Leronlimab (Pro 140) Cliff Notes What is it?

Leronlimab (Pro 140) Cliff Notes


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 [10]. 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. [5]
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

NASH
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

Multiple Sclerosis
P2 protocol already finalized by Dr. Denis Burger following same structure of Biogen's Tysabri. IND submission early 2020

History
In 1994, Stephen Crohn [2] 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[1]. In 1999, from 10,000 hybridoma supernatants screened, and over 100 inhibiting ccr5, seven were selected for testing [3]. 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 [4], 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.


Links to Leronlimab specific papers
https://investorshangout.com/post/view?id=5605721


CCR5/Cancer potential mechanism of actions
CCR5: Enables cancer metastasis, Activates DNA mechanism, Regulates body anti-tumor response, Promotes Angiogenesis and Cancer Recurrence
Paper links:
https://investorshangout.com/post/view?id=5506865
https://investorshangout.com/post/view?id=5554877

CCR5 studies with all major cancer types: breast, lung, prostate, colorectal, melanoma, non-hodgkin lymphoma, kidney, leukemia, pancreatic, liver, gastic, hodgkin lymphoma, cervical
https://investorshangout.com/post/view?id=5446988
https://investorshangout.com/post/view?id=5447120


Other ccr5 connections
Leronlimab, CCR5 and NASH
https://investorshangout.com/post/view?id=5554859
https://investorshangout.com/post/view?id=5341166
Leronlimab, CCR5 and GvHD
https://investorshangout.com/post/view?id=5616457
https://investorshangout.com/post/view?id=5335577
https://investorshangout.com/post/view?id=5356864
Leronlimab, CCR5 and Atherosclerosis
https://investorshangout.com/post/view?id=5554865
Leronlimab, CCR5 and Diabetes
https://investorshangout.com/post/view?id=5556873
Leronlimab, CCR5 and Stroke
https://investorshangout.com/post/view?id=5556876
Leronlimab, CCR5 and Inflammatory Bowel Diseases
https://investorshangout.com/post/view?id=5556877
Leronlimab, CCR5 and Pulmonary Diseases
https://investorshangout.com/post/view?id=5554863
Leronlimab, CCR5 and COPD, Emphysema
https://investorshangout.com/post/view?id=5579736
Leronlimab, CCR5 and Tuberculosis
https://investorshangout.com/post/view?id=5579740
Leronlimab, CCR5, and Hepatitis
https://investorshangout.com/post/view?id=5529824
Leronlimab, CCR5, and Multiple Sclerosis, Alzheimer's, Parkinsons, blood brain barrier
https://investorshangout.com/post/view?id=5455839
https://investorshangout.com/post/view?id=5611149
https://investorshangout.com/post/view?id=5614370
https://investorshangout.com/post/view?id=5616194
https://investorshangout.com/post/view?id=5614503



Extra:
CTC as a possible biomarker when applying for BTD with cancer
https://investorshangout.com/post/view?id=5607820

Estimating Unmet Need Population for Combo
Last survey, people on HAART with CD4 count <=200 (AIDS)
https://investorshangout.com/post/view?id=5335738
https://investorshangout.com/post/view?id=5335594

R5/X4 distribution/correlation with CD4 count
https://www.prn.org/index.php/management/arti...opism_1002

HIV/AIDS stats: https://www.hiv.gov/hiv-basics/overview/data-...statistics

FDA denied ODD for HIV Combo because HIV Mono population size > 200,000
https://www.cytodyn.com/newsroom/press-releas...v-patients



Adding ccr5 inhibitor to HIV HAART to combat added risk with HIV

HIV and NASH
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550355/

HIV and Cancer
https://www.cancer.net/cancer-types/hivaids-r...troduction
https://investorshangout.com/post/view?id=5624803

Market Size and Old Sales Models for HIV
Wainwright Update July 2019
https://investorshangout.com/post/view?id=5479444

Rodman & Renshaw (unit of Wainwright) 2016 Report
https://investorshangout.com/post/view?id=5623635

CYDY BioVid Study (slides showing some data)
https://investorshangout.com/post/view?id=5625737

FS Model
https://cdn.discordapp.com/attachments/282295...ydy-02.pdf
https://cdn.discordapp.com/attachments/282295...ydy-02.ods



HIV cure
Discussion on Dr Sacha’s work with possibly a cure with monkeys using a variety of tools including donor cells, chemo or radiation, possibly gvhd and then leronlimab

https://investorshangout.com/post/view?id=5505597
https://investorshangout.com/post/view?id=5581337


Unmet Need Drugs Appoved compared to Leronlimab
Leronlimab 81% suppressed viral load after 2, MDR2 with limited options or MDR3, N=50

Maraviroc(MVC), MDR3, N=1049, 45% at 24 & 48 weeks,
https://www.nejm.org/doi/full/10.1056/nejmoa0803152

Trogarzo(ibalizumab or IZ) 43% suppressed at 25 weeks, N=40, MDR3


Disadvantages of Trogarzo: biweekly IV, cost 120k per year, MDR3, side-effects (including seriuos IRIS) https://www.rxlist.com/trogarzo-side-effects-drug-center.htm

Disadvantages of Maraviroc: black box warning, MDR3, has resistance within R5, daily pills,
side-effects (inluding serious hepatotoxicity) -https://www.goodrx.com/maraviroc/side-effects


Testimonials
Charlie Sheen talking experience switching from HAART to Pro 140 in 2016 as a patient in the p3 mono investigatory trial. He has not given an update on his status since 2017.



https://www.poz.com/article/ccr5blocking-anti...n/comments



Maraviroc P1 trial results for with Metastatic Colorectal Cancer
https://www.cell.com/cancer-cell/pdfExtended/...16)30087-3


Dolutegravir used with kids because of the high genetic barrier to resistance (link below). The FDA requested BLA part 1 to contain pediatric info and data from mono trial.
https://investorshangout.com/post/view?id=5532206

Importance of Adherence
https://www.ajmc.com/journals/supplement/2013...echer_s231
http://hivinsite.ucsf.edu/InSite?page=kb-03-02-09

Cenicriviroc (ccr5/ccr2 antagonist) buyout NASH for 1.7B

https://www.benzinga.com/general/biotech/16/0...rug-a-key-

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

PrEP and R5 transmission
https://www.prn.org/index.php/management/arti...opism_1002

Quote:

---

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.

---

https://www.ncbi.nlm.nih.gov/pubmed/12815099

Quote:

---

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.

---

AGC Biologics Information
https://investorshangout.com/post/postreplies?id=5617700

wiki links
https://en.wikipedia.org/wiki/CCR5_receptor_antagonist
https://en.wikipedia.org/wiki/CCR5
https://en.wikipedia.org/wiki/CCL5
https://en.wikipedia.org/wiki/PRO_140



[1] https://www.nature.com/articles/381667a0
[2] https://www.npr.org/sections/health-shots/201...ight-virus
[3] https://www.ncbi.nlm.nih.gov/pubmed/10196311
[4] https://jvi.asm.org/content/75/2/579.short
[5] https://www.ncbi.nlm.nih.gov/pubmed/12815099
[6] https://www.ajmc.com/journals/supplement/2013...echer_s231
[7] http://hivinsite.ucsf.edu/InSite?page=kb-03-02-09
[8] https://content.sciendo.com/view/journals/rao...b_body=pdf
[9] https://cancerres.aacrjournals.org/content/79/19/4801
[10] https://aidsinfo.nih.gov/drugs/423/leronlimab/0/professional
[11] https://www.poz.com/article/PRO140-HIV-Entry-12672-5546
[12] https://www.cytodyn.com/newsroom/press-releas...ab-pro-140