Replies to post #120 on Enumeral Biomedical Holdings Inc fka ENUMQ

[Rkmatters]

Wow! These are the kind of articles that get me excited about this immune oncology market! Do you have any idea just how good this newly released finding is, and what it means for ENUM!?

First, let me show you a portion of the article that highlights what adding TIM-3 after anti-PD-1 therapy fails means in terms of extended survival:

TIM-3 antibody addition overcomes resistance to PD-1 blockade.

As we observed PD-1 blocking antibody on TILs as well as TIM-3 upregulation at the time of therapeutic resistance to anti-PD-1 therapy, we treated mice with an anti-TIM-3 antibody at the time of PD-1 treatment failure to investigate whether TIM-3 blockade could provide additional clinical benefit in tumours, which had developed resistance to anti-PD-1 treatment. Because the clinical response to anti-PD-1 antibody was initially more robust in the

EGFR TL model17 (Supplementary Fig. 4a) as compared with the Kras model that only showed disease stability with PD-1 treatment, we utilized the EGFR model for therapeutic studies with a TIM-3-blocking antibody. Mice were treated with a PD-1 blocking antibody until tumours progressed and, then treatment with a TIM-3-blocking antibody was initiated when mice appeared both clinically unwell and demonstrated progressive disease by MRI imaging (Fig. 3a, Supplementary Fig. 4b). Antitumour efficacy (Supplementary Fig. 4b) and a significant survival advantage (Fig. 3b) were observed in the cohort of mice that were treated with the TIM-3-blocking antibody with median survival for anti-PD-1 antibody alone 5 weeks versus PD-1 þ TIM-3 sequential treatment 11.9 weeks (Fig. 3b; P 1/4 0.0008, log-rank test).

The impact of the TIM-3-blocking antibody on T-cell function was investigated by analysing mice at 2 weeks after adding TIM-3 blockade to anti-PD-1 antibody therapy (sequential combination treatment sensitive:Seq combS; Supplementary Fig. 5a). Binding of both anti-PD-1- and anti- TIM-3-blocking antibodies on CD8 T cells was confirmed. Addition of TIM-3-blocking antibody but not an isotype control antibody (Rat IgG2a) enhanced interferon-gamma production and cell proliferation as compared with TIM-3þ CD8 T cells from PD-1-resistant mice (Fig. 3c,d).

Together, these results suggest that TIM-3 blockade could be a reasonable therapeutic option in the setting of resistance to anti-PD-1 therapy because both TIM-3 on T cells and ligand in the tumour microenvironment showed significant increases in PD-1-resistant clinical cases.

Here's the abstract of the article, also the PDF link of it:

www.nature.com/ncomms/2016/160217/ncomms10501/pdf/ncomms10501.pdf

Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that up regulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.

Now, take a long at Competing financial interest section, that paid for the research. Authors initials and their Big Pharma affiliations that have an interest in the findings. I'll bold each company once:

Competing financial interests: G.D. received sponsored research support from Bristol-Myers Squibb and Novartis. He is currently an employee of Novartis. F.S.H. is a Bristol-Myers Squibb nonpaid consultant, Novartis, Merck and Genentech consultant and receives clinical trial support to the institution from these companies. G.J.F. receives patent royalties on the PD-1 pathway from Bristol-Myers-Squibb, Roche, Merck, EMD-Serrono, Boehringer-Ingelheim, Amplimmune/AstraZeneca and Novartis and patent royalties on the TIM-3 pathway from Novartis. D.B.C. is a consultant for Pfizer. S.J.R. receives research support from Bristol-Myers Squibb and the Center for Immune Oncology, DFCI. The remaining authors declare no competing financial interests.

The ONLY company that has a TIM-3 in clinical development right now as we speak is Novartis, testing MBG453 (TIM-3) alone, and also with PDR001 (anti-PD1). Their Phase I-b portion of the study recently began testing in solid tumors (several indications); NCT02608268.

https://clinicaltrials.gov/ct2/show/NCT02608268

Phase I-Ib/II Open-label Multi-center Study of the Safety and Efficacy of MBG453 as Single Agent and in Combination With PDR001 in Adult Patients With Advanced Malignancies

Drug: MBG453
anti human TIM-3 monoclonal antibody
Drug: PDR001
anti-human PD-1 monoclonal antibody

Experimental: Dose escalation MBG453 alone
Intervention: Drug: MBG453

Experimental: Dose escalation MBG453 in combination with PDR001
Interventions:
Drug: MBG453
Drug: PDR001
Experimental: Dose Ranging group
Interventions:
Drug: MBG453
Drug: PDR001

Experimental: Dose Expansion of MBG453 alone
Intervention: Drug: MBG453

Experimental: Dose Expansion of MBG453 in combination with PDR001
Interventions:
Drug: MBG453
Drug: PDR001

Estimated Enrollment: 250
Study Start Date: November 2015
Estimated Study Completion Date: June 2018
Estimated Primary Completion Date:

June 2018 (Final data collection date for primary outcome measure)

Off topic for a second; I'm not sure how Novartis' clinical trial will turn out the way it's currently designed, but I imagine they will consider altering the clinical protocol based on the newly released research. The thing about this clinical study, is it's not taking into account sequential. If one goes according to the findings in the article, TIM-3 timing should be done upon PD1 failure (stops working). Novartis designed this study, this dosage escalation study to test TIM-3 alone or along with their PD1. They are not testing after PD1 failure, except, under the inclusion/exclusion area, they do allow prior PD1 patients to join. Those patients should see benefit:

Prior participation in an interventional, investigational cancer vaccine or immunotherapy study except for an anti-PD-1/PD-L1 study.

Back on topic, again Novartis is the only Big Pharma testing TIM-3 in solid tumors. ENUM has already screened TIM-3 and found some lead candidates which are now in pre-clinical stage testing. Those findings should come out H12016!

Here's info from ENUM about the space:

Estimated sales for checkpoint blockers in 2020 > $27 billion per year* (Estimate only for PD-1/PD-L1 class)

Sales of approved I/O drugs (1st launched in 2011) > $2.8 billion in annualized revenue (Quarter ended September 30, 2015**)

Bristol Myers Squibb, Merck, AstraZeneca, Roche leading development; others actively investing in space
*Cowen and Company **Bristol Myers Squibb, Merck

It is early in the development of the immuno-oncology (I/O) market

Significant opportunity to use differentiated insights to define optimal combination

Commercial oncology franchises without I/O will lag

You can bet your bottom dollar that Merck and BMY, who already have a PD1 sales will be interested in ENUM's TIM-3 candidates (along with their best-in-class PD-1). The use of TIM-3 more than doubled the efficacy of PD-1. AND, it should come after drug failure, so absolutely no risk of loss of sales from the PD-1, it's additional revenue! Every biotech that I highlighted in that paper will be interested in ENUM. This company is going to be unstoppable once it starts moving. :)