Acceleron Pharma Inc. (NASDAQ:XLRN) announced new preclinical results with sotatercept in pulmonary arterial hypertension (PAH) during an oral presentation at the American Heart Association (AHA) 2017 Scientific Sessions in Anaheim, California, on November 14, 2017
TGFBRII-Fc data has been recently published by Dr. Yung, Instructor in Medicine, and Prof. Paul B. Yu, AJRCCM, 2016 [ref]. ACTRIIA-Fc (ACE-011, sotatercept) captures the ligands GDF11, activin A, activin B and activin AC from binding to ACTRIIA.
[Q] why did they use MPAP and then RVSP in the presentation?
Slides 5 and 6 present Mean Pulmonary Artery Pressure (MPAP) data from two distinct animal models of PAH as results of MCT 60mg/Kg and Sugen5416 200mg/Kg (!!) and hypoxia. The first slide reports a SUGEN dose too high, which might be a typo or oddly used in the experimental setting. It is largely reported PAH can be induced with at least 20 mg/Kg and no need to use such large dose [ref], as later reported in the same presentation.
Right ventricular systolic pressure (RVSP) has been largely presented in published manuscripts by Prof. Yu's group and later in the same presentation instead.
As the reason is unknown, we are able to calculate MPAP that is roughly 0.6 time RVSP. Considering RVSP = 40mmHg as largely reported in the published manuscript and slide 9, MPAP should be 26.4 mmHg (RSVP=sPAP in the absence of RVOTO or pulmonic stenosis; MPAP=0.61 x sPAP +2) [ref]. However, MPAP has been reported to be 45mmHg in the vehicle (control).
[Q] Why is the weight ratio (RV/LV+S) so high?
The Fulton index, right ventricle hypertrophy, reported in the current presentation is too high, resulting in a 100% increase from previous experiments from the same laboratory and others authors [ref].
In adult male rats treated with SU5416 (SUGEN) and exposed to hypoxia for 3 weeks, the Fulton index in vehicle control in the presentation is 0.6 (rats received 200mg/Kg, slide 6), 0.29 in the published article (figure 5B SUGEN/HX, 20 mg/kg), and 0.46 after receiving a single subcutaneous injection of SU5416 and being subjected to normobaric hypoxia (FI O2 = 0.10) for 3 weeks, followed by maintenance in normoxia for 3 weeks (figure 6B SUGEN/HX, 20 mg/kg).
Even considering an inter-experiment variation, there is a 100% average percent increase in the weight ratio in the presented data, which increase does not correlate with the similar percent of muscularized vessels (72.5% vs 65%, respectively).
Treatment with ACTRIIA-Fc seems to be correlated with low or absence of any prophylaxis. In fact, slide 9 presentation Sugen-Hx treated rats reports a 0.35 Fulton index that reflects published data. However, the dose trend is not significant since all data within the dose group do not differ but from the control at a higher dose (p=0.05, Not less than 0.05!).
Slide 9 and slide 10 report the same set of redundant data.
In conclusion, we can affirm that controls have been misinterpreted in this presentation to highlight the possible potential prophylaxis and therapeutic effect of ACTRIIA-Fc in PAH animal model. Despite that, it is clearly represented that the information is scarce and do reports neither a dose-dependent nor a statistically significant effect.
Disclosure: I am/we are short XLRN.