Pharmacodynamic biomarkers in people with hemophilia A receiving multiple ascending doses of NXT007
Bibliographic record
Abstract
Abstract Background: NXT007 is a bispecific, monoclonal antibody that mimics the function of activated factor (F)VIII. NXT007 was engineered and optimized based on emicizumab. The Phase I/II multiple ascending dose (MAD) study of NXT007 (NCT05987449) is an open-label, non-randomized, multicenter trial, testing increasing subcutaneous doses of NXT007 in people with hemophilia A (PwHA). NXT007 demonstrated comparable thrombin generation (TG) to FVIII levels in the non-hemophilia range in in vitro spiking experiments (Teranishi-Ikawa et al. J Thromb Haemost 2024). Here, we present the pharmacodynamic (PD) and exploratory biomarker data, as well as pharmacokinetic–PD relationships, from this NXT007 study. Methods: Prior to starting NXT007, participants received one dose of 40 IU/kg of their standard-of-care FVIII treatment during a pre-treatment visit. This dose, based on an average in vivo recovery (IVR) of 2 IU/dL per IU/kg, was expected to achieve plasma FVIII activity of approximately 80 IU/dL. Plasma samples were collected prior to FVIII infusion and 15 minutes (min), 1 hour (h) and 3 h post infusion. During the NXT007 treatment period, samples were collected prior to loading doses of NXT007 at Days 1 and 15, and at trough concentrations during maintenance treatment every 4 weeks from Day 29. PD biomarkers included activated partial thromboplastin time (aPTT), FVIII-like activity (human chromogenic FVIII activity assay, Hyphen BioMed) and FXIa-triggered TG (Ceveron s100, Technoclone), and were measured in plasma samples collected during the pre-treatment and NXT007 treatment visits. To compare the PD effects of FVIII and NXT007, samples collected at Day 29 during NXT007 treatment, when loading doses were completed and maintenance dosing started, were compared with the samples taken 15 min after FVIII administration. In addition, FIX and FX concentrations, prothrombin time (PT), D-dimer, prothrombin fragment 1+2 (PF1+2) and fibrinogen were measured during NXT007 treatment. NXT007 plasma concentrations were measured using a validated immunoassay. Results: Large variability was observed in the measured plasma FVIII activity after FVIII administration during the pre-treatment visit. The 15 min post-FVIII administration time point was used for comparing PD effects during NXT007 treatment, as that is when the highest FVIII activity was generally observed. After the first NXT007 dose in all cohorts, aPTT shortened and remained below normal range throughout the study. FVIII-like activity and TG peak height increased during NXT007 loading doses and were sustained from Day 29 onwards. PD effects increased with increasing NXT007 doses. The maximum effect on aPTT was reached at low, sub-therapeutic NXT007 concentrations. FVIII-like activity increased linearly with increasing NXT007 plasma concentrations and TG peak height increased following an Emax model approaching maximum effect at the highest concentrations. In the lowest dose NXT007 cohort (Cohort 1), mean TG peak height at Day 29 was lower than the mean TG peak height 15 min post FVIII administration (pre-treatment visit). Mean TG peak heights in Cohorts 2 and 3 at Day 29 were close to the mean post-FVIII-infusion TG peak height at the pre-treatment visit, which was expected to achieve FVIII-like activity within the non-hemophilia range. No changes in FIX and FX concentrations, PT, D-dimer or fibrinogen were observed during NXT007 treatment, and increasing NXT007 concentrations had no impact on these markers. A slight increase in PF1+2 was seen, but was not considered to be of clinical significance. Conclusions: PD markers were well correlated with NXT007 concentrations and demonstrated stable activity throughout the maintenance-dosing period, while safety biomarkers remained unaffected. In PwHA receiving prophylaxis with NXT007, the TG peak height during the steady state was in the non-hemophilia range and comparable to that obtained in participants with FVIII levels in the normal range.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".