Great posts today from many contributors on this hub. I was quiet for the day, but have a few thoughts to add to the great info shared by many of you related to today's Orphan disease program related to the compliment cascade.

1) The news release had a key statement "In addition to apabetalone (RVX-208), preclinical testing on other BET inhibitors in the Resverlogix library demonstrates similar effects on important markers in the complement and coagulation cascades. These compounds are under consideration as follow on compounds for complement mediated diseases such as PNH, but also atypical hemolytic uremic syndrome (aHUS), glomerulonephritis, and others."

They have more compounds than just RVX-208 that modulate the compliment cascade. And even though they may start with PNH as their target disease, they already list aHUS and glomerulonephritis as other compliment-related diseases that they may target.

2) Related to above, Alexion's Soliris (Eculizumab) is already approved for treating both PNH and aHUS, and the Wiki page on Eculizumab hints at the usage of this drug for treating several other compliment related diseases. If one searches ClinicalTrials.gov for Eculizumab or Soliris you will find 59 studies! Alexion has found the many diseases most likely to respond to compiment cascade reducing therapy. So Alexion has paved the road for treatment of compliment related disorders, but........

3) Soliris (Eculizumab) is uber expensive. It's crazy to hear that Soliris is the most expensive drug in the world. But it only highlights the special opportunity for RVX-208. Soliris is the same physical form of drug as the recent PCSK9 related drugs, which are monoclonal antibodies delivered via subcutaneous injection. You know, the same PCSK9 drugs that got a lot of heat for costing around $15,000 a year in the U.S.? Compare that price to Soliris, which the Wiki page lists as costing $409,500 a year in the United States. Now, one big difference is between the PCSK9 and compliment-related Orphan diseases is the size of the market (larger for PCSK9). But in addition, some of the Soliris protocols do intravenous injections as opposed to the routine subcutaneous injections of the PCSK9 antibody therapies. Either way RVX-208 is both cheaper to produce (small molecule vs. antibody), longer shelf life and would be cheaper/easier to administer since it is a pill not an injection.

4) In Resverlogix's August 31st new release, they state "Amongst the changes observed, RVX-208 decreased expression in 19 out of 26 genes that encoded components in the complement pathway. Similarly, RVX-208 decreased expression in 20 out of 33 gene that encoded components within the coagulation cascade. Further support of the micro-array data that identified changes in gene expression by probing the messenger RNA (mRNA) levels was pursued by measuring specific proteins within the complement and coagulation cascade using plasma from SUSTAIN and ASSURE trials. Results showed significant decreases ranging from 7-12% vs. baseline in complement (i.e. complement factor 3) and coagulation components."

In biological systems, it is often more advantageous to modulate several enzymes/components of a pathway rather than just a single target. The Soliris approach neutralizes the terminal Complement component 5, or C5, which acts at a late stage in the complement cascade. Resverlogix may (or may not) have the upper hand by being able to hit several members of the compliment cascade to elicit a more robust compliment cascade reducing effect than that achieved by Soliris/C5-targeted therapy alone. Although Resverlogix touted only 7-12% reductions of specific proteins in the blood, these patients may not have had the enormously abnormal high compliment activation to begin with and in the right patient population the reduction may be much more impressive. Hence, the point of the Phase II trials for RVX-208 in compliment related disorders.

5) RVX-208 has already passed Phase I trials and can go straigh to Phase IIs. Many of the Phase II Soliris trials were only 26 weeks long (just like SUSTAIN/ASSURE). And looking at the Soliris Phase II trials, they only needed 50 or less patients. So in theory, a low cost trial with a potentially HUGE reward if they could take a bite out of the Soliris market and offer a much cheaper and potentially more effective therapy for these types of diseases.

You know I love the countdown. Three more market days until the AGM! And the autumnal equinox has passed, so I am officially calling it Fall!

Best,

BearDownAZ