In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia
Yearbook of Paediatric Endocrinology, 2026 · paper · Clinical trials
A phase 1 study of a single infusion of the base-editing therapy VERVE-102 in 35 adults with familial hypercholesterolemia or premature coronary disease. LDL cholesterol fell 9% to 62% by dose, with reductions durable and no dose-limiting toxicity.
0 findings
None that passed a second check.
6 minor (typos and the like; most checked by the judge only)
Wording "We also observed dose-dependent changes from baseline in time-averaged LDL cholesterol levels, which corresponded to reductions in the PCSK9 levels" (and the matching unqualified claims in the Discussion, the concluding paragraph and the abstract Conclusions) is stated without qualification although the cohort means in Table 3 and Figure 2C are not monotonic in weight-based dose: "−9 (−26 to 26) −44 (−57 to −30) −45 (−54 to −34) −33 (−70 to −14) −51 (−86 to −16) −62 (−79 to −45)".
- p. 6 Results, Pharmacokinetics and Pharmacodynamics
We also observed dose-dependent changes from baseline in time-averaged LDL cholesterol levels, which corresponded to reductions in the PCSK9 levels
- p. 8 Table 3, mean percent change from baseline in time-averaged LDL cholesterol, 0.7 mg/kg column
−33 (−70 to −14)
- p. 9 Figure 2, Panel C
C Change in Time-Averaged LDL Cholesterol Level from Baseline
- p. 7 Discussion, first sentence
a single infusion of VERVE-102 produced dose-dependent and sustained reductions in PCSK9 and LDL cholesterol levels
Judge's note: Read the Table 3 page image (main-p008.upright.png): the LDL percent-change row is −9, −44, −45, −33, −51, −62 across 0.3, 0.45, 0.6, 0.7, 0.8 and 1.0 mg/kg, so the 0.7-mg/kg value (−33) is smaller in magnitude than the two lower-dose cohorts; the PCSK9 row (−51, −59, −61, −64, −77, −88) is monotonic. Checked Figure 2 Panel C on the page 9 image: the 0.7-mg/kg bar is visibly shorter than the 0.45- and 0.6-mg/kg bars, so the figure shows the same pattern. Verified the wording verbatim on the crops of pages 6, 7, 9, 10 and the page 1 abstract image; the abstract's "Dose-dependent" is attached to PCSK9, while the Conclusions and the Discussion attach it to both analytes without qualifier. I looked for a qualification: the Results do qualify the PCSK9 statement ("dose-dependent and substantial at the higher doses"), the baseline LDL in the 0.7-mg/kg cohort is the lowest (105 mg/dl), and the authors add an exploratory total-RNA-dose analysis (Pearson r = −0.68), but no sentence qualifies the LDL dose-dependence claim. "Dose-dependent" can legitimately describe an overall trend in cohorts of 4–8 participants, so this is a wording/ambiguity point rather than a wrong number: CONFIRMED_MINOR, S3.
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Wording The Methods give the visit schedule as weekly through day 28 "with additional scheduled visits on days 60, 90, 180, 270, and 365" and state that "Participants who complete their visit on day 365 are expected to transition to a long-term follow-up study", yet Figure 2 (Panels B and D) plots a day-545 time point (3 participants in the 0.3-mg/kg cohort) and the Results report "the last study visit occurring at 28 days to 18 months" and follow-up "to a maximum of 18 months", with no statement of where the post-day-365 data come from.
- p. 5 Methods, Participant Eligibility and Study Procedure / top of page
with additional scheduled visits on days 60, 90, 180, 270, and 365
- p. 5 Methods, end of study-procedure paragraph
Participants who complete their visit on day 365 are expected to transition to a long-term follow-up study.
- p. 9 Figure 2, Panels B and D, x axis and participant counts (0.3-mg/kg cohort = 3)
545
Only the authors can say what is right here.
Judge's note: Opened the crop of page 5 (adjudicate/crops/C001-a.png) and the full page 5 image: the scheduled-visit list ends at day 365 and the next sentence sends participants to a separate long-term follow-up study. Opened the full page 9 image and the Figure 2 crops: the x axis of Panels B and D runs Baseline, 14, 28, 60, 90, 180, 270, 365, 545, and the No.-of-Participants rows give 3 participants in the 0.3-mg/kg cohort at day 545 in both panels. Opened page 7, which states a maximum of 18 months. I searched the Methods, the Figure 2 legend and the Discussion for any statement attributing the day-545 data to the long-term follow-up study or to unscheduled visits and found none (the only mention of the long-term study is on page 5 and in the limitations on page 10, which say participants are "expected" to enrol for 15 years). The ambiguity about the provenance of the post-day-365 data is real but affects no reported number, so S3.
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Wording The Discussion states that the GalNAc-lipid nanoparticle "was not associated with the adverse events observed with our previous in vivo base-editing therapy, VERVE-101" and two sentences later defines those events as "infusion-related reactions as well as increased liver aminotransferase levels and decreased platelet counts", two of which were observed in this study ("Transient infusion-related reactions, all of grade 1 or 2, occurred in seven participants (20%)" and 3 participants with alanine aminotransferase at or above two times the upper limit of normal).
- p. 7 Discussion, first key insight
was not associated with the adverse events observed with our previous in vivo base-editing therapy, VERVE-101.
- p. 7 Discussion, same paragraph
including the previous study of VERVE-101, have noted infusion-related reactions as well as increased liver aminotransferase levels and decreased platelet counts
- p. 5 Results, Safety
Transient infusion-related reactions, all of grade 1 or 2, occurred in seven participants (20%).
- p. 6 Results, Safety
3 had increased alanine aminotransferase levels that met or exceeded two times the upper limit of the normal range
Only the authors can say what is right here.
Judge's note: Read the page 7 crop (C004-a.png) and the full page 7 image: the two sentences appear in the same paragraph as quoted, and no qualifier such as "serious", "severe" or a grade threshold is attached to the first. Read the Safety results on the page 5 crop and full page (seven participants, 20%, with grade 1 or 2 infusion-related reactions) and on page 6 (3 of 35 with alanine aminotransferase reaching 2.0, 2.2 and 2.4 times the upper limit of normal), and Table 2 on page 7, which lists infusion-related reaction in 7 (20%) as a treatment-related event. So two of the three event types listed for VERVE-101 did occur here; the later hedges ("with varying severity", "relatively safe", "must be considered with caution") suggest the intended comparison is one of severity, but that is not what the sentence says. This is an overstatement in wording rather than a wrong number, so S3; only the authors can supply the intended qualifier.
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Wording "PCSK9 and LDL cholesterol levels at day 28 were consistent with the time-averaged values over the duration of follow-up, reflecting a stable pharmacodynamic response (Table 3)." is unqualified, but in Table 3 the 0.3-mg/kg cohort has mean LDL cholesterol "114 (47 to 147)" at day 28 versus a time-averaged "143 (50 to 234)" mg/dl, and the 0.45-mg/kg cohort has PCSK9 251 µg/liter at day 28 versus 199 time-averaged.
- p. 7 Results, "Durability of PCSK9 and LDL Cholesterol Reductions"
PCSK9 and LDL cholesterol levels at day 28 were consistent with the time-averaged values over the duration of follow-up, reflecting a stable pharmacodynamic response (Table 3).
- p. 8 Table 3, LDL cholesterol rows, 0.3 mg/kg column
114 (47 to 147)
- p. 8 Table 3, time-averaged LDL cholesterol row, 0.3 mg/kg column
143 (50 to 234)
- p. 8 Table 3, PCSK9 at day 28 and time-averaged PCSK9, 0.45 mg/kg column
251 (45 to 535)
Only the authors can say what is right here.
Judge's note: Read the durability paragraph on the page 7 crop (C003-a.png) and the full page 7 image: the sentence is printed exactly as quoted, with no restriction to particular cohorts. Read Table 3 on main-p008.upright.png. Day-28 versus time-averaged values are close in most cells (LDL: 82/77, 67/69, 65/70, 73/68, 51/51; PCSK9: 201/220, 181/173, 193/176, 101/98, 58/53), but the 0.3-mg/kg LDL pair is 114 versus 143 mg/dl (time-averaged value 29 mg/dl higher than day 28, against a baseline of 154) and the 0.45-mg/kg PCSK9 pair is 251 versus 199 µg/liter. The table footnote explains only how time-averaged values are computed (trapezoidal rule from day 28 onward, day-28 value substituted when day 28 is the last visit); it does not account for the divergence. The blanket wording therefore overstates the stability shown in the cited table for two cohorts, but no reported number is wrong, so S3.
Second check: another model agreed
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Typo The affiliation list carries the same institution twice under two numbers: "4 Institute of Cardiovascular Science, University College London, London" (page 10) and "19 Institute of Cardiovascular Science, University College London, London." (page 11), used for R.S. Patel and S.E. Humphries respectively.
- p. 10 Author Information, affiliation 4
4 Institute of Cardiovascular Science, University College London, London
- p. 11 Author Information (continued), affiliation 19
19 Institute of Cardiovascular Science, University College London, London.
- p. 1 Author list
Steve E. Humphries, Ph.D.,19
Judge's note: Read the Author Information block on the page 10 image (entries 1-14) and its continuation on the page 11 image (entries 15-19). Entry 4 reads "Institute of Cardiovascular Science, University College London, London" and entry 19 reads "Institute of Cardiovascular Science, University College London, London." — character-for-character the same institution string, with no distinguishing department or centre. The author list on page 1 shows Patel as 4,5 and Humphries as 19, so the two numbers are both in use. Purely a numbering duplication in the affiliation list; no data or pointer into the article is affected, hence S4.
Second check: none (judge only)
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Typo Reference 22 ends with a space before the closing period: "J Clin Lipidol 2024;18(4):e515-e516 ."
- p. 11 Reference list, reference 22
J Clin Lipidol 2024;18(4):e515-e516 .
Judge's note: Read the reference list on the page 11 image: entry 22 (Popadic L, Ma X, Ali Y, et al.) ends "...J Clin Lipidol 2024;18(4):e515-e516 ." with a visible gap between the page range and the terminal period. Checked the comparable entries with article-number style page citations in the same list — 19 ("Circ Cardiovasc Qual Outcomes 2019;12(8):e005404.") and 23 ("J Am Heart Assoc 2022;11(14):e025813.") — which have no such gap, so the spacing is specific to reference 22 rather than a general rendering of the list. Both extraction files (extract/main.txt line 1308 and extract/main.layout.txt line 725) also carry the space, consistent with the image. Cosmetic typesetting slip only.
Second check: none (judge only)