What is it?
Leronlimab is a humanized monoclonal antibody targeted against the CCR5 receptor expressed on sub-population of T cells, macrophages, dendritic, eosinophils, microglia, and several cancers types.
Why so many indications?
CCR5 is a chemokine receptor interacting with CCL3, CCL4, and CCL5 (RANTES). CCL5 has an active role in recruiting leukocytes into inflammatory sites, which leronlimab can block. CCR5 also has many other roles: [8,9]
- governing DNA damage repair,
- repolarization of tumor-associated macrophages,
- promoting leukocytes (and metastatic cancer ccr5+ cells) trafficking to the brain, bones, liver and lungs.
What makes it to stand out from than other ccr5 antagonists, HAART, and cancer drugs ?
Low toxicity: Doesn't block natural activity of ccr5 including no hepatotoxicity causing many others to fail their trial safety metric.
No R5 resistance: Competitive inhibitor blocking direct entry to target a specific site on CCR5 that is utilized by HIV vs allosteric in small molecule, which enables resistance development in all small molecule antagonists. With the highest barrier to resistance so far than any other HIV drug, it could be first monotherapy approved drug for HIV.
Weekly dosing/Adherence : Longer half-life (10-14 days) [11,12] allows weekly dosing vs daily pills with others. A large 2013 survey [6,7] of 19 studies showed the association between adherence and specific AEs associated with ART. The same study showed an association with adherence rate and the number of daily pills, 95% adherence from 47% taking one pill daily to 34% with three pills daily. NNRTI, which has traditionally been given as part of core with ART, needs a very high level of adherence to limit mutations Adherence is the second strongest predictor of progression to AIDS after CD4 count. Weekly dosing offers a tremendous advantage in increasing adherence, specifically those in the unmet need category where typically adherence has been the lowest. Note PrEP study will have one arm with monthly dosing as daily pills is one main reason people at risk have stated they avoided PrEP, longer options are better.
Safety: No serious side effects or serious adverse events in over 830 patients. No discontinuing thus far from AEs in mono p2 trial. This makes leronlimab unique among many HIV and cancer drugs. Recognizing overall's drug’s safety FDA has allowed P1 to be skipped in several new indications. This is also helps reduce the added compounding side-effects when using several drugs with HIV or cancer.
Low drug/drug interactions. Leronlimab is eliminated via a saturable, antigen-mediated clearance process . Many other HIV drugs are metabolized by CYP enzymes enabling drug interactions. For example Maraviroc and Rilpivirine are metabolized by CYP3A4, as are many other drugs.
Special Note: HIV has a positive association with NAFLD and cancer, two indications where leronlimab is in p2, which combined with the above benefits, if approved for all indications would make a extremely compelling synergistic treatment for all R5. See end footnote for more details.
Video: Pro 140: How it Combats HIV
Science Advisors : Dr Sacha/OHSU, Dr. Patterson/IncellDx, Dr. Lindner/ Cleveland Clinic, Dr. Dennis Burger/ex-CSO CYDY, also CEO of several nasdaq bio, Dr. Maddon (inventor or leronlimab and discovered CD4/HIV connection)
Clinical Advisors : Dr Dhody/Amarex Clinical Research, Dr Dolezal/Pacific Hematoloty, Dr. Lalezari/Quest Clinical Research
Manufacturing : AGC & Samsung Biologics (mAb global leader which approved deal with no upfront payment)
HIV: Combo: Unmet Need R5 Population. Fast Track Designation, Completed Phase3 with BLA submission December/January, BLA rolling review Mono: R5 Population suppressed V.: In Phase 2b/3 investigatory trial. Phase 3 pivotal could start 2020 with FDA approval,
5 patients on mono five years with no drug resistance; over 150 patients on mono for over 1 year PrEP: Coordinating with Thai Red Cross/Dr Sacha funding for 1200 patient study, one arm monthly dosing
Potential partner US Army, talks with US Senators with funding, first goal BTD submission.
Though an estimated 70% of HIV population is R5, over 90% of HIV sexual transmissions occur throuh the CCR5 pathway.  Licensing: Vyera US/HIV only, 50% net sales & 87M milestone. Other global and US non-HIV still open.
FDA denied ODD stating population larger than 200k is a possibility
Cancer Animal: 98% metastatic tumor burden reduction in tnbc mice model mTNBC — Fast Track Designation: Phase 1b/2: Patient 1 CTC reduced to zero in first eight weeks, matching similar results in animal model. Enrolling next two soon. Will Apply for BTD if similar results Colon —Phase 2 approval, 30 patient with Regorafenib, enrollment not started Compassionate use approved: melanoma, pancreatic, lung, liver, breast, and prostate Basket trial with in works with melanoma, pancreatic, lung, liver, breast, and prostate
Animal: inhibited lipid uptake, liver fibrosis, and fatty liver development
Phase 2 approval, 60 patients, random, double blind-enrollment not started
Brenden Rae, “ we expect there to be a significant interest from industry stakeholders in the development of leronlimab for the treatment of NASH.”
GvHD : Orphan Drug Designation
Animal: 100% survival with leronlimab vs 0 without
Phase 2 approval 60 patient, enrollment not started
Note: P2 maraviroc trial with GvHD successful
P2 protocol already finalized by Dr. Denis Burger following same structure of Biogen's Tysabri. IND submission early 2020
In 1994, Stephen Crohn  became the first person observed to have some genetic resistance to HIV, he had mutation later known as ccr5-delta-32. Ths mutation has been used to aid two 'sterilizing' cures known to date with using a high-risk delta 32 stem cell transplantation to treat life-treating leukemia and Hodgkin's lymphoma respectively for Timothy Brown original referred to as the Berlin Patient (2007) and London Patient (2019).
Progenics, founded by Paul Maddon in 1986, originally developed leronlimab. Their scientist and collaborators on the original team that in 1996 discovered CCR5 is necessary as a co-receptor for entry macrophage tropic HIV in strains now called R5. In 1999, from 10,000 hybridoma supernatants screened, and over 100 inhibiting ccr5, seven were selected for testing . From those seven, leronlimab was selected partly due to its wide coverage in all tested R5 strains and the observation that it does not antagonize natural receptor activity , which gives low treatment-related toxicities compared to other ccr5 antagonist or highly-active antiretroviral therapy used in HIV.
At Progenics, leronlimab, entered phase 1 in 2006 followed by two phase 2 studies in 2008, one IV and the other subcutaneous for HIV R5 strain with results published in 2010. Progenics switched focus in 2010 to other potential drugs in their pipeline, partly influenced by the FDA pathway given of leronlimab through unmet need estimated taking many years. In 2012, CytoDyn, purchased leronlimab from Progenics through a licensing agreement.
CCR5 Antagonists in HIV trials Aplaviroc discontined trials: liver toxicity and poor efficacy http://www.thebody.com/content/art39205.html Vicriviroc was canceled phase 3 for possibly both side-effects and efficacy. Cenicriviroc after phase2b with HIV switch focus to NASH Maraviroc approved R5 HIV unmet neet and naive population
The vast majority (up to 90%) of newly transmitted HIV uses the CCR5 coreceptor also known as M-tropic virus due to its ability to infect macrophages, is more likely transmitted sexually due to the fact that the virus can infect CCR5-expressing macrophages and dendritic cells on mucous membranes of the genital and gastrointestinal (GALT) tract, which carry HIV to the regional lymph nodes and facilitate contact with and infection of activated T helper cells.
LCs express CD4 and HIV chemokine coreceptors, and these molecules have been shown to mediate infection of LCs (11–14). Immature LCs express surface CCR5, but not surface CXCR4, immediately after isolation from skin; CCR5 on LCs also mediates fusion with cells expressing the HIV envelope protein gp120 (11). Likewise, Patterson et al. (15) examined human cervix and found that CCR5 mRNA expression was at least 10-fold higher than CXCR4 mRNA expression in this tissue. These reports suggest that the HIV coreceptor expression pattern on LCs, or perhaps on other resident cells in genital tissue, confers a “gatekeeper” status on these cells at mucosal surfaces, allowing preferential entry of R5 HIV, but not X4 HIV.