Enjoy.
Thank you. [Operator Instructions] Your first question comes from Marc Sinatra from Lodge Partners. Please go ahead.
Marc Sinatra
So I guess the first one is and it's just because I don't know a whole lot about it. If David could run through how sort of the ddRNAi molecules or drugs have been manufactured in the past? And then talk about the difference with baculovirus system that they're now using in sort of more specifically homing on what the advantages are?
Greg West
David, just before you do maybe I could just make an emphasis this point here and that is that this is new technology and it is quite novel and something very exciting for us. So with that as a prefix, I'll just pass over to David.
David Suhy
Yes and thanks for the question Mark. Again, this is not our first ordeal in producing or manufacturing products that have made it into the clinic. As you're aware, we had the TT-034 clinical study, which was maybe a based particle as well. Traditionally, many of these gene therapies have been produced by a technique called triple transection which is quite a labor intensive, plastic ware intensive. Methodology utilized to produce these complex biological molecules or moieties. And by and large some of the astronomic cost that you see associated with some of these gene therapy products, not only are priced out of having a one-time therapy for a lifetime of treatment, but it's also related to the cost of goods associated with producing many of these types of vectors.
And so when you a classified triple transection it becomes very costly in the long term to be able to control the overall pricing associated with your products. By moving into baculovirus-based technologies not only can we get much higher yields and efficiencies from these types of processes, but we can scale you know typically while one may run thousands of roller bottles, we can essentially accomplish much the same output from a single 250 liter unit run, producing these types of products. And it's not uncommon to get doses depending upon the therapeutic indications that cover dozens, if not hundreds of potential patients from a single run.
And so by scaling into baculovirus-based technologies which can be run at anywhere from a shaper class level up to 2,000 liters I think is the current max that people been producing these types of products, ultimately gives you the ability to produce high quality, highly cost efficient material by scaling into sort of an industrial scale the actor and hopefully gives us a competitive advantage not only for producing materials as we move into the clinic but as we move these programs towards commercialization which is really a team quoted factor.
Marc Sinatra
Thanks for that, I guess a more of broad question for Greg. I mean you've been or maybe David and Georgina, you guys have been talking about licensing activity I mean looking at targets for other pharmas and really been talking about the silence and replace technology could you give us just a few examples of additional orphan disease, not necessarily the one you are working on of course, where you might use that balance in base technology?
Greg West
Yes, just before I hand over to David of course we are in the process of articulating the top of pipeline we might have that takes the benefit of that, that silence and replace top technology forward in other indications. But that course supported but that is -- but we can’t really disclose what the demand until we progress on two stages where it’s appropriate. But David maybe you could do with more general scientific view of the monogenic orphan dieses to aspects, so I will have to silence and replace.
David Suhy
Yes, thanks Greg. So if you think about traditional gene therapy [indiscernible] the way it's been implied historically in the past. And particularly in cases like Luxturna product that Spark just gained approval for. Essentially in those cases, you are using gene therapy vectors to express proteins where otherwise the genetic disease may have caused the loss of functions. So again if a person is deficient in a type of gene expression by having a gene therapy vector develop a healthy copy of that same protein, you can essentially restore function. At the other end of the spectrum, companies that use technologies like CRISPR-Cas9 or three things nucleotides have the ability to knock out or silence dieses cause in gene simply by altering the DNA genome through some of these genes added in base techniques.
The problem for at least most of those cases are not problem, but one of the implementations for mostly with technologies is that we need to have a genome editing event occurred, you often times need to knock-in the expression of those proteins such as the Cas-based to essentially have the genome editing more mortalities. But you need to that earning eye is that we tell you the machinery that you need to silence genes is already present in every single one of our cells that we have with human beings. And so for us to utilize the function of gene knocked down, we don’t believe that not being complex proteins. We simply add a short therapy RNA they'll produce some factors. These take a very little capacity of the vector space and by introducing those end you can knockout the disease causing genes.
In many cases what I’ll also tell you is that there is a lot of vector packaging capacity leftover with the need. So much so that it gives us the ability within the same therapeutic sector to express a healthy copy of the same gene. And so really, we see RNA interference one of the key technologies that can use what we call a single vector system or an all-in-one vector with one clinical product, one set of regulatory pathway where you have the ability to silence the disease cause of gene, and within the same therapeutic sector express the healthy copy. So basically it's simply is knocking out the and bad and bringing in new.
And then there is several diseases that are out there, that would be amendable to these types of approaches, again as I said I don’t think we have liberty to expose which one is we have been looking at. But that being said, it would certainly be at least for Benitec from a business perspective advantageous to us to advantageous of this competitive advance where the disease indication, you have ability to knock out the disease causing protein, but not remain a good copy at the same time.
Marc Sinatra
Last question and then I may just jump in the queue. This one's for Georgina. Could you just, I just missed it, could you just talk about the trial sites the site overseer that you're using the CMO and -- sorry CRO and where those sites are?
Georgina Kilfoil
Sure, so we are I'm assuming the city oncology study, we're running the study in both Australia and in Russia, about five to eight sites total looking at probably three sites in Australia and the remainder of the sites, five sites in Russia. I don't want to disclose the name of the two CROs we're working with right now but can say that they're large fairly well known CROs who have a lot of local experience in both the countries that we're working in.
Operator
Thank you. Your next question comes from Tim Boreham from Biotech Daily. Please go ahead.
Tim Boreham
Similar to Mark's question just to the OPMD trial, can you sort of elaborate on that a bit in terms of sort of patient numbers and location? And I guess sort of how you, how you measure the endpoints, and in terms of swallowing improvement?
Georgina Kilfoil
Sure happy to do that Tim. So first in terms of locations, still to be finalized but I think as you're probably aware OPMD is very much a cluster disease with large clusters in French speaking Canada, there's a large cluster in New Mexico in the United States, a large cluster in France and also a large cluster of patients in Israel. So we are currently looking at all of those locations but a final decision on that is yet to be made. In terms of patient numbers again still to be finalized as we finalize the study design but I would anticipate in the study we'll probably end up with somewhere between 20 to 30 patients and that would depend on some of the activity signals that we see.
So then looking at, I think your last question was around the endpoints of the study. So this is a first demand study the primary objective will be obviously to assess the safety and tolerability of a pending intramuscular does of BB301. But because this study is in patients with OPMD, we will be looking at the impacts on swallowing or dysphasia and just to give you a little bit more detail around that. So historically the standard measure of dysphasia of swallowing function has been a test called the water swallow test, really a very non-quantitative test where they measure the time it takes the patient to swallow a glass of water. We will obviously be including this so there's look as a standard measure but we're putting lot of emphasis on some of the newer more quantitative measures of swallowing such as video fluoroscopy and high resolution pharyng-oesophageal manometry. So the video fluoroscopy is a real-time x-ray using barium which allows them to evaluate the ability of swallowing safety and also the efficiency of swallowing.
And then behind the high solution manometry really is able to measure the pressure during swallowing along the entire length of the pharangy and the esophagus, which translates into the efficiency swallowing. And both of these really combined together give a very nice quantitative measure of how would all the patients swallowing and how that swallowing is improving. And this is why as well as working with some of the key opinion leaders in the OPMD field. This is why we have engaged with some of the swallowing experts to assist in the study design. And then I think finally we will obviously be looking at several patients reported outcomes such as swallowing related quality of life and patient reported changes than both swallowing function and their ability to taking food.
Tim Boreham
So in terms of [indiscernible] atomic sector to swallow the glass or otherwise.
Georgina Kilfoil
Yes, exactly and that’s why I have said we will use that but we do want to try and put some measures that they're quantitative as possible, so we can be looking at more definitive changes in and improvements in swallowing.
Tim Boreham
And just to pick up on that the head and neck show that chart I’m just wondering what worry Russia on that gets why not Russia it’s got to be some way, is there a particular reason?
Georgina Kilfoil
There is a high prevalence of having neck capture in Russia primarily due to the large amounts of smoking and alcoholics drunk there. So, there is a large number of patients I think Russia if you go to high quality sites and working with a high quality CRO, they do very good clinical trials and it is a place where you can enroll patients fairly effectively.
Operator
Your next question is a follow up from Marc Sinatra. Please go ahead.
Marc Sinatra
Just with head and neck and delivery I mean systemic delivery would be fantastic, in my opinion, but I’m just wondering I mean head and neck cancer just seems to be a little bit different from most of the other solid tumors. How often do you see metastatic disease in head and neck cancer? And just how often where the systemic delivery therefore more idea being into tumor delivery?
Greg West
David.
David Suhy
Sure. So, currently roughly half the patients wind up with metastatic cancers that are untreatable through current standard of care. This now includes even adding PD-1 inhibitors like Keytruda into the mix. I think the idea for BB-401 to be clear is that the initial clinical studies that will run with the compound were done using direct local injection. And the idea is just to go into the most prevalent lesion that is causing the patient, the most amount of health problems. And so the idea is that in the metastasis, firstly you start to deal with multiple lesions then you do worry about whether or not treating a single lesion or the direct intratumoral injection leads that abscopal effect. Anytime large with understanding with BB-401 given that the initial Phase 1 clinical studies will run with direct intratumoral injection.
The decision was made to run with that rather the administration moving forward into the Phase 2 result. And the reason for that is we still believe that there could be a significant benefit to the primary treated lesion that's causing the patient the most amount of local regional problems related to mortality. That being said as we develop BB-501, we'll not put on these restrictions whatsoever. We don't want to have clinical data in fact I think the preference for us Mark is to skew towards the systemic delivery where you may have broader distributions across the lesions as a whole looking to treat the metastatic disease as opposed to focusing in on one or two primary lesions that might be causing at least the nearest term mortality events associated with these patients. So we understand the restrictions of BB-401, but we understand that the idea with 501 is just to follow on very quickly from the clinical learnings and take advantage of some of the near delivery technologies that would allow us to potentially go systemically for these types of applications.
Marc Sinatra
My last question is also on the same program. In terms of the 401 and 501 duration of drug activity, what sort of difference is do you expect to see, so not necessarily effect on the tumor, but how long will the drug keep working in the cells -- in the cells of the targeted muscle -- the targeted tumor, sorry?
Greg West
Yes, that's a great question in fact for 401 that data is pretty well defined. The University of Pittsburgh and Jennifer Grande [ph] she was the PI and the inventor, the original inventor of the BB-401 technology. We understand that you know there's a limited durability due to the way the DNA plasmas are put in and particularly because there's nothing modified about this DNA plasma. So you're not talking about integrated vectors, it's a very self-limited just like of how long do you expect for the impact to occur.
Now that being said it's important to note that with BB-401 there was many instances in both clinical trials, we've treated lesion with BB-401 resulted in the complete ablation of that lesion. So thing you're looking for is that you put the drug into the specific lesion or tumor, we're completely disappeared when durability is not quite as an impactful long discussion particularly in the local regional tumor that causes the health problems.
Now again scurrying that pivoting that answer into BB-501 durability is important as a fact particularly if you're talking about the metastatic condition where you want to have multiple lesions being hit from the dosing regimen that you're applying. This is often times not only a function of the type of delivery vehicle. For instance we understand what certain biocytes that depending upon the tissue and other factors, durability can be fabulous can be weeks, months or even years following a single administration.
In addition to the delivery methodology, we are doing some very unique things with the structures of the nucleic acid that will be introduced to at least with the RNA effect. There has recently been described although we are not going to change the goals, but there has been several technologies that have been out there that demonstrate that this altered nucleic acid can surface transitional template and have remarkable durability expression. In fact we have primary data in certain animal models that we've seen six months of expression or more, coming on by our delivery system.
So as we think about how the design is compound optimally to be applied particularly in a systemic way, these are our critical factors and it’s a great question, and rest assure this is a very important consideration as we develop 501 moving forward, and to understand the availability and robustness of expression coming from those treatments.
Operator
Your next question comes from Yasmeen Rahimi from Roth Capital Partners. Please go ahead.
Yasmeen Rahimi
A number of questions all zooming in onto your OPMD program. So question number one is as you are in front of the FDA and EMA with the pre-IND discussions, were the communication between the two major regulatory agencies the same or different? If there are any differences that you could highlight to us that would be helpful? Also if you could give us also some thought process of length of time that you are thinking it will take for enrollment to take place given the rarity of the disease? And then also maybe a few words on the PKPD modeling that allows you to really go in and determine the effect of dosing regimen for upcoming study?
Greg West
Georgina.
Georgina Kilfoil
Yes, I can pick the first two questions and then I might turn over to David to talk a little bit about the PKPD modeling. So in terms of the regulatory agencies I think the feedback we received from all of them as we have said was very positive and I think very consistent amongst all the agencies which is a good thing. So there was no large significant difference between the FDA and health Commodore in the European agencies, so positive and both consistent feedback. The second question was the time it will take to enroll the first study. I think there are few things you need to look out.
One is that it is a rare disease but I think the advantage we have here is that it is a geographically coasted disease. So the patients do occur in clusters. The patients also because they have no treatments very open to and very educated as to what’s coming up. So we have almost weekly communications with patients and we do maintain the list of patients who are interested in participating in the study. So my hopes are, I don’t want to comment for the timeframe at this point and time but my hopes that it won’t be a study with the long enrollment timeframe. I think it should go fairly quickly. And I think pass over to David, if you want to break a little bit on PKPD.
David Suhy
Sure, now I'd just add -- I don't know what your end of question number two. The other thing is that because these are in geographically restricted locations that we're already dealing with the clinicians almost on a weekly basis, if not more frequent in terms of communication for the advice on clinical protocol development and other key important aspects as we move this compound towards the clinic. The other thing is that we've taken a page out of this [indiscernible] vectors, take the playbooks where we're dealing with patient advocacy groups again on a fairly regular basis, that way the patients that have the disease probably know as well as anyone who's listening on this call what stage of development we're at, where we're at in terms of regulatory meetings and when we do release the clinical sites they'll have enough data. We've had people say I'm willing to fly half way around the world to participate in these locations even if you don't quite sit in my country.
Regarding the PKPD it’s a great question because what stage the relative administration is very novel again direct intramuscular injection has been used in a number of animal models and they have been shown to have persistently as expected there's wealth of data both in preclinical as well as clinical models where they show the durability of expression following these local administrations. What's new or what's different about this process is that we're going into historically damaged muscles within these individuals and so there's the question is whether biology still functions as appropriately as it needs to. The best way we can address is to use things like the A-17 animal model where we knock in a disease causing protein that causes many of the same disease phenotypes.
Currently our studies have run out just one week so we understand expressing kinetics at multiple time frames starting roughly around week 10 through week 20 in terms of levels of expression we understand how that builds in not only from the silence the disease causing gene but also express the other gene. The replacement gene therapy to restore function and we continue the clinical development plan I would anticipate that that would be the primary source of additional data as we go down that development path, understand the PKPD but again we're already pleased to say that the best animal model for testing is human beings but so in many respects you do your best in what the animal models you have but it is science and you really don't know until you physically get into the clinic what that outcome will be and how long that durability will last.
Operator
Thank you.
Greg West
Operator, I think that's probably coming towards the end of our time. So I'm thinking of what we might do as respond to the unanswered little questions that we may have through our website or other means and just move to a closing. So in closing, I'd just like to say that the efforts and services for recent years and that delivering with our orphan and ocular programs back to enter the clinic. And clearly, we are transitioning to becoming a clinical stage company once again and we're hopeful this will result in significant patient benefit and shareholder value for the shareholders of Benitec.
So thank you to all of our participants today and especially those shareholders and analysts who provided questions. I would like to thank all of our investors for their continued support. Thank you, very much.
Expand
