With Combo we are at 99.9% of approval in my opini

With Combo we are at 99.9% of approval in my opinion. Hard to imagine turning down a drug approval with this safety, efficacy, on a unmet need population. Just a matter of jumping through the FDA hoops at this point.

With Mono , they have the numbers at 700mg, 92%, but full mono is a wild card in my opinion, since this would be the first ever FDA approved. Though expanding combo to all HAART seems very likely, at it has much less side-effects than the other approved ccr5 drug, Maraviroc, and more efficacy. My gut with this 50-50 on mono only approval, 90% chance for expanding to all HAART patients

With Metastatic Cancer , great results in animal studies, first human trial showed great potential. My gut 80%+ success here

With GvHD Great results in animal study. First 10 patients on leronlimab on random trial with placebo, where we don't know results, but we do know they modified the trial after this removing the placebo. So the data must have been positive. This new open trial starting means we get to peek at data earlier. My gut 75%+ success here.

https://www.cytodyn.com/media/press-releases/...l-with-pro


Other indicators:

Rheumatoid Arthritis My gut 15% chance, mixed results in research. Leronlimab could succeed where other failed possibly with a higher dose or maybe two inhibitors?

Positive:
https://www.frontiersin.org/articles/10.3389/...01981/full

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In rheumatoid arthritis, increased levels of CCR5 ligands CCL3, CCL4, and CCL5 are found in the synovial fluid (37, 38), and the CCR5Δ32 variant seems to protect from the disease (39)

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37 https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed...h=10323454
38 https://www.sciencedirect.com/science/article...via%3Dihub
39 https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed...h=15331395

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104293/
Negative association between the chemokine receptor CCR5-Δ32 polymorphism and rheumatoid arthritis: A meta-analysis

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This meta-analysis of all published case-control association studies confirms the negative association between CCR5-Δ32 and RA (Odds Ratio = 0.65; 95 % confidence intervals = 0.55 - 0.77; p < 0.0001), suggesting that CCR5-Δ32 is protective against the development of RA. CCR5 blockade in animal models of RA results in amelioration of arthritis, suggesting that CCR5 blockade could also modify disease in patients with RA.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927816/
Association of two functional polymorphisms in the CCR5 gene with juvenile rheumatoid arthritis

Negative which came later
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104293/

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The protection conferred by CCR5-Δ32 against the development of RA, however, does not seem to be absolute, as demonstrated by the small numbers of individuals with RA who are homozygous for CCR5-Δ32. The chemokine system is redundant, and it is likely that other receptors and pathways play a role in the development of RA in these individuals.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446428/

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Fleishaker and colleagues reported on a double-blind placebo controlled clinical trial of a C-C chemokine-receptor type 5 (CCR5) antagonist, maraviroc, in rheumatoid arthritis (RA) patients with inadequate response to methotrexate, showing that it was ineffective. Two additional CCR5 antagonists, SCH351125 and AZD5672, also failed to demonstrate clinical efficacy. In addition, CCR5-blocking antibodies could not inhibit synovial fluid-induced monocyte chemotaxis. Thus, CCR5 appears not to be a desirable target in RA treatment. Given the multiple functions of CCR5, redundancies in the chemokine system, and patient selection in the trial, we overview the recent understanding for chemokine receptor blockade in the treatment of RA

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Maraviroc Trial failed
https://clinicaltrials.gov/ct2/show/NCT00427934

https://www.ncbi.nlm.nih.gov/pubmed/22251436

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Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial.

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RESULTS:

Sixteen patients were treated in the safety/PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients (38 maraviroc; 21 placebo) had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc (23.7%) and placebo (23.8%) groups (treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504). The most common all-causality treatment-emergent adverse events in the maraviroc group were constipation (7.8%), nausea (5.2%), and fatigue (3.9%).

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SCH351125 Trial Failed
https://ard.bmj.com/content/69/11/2013

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Abstract

Objective C-C chemokine receptor type 5 (CCR5), a chemokine receptor expressed on T cells and macrophages, and its ligands are found in inflamed synovial tissue (ST) of patients with rheumatoid arthritis (RA). The rationale for testing CCR5 blockade in patients with RA was supported by the effects of a CCR5 antagonist in collagen-induced arthritis in rhesus monkeys. The effects of CCR5 blockade in patients with active RA were explored.

Methods In this phase Ib randomised, placebo-controlled trial, treatment with an oral CCR5 inhibitor (SCH351125) in patients with active RA was evaluated. Clinical efficacy was assessed using European League Against Rheumatism and American College of Rheumatology response criteria. ST biopsies were taken before and after 28 days of treatment, and analysed for CCR5+ cells. In a subset of patients, MRIs of an inflamed joint were obtained before and after treatment.

Results In all, 32 patients were included; 20 received SCH351125 and 12 placebo. Three patients who received SCH351125 did not complete the study due to adverse events; none of these were serious. No improvement was observed in the active treatment group compared to placebo. Results were consistent for clinical evaluation, ST analysis and MRI.

Conclusion This proof of concept study does not support the use of CCR5 blockade as a therapeutic strategy in patients with active RA.

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