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Titan, I am a bit concerned about any drug supply deal. At this point in the game, I am quite doubtful any supply deal will be finalized - it should have happened already IMO. I get the impression that something has really gone awry here.
http://www.biomarkerworldcongress.com/Personalized-Immunotherapy/
May 2
1:35 In situ Vaccination: Potential Mechanism(s) of Action and Biomarker Development
Robert Pierce, M.D., Scientific Director, Immunopathology Core, Fred Hutchinson Cancer Research Center
1:35 In situ Vaccination: Potential Mechanism(s) of Action and Biomarker Development
Robert Pierce, M.D., Scientific Director, Immunopathology Core, Fred Hutchinson Cancer Research Center
In situ vaccines (ISVs), intratumoral therapies that aim to enhance tumor immunogenicity, offer the potential to generate tumor antigen-specific TIL and augment anti-PD1 blockade. Multiple ISVs are in clinical development, including TLR agonists, STING agonists, oncolytic viruses and proinflammatory cytokines. ISVs offer a potential safety advantage due to relatively low systemic exposure and may be useful in combination with systemic immunotherapies. Mechanism of action-based biomarker development will be discussed./quote]
Response rates of 33% in actual non-responders would be quite the accomplishment. I think it's possible, especially considering that they aren't using a predictive biomarker that excludes non-responders with greater than 25% PD-1/CTLA-4 positive CD8 phenotypes. As a general rule, the higher that phenotype percentage, the greater the odds of responding with anti-PD-1 therapy.
In fact, the highest PD-1/CTLA-4 positive CD8 phenotype percentage in the predicted non-responder trial was 21.8%. In other words, the predicted non-responder combination trial likely excluded non-responder patients who are more likely to respond to an anti-PD-1/EP IL-12 combination therapy, i.e. because they have higher PD-1/CTLA-4 positive CD8 phenotype TIL.
In terms of monotherapy anti-PD-1 non-responders in metastatic melanoma, neither Oncosec nor Dynavax are accomplishing much in their combinations with Keytruda. However, it's important to maintain perspective: the current standard for anti-PD-1 non-responders in metastatic melanoma is Yervoy (an anti-CTLA-4 checkpoint inhibitor). But Yervoy is only achieving 10% ORR in that failed population. Sometimes Yervoy is combined with an anti-PD-1, and the results are slightly better than Yervoy alone, but the SAEs are terrible (greater than 50% grade 3-5). I wouldn't say ONCS is falling behind in the non-responder treatment population despite the few actual responses.
It's difficult to say how well EP IT IL-12 and Keytruda combination would do in an anti-PD-1 naive study - the data just don't exist.
Judging by patent applications and claims opinions, I would say they are quietly leapfrogging.
This was a small, yet very intriguing trial by Dynavax, and that 86% BORR should really catch some attention even though it pertains to anti-PD-1 naive advanced melanoma patients. There are no studies that come close to 86% BORR in an anti-PD-1-naive population. Their TLR9 agonist/Keytruda approach is looking quite promising, but you would obviously have to look closer at the inclusion and exclusion criteria to really understand the trial a little better. I haven't done so in this case.
Like Keytruda/EP IT IL-12, combination Keytruda/TLR9 agonist is having a difficult time getting responses in progressive metastatic melanoma patients who were on anti-PD-1 monotherapy. If you look at the immune monitoring data in the ONCS combination trial, the combination's non-responders aren't observing statistically significant changes in interferon gamma and upregulation of PD-L1 on immune cells. Based on these data, I am of the opinion that anti-PD-1 monotherapy nonresponders or progressors are experiencing inadequate adaptive immune responses, and rescue treatments like Keytruda/EP IT IL-12 and Keytruda/TLR9 agonist combinations are having a difficult and/or slow time elevating the adaptive immune responses following checkpoint inhibitor therapy. When cytotoxic CD8 Tcells become activated by antigen presenting cells, they release interferon gamma. Anti-PD-L1 becomes upregulated in the presence of interferon gamma. The bottom line: adaptive immune responses need to improve.
TLR9 agonist in combination with Keytruda - Dynavax results.
http://investors.dynavax.com/releasedetail.cfm?releaseid=1015969
Results evaluating 17 patients for efficacy and 22 patients for safety were reported. In patients naïve to anti-PD-1 treatment, responses were observed in six out of seven patients, for an Overall Response Rate (ORR) of 86%. This includes two (29%) complete responses (CR) and four (57%) partial responses (PR). Target tumor shrinkage was observed in all 7 evaluable patients. In 10 patients with progressive disease who initiated KEYTRUDA anti-PD-1 monotherapy prior to enrollment, one PR was observed and five patients had stable disease (SD) while receiving KEYTRUDA and SD-101, with four of the 10 patients experiencing target tumor shrinkage
OncoSec is excited about the 41% response rate from the IL-12/Keytruda combination because it's higher than the 33% response rate typically seen with Keytruda alone in melanoma patients
There has never been a Breakthrough Therapy designation for ONCS.
One way to know what's sort of going on behind the scenes of any biotech is to look at patent filings, or lack thereof in some cases. When you look at a couple of the more recent ONCS applications you get the sense that their multigene constructs can take many different forms. Some of these multigene products may even contain encoded checkpoint inhibitors, like an anti-CTLA-4 antibody. The titers and some preclinical data are right there in the patent filings. Then you have additional confirmation that they are pursuing encoded antibodies through their relationship with KL.
Now imagine you're Merck or BMY and you see that a company is actively testing various multigene combinations that might literally negate the need for recombinant proteins like Keytruda, Opdivo, Yervoy, etc. because your body can produce them on its own, either systemically or locally, i.e. intratumorally. In theory, just like with mRNA being tested by Moderna, you can virtually encode any antibody or protein you desire. The trick is to find a safe and effective delivery method into cells so that encoded therapies can be expressed at desired levels and durations. Imagine the negotiating leverage when little ONCS can say, "look, we can produce encoded checkpoint inhibitors at perhaps half the cost of one of your checkpoint inhibitors and combine them with immune stimulatory molecules in one product."
Based on recent ONCS patent filings, there are unpublished preclinical data that Merck et al are privy to. You don't just start encoding anti-CTLA-4 if it can't be used in combination with an anti-PD-1. Stick the encoded anti-CTLA-4 on a plasmid with encoded IL-12, co-stimulatory molecules, antagonist antibodies, etc, electroporate intratumorally, and allow Merck to use their systemic anti-PD-1 therapy, i.e. Keytruda in combination - this would be a win-win-win for Oncosec, Merck, and patients.
No worries, I interpreted your response to be facetious.
What is the short thesis?
I suppose they could do that, although it would be an added expense.
Taking a close look at the handout, did anyone else notice that there was really only 1 out of 8 actual anti-PD-1 non-responders who responded on the combo treatment at 24 weeks? The 33% includes one anti-CTLA-4 non-responder, one anti-PD-1 non-responder, and one stable anti-PD-1 non-responder who had a partial response at 48 weeks.
Anyone who looks closely at these data will probably ask some important questions, for example:
1. Why base a registration study on data that truly don't instill confidence in turning actual anti-PD-1 non-responders into responders? This population appears to have a very difficult time responding to the combination, perhaps due to greater percentages of suppressor cells or other checkpoints, or poor immunogenicity?
2. Are these anti-PD-1 non-responders pseudoprogressing, and thus responses will only be observed after 24 weeks? If so, are endpoints going to be tailored to longer treatment cycles?
3. Based on the small relevant subset of data and inconclusive support for really turning actual anti-PD-1 non-responders into responders, is the registration study going to wait on more data from the current trial before proceeding?
4. Why in the world wouldn't you open the door to patients who are failing any treatment regimen for second or third line? Or why not just go straight for the first line setting? Why limit the patient pool to just anti-PD-1 non-responder patients? The overall response data for the current phase two trial is absolutely incredible, with a very high percentage of patients becoming complete responders - those are the data that should be guiding decisions to broaden the scope of the patient pool. To get BORR in the neighborhood of 48% in patients who have failed an assortment of prior treatments shouldn't be ignored - these numbers can barely be achieved in first-line, i.e. treatment-naive patients. The approach for refractory anti-PD-1 patients may require additional agents to get quicker responses.
While I have great confidence in the long term vision of this company, I think there could be greater near term value if they broadened the scope of their registration study to allow for any treatment failure patients, not just anti-PD-1 non-responders. Merck would have an even greater reason to invest in Oncosec if that were to happen.
Looking at the data from a hypothetical Merck perspective...
Knowing second-line anti-PD-1 non-responder treatments for advanced melanoma are reserved primarily for Yervoy (around 10% ORR in anti-PD-1 non-responder population), you can either go the route of combining Keytruda with Yervoy and get on the order of 50% grade 3-4 AEs, 35% dropouts, and 20% best overall responses, or you put a patient on an ImmunoPulse IL-12/keytruda combination that observes less than 5% grade 3-4 AEs, 0% dropouts, and thus far achieves 30% responses (including complete response).
Merck needs a therapy in the anti-PD-1 non-responder setting for advanced melanoma - they don't have an anti-ctla-4 checkpoint inhibitor like BMY's Yervoy. This is clearly an untapped market for Merck.
Don't ask me why the market reacted the way it did to the data announcement - these aren't treatment naive first-line patients. Existing therapies in the anti-PD-1 non-responder second line setting for advanced melanoma are clearly more toxic and less effective.
https://www.researchgate.net/publication/301696831_Efficacy_and_toxicity_of_treatment_with_the_anti-CTLA-4_antibody_ipilimumab_in_patients_with_metastatic_melanoma_after_prior_anti-PD-1_therapy
40 anti-PD-1 monotherapy non-responders were subsequently treated with Yervoy, currently the most common second and third line treatment regimen in advanced melanoma - 0% COMPLETE RESPONSE, 10% ORR, AND 35% GRADE 3-5 SAEs. That's right, not one single complete response out of 40 patients.
We will see tomorrow how actual anti-PD-1 monotherapy non-responders do on a combination of ImmunoPulse IL-12 and Keytruda...
This is the first glimpse of correlative immune data for responders and non-responders in the trial.
Also, according to PD there will be data on 22 patients, but the abstract doesn't reflect those additional responder/non-responder data points.
Having the ability to replace current checkpoint inhibitors like Keytruda, Opdivo, Yervoy with DNA encoded antibodies expressed both systemically and/or locally would completely upend the status quo. Analysts expect these drugs alone to exceed $25B in annual sales collectively by 2025. We know that ONCS has already been working on CTLA-4-encoded antibodies based on patent illustrations, so there is a real threat to Merck and BMY's future revenues if Hollevoet and company's approach is validated using ONCS's proprietary EP device.
There is too much at stake, in my opinion, for ONCS or Inovio or any other company capable of achieving in vivo production of antibodies to be simply ignored. I don't know how this will all play out in terms of partnerships and licensing deals, but the potentially enormous implications lead me to believe that some deals will most certainly be made with Oncosec - no other company uses tissue sensing technology to maximize DNA encoded delivery into cells of any type. To have this ability is akin to being given a key to the kingdom, yet we are valued at less than $30M.
Titan, are you familiar with the privately held company Moderna Therapeutics? Take a look at what they are hoping to accomplish and how much venture capital has been invested despite very little data. Their primary mission is similar to Hollevoet's startup and Oncosec, only using mRNA instead of DNA.
No one can put a real pricetag on technology that allows your own body's cells to manufacture antibodies and countless other therapeutic proteins - to do so would be completely disruptive to current production methods. The only company that has demonstrated targeted protein expression in any tissue type is Oncosec.
The platform should work in all sorts of indications - my first thought was CRISP-Cas9. I definitely think at least one of the partnerships will be non-oncology.
ONCS has been absolutely silent on the technology access program for the new EP device using TRACE technology. They had mentioned back in November that they would put information up on their website and they haven't done so yet. I'm certainly wondering why the TAP is so under wraps just like the preclinical data.
Yeah, it was in his last presentation.
By the way, Titan, did you catch the reference to expanding usage of the Genesys to non-oncology indications through the TAP?
public information
Sid, there will be new data on 22 patients next week.
Correct, updated data on 22 patients next week.
SS, the agreements between BLRX and Merck do not involve a licensing agreement or sale of rights with financial significance - they are essentially supply agreements, which is already what ONCS has with Merck's Keytruda. Merck has many of these supply agreements in place with numerous companies, but commercial/licensing agreements are rare (one exception is with Incyte's Epacadostat in combination with Keytruda). I think Merck is trying to see what combinations work the best, and then aggressively pursue co-development, which is exactly what recently happened between them and Incyte.
In terms of the BLRX's BL-8040, it is a protein applied systemically as an antagonist to CXCR4 receptors (found in numerous cancer types), thus blocking interaction with its ligand (CXCL12). According to published reports, this interaction may prevent migration of tumor cells, thereby preventing or slowing down processes of metastasis. In other words, elevated CXCR4 expression is correlated with aggressive metastasis and disease progression. While this mechanism of action may help to slow down disease progression, there are two major missing puzzle pieces that neither BL-8040 nor Keytruda can overcome: elevating and activating CD8 TIL and upregulating PD-1/PDL1 expression in the TME (necessary for priming an anti-PD-1 checkpoint inhibitor). I don't see this combination leading to response improvements, but it might help with slowing disease progression.
I personally base my investment decisions on whether or not a company is undervalued by several metrics. One of these metrics is cash on hand relative to market cap. To place zero value on ONCS's ImmunoPulse IL-12/pembrolizumab combination program for advanced melanoma is quite interesting considering they are rapidly approaching a Registration trial and have produced monotherapy data that align favorably with the best checkpoint inhibitors on the market.
According to KOLs, most anti-PD-1 non-responders in advanced melanoma turn to monotherapy Yervoy as a second-line therapy. Unfortunately only 10% of these patients actually see a response on monotherapy Yervoy after failing anti-PD-1. And none of these patients observe complete responses. Yet this is a standard of care right now for these patients. This is what ImmunoPulse IL-12/Keytruda's competition in the second-line setting for advanced melanoma looks like.
Failing on anti-pd-1 (e.g. Keytruda, Opdivo) monotherapy leaves very few options for patients in second-line advanced melanoma. Another option for these patients is combining anti-pd-1 and anti-ctla-4 drugs, but the SAEs are horrendous and it's not clear how effective the combination is following monotherapy anti-pd-1 failures.
I think Immunopulse IL-12 in combination with Pembrolizumab (Keytruda) will be an improvement upon anti-ctla-4 (Yervoy) second line therapy.
What options do monotherapy anti-pd-1 nonresponders have in advanced melanoma? Here is one of those approved second-line therapies, i.e. Yervoy, when they looked at 40 patients:
https://www.ncbi.nlm.nih.gov/pubmed/27124339
Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient.
The primary question in my opinion is whether or not immunopulse IL-12 in combination with keytruda is elevating the CTLA-4hiPD-1hi CTLs relative proportions. Raising these CD8 TIL phenotypes is strongly associated with responses when keytruda is administered.
Let this graph be your friend. It will help you understand the implications for the upcoming data release.
https://www.jci.org/articles/view/87324/figure/2
Or Keytruda (systemic) plus electroporated DNA encoded anti-CTLA-4/IL-12 (intratumoral) combination in multiple solid tumor types... see ONCS patent applications, they are already testing electroporated DNA encoded anti-CTLA-4.
How do you get efficacy without increasing serious adverse events? Combine checkpoint inhibitors with EP IL-12, but mitigate systemic exposure by allowing one or more of those checkpoint inhibitors to be DNA encoded and administered intratumorally through electroporation. An anti-pd-1 like Keytruda can continue to be applied systemically in combination.
Update on Melinda Welsh's story - I wish her the very best.
http://www.pbs.org/newshour/bb/cancer-immunotherapy-life-saving-powers-limits/
Antibody protein therapy continues to gain impact in oncology, most recently taking the field of cancer immunotherapy by storm. The extremely high costs and patient discomfort, however, can limit accessibility.
Our Antibody Gene Transfer Program addresses these challenges by developing a DNA platform for innovative production and delivery of these biologicals. Specifically, our technology enables in vivo antibody expression via the generation and delivery of antibody-encoding DNA constructs. Following DNA electrotransfer to the host, the delivery site is turned into an antibody ‘factory’, allowing cost-effective and prolonged production in vivo. We have previously reached pre-clinical proof-of-concept for intramuscular antibody gene transfer, and are now seeking to expand the vast potential of this innovative therapeutic platform
Just some quick thoughts to bounce off folks on this board...
First, the preclinical data presented at SITC in November are actually quite intriguing. I think the company will be successful if they aggressively pursue combination therapies with checkpoint inhibitors. I say this based on the presented immune and correlative response data. This approach might actually bear fruit, unlike other combinations they have tested. I think they need to move away from the chemo combos altogether. The MOA for PS, in my opinion, is its ability to reduce anti-inflammatory cytokines, and not necessarily to improve CD8 TIL levels, although there is some downstream negligible improvements in the CD8 tcell levels. This MOA is going to be complementary to any treatments that increase activated CD8 tcells and/or block checkpoints.
Second, I am quite astounded that the revenues coming in aren't helping the company's valuation. Their earnings are improving significantly, and its just a matter of time before they start observing improved margins from long term contracts.
Overall, I think this company is undervalued relative to its future earnings potential from manufacturing contracts. On the drug development side, they are going to be throwing money into a bottomless pit if the continue down the road of chemo combinations. I think they are beginning to realize that PS works with IO agents, but they need to focus on developing these programs further. This is all in my opinion, and I am neither long nor short.
MighTy is dedicated to the development of an innovative DNA platform for antibody therapy. Antibodies are recombinant biological proteins that have an enormous impact on the treatment of cancer and inflammatory diseases. However, the high production costs, long-term need for repeated delivery, and often limited single-agent effect of conventional antibody protein therapy hamper accessibility and implementation in other disease areas.
MighTy’s elegant technology addresses these hurdles by enabling the patient’s body to produce its own medicine, thereby avoiding the need for expensive production facilities. Following administration of the DNA that encodes a therapeutic antibody, the site of DNA delivery (muscle, skin or tumor) is turned into an antibody ‘factory’, which releases the therapeutic into the bloodstream for a prolonged period of time. This swift and cost-effective approach also allows for the simultaneous in vivo production of multiple antibodies, increasing the success rate of these biological therapeutics in fighting a disease.
What we know about TRACE is that it can be used effectively with any tissue type, meaning it can be used on heterogeneous visceral tumors where a local immune effect is needed. There simply are no other electroporation devices available on the market where DNA encoded plasmid agents can be delivered in this manner - they are all skin or muscular EP devices.
I have a strong gut feeling - based on Kevin Hollevoet's antibody investigations and recent patent filings - that ONCS is quietly pursuing a program to use their TRACE technology with multiple DNA-encoded checkpoint inhibitors. Again, this is just my opinion on where I think things could be heading in terms of collaborations with their TAP using TRACE technology. I don't know as though a big pharma would be involved, but nevertheless such a development program is going to attract a lot of attention if the approach demonstrates proof of principle.
Monoclonal antibodies are effective when used in combination, including yervoy and opdivo - both BMY mAbs - and they demonstrate greater efficacy than either one used alone, but they are simply too expensive to produce. Moreover, their safety profiles aren't particularly all that encouraging when they are applied systemically together at the current dose regimens.
All monoclonal antibodies need to come down in price. A combination anti-ctla-4 and anti-pd-1 treatment would likely cost over $250k per patient per year. No company is ever going to achieve significant market share priced like that.
One solution to this problem is to have your body manufacture the antibodies in vivo, either in muscle cells or intratumorally. Both applications should theoretically work. DNA encoded antibodies are reportedly MUCH more scalable and they would require far fewer injections than lab produced mAbs like opdivo, yervoy, keytruda, etc. Improved safety and cost seem like a paradigm shift to me if efficacy is equivalent or better.
If anyone is interested in learning a bit more about electrogene transferred mAbs, here is a good starting point:
Expert Rev Vaccines. 2015 Feb;14(2):205-19. doi: 10.1586/14760584.2015.1001375. Epub 2015 Jan 12.
In situ production of therapeutic monoclonal antibodies.
Suscovich TJ1, Alter G.
Does anyone else find it bizarre that there hasn't been much discussion on preclinical developments? We have some notion of what the next product will contain - a combination of encoded genes delivered intratumorally via EP - but in what indication(s)? We haven't seen any preclinical data for quite some time. Sounds like it will be used with their new TRACE technology, but that is about all we know.
Could they also be aggressively pursuing a program for electrogene transferred monoclonal antibodies, i. e. checkpoint inhibitors, which were the subject of a recent worldwide patent application? I had mentioned this before and I will repeat again here, if they are seriously pursuing the development of gene encoded monoclonal antibodies that can be delivered and expressed either intratumorally or systemically (intramuscular EP) - and to be used with their new TRACE technology - then I think everyone will be in for quite a surprise. I think Kevin Hollevoet's presentation at the investor and analyst day on November 17 was more meaningful than people realize.
The actual pembrolizumab non-responders in ONCS's phase 2 metastatic melanoma trial - 83% of them if my memory serves me correct - had baseline CTLA-4hi/PD-1hi TIL levels below 5%. Those are very low percentages, so to get the phenotype percentages over 20% would be quite amazing.
By the way, for the exploratory and validation pembrolizumab monotherapy cohorts examined by UCSF in their biomarker study, only 17% were under that 5% phenotype level! So to have 83% of your pembrolizumab non-responders under 5% is quite anamolous if the exploratory and validation cohorts in the biomarker study are representive of the non-responder population.
Looks like oral and poster presentations.
The UCSF metastatic melanoma exploratory and validation studies with pembrolizumab monotherapy demonstrated that 0% of patients with <20% CTLA-4hi/PD-1hi CD8 TIL phenotypes responded to Pembrolizumab; 60% of patients with 20%-30% CTLA-4hi/PD-1hi CD8 TIL phenotypes did respond to Pembrolizumab; and 100% of patients with >30% CTLA-4hi/PD-1hi CD8 TIL phenotypes responded to Pembrolizumab.
I want to see how much of a change immunopulse IL-12 can make in these exhausted phenotype percentages for CD8 TIL. We know that, based on interim phase 2 data, immunopulse IL-12 is able to convert 40% of predicted non-responders into responders (and some of these patients were actual non-responders to a variety of prior therapies including pembrolizumab). ARE THEY PRIMING THESE PATIENTS FOR PEMBROLIZUMAB BY ACTUALLY ELEVATING THEIR CTLA-4hi/PD-1hi CD8 TIL PHENOTYPE PERCENTAGES ABOVE 20%?