Was the hyperphosphatemia market in ESRD built over night? Nope. Right now, approximately 70% of hyperphosphatemia cases are being addressed by binders in CKD ESRD. HK treatment is on the same trajectory, but the market size is nearly six times that of hyperphosphatemia.
The primary market is in episodic, or "chronic" if you prefer, hyperkalemia. If a nephrologist only sees patients several times per year, of course the majority of nephrologists and cardiologists will prefer maintenance therapy rather than waiting for emergency room situations. This isn't always the case from what I can tell, but it sure looks like the majority of script writers will be heading in this direction.
There are also emergency room situations in which the symptoms of HK will be identified, but the condition won't be life threatening. I suspect non-emergent acute use is reasonable in these situations. I'm not a doctor, but this seems like a logical conclusion.
As far as ZS-9 is concerned, they can't seem to produce any long term safety and efficacy data for their product, so how can anyone reasonably conclude that they will be competitive with V? I am betting that the manufacturing issues weren't the only CRL concerns, and that long term sodium zirconium cyclosilicate use is leading to cardiovascular events and increased resistant hypertension.
It looks like a lot of milestones will be achieved before any hypothetical dilution talks. They have enough runway to take them through at least mid 2017 based on current spending.
The company seems to be well aware of the synergy between checkpoint inhibitors and their electroporated IL-12 platform - they put the monotherapy head and neck study on hold to aggressively pursue a registration anti-pd-1 and electroporated IL-12 trial. The interim metastatic melanoma data, if it demonstrates greater efficacy over anti- pd-1 antibody therapy used alone, could theoretically be applied to many types of solid tumor indications. ONCS's electroporated IL-12 platform could be akin to checkpoint inhibitor applications in that it might be capable of addressing a multitude of cancer types. We will, however, have to wait on interim data to see if this is really the case. If it achieves what I think it is capable of achieving, then any hypothetical future dilution will be a moot concern.
Yep, almost a year now on the zs004e completion and nothing has been reported. AZ SHOWS NO CONFIDENCE IN ZS-9's ABILITY TO ADDRESS LONG TERM HK MAINTENANCE. The buyout price for ZS was predicated on its purported ability to be used on a chronic basis. Yet, no one is confident enough to report on its long term efficacy or safety.
There are a lot of people who are fixated on ZS-9 prospects after manufacturing concerns are mitigated. The real issue, I think, is safety related. I am willing to bet that ZS-9 will use its existing shorter term data to file for acute use only after meeting with the FDA. The FDA didn't call for more data because they are probably already convinced with the existing data that the drug doesn't benefit CKD patients for open-ended duration of use.
Yes, this is one of the most important points that I also noted in the call. They will have interim combination anti pd-1 and electroporated il-12 data out soon for melanoma. Sounds like absolute urgency to get this to a registration trial asap. All due diligence points to increased double positive pd-1 TIL following il-12 DNA plasmid injection.
HTBX is one of them. The FDA hold was lifted, but everything else you list is correct about the company. I'm not making any investment recommendation, just addressing the technology.
Electroporated GP96 with FC-OX40L DNA uses synergistic platforms developed by Oncosec and Heat Biologics. The GP96 heat shock protein is secreted directly from the ER in tumor cells, which allows for tumor-specific neoantigen presentation. The expressed FC-OX40L co-stimulates killer t-cell and memory precursor cell production. Again, this is all in early development.
Oncosec, Ziopharm, and Celsion are all developing IL-12 DNA therapies. Oncosec appears to be demonstrating early success with their electroporated version of DNA delivery, perhaps because the DNA expression remains in the tumor microenvironment. Correspondingly, PD-1 TIL appear to be increasing significantly following IL-12 electroporation - this signals improved neoantigen presentation by dendritic cells and robust stimulation of t-cells; it is essentially a "vaccine" although it doesn't provide the same level of epitope presentation that gp96 would provide. Again, these are early days, but I'm still very much intrigued by the synergistic platforms shared between ONCS and HTBX. I wouldn't be too surprised to see a trial soon that uses a combination of electroporated gp96 w/ FX-OX40L DNA, electroporated IL-12 DNA, and anti-PD-1.
Thanks for your post. I appreciate Agenus' personalized vaccine approach - a vaccine will be matched to at least one tumor's neoantigens following the algorithms. Most epitope vaccines have failed to achieve robust responses in part because they did not account for the heterogeneous nature of solid tumors and/or they were not used in combination with checkpoint inhibitors. Agenus should theoretically be capable of achieving greater responses due to their informed combination approaches.
With that said, I think there are a couple areas that need improvement. First, I don't think they have a strong enough adjuvant to stimulate and clone CD-8 "killer" t-cells following activation by APC. Second, nothing convinces me that the response is going to include significant memory precursor cells to maintain response durations. Third, there are new approaches being developed elsewhere that would allow tumors to actively secrete chaperoned neoantigens in vivo and in the context of an inflamed tumor microenvironment; this would eliminate all complexities associated with tumor sampling, algorithm crunching, and matching vaccine development.
Like I said, I think we will see improvements over SOC anti-pd-1 monotherapy. Unfortunately, there are a couple companies that appear to be leap frogging Agenus. To be fair, these other companies still have to complete mid stage trials, so it is all theoretical at this point.
It seems like the frustration would be limited to first time script, not refills. So you are saying that you would rather see an uncontrolled recurrent hyperkalemic patient rather than initiating the vkonnect process during the first script? That seems absolutely unethical, because most of these patients are episodic as you should know. Also, you wouldn't encounter the same processing obstacles with Veltassa refills.
Kionex isn't prescribed chronically to my knowledge, and hyperkalemia is episodic in CKD patients, so you imply that you prefer to see patients roll the dice on hyperkalemia and just wait for episodes to arrive. And if they reach a severe level, oh well, that's just part of doing business in private practice? A cardiac arrhythmia is preferred over processing paperwork during the initial script?
The vkonnect paperwork is limited to first time prescriptions, not refills. That is why the poster's comments seem strange.
How does the vkonnect impact refills for maintenance therapy? It sounds a lot like you are referencing acute indication. Am I correct? We all know kionex isn't prescribed on any long term basis. So you're saying you would rather roll the dice and potentially miss recurrent hyperkalemic episodes rather than complete paperwork at initial prescription?
So what happens if folks short it through a reverse split whereby the float ends up less than 1 million shares and the market cap is around $12M?
Aint nothing like a low float stock with high short interest leading up to several major clinical readouts in a cancer research company with a MC less than $13M. Don't worry, I won't ignore THAT.
They surprisingly have enough runway to get them to several data readouts. They don't have a lot of cash, but burn rate has gone down after laying off 22% of their staff. There are no signs of any immediate dilution threat.
My dd tells me that anti PD-1 therapy used in ombination with neoantigen-targeting vaccines like Heats COMPACT will demonstrate improvements over either one used alone. COMPACT stands out in the crowd because it provides a suite of tumor associated antigens to dendritic cells, which in turn present to killer t-cells. Most vaccines target just one tumor antigen. Solid tumors are much more heterogeneous than blood cancers for example, so the vaccines must be more diverse in terms of antigens. COMPACT also has the ability to stimulate expansion of t-cells in vivo- that is also extremely important.
Most likely rolling submittal of zs005 data. Shorts assume approval is still in the bag. Too bad the bag is full of manure. Would be interesting if one day ZS and AZ decide to give up on the chronic indication. If the FDA expressed concern over long term use in the CRL, a shift in focus should become apparent.
We know nothing about the FDAs opinion of the drug's efficacy or safety as well. The questions that remain aren't just limited to manufacturing.
There are underlying data concerns that will come out imo. I am willing to bet that the "recently submitted data" were frought with safety issues, enough to deny approval. I don't for a second believe it is just manufacturing issues. That is the piece of information that we aren't hearing about. CRL interpretations found in company releases are typically half truths. And Pascal, who threw down $2·7B on this one, needs to save face.
A hypothetical CRL announcement - if it does amount to that - will be followed by not only short covering in the context of 98% tute ownership, but also by waves of buyers who have been waiting on the sidelines.
Despite all of the benefits of patiromer, a fair price can't be achieved without first knowing the FDA's verdict on zs-9.
Interesting read by Natasha Persaud, posted today on Renal and Urology News. The data are also published in JAMA. There were strong correlations observed between excreted sodium and CVD events including heart failure, myocardial infarction, and stroke in CKD patients.
Remember those "other adverse events" reported for the zs005 interim data release? Hmm...