Kind of just writing a therapeutic post on remaining data/analyses yet to come to help me cope with the days news.

The synergy of rosuvastatin (Crestor) with apabetalone

From the Sept 3, 2013 news release post-ASSURE "In patients with low HDL receiving RVX-208 and Rosuvastatin (Crestor), plaque regression was twice as pronounced as compared to the pre-specified primary endpoint.....Those patients taking Rosuvastatin and RVX-208 had a highly statistically significant Percent Atheroma Volume (PAV) plaque regression of -1.43% with probability value of p<0.002. This PAV regression exceeded the trial's pre-specified PAV endpoint (-0.6%) by more than two-fold. But those patients taking Atorvastatin (Lipitor ) together with RVX-208 had a PAV plaque progression of +0.19% with a non-significant probability value. The synergistic effect of the Rosuvastatin and RVX-208 combination is the basis for two recent provisional patent applications by Resverlogix......The responder population (i.e. HDL <39 mg/dL taking Rosuvastatin and RVX-208) exceeded the primary endpoint and also surpassed secondary endpoints reflecting regression in coronary atherosclerosis. These measures included total atheroma volume (TAV) and changes in the 10 mm most diseased segment of the coronary arteries, we noted marked regression versus baseline of -12.3 mm3 ( p< 0.0001) and -4.3 mm3 (p<0.0001), respectively." You can see the data for yourself in this patent "COMPOSITIONS AND THERAPEUTIC METHODS FOR ACCELERATED PLAQUE REGRESSION." As discussed previously, Resverlogix wanted to just do BETonMACE with rosuvastatin; however, the story goes that the FDA and other regulatory agencies pushed for both atorvastatin and rosuvastatin to be included. They have pre-specified looking at the primary 3-point MACE endpoint in those treated with atorvastatin vs. rosuvastatin. Today's top-line was just for the combined statin group. So we will have to cross our fingers and wait and see in the rosuvastatin/apabetalone synergy occured for MACE reduction in BETonMACE as it did for plaque reduction in ASSURE. Other pre-specified sub-group comparisons for the primary outcome are mentioned in the appropriate sections below. How will the FDA, EMA, and other regulatory agencies treat pre-specified sub-group comparisons for the primary endpoint in their consideration of drug approval? Great question that I do not have an answer to. 

Chronic kidney disease sub-study to look at change in eGFR

Changes in eGFR in those patients with baseline eGFR below 60 mL/min will be examined as a secondary endpoint (see sub-study poster here). In a post-hoc analysis of ASSURE and SUSTAIN,"Patients who received apabetalone (n=35) versus placebo (n=13) over 6 months showed significantly (p=0.02) lowered serum ALP -14.0% (p<0.0001 versus baseline) versus -6.3% (p=0.9 versus baseline). The eGFR in the apabetalone group increased by 3.4% (1.7 mL/min/1.73 m2) (p=0.04 versus baseline) and decreased by 5.8% (2.9 mL/min/1.73 m2) (p=0.6 versus baseline) in the placebo group. Apabetalone was well tolerated." This was published in this paper "Apabetalone Mediated Epigenetic Modulation is Associated with Favorable Kidney Function and Alkaline Phosphatase Profile in Patients with Chronic Kidney Disease." Apabetalone has also been shown to elicit huge effects on the plasma proteome in stage 4/5 CKD patients after a single dose as detailed in this paper "Benefit of Apabetalone on Plasma Proteins in Renal Disease." So tons of potential here in renal disease. They have also pre-specified looking at the primary 3-point MACE endpoint in those with eGFR >60 mL/min and < 60 mL/min. The annual American Society for Nephrology (ASN) Kidney Week meeting is coming up early November. Perhaps we will see something BETonMACE related presented there.

Cognition sub-study to look at change in MoCA score.

Cognition is a pre-specified exploratory outcome in BETonMACE and was assessed at baseline and annually in patients 70 years and older by the Montreal Cognition Assessment (MoCA). A score of ≤25 indicates cognitive impairment. Subgroups of patients with MoCA score <26 and <21 at baseline  will also be analyzed. Check out the sub-study poster and this presentation by Dr. Jeffrey Cummings. Huge need for a novel drug to help combat cognitive decline. A benefit in this sub-study has the potential to be huge. Tada has broken down this market opportunity many times before. Perhaps Tada can link to a former post that discusses this potential. CTAD Asia conference (https://www.ctad-asia.com/) is coming up next month. Although Dr. Cummings is one of the organizing committee members, I don't see a Resverlogix/BETonMACE/Apabetalone presentation listed. There might be a poster, but no talks listed in the current program. A more likely venue for this may be at the larger CTAD meeting in December in San Diego (https://www.ctad-alzheimer.com/).

Secondary endpoint: Change in alkaline phosphatase (ALP).

There is growing interest and respect for alkaline phosphatase levels being associated with MACE incidence. Just recently, this paper "Apabetalone lowers serum alkaline phosphatase and improves cardiovascular risk in patients with cardiovascular disease" was published. Alkaline phosphatase is also relevant to vascular calcification, and the recent paper "Apabetalone downregulates factors and pathways associated with vascular calcification" demonstrates effects on both ALP and vascular calcification." The effect of apabetalone on lowering ALP is also associated with improved kidney function, as documented in this paper "Apabetalone Mediated Epigenetic Modulation is Associated with Favorable Kidney Function and Alkaline Phosphatase Profile in Patients with Chronic Kidney Disease." Lastly, in addition to the late breaking presentation at AHA for the BETonMACE trial, there is a presentation by Dr. Kausik Ray and company entitled "ALP Levels Predict Adverse Cardiovascular Outcomes and Cognitive Impairment in High Risk Patients." Could ALP be the key?

Secondary endpoints: 5-point MACE, all-cause mortality.

Although the 3-point MACE endpoint whiffed as we found out today, it could be that the 5-point MACE secondary endpoint still hits. Although achieving significance with 5-point MACE doesn't carry as much weight as achieving significance with 3-point MACE, it could still show benefit and confirm the findings from the Phase 2 5-point MACE post-hocs. See this paper "Selective BET Protein Inhibition with Apabetalone and Cardiovascular Events: A Pooled Analysis of Trials in Patients with Coronary Artery Disease." I have also broken down the 5-point MACE vs. 3-point MACE issue before in this post. Once full data is presented and published, we will be able to see which, if any, of the 3-point MACE components (cardio death, non-fatal MI, non-fatal stroke) and addition 2 for 5-point MACE (coronary revascularization, hospitalization for cardiovascular causes) may have been affected. Furthermore, all-cause mortality (beyond just cardio death) is very important and this is a secondary endpoint. Lastly, total event analysis (not just looking at time to first event) can be extremely informative. As published for the EXAMINE trial "Total cardiovascular events analysis of the EXAMINE trial in patients with type 2 diabetes and recent acute coronary syndrome" many diabetic recent ACS patients have multiple MACE events during the course of the trial. Apabetalone may show benefit on total events. The recent diabetic recent ACS population is a difficult one with very high residual risk. Recall that the EXAMINE, ELIXA and ALECARDIO trials all failed to lower MACE incidence in this population. They have also pre-specified looking at the primary 3-point MACE endpoint in those with ACS event within < 30 days of trial start vs. those > 30 days. Maybe something there, maybe not.

Secondary endpoints: Changes in HbA1C, fasting glucose, fasting insulin. 

All BETonMACE patients are diabetics with median dosing period over 2 years. From this 2014 news release: "In the ongoing analysis of pooled ASSURE and SUSTAIN data, many biomarkers of cardiovascular risk were examined but the above findings made blood glucose levels of specific interest. Results of analysis showed that patients with DM given RVX-208 tended to have lower blood glucose vs. placebo. But specifically in patients with DM who had low HDL, the blood glucose was significantly lower following treatment with RVX-208 vs. placebo. Furthermore, the time required for RVX-208 to reduce blood glucose was not observed until at least 12 weeks following initiation of treatment." Aside from this, there isn't much clinical or pre-clinical data to support apabetalone eliciting improved glucose/insulin control. A small study in 20 pre-diabetic males treated with apabetalone for about 1 month showed some interesting changes in certain facets of glucose metabolism. But there isn't much need right now for another drug that offers improved glucose/insulin control unless it has proven cardiovascular benefits. SGLT2 inhibitors and GLP-1R agonists lower glucose AND lower cardiovascular events. Apabetalone would need some other major benefit to carry the torch, but added benefit of improved glucose/insulin control tag along for the ride. They have also pre-specified looking at the primary 3-point MACE endpoint in those with HbA1c above and below median.

Secondary endpoints: Changes in apoA-I, apoB, LDL-C, HDL-C, TG.

It is already expected that apabetalone will modestly but significantly increase apo-AI and HDL-C based on prior trials. Problem is that HDL-C and apo-AI are not established cardio risk factors like apoB, LDL-C, and TG. No drug will be approved for increasing HDL-C or apo-AI unless there is proven cardiovascular benefit to go along. Any effect of apabetalone on apo-B, LDL-C and TG will likely be modest if any effect at all. There are already good approved drugs (Vascepa, PCSK9 antibodies) or soon to be approved drugs (inclisiran, bempedoic acid) for dramatically lowering apo-B, LDL-C and TG. They have also pre-specified looking at the primary 3-point MACE endpoint in those with LDL/HDL/TG’s above and below median. 

There are some other outcomes being examined too: Changes in hsCRP, fibrinogen, mRNA changes in whole blood, Health Related Quality of Life (HRQOL) as measured using the EQ-5D-5L. I don't know much about the fibrinogen changes or HRQOL testing. The mRNA profiling seems too broad to mean anything. Changes in hsCRP could be interesting as a marker of inflammation/acute phase response, but only if these changes are associated with an improved clinical outcome.

OK. Therapy session over.

BearDownAZ