I feel the following may be great to review prior to the

Quote:

Sacha to discuss : Now, as Antonio mentioned, we do have some exciting news to announce regarding an NIH grant for HIV cure. We will be announcing this shortly, but OSHU has received ~$5 million grant from NIH to evaluate the role of LRM in HIV cure. The project director is Dr. Jonas Sacha . As you are aware, only 3 people have ever been cured of HIV and they received immune cells void of CCR5 receptor which is the same receptor that LRM blocks. What is unique about this grant, centers around the technology. We'll will be using a AAV vector (adeno associated virus vector), which delivers a gene encoded LRM into immune cells. Adenovirus is a promising vector platform due to safety and ability to stimulate immune responses in multiple species. This is essentially, a gene therapy designed to induce the body to produce LRM. If successful, this work could lead to a single injection that suppresses HIV replication long term without needing ART and this is one of the many projects we are working on to obtain non-dilutive capital financing of trials. We will keep you up to date as these progress.

Regarding long acting LRM, we believe that the future of HIV is long acting injectables. We know that LRM can persist for 3 months and we believe this could impact the pre-exposure prophylaxis market, as well as the combination therapy market. This could obviously be a game changer in HIV. For HIV and NASH patients have multiple risk factors, including inflammation from HIV infection, heart therapy as well as bacterial transplant patients. Liver disease is 13-18% of all cause mortality in HIV infected patients. Liver disease is one of leading causes of non AIDS related death. Many of these HIV patients are excluded from the current NASH trials due to hepatic limitations. The HIV virus may cause direct injury to the liver.


24:25 Chris Recknor: Thanks Dr. Kelly and thanks for the investors calling in. We've made good progress on investigating the MOA of LRM and wanted to give an update. We believe that LRM may work in several different ways and understanding how LRM works informs us about potential clinical developments, and helps us to identify key strategic partners that synergistic opportunity looking for key biomarkers and MOA. Dr. Kelly mentioned the issues that HIV patients have with liver inflammation and it is significant.

The mechanism for preventing HIV for viral entry for LRM is thought to really to coding or binding CCR5 to prevent HIV from entering the cell and in our Phase 3 HIV trial Optimize, we showed a reduction in plasma HIV w/ LRM 350mg vs. placebo with a p 0.0032 that extended to a 24 week extension phase where by 80% of patients remaining in follow up had HIV RNA levels < 50 copies/ml. The interesting thing is they also had improved CD4 counts. So in addition to viral entry inhibition, LRM appears to work as immunomodulator, such that at lower doses, it may reduce inflammation but yet at higher doses, may affect immune system by increasing CD8, the natural killer cells. This places our company in the unique position to be able to look at those pathways where most drugs aren't able to perform.

There are 2 places where LRM can bind CCR5. And the inflammation or immunomodulation may work by (1) LRM mab binding simultaneously to 2 regions on the CCR5 to alter the geometry of the receptor and enhance its function. So if you have higher doses, or amounts of LRM in an individual binding in a 1:1 ratio, meaning (1) LRM mab for each binding site, may lock the receptor in place without a conformational change. And we are investigating how this works in the lab, but it is interesting, because, we are looking at different doses and seeing different ways that LRM can work.

Noureddin to discuss : On June 25, Dr. Mazen Noureddin, a NASH leader, presented a poster at the EASL conference about NASH 01, exploratory phase 2 clinical study of LRM in patients with a diagnosis of NASH, in base line MRI showing fatty liver and fibro-inflammation. Main part of study part 1 is randomized comparing treatment of LRM 700mg to placebo. There was also a non randomized, open label part of the study, part 2, that after completion of enrollment in the randomized phase, enrolled additional patients according to the same inclusion/exclusion criteria, but assigned them to 350mg LRM, allowing us the opportunity to compare 700mg vs placebo and 350mg vs placebo and to look at the effects of biomarkers.

The primary and secondary endpoint MRI, liver fat PDFF, and the MRI fibro-inflammation cT1, were not met by 700mg group in Part 1 in this exploratory study of LRM treatment of NASH. However, in Part 2, PDFF and cT1 were reduced in the 350mg group compared to placebo and additionally, these reductions correlated with reductions in key biomarkers known to be associated with NASH.

There are genetic differences in CCR5 that have been studied as related to the risk for HIV and HIV progression and some CCR5 haplotypes over produced CCR5 thus increasing the risk for HIV b/c there is more CCR5 that the virus can use to enter. Since these patients have increased CCR5, from these HIV studies, we have hypothesized that they may need more LRM in the NASH study. The exploratory analysis showed a 28% reduction in MRI PDFF fat, with corresponding reduction in MRI cT1 fibro-inflammation for patients with over expressed CCR5 haplotypes, when treated with 700 mg of LRM. and the number of patients were small, (5) representing only 23% of those in the 700mg group, but we noticed key distinct changes in biomarkers for this haplotype group, perhaps suggestive that these CCR5 haplotype patients may have a different etiology for NASH. But further exploratory studies need to be performed.

LRM binding to CCR5 is thought to be essentially associated with alterations in CCL5 or RANTES and then NASH in this exploratory biomarker analysis, showed that LRM reduces CCL5, and other chemokines CCL2, 3, 11 and 18. These chemokines act as a beacon to attract other cells in the area. The difference is really big because we thought we just worked on CCR5, but we are also working on CCL2, 3, 11 and 18. In NASH studies, we can see correlation b/w CCL3 which is Macrophage Inflammatory Protein Alpha 1 levels and they increase in severity of NASH on biopsies. So patients in full blown NASH, show highest levels of CCL3, but LRM reduced CCL3 with 350mg compared to placebo from baseline from week 14. CCL2 is another one that moves monocytes, called Monocyte Chem-Attratic Protein and is a key biomarker associated with NASH. LRM reduced mean CCL2 from baseline to week 14 in 350mg group compared to placebo.

Now when dr. Chung was talking about HIV and NASH, this has great application, because CCL2 applied to the treatment of the HIV patients is important because lower CCL2 levels correlate with less viral replication in effect to macrophages, less rapid feeding, of the latent HIV reservoir and less chance HIV central nervous system invasion. The ability to reduce CCL2 may have application to HIV and NASH and may really position LRM very effectively now to outpatients.

Once other key biomarker is molecule Vascular Cell Adhesion Molecule VCAM is very important because VCAM allow immune cells to migrate through blood vessel walls. We did not know that LRM reduces VCAM until NASH, but now we have now observed a reduction from mean change to baseline in week 14 for the NASH 350 mg for VCAM and this is important because it has application to other inflammatory markers that are reduced. So further trials need to be conducted with larger numbers, but the exploratory biomarker analysis may be very relevant for informing about future research in other disease states including cancer. Dr. Kelly can you provide an update in oncology.

Dr. Gluck to discuss :

32:20 Dr. Scott Kelly: Yes, Chris left with a perfect thing about VCAM b/c we do believe VCAM is important for oncology in LRM. What we are doing now, we are currently evaluating opportunities KOM Smithing ford, in mTNBC program for LRM in combo with a current SOC as well as colon cancer trial, we have animal and human data for mTNBC as well as animal data on the effects of LRM on colon cancer.

We are very encouraged by the exploratory biomarkers data from NASH at the 350mg dose as many of the biomarkers that LRM appeared to effect in NASH are important for oncology program and this exploratory data may inform future trials in oncology.


Partnerships, we will continue to pursue partnerships both internationally and domestically for Pharma companies, Academic Institutions, and government funding. We are doing this across multiple indication and we will announce any progress to investors when appropriate.


Regarding publications, we published an HIV monotherapy paper which is entitled Suppression of Human and Simean, Immunodeficiency Virus Replication with the CCR5 specific antibody LRM in 2 different species. We also submitted a paper on HIV and DR regarding CVO2 trial and we are awaiting response.