The Pestell paper does discuss the rationale for studying LL is that it may have an improved safety profile:
Still trying to understand the if and why of maraviroc toxicity. Here is one recent small study looking at liver toxicity of maraviroc in HIV patients:
https://pubmed.ncbi.nlm.nih.gov/27924779/
An older summary of clinical trial AEs with MVC:
https://journals.lww.com/aidsonline/Fulltext/...oc.19.aspx
Apparently the FDA disagreed though, and had them slap on a black box warning for possible liver toxicity, at least based on trials for the HIV indication.
It's hard to judge the truth sometimes, but all signs point to leronlimab having a better safety profile, despite maraviroc appearing pretty safe. If there was a good explanation for maraviroc liver toxicity I'd feel better about that notion.
But enough about this topic, just wanted to point out one nagging fear that we may have competition (given the Pestell paper showing the small molecule CCR5 antagonists work just as well or better than leronlimab in breast cancer mets model), and hoping that others can convince me otherwise that it isn't that big of a deal.
Quote:CCR5-specific small molecular inhibitors prevented metastasis of isogenic oncogene-transformed breast cancer cells in NOD/SCID mice [12] and prostate cancer metastasis in immune-competent mice [22]. Unfortunately, maraviroc carries a “black box” warning due to the associated serious adverse including hepatotoxicity.
..
Given the safety profile of leronlimab, and potential adverse events with the small molecular inhibitors, we conducted studies to determine whether leronlimab could bind and block CCR5 signaling in human breast cancer cells.
Still trying to understand the if and why of maraviroc toxicity. Here is one recent small study looking at liver toxicity of maraviroc in HIV patients:
https://pubmed.ncbi.nlm.nih.gov/27924779/
Quote:Use of maraviroc did not increase hepatotoxicity in this population through 144 weeks. Further investigation regarding possible beneficial effects of maraviroc on liver fibrosis may be warranted.
The potential for hepatotoxicity with maraviroc hasbeen previously studied. The esults reported here areconsistent with the findings of a previous study by Ayoub and colleagues, which investigated the hepatic safety of maraviroc across Pfizer-sponsored Phase –3clinical trials.18 These data together with data from clinical studies of the CCR5 antagonist vicriviroc, which showed no evidence of hepatotoxicity through48 weeks of therapy, support our results that there is not a class effect among CCR5 antagonists.19,20 Furthermore, hepatotoxicity associated with the CCR5 antagonist aplaviroc that led to its discontinuation was considered likely to be unrelated to the mechanismof action (i.e. CCR5 inhibition) but rather due to the properties of the molecule itself.21 In conclusion, the data reported here suggest that maraviroc does not increase hepatotoxicity in HIV-1-infected subjects co-infected with HCV and/or HBV
An older summary of clinical trial AEs with MVC:
https://journals.lww.com/aidsonline/Fulltext/...oc.19.aspx
Quote:Maraviroc is the first CCR5 antagonist to be approved for the treatment of HIV-1 infection. It is generally well tolerated, with a similar side-effect profile to placebo in controlled studies. Many agents used to treat HIV disease are associated with the potential for hepatotoxicity. The hepatic effects of maraviroc were analyzed across all Pfizer-sponsored maraviroc clinical trials, in which 2350 volunteers received maraviroc. Although sporadic hepatic enzyme abnormalities were reported in 34 phase 1/2a studies of up to 28-day duration, they demonstrated no dose relationship or association with hyperbilirubinemia. In the four phase 2b/3 studies in antiretroviral -naive and antiretroviral-experienced patients, there was no significant imbalance in hepatic enzyme abnormalities or hepatobiliary adverse events in maraviroc versus comparator arms up to week 96. The findings were similar in patients coinfected with hepatitis B and/or C virus, although the number of coinfected patients was small. No patient met the strict definition for Hy's Law. Two participants reported severe hepatotoxicity and although other potential causes were present, the contribution of maraviroc to these events could not be excluded. This analysis suggests that maraviroc does not present significant risks to hepatic safety when taken at the recommended doses in the populations studied.
Apparently the FDA disagreed though, and had them slap on a black box warning for possible liver toxicity, at least based on trials for the HIV indication.
It's hard to judge the truth sometimes, but all signs point to leronlimab having a better safety profile, despite maraviroc appearing pretty safe. If there was a good explanation for maraviroc liver toxicity I'd feel better about that notion.
But enough about this topic, just wanted to point out one nagging fear that we may have competition (given the Pestell paper showing the small molecule CCR5 antagonists work just as well or better than leronlimab in breast cancer mets model), and hoping that others can convince me otherwise that it isn't that big of a deal.
