A Phase 1 Research Study to Evaluate Safety, Tolerability, and Pharmacokinetics of WVE-006 in Healthy Participants With Wild-type AAT Expression (RestorAATion-1): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 1 Research Study to Evaluate Safety, Tolerability, and Pharmacokinetics of WVE-006 in Healthy Participants With Wild-type AAT Expression (RestorAATion-1) (NCT06186492), a randomized phase 1 study. The primary outcome is The Proportion of Participants With Adverse Events.

2. Clinical Question

This was a first-in-human study in the RestorAATion clinical program. Its stated purpose was to compare WVE-006 with placebo in healthy participants after single dosing and multiple dosing. The registry record describes the information as intended to inform doses and regimens for later study in patients with Alpha-1 antitrypsin deficiency, and to assess a maximum safe and tolerable dose for those patients. Those are development aims, not conclusions established by the posted participant counts.

3. Trial Design

The registry record describes a Phase 1, randomized, double-blind, placebo-controlled study with a sequential model. It evaluated single ascending doses in Period 1 and multiple doses in Period 2. The study status is completed, with 47 participants enrolled. The recorded start date is 2023-11-14 and the primary completion date is 2025-02-13.

Period 1 included five WVE-006 dose cohorts: 30 mg, 100 mg, 200 mg, 400 mg, and 600 mg, alongside pooled placebo. Period 2 included WVE-006 600 mg every 2 weeks and placebo every 2 weeks. The posted participant counts differ across these groups. The record does not describe a single common allocation ratio across cohorts, and the Period 1 placebo group should not be assumed to represent a separately randomized comparator for every dose unless the registry record says so.

Randomization and double blinding are design features intended to reduce selection and assessment biases. A sequential model is consistent with examining dose cohorts in sequence, but the detailed dose-escalation rules, decision criteria, and any safeguards governing progression are not reported in the registry record. It also does not report whether any changes to the planned design occurred.

The primary endpoint concerned adverse events. Six secondary pharmacokinetic outcomes are listed: area under the plasma concentration-time curve and maximum plasma concentration after single dosing, and the corresponding measures after multiple dosing on Day 1 and Day 29. Results for these secondary outcomes are not reported in the registry record. The study's stated safety follow-up extends from consent until up to 85 days after the Period 1 dose and up to 113 days after the first Period 2 dose.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Participants were screened to the inclusion/exclusion of the protocol. The following assessments were performed: Consent, Demographics, Medical History, Prior/Concomitant Medications, AAT Testing, Pregnancy/FSH, Vital signs, Physical examination, Laboratory Safety Testing, ECG, Urine Drugs of Abuse Testing . The study included 2 distinct periods: Period 1 (SAD) and Period 2 (multiple dose). A total of 39 participants were randomised to Period 1 and 8 participants were randomised to Period 2.

Only the first 6 of 8 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: This analysis population included 47 enrolled participants who received at least one dose of WVE-006 or matching placebo.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: This analysis population included all 47 enrolled participants.

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as The Proportion of Participants With Adverse Events, measured over Adverse events are collected from the date of consent until up to 85 days after the dose in Period 1 and up to 113 days after the first dose in Period 2..

The primary endpoint is the number of participants who reported at least one adverse event. An adverse event is a participant-level safety outcome: the endpoint counts whether a participant reported an event, rather than counting every event separately. As a result, it does not describe the total number of events, their duration, or their severity. Those details require separate event-level summaries.

Safety and tolerability are central questions in a first-in-human study. Counting participants with adverse events offers a direct descriptive way to characterize events reported during the study's follow-up. The registry record specifies that adverse events were collected from the date of consent until up to 85 days after the dose in Period 1 and up to 113 days after the first dose in Period 2. Follow-up differs by study period, which matters when interpreting group counts: the opportunity to observe events was not described as identical across periods.

The posted endpoint results are counts by cohort. They do not establish that an event was caused by WVE-006, and the endpoint's name alone does not imply that every reported event was treatment-related. The record does not provide an adjusted comparison, uncertainty interval, or statistical test for the endpoint. Thus the counts are descriptive evidence of what was reported in the listed groups, not a precise estimate of comparative safety.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is binary at the participant level: each participant either was or was not reported to have an adverse event over the specified follow-up. The results are presented as counts of participants with events alongside the number of participants in each group. This descriptive format keeps the underlying observations visible and avoids implying a more elaborate model than the registry record reports.

What can group counts tell us?

Counts show how many participants in each group met the endpoint. They are easy to interpret, but their precision depends on the amount of information in each group. With small groups, one participant's outcome can noticeably affect the apparent pattern. A count should therefore be understood as a summary of the participants observed, not as a guarantee of what would occur in a larger population.

A comparison between treatment and placebo requires more than placing two counts side by side. The groups may differ in size, dose, period, follow-up, or other factors. A statistical comparison would need to define the contrast of interest and its assumptions. The registry record does not report an inferential analysis for this primary endpoint; it explicitly indicates that values are missing or not estimable for a two-arm comparison. Consequently, no treatment-versus-placebo p-value or confidence interval is available in the posted results.

What would an uncertainty interval mean?

General explanation: a confidence interval expresses the range of effect estimates compatible with the data and the statistical method used. It communicates uncertainty more directly than a single point estimate. It does not show that every value inside the interval is equally plausible, and it does not replace consideration of study design or clinical context. No confidence interval is reported for the adverse-event comparisons in this record, so their comparative precision cannot be described using that measure.

Why can small samples be difficult to interpret?

General explanation: when few participants contribute to a group, estimates can be unstable and may vary substantially across samples. A difference in observed counts may reflect chance variation as well as any real underlying difference. This is one reason why descriptive counts should not be translated into a claim of benefit or harm without an appropriate analysis and adequate uncertainty assessment. In this study the posted cohort sizes are small, and no inferential comparison is reported.

What does the sample-size illustration represent?

The planning illustration is described as a calculation based on the observed effect, not on the trial's own design. Its stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect defined as a stated fraction of the observed effect. Such calculations can illustrate how a hypothetical future comparison might be planned under specified assumptions. They do not show the power of the completed study, and they are not evidence that the study was designed around those assumptions. The sample-size justification used for the trial is not reported in the registry record.

General explanation: power is a design concept describing the chance that a specified statistical procedure will detect a specified effect under its assumptions. It is not a measure of whether the observed result is true, and calculating power from an observed result does not make a non-significant or descriptive result more conclusive. Sample-size planning should be distinguished from results-based interpretation. Any sample sizes in a planning illustration are hypothetical planning quantities, not observed outcomes.

How should the sequential dose structure be considered?

The study is described as sequential and includes multiple dose cohorts, with single dosing in Period 1 and multiple dosing in Period 2. Dose-specific counts are informative descriptions of the individual groups, but interpreting them as a trend requires a prespecified dose-response analysis and attention to the cohort structure. The record does not report the rules for escalation, a dose-response model, or an inferential method for comparing dose levels. Those details should not be inferred from the sequence of cohort labels alone.

Randomization and double blinding are methodological strengths in principle. Randomization can help balance measured and unmeasured characteristics between assigned groups, while blinding can reduce the influence of expectations on participant reports and outcome assessment. These features do not eliminate uncertainty, especially in small cohorts, and they do not establish that every comparison was powered or statistically tested. The record does not report the allocation procedure or the success of blinding.

Finally, adverse events are collected over stated observation windows. Counts can only describe events captured under those windows and the registry's collection procedures. The record does not report details of missing observations, event adjudication, or sensitivity analyses. The interpretation should therefore remain tied to the reported counts and the stated follow-up rather than extending to unreported analyses or outcomes.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Period 1: Pooled Placebo", "Period 1 Cohort 1 - WVE-006 30 mg", "Period 1 Cohort 2 - WVE-006 100 mg", "Period 1 Cohort 3 - WVE-006 200 mg", "Period 1 Cohort 4 - WVE-006 400 mg", "Period 1 Cohort 5 - WVE-006 600 mg")
n      <- c(10, 6, 5, 6, 6, 6)
events <- c(8, 5, 4, 3, 3, 3)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Period 1: Pooled Placebo  10  8  80.0  44.4  97.5  49.0  94.3  48.2  94.0
ARM  Period 1 Cohort 1 - WVE-006 30 mg  6  5  83.3  35.9  99.6  43.6  97.0  42.1  96.3
ARM  Period 1 Cohort 2 - WVE-006 100 mg  5  4  80.0  28.4  99.5  37.6  96.4  35.9  95.7
ARM  Period 1 Cohort 3 - WVE-006 200 mg  6  3  50.0  11.8  88.2  18.8  81.2  18.4  81.6
ARM  Period 1 Cohort 4 - WVE-006 400 mg  6  3  50.0  11.8  88.2  18.8  81.2  18.4  81.6
ARM  Period 1 Cohort 5 - WVE-006 600 mg  6  3  50.0  11.8  88.2  18.8  81.2  18.4  81.6

11. Multiplicity, Missing Data and Analysis Populations

The study lists one primary safety outcome and six secondary pharmacokinetic outcomes. The record does not report a multiplicity plan, such as a hierarchy among outcomes or a method for adjusting inferential testing across multiple outcomes. Because numerical results for the secondary pharmacokinetic outcomes are not reported in the registry record, their findings cannot be assessed alongside the primary endpoint. No p-values or confidence intervals for the primary endpoint are reported either.

The registry record identifies the primary analysis population as 47 enrolled participants who received at least one dose of WVE-006 or matching placebo. It does not report an intention-to-treat population, a per-protocol population, or a separate safety population definition beyond that description. The group-specific counts are reported for the dose cohorts and placebo groups.

Missing outcome data, withdrawals, and the handling of incomplete follow-up are not reported in the registry record. The record also does not describe imputation methods, sensitivity analyses, or whether all participants completed the full adverse-event observation period. These omissions make it difficult to determine whether the posted counts reflect complete follow-up for every participant.

General explanation: missing data can affect estimates when the participants with available outcomes differ systematically from those without them. The impact depends on why data are missing and how the analysis handles them. Without information on completeness and missing-data methods, the extent of any influence cannot be assessed. Similarly, multiplicity matters when several outcomes or comparisons are tested, because repeated testing can increase the chance of a false-positive result if no adjustment or prioritization strategy is used. The registry record does not say whether such a strategy was specified.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse-event summaries report zero participants with serious adverse events in every listed group. The death count is also zero in every listed group. These are observed counts over the study follow-up, not proof that serious events or deaths cannot occur. The number of participants at risk is small in each cohort, so the absence of reported events provides limited information about rare outcomes.

The primary adverse-event endpoint is broader than the serious-event summary. The posted results include participants with non-serious adverse events, while the serious-event counts remain zero. The counts should not be conflated: reporting any adverse event does not mean that the event was serious, and the registry record does not establish that an event was caused by study treatment.

General explanation: a zero count in a small study can be compatible with a range of underlying event risks. It does not by itself provide a precise upper bound or comparative estimate; those would require an appropriate statistical method and assumptions. No uncertainty interval for serious adverse events is reported. The follow-up windows also differ by period, so the serious-event summaries should be interpreted within the time observed in each period.

13. What the Result Does, and Does Not, Mean

The posted results establish that adverse events were reported among participants in each of the listed cohorts, with counts varying by dose group and study period. The serious adverse-event and death summaries report zero events in all listed groups. These observations describe what was recorded in this completed Phase 1 study among healthy participants with wild-type AAT expression.

They do not establish a comparative causal effect of WVE-006 versus placebo. The registry record does not report an inferential analysis, a confidence interval, or a p-value for the primary endpoint. The cohort sizes are small, and the groups differ by dose and period. The available counts therefore do not support a precise estimate of how event occurrence would compare in a larger population or under a single pooled treatment contrast.

The counts also do not establish that WVE-006 is safe or unsafe, nor that a reported event was caused by the study drug. Safety interpretation requires context about event type, severity, timing, relatedness, completeness of follow-up, and uncertainty. Those details are not fully reported for the primary endpoint. Zero serious adverse events and zero deaths in the posted groups are reassuring as recorded observations, but they do not rule out uncommon or later events.

The study's purpose included assessing pharmacokinetics and informing later development. Six pharmacokinetic outcomes are listed, but their results are not reported in the registry record. The record therefore does not establish exposure patterns, dose proportionality, or pharmacologic activity. Nor does a healthy-participant study answer whether a dose or regimen has a particular effect in patients with Alpha-1 antitrypsin deficiency.

The appropriate reading is descriptive and limited: these are counts observed in the listed study groups, under the follow-up described. They offer information about events recorded during this early-stage study, while leaving comparative estimates, pharmacokinetic findings, and applicability to patients unresolved in the registry record.

14. Why This Trial Matters Statistically

Early-phase trials often have a different statistical role from large confirmatory studies. This randomized, double-blind, placebo-controlled Phase 1 study was designed to assess safety, tolerability, and pharmacokinetics in healthy participants, using single ascending doses and a multiple-dose period. Describing the study's structure and the information actually reported helps distinguish its development purpose from a definitive test of clinical outcomes.

The cohort-level adverse-event counts make the size and distribution of the observed data visible. That is statistically important: a pattern across dose groups may look suggestive, but small cohorts yield limited precision, and differences across cohorts cannot be treated as a formal dose-response finding without an appropriate analysis. The record reports no inferential comparison for the primary endpoint, so interpretation must remain descriptive.

The registry also lists pharmacokinetic outcomes, which are central to understanding exposure in dose-finding research. Their absence from the posted results is an important information gap. Without those numerical results, readers cannot connect the safety counts to measured plasma concentrations or assess the stated pharmacokinetic aims.

Finally, the study illustrates why statistical conclusions depend on more than a point count. Follow-up duration, cohort structure, analysis population, missing data, and uncertainty all shape interpretation. Several of these details are not reported in the registry record. Recognizing both the observed counts and the unavailable analysis details supports appropriately cautious reading without treating an early-stage safety summary as a final answer about treatment effects.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record gives a limited account of the statistical methods. It does not report a statistical analysis plan, a sample-size justification, the allocation procedure, or the criteria used for sequential dose escalation. It also does not describe whether there were interim reviews or how decisions about progression between cohorts were made. Those aspects should not be inferred from the study's sequential label.

The primary results are participant counts without reported confidence intervals or inferential comparisons. The cohorts are small, and the placebo groups differ across periods. Period 1 pooled placebo and Period 2 placebo are not interchangeable comparators, and the registry does not provide an adjusted analysis that reconciles these distinctions. The posted counts therefore have limited ability to quantify comparative uncertainty.

The record does not report adverse-event types, seriousness determinations beyond the separate serious-event summary, severity, relatedness, or event timing by cohort. It does not report completeness of follow-up, withdrawals, missing outcome handling, or sensitivity analyses. Although follow-up periods are described, the actual observation time for each participant is not reported.

Six secondary pharmacokinetic outcomes are listed, but numerical findings are not reported in the registry record. This leaves the study's pharmacokinetic results unavailable for interpretation. The study population is healthy participants with wild-type AAT expression, so results cannot be assumed to describe patients with Alpha-1 antitrypsin deficiency. Overall, the available registry results support a description of reported events, but not a complete assessment of safety, exposure, or comparative treatment effects.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Phase 1 Research Study to Evaluate Safety, Tolerability, and Pharmacokinetics of WVE-006 in Healthy Participants With Wild-type AAT Expression (RestorAATion-1) — NCT06186492.
• Registry record last updated 2026-03-23; status last verified 2026-03.
• Results first posted 2026-03-23.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT06186492 is a completed Phase 1 randomized, double-blind, placebo-controlled study of WVE-006 in healthy participants with wild-type AAT expression. It enrolled 47 participants and included single ascending doses in Period 1 and multiple dosing at 600 mg every 2 weeks in Period 2. The primary endpoint was the number of participants reporting adverse events.

The posted primary results give adverse-event counts for each listed dose and placebo group. No serious adverse events or deaths are reported in the groups. The registry lists six secondary pharmacokinetic outcomes, but their numerical results are not reported in the registry record. No inferential comparison or uncertainty interval is reported for the primary endpoint. The available results therefore describe observed events in this study but do not provide a precise comparative estimate or establish findings in patients with Alpha-1 antitrypsin deficiency.