT result, where vormatrigine showed a 56.3% median reduction in monthly focal seizure frequency in the active arm. This is treated as evidence of a meaningful underlying drug effect.
Adjustment for Phase 3 realism. The forecasts then discount that Phase 2 result to reflect likely regression to the mean, broader Phase 3 populations, and the fact that placebo-controlled confirmatory trials usually perform less strongly than early studies.
Placebo response as a key swing factor. A major source of uncertainty is the assumed placebo reduction, with most estimates centering around a typical Phase 3 placebo response in the low-to-mid teens or around 20%. This assumption materially drives the placebo-adjusted result.
Benchmarking against Praxis’s own standard. Praxis’s stated view that roughly a 30 percentage-point placebo-adjusted reduction would be clinically meaningful appears to serve as a reference point, and the forecasts cluster near that level.
The collective reasoning suggests that vormatrigine’s POWER1 result is most likely to land around a mid-20s to low-30s placebo-adjusted reduction in monthly focal seizure frequency, with the estimate driven by a strong Phase 2 anchor, tempered by expected Phase 3 regression, and highly sensitive to placebo response. The distribution is intentionally wide because epilepsy seizure-frequency endpoints are noisy and confirmatory trials can vary substantially in both directions.
— Iteration 3 — Overall, the forecasts converge on a moderate placebo-adjusted benefit in the mid-to-high 20 percentage-point range, with substantial uncertainty.
The collective reasoning supports a mid-to-high 20s placebo-adjusted reduction, with the key drivers being strong but preliminary open-label efficacy, expected placebo response, and the usual attenuation when moving into a controlled pivotal epilepsy trial.
Here is a synthesis of the qualitative reasoning from the provided rationales:
Baseline Efficacy and Phase 2 Precedents Forecasters broadly agree that vormatrigine is a highly potent, functionally selective sodium-channel modulator with the potential to be a “best-in-disease” therapy. The drug’s open-label Phase 2 RADIANT study demonstrated massive reductions in focal seizure frequency, placing its raw efficacy on par with top-tier, next-generation anti-seizure medications (ASMs) like cenobamate and azetukalner (XEN1101), rather than older, less effective legacy ASMs.
The Open-Label Discount and “Placebo Creep” Despite the strong Phase 2 data, the rationales highlight significant downward pressures when transitioning to a double-blind, placebo-controlled Phase 3 trial. First, open-label trials inherently inflate efficacy due to expectancy bias; a natural attenuation is expected in a blinded setting. Second, modern focal epilepsy trials suffer from well-documented “placebo creep.” Due to regression to the mean, less refractory trial populations, and improved clinical compliance, contemporary placebo arms routinely demonstrate robust seizure reductions. This elevated placebo baseline will inevitably compress vormatrigine’s placebo-adjusted efficacy margin.
POWER1 Trial Design and Structural Headwinds The specific design of the POWER1 trial introduces structural variables expected to dilute the headline efficacy:
Conclusion Overall, the consensus balances vormatrigine’s exceptional pharmacological potency against the harsh statistical realities of modern Phase 3 epilepsy trials. While the drug is heavily favored to outperform standard-of-care ASMs, matching the absolute ceiling of the strongest next-generation peers will be structurally challenged by the trial’s titration dilution, strict dropout penalties, and historically high placebo responses.
Question: What will be the placebo-adjusted reduction in monthly focal seizure frequency in Praxis Precision Medicines’ POWER1 trial of vormatrigine? Final Prediction: Probability distribution:
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Forecaster 1: Probability distribution:
Forecaster 2: Probability distribution:
Forecaster 3: Probability distribution:
Praxis’s POWER1 Phase 2/3 registrational study of vormatrigine (PRAX-628) is a randomized, double‑blind, multicenter, placebo‑controlled trial with a 12‑week treatment period and a primary endpoint of median percent change in monthly (28‑day) focal seizure frequency versus baseline. Topline POWER1 results were expected in Q2 2026 but, as of May 23, 2026, no topline data had been publicly released. The most directly relevant prior data come from the open‑label Phase 2 RADIANT study, which reported roughly a 54–56% median reduction in focal seizure frequency (about 58–61% ≥50% responder rate and ~22% seizure‑free in the last 28 days) over eight weeks; because RADIANT was single‑arm and open‑label, those figures cannot be directly translated into a placebo‑adjusted effect. Published comparator data from other anti‑seizure drug trials (for example cenobamate) show substantial placebo responses in focal seizure trials (placebo ≥50% responder rates reported near ~26% in some analyses), and blinded Phase 3 placebo‑controlled results therefore typically yield smaller active‑placebo differences than open‑label Phase 2 figures.
Searches for prediction‑market lines on POWER1/PRAX‑628 (Metaculus, Manifold, Kalshi) returned no active markets for this specific placebo‑adjusted median percent change outcome. Analyst commentary (e.g., BTIG coverage) described the RADIANT Phase 2 results as strong and characterized POWER1 as potentially “competitive,” but no POWER1 efficacy numbers were available to report. Key uncertainties noted in the underlying research include the lack of placebo control in Phase 2, variability in placebo response across epilepsy trials, potential Phase‑2→Phase‑3 effect size regression, and differences in trial populations and dosing across studies.
Sources / websites searched and referenced (links copied where applicable):
(If you want, I can re-run targeted searches and return direct press‑release links and the exact clinicaltrials.gov identifier for POWER1.)
I’ll help you research this question about Praxis Precision Medicines’ POWER1 trial. Let me conduct a comprehensive investigation across multiple angles.
Agent Forecast (discrete, confidence: medium)
Base Rate: Recent Phase 3 focal seizure RCTs: cenobamate ~31pp placebo-adjusted (55% vs 24% placebo); XEN-1101 XTOL-2 ~42.8pp placebo-adjusted (53.2% vs 10.4% placebo). RADIANT open-label vormatrigine 30mg active arm median: 56.3% (verified median, not mean). Conditional on POWER1 success, placebo-adjusted result most likely 25-45pp.
Initial Reasoning:
POWER1 results are pending as of May 23, 2026 (expected Q2 2026).
POWER1 results are not yet announced (confirmed as of May 21, 2026; e
Key Uncertainties:
Evidence Sources (19):
Grounding Facts (passed to reviewers):
Draft: 30-40: 26.7%, 40-60.3: 19.3%, 25-30: 15.3%, 20-25: 11.3%, 15-20: 9.0%
Reviewer Panel:
Reviewer (reasoning)
The draft leans heavily on a small, open-label Phase 2 study as its primary anchor without adequately adjusting for the well-known inflation of efficacy in unblinded trials or the specific titration/maintenance design of POWER1, both of which could materially dilute the active-arm effect. It also treats median and mean percent changes interchangeably across studies and glosses over the wide variability in placebo-arm responses observed in comparable RCTs. Finally, it omits consideration of key design differences (e.g., length of maintenance period) that have systematically shifted results in other add-on epilepsy trials.
Objections:
Reviewer (calibration)
The draft forecast provides a reasonable range based on open-label Phase 2 data and comparisons to other sodium channel modulators. However, it may not fully account for the significant variability in placebo response rates observed across similar trials, which is a critical driver of the placebo-adjusted outcome. The impact of the dose ramp on the overall efficacy over the trial period also warrants deeper consideration.
Objections:
Reviewer (fact-checker)
5 unsupported claim(s). Verdict: minor_issues
Unsupported claims:
Adjustment Rationale:
Verified the RADIANT 56.3% figure is explicitly median (matches resolution criteria), so the open-label Phase 2 anchor stands. Adjusted slightly relative to the most bullish trajectory: shifted ~3pp of probability from the 40-60.3 bin toward the 25-30 and 20-25 bins to reflect the calibration reviewer’s correct point that placebo-response variability (10-25% range across comparators) creates wide uncertainty in placebo-adjusted outcomes, and the reasoning reviewer’s correct point that open-label inflation plus a 12-week titration/ramp design tend to dilute median reductions vs. flat-dose Phase 2 results. Mode remains 30-40pp, anchored by cenobamate Phase 3 (~31pp placebo-adjusted) and XEN-1101 XTOL-2 Phase 3 (~42.8pp). ~23% probability is allocated to weak/failure scenarios (<20pp), reflecting historical Phase 3 CNS failure rate (zandatrigine, padsevonil precedents) despite no vormatrigine-specific red flags. Did not adjust based on the fact-checker’s objection because forecast-bin probabilities are derived outputs of probabilistic analysis, not citable factual claims.
forecast_sdk | 808.4s | research $1.7923 + reviewers $0.0136 + reconcile $0.3603 = $2.2058
Trial architecture fixes a 12-week blinded window, a median-percent-change seizure-frequency endpoint, and patients on 1–3 background antiseizure medications.
Dose-titration (six weeks at a lower dose then escalation) and multicenter recruitment constrain how much open-label efficacy can translate into randomized effect sizes.
Early uncontrolled program results reported median active-arm reductions in the mid‑50s, anchoring an upper-support translation case.
Contemporary randomized controls in this indication show placebo medians clustered in the high teens, which systematically reduces the net placebo-adjusted gap.
A low placebo median in the randomized setting would lift the gap into the low‑40s even if the active signal is conservatively scaled down.
Open-label inflation, regression to the mean, and duty-cycle effects from the dose ramp can pull the translated active median toward the mid‑20s or lower.
Principal uncertainties are regional/site placebo behavior, baseline seizure burden and diary completeness, and missing-data handling in the median calculation.
Sensitivities produce tail risk below ~10 percentage points and a smaller chance above ~50; central best estimate is about 34 percentage points.
Forecast: 25.3 percentage points
RADIANT Phase 2 signal as primary anchor: The open-label RADIANT trial showed 56.3% median seizure reduction at fixed 30mg. This is the strongest available efficacy signal, but requires downward adjustment for the transition to a blinded, placebo-controlled design and the titration regimen (6 weeks at 20mg, then 6 weeks at 30mg).
Open-label to double-blind attenuation: Converting from open-label to double-blind RCT typically reduces effect estimates by 5–15 percentage points in CNS trials due to removal of expectancy effects and regression to the mean. Combined with the titration design spending half the treatment period at a lower dose, the active arm is estimated at 45–48% reduction rather than RADIANT’s 56.3%.
Placebo arm anchored by historical comparators: Refractory focal epilepsy trials consistently show placebo response rates of 16–24%, with most clustering around 18–20%. This range is well-established across lacosamide, eslicarbazepine, cenobamate, and XEN1101 trials. POWER1-specific factors (high background sodium channel blocker use, patient refractoriness) are unlikely to shift this materially.
Reference class of approved sodium channel modulators: Placebo-adjusted deltas in comparable Phase 3 adjunctive focal epilepsy trials range from ~12–35 percentage points, with most successful drugs landing at 15–31 pp. The central tendency is approximately 20–25 pp. Vormatrigine’s strong Phase 2 signal and management confidence (characterizing ~30 pp as “meaningful”) suggest positioning in the upper-middle to upper range of this class.
Modest trial failure risk: While
Forecast (percentiles, aggregated):
Per-model forecasts:
Rationale: Summary The estimate centers around a 29 percentage-point placebo-adjusted median reduction in monthly focal seizure frequency. This assessment heavily weights the promising results from the Phase 2 RADIANT study, an open-label trial where vormatrigine demonstrated an impressive 56.3% absolute median reduction at 30 mg/day over eight weeks. However, because open-label studies reliably overestimate efficacy relative to double-blind, placebo-controlled trials, some regression to the mean is anticipated. Furthermore, the POWER1 trial uses a 12-week titration design—six weeks at 20 mg/day followed by six weeks at 30 mg/day—which may dilute the overall median efficacy compared to a consistent 30 mg dose. Assuming a strong but tempered active arm median reduction of 45% to 50% and a typical placebo response in focal epilepsy trials of 15% to 25%, the expected placebo-adjusted reduction lands cleanly in the mid-to-high 20s. This aligns with recent highly regarded anti-seizure medications like cenobamate and azetukalner, which achieved placebo-adjusted median reductions of roughly 31% and 35% to 43%, respectively.
Strongest Arguments for Higher Values
Strongest Arguments for Lower Values
Key Uncertainties
As of Saturday, May 23, 2026, Praxis has not yet publicly disclosed POWER1 efficacy results. Its May 7, 2026 corporate update still said topline POWER1 results were expected in Q2 2026. (investors.praxismedicines.com)
POWER1 is the relevant study for resolution: a randomized, double-blind, placebo-controlled Phase 2/3 registrational trial in adults with focal onset seizures, enrolling about 230 participants 1:1 to vormatrigine 20 mg once daily for 6 weeks then 30 mg once daily for 6 weeks, versus matching placebo for 12 weeks. The primary endpoint is the median percent change in monthly focal seizure frequency from baseline to the treatment period. (praxismedicines.com)
The main efficacy anchor is Praxis’ open-label Phase 2 RADIANT study. In the initial focal-onset-seizure cohort, patients received vormatrigine 30 mg daily for 8 weeks, and the reported median reduction in focal seizure frequency from baseline to Week 8 was 56.3%; the overall responder rate was about 60%, with more than 20% seizure-free during the last month of treatment. RADIANT was single-arm and open-label, so that result is encouraging but not directly the placebo-adjusted value that POWER1 will report. (cms.aesnet.org)
The later AES 2025 RADIANT poster strengthened the signal qualitatively: it reported continued improvement over time, with median weekly seizure reduction reaching 100% by Week 8 and being maintained through Week 16 for continuing patients, and it stated that exposure-response modeling supported the POWER1 and POWER2 study designs. That makes it more plausible that the blinded active arm in POWER1 will still be strong, even though POWER1 uses 20 mg during its first 6 weeks before moving to 30 mg. This is an inference from the design and the poster, not a reported POWER1 result. (praxismedicines.com)
For placebo-controlled benchmarks in similar adjunctive focal-seizure populations, XEN1101 25 mg achieved a 52.8% median reduction versus 18.2% on placebo in the X-TOLE Phase 2b trial, a 34.6-point placebo-adjusted effect. Cenobamate produced 55.0% versus 24.0% in one randomized study and 55.6% versus 21.5% in another, implying placebo-adjusted effects of 31.0 and 34.1 points. These are useful comparators because they are modern randomized adjunctive focal-epilepsy trials rather than open-label studies. (pubmed.ncbi.nlm.nih.gov)
My base case is therefore: POWER1’s blinded active-arm median reduction lands a bit below the 56.3% open-label RADIANT figure, roughly around the low-50s, because POWER1 includes six weeks at 20 mg and removes open-label expectancy effects; placebo in a contemporary adjunctive focal-seizure trial is likely to be around the high teens to low 20s, consistent with XEN1101 and cenobamate. Pairing, say, about 50%-52% active efficacy with about 18%-24% placebo yields roughly 28-34 percentage points placebo-adjusted. That is why I center the forecast near 30 percentage points. This is my inference from the trial designs and comparator studies. (praxismedicines.com)
The downside case is that RADIANT’s open-label effect overstates true blinded efficacy, or that placebo response in POWER1 is unusually high; in that world the readout could fall into the teens or even single digits. The upside case is that vormatrigine’s rapid-onset, no-titration profile translates unusually well in blinded testing, putting the placebo-adjusted number in the high 30s or low 40s. Because the evidence base is still one open-label efficacy study plus design/materials for POWER1, I keep meaningful probability mass on both sides of the base case. (cms.aesnet.org)
Bottom line: I would summarize my forecast as centered at about 29.9 percentage points, with the densest part of the distribution in roughly the mid-20s to mid-30s and a smaller but real tail into the high 30s/low 40s.
As of Saturday, May 23, 2026, Praxis had not yet publicly disclosed POWER1 topline efficacy; its May 7, 2026 update still said POWER1 topline results were expected in Q2 2026. POWER1 is a randomized, double-blind, placebo-controlled registrational focal-onset seizure study in roughly 230 patients on 1-3 background ASMs, using vormatrigine 20 mg once daily for 6 weeks followed by 30 mg once daily for 6 weeks versus placebo. The primary endpoint is the median percent change in monthly (28-day) focal seizure frequency from baseline to treatment. (investors.praxismedicines.com)
The key prior efficacy signal is the open-label RADIANT study. In Praxis’ December 2025 AES update, 62 focal-onset seizure patients on background ASMs had a 54% median reduction in seizures over 8 weeks; 58% achieved at least a 50% reduction in week 1 and 61% by week 8; more than 11% were seizure-free for the full 8-week period. The earlier 37-patient cohort showed a 56.3% median reduction. Those numbers are impressive, especially because baseline treatment burden was substantial (mean about 2.1 background ASMs) and about 35% of focal-onset seizure patients were already on cenobamate, but RADIANT was single-arm and open-label, so I treat it as an informative upper-leaning signal rather than a direct predictor of the placebo-adjusted POWER1 result. (ir.praxismedicines.com)
Controlled focal-seizure benchmarks give a useful reality check. In the X-TOLE phase 2b study, XEN1101 25 mg produced a 52.8% median reduction versus 18.2% for placebo, a 34.6-point gap. In controlled cenobamate studies, the relevant gaps were about 31 points (55.0% vs 24.0%) and 34.1 points (55.6% vs 21.5%). My inference from these high-performing comparators is that a clearly best-in-class placebo-adjusted POWER1 outcome would likely land in the low-to-mid 30s, not near the raw 54% open-label RADIANT number. (jamanetwork.com)
I then discount the RADIANT signal for translation into POWER1. The biggest reason is design: POWER1 is blinded and placebo-controlled, whereas RADIANT was not. The second reason is dosing: POWER1 spends half of the treatment period at 20 mg, while Praxis’ materials show POWER2 is the dose-optimization study exploring 20, 30, and 40 mg, and phase 1 data showed dose-proportional exposure and tolerability up to 45 mg. That combination suggests POWER1 can work well without necessarily being fully dose-maximized. Offsetting that, Praxis says exposure-response modeling supports the POWER1/POWER2 designs, and the RADIANT efficacy signal on top of modern background therapy makes a completely flat result look unlikely. Putting those together, I center the forecast at about 26 percentage points, with most probability in roughly the 18-35 range, a smaller left tail for a miss or only weak separation from placebo, and a thinner right tail above 40 if the open-label signal translates unusually well. (praxismedicines.com)
As of May 23, 2026, I did not find a public POWER1 efficacy topline in the official Praxis materials I checked; on May 7, 2026 Praxis was still guiding to POWER1 topline results in Q2 2026. POWER1 is a randomized, double-blind, placebo-controlled Phase 2/3 registrational trial in adults with focal seizures, with estimated enrollment of about 230, 1:1 randomization, and vormatrigine dosed at 20 mg once daily for the first 6 weeks and 30 mg for the second 6 weeks. The primary endpoint is the median percent change in monthly 28-day focal seizure frequency from baseline to the 12-week treatment period versus placebo. (investors.praxismedicines.com)
The strongest efficacy anchor is the open-label Phase 2 RADIANT study. Praxis reported on August 4, 2025 that vormatrigine produced a 56.3% median reduction in seizure frequency over 8 weeks, with about 22% of patients reaching 100% reduction in the last 28 days on treatment and more than 54% achieving a 50% response in the first week. At AES 2025, Praxis updated that focal-onset seizure patients had about a 54% median reduction over the first 8 weeks, baseline median seizure frequency of 9.0 per 28 days, and roughly 11% complete seizure freedom during the treatment period; the same poster said exposure-response modeling supported the POWER1 and POWER2 designs. (investors.praxismedicines.com)
Historical blinded adjunctive focal-seizure trials suggest that very strong modern agents usually land in the low-to-mid 30s on a simple placebo-adjusted median-difference basis. Cenobamate showed 55.6% versus 21.5% in one randomized study, and 55.0% versus 24.0% in a dose-ranging trial, implying gaps of 34.1 and 31.0 percentage points. XEN1101 25 mg showed 52.8% versus 18.2%, a 34.6-point gap. By contrast, weaker or mixed programs can be much lower: brivaracetam showed 26.9% versus 18.9%, and perampanel 12 mg showed 34.5% versus 21.0%. (pmc.ncbi.nlm.nih.gov)
A small resolution wrinkle is that Praxis sometimes headlines a directly modeled placebo-adjusted seizure-reduction figure rather than only giving arm-specific medians. For relutrigine, Praxis reported a 46% placebo-adjusted monthly motor seizure reduction in 2024 and later cited 53% placebo-adjusted reduction from updated data. That makes me leave a bit of extra uncertainty around the exact reported POWER1 value even if the underlying arm medians are in the expected range. (investors.praxismedicines.com)
My synthesis is: RADIANT makes a materially positive POWER1 readout more likely than not, but because RADIANT was single-arm and open-label, I discount it for expectancy effects and regression to the mean. I also make a modest downward adjustment because POWER1 spends its first 6 weeks at 20 mg, whereas RADIANT used 30 mg daily during its 8-week treatment period. On the other hand, POWER1 is larger, placebo-controlled, and Praxis has said enrollment exceeded its original target, which should make the estimate more stable even if it does not change efficacy itself. Putting that together, I center the forecast around 32 percentage points placebo-adjusted. A reasonable blinded outcome is active-arm median reduction roughly in the 50-55% range with placebo around 18-22%, pointing to something like 28-37 points, while retaining a meaningful left tail for a disappointing or near-null result and a smaller right tail above 40 if vormatrigine truly proves best-in-disease. (praxismedicines.com)
As of May 23, 2026, POWER1 has not yet publicly disclosed efficacy, and Praxis said in its May 7, 2026 first-quarter update that topline POWER1 results are expected in Q2 2026. POWER1 is a randomized, double-blind, placebo-controlled Phase 2/3 study in about 230+ adults with focal onset seizures on 1-3 ASMs; patients are randomized 1:1 to vormatrigine once daily at 20 mg for the first 6 weeks and 30 mg for the second 6 weeks, or placebo, with the primary endpoint being median percent change in monthly focal seizure frequency from baseline to the 12-week treatment period. Praxis has also said enrollment exceeded the original plan. (investors.praxismedicines.com)
The main efficacy prior is RADIANT. Praxis first reported 56.3% median seizure reduction over 8 weeks in the initial 37 focal-onset seizure patients receiving 30 mg daily. In December 2025, the company updated the focal-onset seizure dataset to 62 patients and reported a 54% median reduction over 8 weeks, with 58% achieving at least a 50% reduction in week 1, 61% by week 8, and more than 11% seizure freedom over the full 8-week period. Those are strong signals, but RADIANT was open-label and single-arm, so I apply a meaningful haircut when translating it to a blinded placebo-controlled readout. (ir.praxismedicines.com)
Controlled benchmarks for modern focal-seizure drugs set the upper-middle part of the plausible range. In X-TOLE, XEN1101 25 mg produced a 52.8% median reduction versus 18.2% on placebo, implying about 34.6 percentage points by the resolution rule. In a randomized Phase 2 study, cenobamate 200 mg produced 55.6% versus 21.5% on placebo, implying about 34.1 points. So a very strong POWER1 result plausibly lands in the low-to-mid 30s, but that is the standard set by some of the best contemporary controlled datasets. (cris.unibo.it)
Why not center the forecast in the mid-30s? Two reasons. First, POWER1 uses 20 mg for the first 6 weeks before stepping to 30 mg, while RADIANT used 30 mg throughout its 8-week treatment period. Second, placebo response in focal-epilepsy trials has drifted upward over time, and higher placebo response is associated with lower baseline seizure burden and fewer concomitant ASMs. That matters because the mature RADIANT focal-onset seizure cohort averaged about 2.1 background ASMs and had a baseline median of 9 seizures per 28 days, which is not an ultra-refractory population; POWER1 also enrolls adults on 1-3 ASMs. Praxis’s own exposure-response modeling said the dose range supports POWER1 and POWER2, which keeps me from going too low, but I still expect the blinded placebo-adjusted figure to come in below the raw open-label RADIANT reduction. (praxismedicines.com)
My base case, explicitly an inference, is an active-arm median reduction around 46-48% and a placebo median reduction around 19-21%, which gives a simple active-minus-placebo resolution value around 26-29 percentage points. I therefore center the distribution at 27 percentage points, with most mass from about 20 to 35. I leave a meaningful but smaller left tail for a disappointing readout in the low teens or single digits if the open-label signal shrinks sharply or placebo is unusually high, and a smaller right tail into the 40s if vormatrigine behaves like a best-in-class controlled therapy despite the step-up dosing schedule. (ir.praxismedicines.com)
In the official Praxis materials available through May 23, 2026, I did not find a public POWER1 efficacy disclosure yet. Praxis’s May 7, 2026 first-quarter update still said topline POWER1 results were expected in Q2 2026, and February 2026 materials said the Phase 3 study had completed enrollment and exceeded its original target. (investors.praxismedicines.com)
POWER1 is a randomized, double-blind, placebo-controlled Phase 2/3 registrational study in adults with focal onset seizures taking 1-3 concomitant ASMs. The active regimen is 20 mg once daily for 6 weeks and then 30 mg once daily for 6 weeks, versus matching placebo for 12 weeks, with about 230 participants randomized 1:1. The primary endpoint is the median percent change in monthly (28-day) focal seizure frequency from baseline to treatment for vormatrigine compared with placebo. (index.mirasmart.com)
The strongest direct efficacy clue is the open-label RADIANT study. Praxis reported a 56.3% median reduction in seizure frequency over 8 weeks with vormatrigine 30 mg daily. In the AES 2025 poster, the focal-onset-seizure cohort had N=65, used a mean of 2.1 background ASMs, 77% were already on a sodium-channel blocker, 35% were on cenobamate at baseline, and Praxis reported seizure freedom within the treatment period in a little over 11% of patients. That is a meaningful efficacy signal, but because RADIANT was single-arm and open-label, I discount it before mapping it into a blinded placebo-controlled study. (investors.praxismedicines.com)
I adjust in both directions for dosing and exposure. Downward, POWER1 averages less drug exposure than RADIANT because patients spend the first 6 weeks at 20 mg before moving to 30 mg, and Praxis’s later POWER2 study adds a 40 mg arm based on PK/PD analysis to optimize efficacy opportunity, which suggests 30 mg may not be the absolute top of the exposure-response curve. Upward, the Phase 1 healthy-volunteer study said 20 mg and 30 mg already exceeded the predicted efficacious exposure level, and Praxis said exposure-response modeling from RADIANT supported the POWER1 and POWER2 designs. Net, I expect substantial activity in POWER1, but not simply the full 56.3% RADIANT number to carry over unchanged. (index.mirasmart.com)
For placebo, modern focal-seizure trials show a wide but usually positive median reduction, roughly from the low teens to low 20s. In the randomized cenobamate Phase 2 study, median reduction was 55.6% on drug versus 21.5% on placebo, a 34.1-point gap. In XEN1101 Phase 2b X-TOLE, the 25 mg arm showed 52.8% versus 18.2% for placebo, a 34.6-point gap. In the later Phase 3 X-TOLE2 study of azetukalner, the 25 mg arm showed 53.2% versus 10.4% for placebo, a 42.8-point gap. These are not head-to-head comparisons, but they anchor the plausible placebo-adjusted band for a genuinely strong adjunctive ASM in this setting. (neurology.org)
Putting those pieces together, my central translation is about 52% median reduction for the POWER1 active arm and about 15-16% for placebo, implying roughly 36-37 percentage points placebo-adjusted. I keep a meaningful left tail because open-label epilepsy signals can shrink in blinded studies and because placebo response in seizure trials is noisy. I also keep a smaller right tail into the mid-40s or low-50s because RADIANT was strong, Phase 1/PK data suggest 20-30 mg is pharmacologically active, and the best modern focal-seizure programs have already shown placebo-adjusted results in the low 40s. My point forecast is 36.5 percentage points, with most probability mass from about 28 to 46. (investors.praxismedicines.com)