Mark Sirgo - President and Chief Executive Officer
Dr. Joe Pergolizzi - Pain Medicine Specialist, Assistant Professor of Medicine, Johns Hopkins School of Medicine
Dr. Andrew Finn - Head of Product Development
Dr. Greg Sullivan - Addiction Medicine Specialist, Parkway Medical Center, Birmingham, Alabama
Al Medwar - Head of Corporate Development and Marketing
Dr. Genie Bailey - Addiction Medicine Specialist, Medical Director, Stanley St. Treatment and Resources Faculty, Brown University
BioDelivery Sciences International, Inc. (BDSI) R&D Day Conference March 7, 2013 12:00 PM ET
Good afternoon, everyone. I am Mark Sirgo, the President and CEO of BioDelivery Sciences. We are pleased to have you join us today for what we believe will be a very provocative and educational program. Now, while I am providing some opening remarks, I’d ask you to please take a look at our forward-looking statements on this next slide.
We plan to cover two very relevant therapeutic topics today that include the treatment of chronic pain with opioids focusing on BEMA Buprenorphine and the treatment of opioid dependence would focus on Buprenorphine/Naloxone or our BNX product. To assist us with this program today, we have had a group of outstanding physicians who have hands-on experience in not only treating these conditions, but also in using our Buprenorphine products through their participation in our clinical trial programs. We will also be sharing with you some clinical and pharmacokinetic data that has not been shared before as we update you on the status of our two extremely important clinical development programs for the company.
Our objective behind today is presentations, is to have you leave here with the understanding that Buprenorphine is just not another opioid for treating pain. And two, that BNX offers meaningful differences compared to the market leader Suboxone. We believe both products are going to make substantial differences in the marketplace in the lives of the patients that we will be treating.
So, let me quickly review our agenda for today and our corresponding presenters for whom you have been provided biographical sketches, so I won’t repeat that here. First, we have Dr. Joe Pergolizzi reviewing the unique pharmacological properties of Buprenorphine and how these made translate into patient benefits and treating chronic pain. Dr. Pergolizzi will be followed by Dr. Andrew Finn who is BDSI’s Head of Product Development. Dr. Finn will be providing insight into our Phase 3 Buprenorphine chronic pain program that we have partnered with Endo. Dr. Finn will be followed by Dr. Greg Sullivan. Dr. Sullivan will educate us on opioid dependency in its treatment with Buprenorphine.
Following Dr. Sullivan’s presentation, Dr. Finn will rejoin us to provide an update on our BNX NDA program, and in doing so providing data not yet previously disclosed. We will then the close the formal presentation with Al Medwar, who is BDSI’s Head of Corporate Development and Marketing. Al will cover the market opportunities for a two Buprenorphine products. We will then move to Q&A, where Dr. Genie Bailey, Psychiatrist and Addiction Specialist would join us along with Dr. Pergolizzi and Dr. Sullivan to answer any questions that you may have. And we will be passing out cards during the course of today’s presentation whereby you can list your questions. We will do our best to answer each and every one of those before the session is completed. The presenters will also remain here after the close of the presentation to answer additional questions that you may have.
So, with that, I would like to turn the podium over to Dr. Pergolizzi. Thank you.
Thank you very much, Mark. Thank you all for coming out and braving the weather today. You can see from my affiliations that I split time at various medical schools in different departments, so in Johns Hopkins in the Department of Medicine, at Georgetown in the Department of Anesthesia and Pain Medicine, and at Temple, I am in the Department of Pharmacology.
I do that while also practicing down in Naples, Florida taking care of older patients. And all of you are welcome to Naples, come visit me anytime you like. It’s jut you are about 30 years too young right now. This is what we are all missing today by not being in Naples. So, but I am also missing this right, my good colleagues and friends that I take care of down in the Naples Beach area.
And again, you are invited to come visit me in any of my institutions if you like, because today we are going to talk about pain and the unique opportunity that Buprenorphine brings to the chronic pain market. And I can tell you this that pain, chronic pain is on the present due to the epidemiological prevalence here in the United States. It’s about 14.5% the adult population and the most conservative CDC reports, that’s approximately 42.5 million adult Americans that are complaining of chronic pain average annually. And then you have other reports that the chronic pain over 100 million patients and the burden related to healthcare dollars is about $600 billion a year. We have no one golden bullet currently that works in 100% of the patients, 100% of the time without adverse events, and we are in very much need of products like this.
So, today, I am just going to give you my understanding of Buprenorphine, and how I think it can help chronic pain here in the United States. So, let’s look at some of those areas of interest related to the point prevalence. Here, again another CDC National Survey says that about 100 million adults in the United States suffered from chronic pain. So, think about other hallmarks for chronic disease. That means the prevalence is higher than combining hypertension or a cardiovascular disease, diabetes, and cancer. So, it’s on the present and ever growing, particularly with the population period with upside down, more and more people who present with chronic pain. And it’s the primary reason for healthcare access in the United States. It has been inadequately managed or reported to be adequately managed in about 60% of the patients, and part of it is we just have to appreciate that pain is very subjective, and there is lots of variability when it comes to it. It’s not uncommon that we have to use multi-mechanistic meaning two analgesics together or multimodal therapy meaning non-pharmacological therapy with pharmacological therapy.
An important aspect of chronic pain is that we are never looking to totally remove the patients’ pain. So, we are more or less very focused on improving quality-of-life and other outcome measurements like activities of daily living and functioning in patient satisfaction. So, when you think about an ideal analgesic and you think about what this formulation of Buprenorphine brings to our patients is start to realize why, it’s so attractive to pain specialists like myself.
There are gaps in the management of pain, and this is mainly due to concerns related to safety and tolerability. There is, if you can imagine this, there is very delicate vicious circle with the currently used compounds that we have now whereby patients may get an effect and the analgesic may work initially, but then as you increase the dose of that drug, you start to increase the tolerability or side effects to a point, where sometimes that limits your ability to use that drug. And this vicious circle is on the present problem, when it comes to management of chronic pain. So, compounds that may mitigate that or may have more universal or broad approval or appeal its application, grounded in acknowledged safety and effectiveness like Buprenorphine again become a very attractive opportunity.
So, there is a need for new analgesics and delivery technologies to improve efficacy, effectiveness, safety and tolerability. This year is the WHO Pain Ladder and it’s very interesting, because this was designed for cancer patients. And we all live in a world, where we talk about evidence-based medicines from a group that I led pan-European group, looked at the evidence we were around the WHO Pain Ladder. Unfortunately, there is not a lot of real evidence that builds this ladder, but it really is the way that we treat and handle our patients.
And we see that not just anecdotally in the clinic, but we also see that if you look at large IMS prescribing databases that it’s a stepwise approach. And this stepwise approach is really based on intensity of pain and not the mechanism of action. So, I bring your attention to that, because drugs that maybe affected across various types of mechanisms of action, nociceptive or musculoskeletal type pain, neuropathic or nerve pain or mixed pain. Drugs that have efficacy across the spectrum of different types of generators of pain are again going to be very helpful, and I’ll show you in the literature that Buprenorphine has that quality.
Now, wherever Buprenorphine fit in here, when you look at this, it’s probably going to fit somewhere around the step two part. And what we have right now currently in the United States with the only approved Buprenorphine for chronic pain, which is a low-dose transdermal patch is the ability to go around step two. When we go above that, we are limited by the dose with the currently available transdermal patch. So, what this product I think will bring for us is an ability to go to step 2.5 and above, and that’s very exciting when it comes to clinical practical use. Noting that the majority of patients who experience moderate-to-severe chronic pain have usually had that condition for about 12 years and it’s some type of now mixed pain syndrome meaning it may have started off with just as an osteoarthritis hip-related pain, but over time, your body changes and your nervous system changes and up regulates. So, that now there is a neuropathic component to that.
So, if we look at the ideal therapy for chronic pain, what should it be? Well, it should by provide continuous relief for chronic pain. Think about it if you have chronic pain, it’s like if you have chronic benign hypertension, you have that medication, which is in the background constantly working providing the continuous relief. Now, if you have chronic pain and you exacerbate you start shoveling your hard and picking up heavy things maybe you will have exacerbations on pain and that’s where immediate release on medications come. If you have cancer and you have what we call breakthrough pain, again that’s we may use rapid onset opioids and things to that effect, but continuous pain relief of chronic pain is important. Remember with the goal of not totally eradicating the pain, but providing enough analgesia, so that it’s optimal. So, we can get people back functioning and working and that’s important, the ability to have clear cognition while being on one of these divisions is extremely important, and I am going to show you study that again lends itself to believe that Buprenorphine is an excellent opportunity in that field.
To have a low incidence of potentially harmful side effects, including respiratory depression, if you go to any package inserts or any of the opioids out there for chronic pain, you will see that respiratory depression is achieved, has been concerned, and that probably will stay in every package insert of the FDA, you are watching fine, is it a unique pharmacological, pharmacodynamic meaning how the drug is active in the body related to Buprenorphine and respiratory depression. And again, it’s favorable. Psychometric impair as well as decreased testosterone. So, once we all thought we had it down, we know how to soon get on your own how to manage chronic pain in transgenic type side effects like using opioids for extended period of time can cause things like osteoporosis, immune C essence and depression of immune system, hypogonadism. These are all real problems.
Why is hypogonadism is such a problem, because of the symptomatology related to it. Some of that symptomatology is not only decreased libido, but it can mimic itself as depression, when you look some of the incidences of comorbodities of depression and chronic pain, it’s as high as 30% to 40%. The question is when do they actually get depressed? After they were on an agent or before they were on an agent, and then potentially if it was after they have been on an agent for a long time, could it be related to testosterone level, and can that be the reason why they got that anti-depressant that they really didn’t need. So, it’s a real clinical concern out there. Drugs that have a low impact on testosterone again have an advantage you will see that when you go and do a deep dive on Buprenorphine that there is a minimal impact if any at all. And I think it’s on depressant, the last bullet point, both in the lay population and also in the medical professionals. And that is the issues of abuse and misuse, diversion and addiction. And those drugs would have a low abuse or addiction potential or low likability or desirability, again are advantageous.
So, I come to you humbly after publishing about 20 papers or so, on Buprenorphine. This year is one that I led, which it includes all the heads of the various pain societies in Europe. I am on my way this month to use same thing in Asia, where I have been asked to do the pain guidelines with China, where again in China, you are not allowed to use opioids more than eight weeks and Malaysia as well and Korea. So, I had some humble experience with these molecules. And what we have in the United States and our armamentarium right now with the approval for Buprenorphine, as you see here is what our friends down in Silver Springs have already approved. And we can put this into two buckets, basically opioid dependence and those for chronic or moderate to severe pain chronic or none.
So, how do we start to? Then wonder the value proposition, what is that value proposition of Buprenorphine in the chronic pain space? I think there are two unique value propositions. One is for the patient and one is for the providers. Right, the reverse value proposition, how is it going to make my life easier and better, how am I going to be able to get my patients to be functional and have reduced pain. It starts at the pharmacology level. Buprenorphine is considered a pure – is considered a partial opioid agonist, which is different than a purely opioid agonist. There is a lot of good work by (Bob Radford at Temple) that you could read on this. And what we find is that it comes down to conformational change and receptor capability or occupancy. So, the drugs come in to the body and then they bind to these receptors, and whether or not, they bind to the receptor fully or a large amount of the receptors or not will tell us whether it’s a full or partial type of agonist.
Then, if you picture a square, when the drug binds with 100% new occupancy, the square box may become a triangle, and then you are going to have a response, right. So, that’s called the affinity to bind, the intrinsic activity to change the receptor and extrinsic response the turn the switch on, in this case, pain relief. So, partial agonist, you have your box, the receptor here, that Buprenorphine binds the box and you have a partial conformational change. What we find is that even with the partial conformational change, the light switch gets turned on. You see that based on the side effect profile, skin, GI, and CNS type adverse events, and based on the effectiveness in sense of pain relief in the level of chronic to moderate, severe type pain.
There are other receptors too that are involved in this, and that these are important to know, they are not fully defined as of yet. One nice thing that Buprenorphine has is that, because of the partial receptor occupation and change, you are going to have a reduced type of respiratory depressions. You are going have a ceiling effect on the respiratory depression. This was always a concern related to the analgesia. What we find is that in order to have a ceiling effect in the analgesia, you have to be using very, very high doses of the drug and I’ll show you that graphically. So, in the dose range that we are looking at for this particular product, you are well within that space to provide analgesia and yet benefit from the partial respiratory ceiling effect.
Let’s look at pharmacology then, and this is sort of what I try to describe to before, even though medicinally, we describe it as a partial agonist in terms of analgesia in animal models that you can show to produce a full analgesic effect, that is depended upon the intensity of the stimulus. And therefore, we don’t need 100% occupation on conformational change. The other nice thing about Buprenorphine is that it binds very tightly to and is a potent receptor agonist and dissociates slowly from. That’s really important, because end-of-dose pain right, when we transition from one dose to the next dose, here is the drug that’s releasing slowly. So, you have a nice overlap from a pharmacodynamic event meaning that you won’t have end-of-dose pain with these type of patients from a modeling perspective.
So, let’s talk about analgesic qualities, efficacy and safety related to Buprenorphine. And I really prefer the term effectiveness as opposed to efficacy, because efficacy denotes against placebo. So, I think when you look at the literature, you will see on deniable expression in favor of effectiveness in Buprenorphine from moderate-to-severe pain. Let’s take it from the perspective how much of a therapeutic window can we work within? The therapeutic index for this drug is rather wide with the lethal dose and the effective dose of 50% being a very distant evidence you have a long place to work with IV, its safe. If we look here at the analgesic quality, I think well morphine being the gold standard, we see that we either manage or exceed what morphine is able to provide from an analgesic quality standpoint.
And this is that window that I spoke to you about. So, if any of you walk away saying partial, I heard some of that is partial agonist, what does that mean, listen what you need to look at, where is the partial agonist and the range that we are talking about and the range that you will see for this particular moving Buprenorphine preparation is well within the analgesic dose range. This is the event that I mentioned as far as its pharmacodynamic effect on respiratory depression. Usually as we increase the dose of a pure opioid agonist it will have a linear decrease in respiratory depression. Here what happens is we increased the dose of Buprenorphine and then we factor off, we’ve got a ceiling effect when it comes to respiratory depression. Think about that, think about how common it is to prescribe opioids in outpatients, think about how many patients in the United States may present that are obese or may have apnea. That’s a big issue. These are important things when you are able to have a drug that has these type of pharmacological benefits to it.
So, how can Buprenorphine in older patients and renal patients? And this is not a niche product by any chance, but let’s look at those patients that really scare everybody, right. Because that maybe a question, well in older patients and we don’t use the word elderly anymore and try to get a publication in January and they came back and hit me and they said, it’s older and if you are over 75 it’s oldest of the earth. And then you can be older for else, it is lots of things when it comes to that, I’m very grateful be part of the FDA safety, initiative, and pain in the elderly and we look for these drugs. There were not a lot of many drugs that meet the ICH guidelines related to very clinical trials in older patients meaning at least 100 patients in your portfolio. What we find the Buprenorphine that there is an established efficacy, effectiveness, and safety for this molecule for moderate-to-severe pain in those patients. And when we look at those patients and real patients, remember that Buprenorphine is the only opioid who is metabolite an active compound is not going to eliminated via the kidney. So, there is no dose adjustment necessary in those patients as well.
What about Sunday drivers and I just don’t mean the ones down in Naples, right. But big question is about the ability to impair patient’s ability to perform mental and complex having these skills, which you will see from driving studies, again is that when we looked at patients receiving stable doses of transdermal Buprenorphine compared to the mentally matched healthy controls there was very little differences.
Scheduling an abuse liability, a major concern for practitioners and providers as well as healthcare givers at home and patients, so what can I tell you about Buprenorphine in this short-time? Buprenorphine’s DEA classification is scheduled through and I am very, very confident that Buprenorphine will be not moved out of the schedule to reposition as what might happen with the immediate release hydrocodone/APAP combination that’s still yet to be determined. So, it’s extremely important to realize the benefits of having it scheduled for the patient. It provides I think a better level of access for the provider, it allows me to write up to 90 days worth of prescriptions and that’s very important because as more and more patients present to their clinic related to pain and other types of problems there are less and less of us out there to take care of them, so we need to have that capability.
There is less abuse potential than other drugs when we try to look at why there is scheduling. So, looking at Schedule I, II, you can appreciate why Schedule III again it’s attractive from the patient standpoint and also from the provider standpoint when we look at abuse potential. And we find that there is moderate to low physical dependence as well associated with Schedule III. Again that’s good for the patient and it’s a reversed value proposition for the providers.
If we look at the literature for some answers too (Colmar) colleagues showed us this here, where they did a study in a double-blind placebo control in patients using morphine maintains abusers and Buprenorphine injection and what did we find. We found that and this is very interesting study if you like I can get you more of it from a graphical display. But just to give you bullets, its a little good effect with the subjects moderately interested in the product. So, really doesn’t float their boat, increased reading of bad drug meaning if I can get other ones I would rather do that and it’s not administered above placebo at any dose.
So, again I think that all leads to the fact that this is a drug, which really will help the patients and providers particularly when we discussed abuse misuse diversion problems. So, to keep on-time and to answer the question is Buprenorphine a good option for chronic pain management, I think undeniably in the literature and anecdotally in clinical practice globally you will find the answer is yes, that’s why this molecule is finding its way in the countries like China and into the Asia-Pacific Rim.
There was proven, reliable safety and effectiveness for moderate-to-moderate severe pain and severe pain, a long duration of action based on its pharmacokinetics and pharmacodynamics provide sustainable pain relief, it has a respiratory ceiling effect, it has advantageous. There are fewer typical opioid like side effects. I didn’t have the chance to go through that, you can look at that in the reviews. The abuse potential and addiction potential is low. It can be used safely across a large variety of patients including but not limited to. Those patients that, of course, has more concern like renal impaired patients and the older patients and can be administered in a variety of routes including the buccal mucosa. So, think about this as adding on or being able to improve what the existing we have now with the transdermal Buprenorphine, where the trans Buprenorphine may be doing very well in a patient, but they require higher dose when limited. Now we can go from step 2 and above with this medication all the way to what we need to control severe pain. And titration may improve that tolerability, the bottom line is the new delivery system makes it simple and convenient.
With that, thank you over much for your time, and I look forward to questions. This is just another summary of those bullet points, but I do want to stay in time. One last point, I will say from the pharmacology of the drug, there has been some indication that it may actually worked as an anti-hyperalgesic. That’s really important, because this will allow us to get a broader type of ability to address pain from different generating type of situations like visceral pain, neuropathic pain etcetera. So having an anti hyperalgesic aspect to at least in the preclinical model is very favorable.
Okay, thank you very much, and I’ll turn it back over to Mark.
Dr. Andrew Finn
Obviously, I am not Mark. I am Drew Finn, the Executive Vice President of Product Development at BioDelivery Sciences. In the next few minutes, I want to introduce or reintroduce you to our proprietary drug delivery technology, BEMA, review with you and examine some of the outcomes of our initial Phase 3 study and chronic pain management, and then describe the design of our ongoing Phase 3 program with our partners Endo in chronic pain management. BEMA is an acronym for Bioerodible Mucoadhesive as a name applies the drug the delivery system adheres to the buccal mucosa inside the mount.
It is a unique Bi-layer film technology where the active ingredient is contained in the mucoadhesive layer apply directly to the mucosal membrane. On hydration the drug effuses out of that mucoadhesive layer and into the mucosal tissue and then is distributed throughout the body. One of the unique features about the BEMA technology is its bi-layer nature. It has a backing layer that prevents the drug from defusing out into the saliva, where it comes in contact with the throat, comes in contact with the taste buds and is swallowed. The net result is a relative unidirectional drug flow out of the film into the tissue and high level of bioavailability.
Entire product is more desirable, so it dissolves completely in about 15 minutes. There is nothing for the patient to remove or take out at the end of the dosing interval. At BioDelivery Sciences, we are developing two Buprenorphine base products in the BEMA technology as Dr. Sirgo indicated we are developing a low dose formulation for chronic pain and high dose formulation with Naloxone as an abuse deterrent for Opioid dependents. We conducted our initial Phase 3 study, BUP-301 with the low dose formulation beginning in 2011. The patient pop – it was a designed as an enriched enrollment randomized withdrawal study in moderate to severe chronic pain patients with low back pain.
Importantly, it was a mixed population, both patients that were opioid naïve and experienced were included in the same study. The study was of the standard design in enriched enrollment where patients go to an open label titration period to find and identify an effective dose and then dose that identify an effective dose are randomized to continue on that dose or to placebo. The entire randomized double-blind portion of the study is 12 weeks and we then analyzed the change in pain scores from the time of randomization to the completion of the study. The weighted comparatives between the active and placebo groups is to subtract the results from the – with the placebo from the active and then a negative number indicates a positive effect for the active agent.
As you can see here in the total population, we had a small improvement in pain in the total population, but it did not reach statistical significance. On examination, we found that there were the high placebo effects at the low or starting dose for the trial. And when we removed that group from the entire study, at the end of the 174 remained, so approximately two thirds of the study population remained, we found a much more robust change in between active and placebo. This difference here nearly 0.6 is very similar to the difference reported with Butrans and trials with similar design and population. And you recall that I mentioned that the study included both opioid naive and opioid experienced subjects.
On the right side of the slide is the results in the opioid experienced sub-population. If you do the analysis in the total group of patients whether they were opioid experienced regardless of dose, you find that even more robust lining with the delta now of 0.8 between active and placebo, again approaching statistical significance, but not quite statistically significant.
When we did the same exercise in the opioid experienced population as we did in the total population removing the low dose from the analysis, we found a very robust finding 1.2, that difference was statistically significant, you know that is consistent with the difference that you would find in a – with a schedule to narcotic in the same kind of study design. So, with that as background what do we learn from this exercise and how do we apply it to our new program. One of the things was that we needed to modify our study design to separate studies for opioid naive and experienced patients. We needed a larger Phase III sample size. We increased their from a sample size of 235 in the initial study to 725 randomized patients in the ongoing Phase III program. One of the factors was the duration of chronic pain in the patients that we felt like they may not have been as chronic a pain as we would like. We extended the duration in the ongoing program from three months to six months before prior to entry, so again trying to get a better assay sensitivity by enriching the population with those patients that have true chronic pain.
One of the features that was also noted in the initial study was that patients that randomized after one week of exposure at a dose had a very high placebo rate. So, we corrected for that by extending the dose interval that’s required on the final dose before they could be randomized from one-week to two. And finally we asked for even more robust change in pain scores on the – in the titration period than we had in the original study. In the original study, you could randomize at a pain score of four or less, but there was no requirement for a minimum level of change in pain from the beginning of titration to the point of randomization. In the new program we required the patients have at least the two point drop in their pain score along with having a pain score less than or equal to four at the time of randomization.
We want to address the lack of response to the starting dose, how did we do that? Well, we increased the range of doses in both studies, so we now go from a dose range of x to 6x in the naive patients and from 2x to 12x in the opioid experienced population. So, a wide range of doses we have expanded the dose range, this translates into approximately a doubling of the high done in the ongoing naive population and almost a four fold increase in the dose range for the opioid experienced population. One critical feature is that we did not allow the opioid naive patients to randomize at the starting dose. The starting dose for the opioid naive population is Dr. Pergolizzi mentioned was to try it the objective there is to find a well-tolerated dose to introduce Buprenorphine to the patient, then to move them into what is considered to be a more therapeutic dose range. The starting dose is not designed to be a very effective dose, so having patients randomized with that dose there is no real surprise that they can’t distinguish it well from placebo. In the ongoing program, we have corrected for that by not allowing patients to randomize at the first dose in the opioid naive portion of the study.
Now let me describe for you the some of the details of the Phase – ongoing Phase III program with our partners, Endo. The two studies that we are talking about are BUP-307 which is the opioid experienced study and BUP-308, the opioid naive study, both studies are of the same design and the same design that we used previously that is their enriched enrollment randomized withdrawal studies where patients with moderate to severe chronic low back pain are titrated to an effective dose and then randomized to either continue on that dose or receive placebo. The same primary outcome measure is for both studies as well as for the previous study, but that’s where the difference is pretty much soft.
Looking at the opioid experienced population, you can see that we really expanded the range of morphine doses that someone can have and enter the trial. In the previous study, it was zero to 60, now we will not even allow patients to enter the study if there are all less than 30 milligrams of oral morphine a day. And we have extended the upper end of the range to 160 milligrams, again improving assay sensitivity because now we have got patients that have really self identified as needing an opioid to manage their chronic pain and a significant doses of oral morphine. So, 30 to 160 milligrams of oral morphine a day to enter the opioid experienced study, we are enrolling 475 patients into this trial and randomizing 284, 284 being randomized is approximately 20% larger in total sample size than the entire initial study that we performed. So now, we are focused in on the opioid experienced the most discriminating population possible and we’d expand the sample size by about 20%. I have already mentioned that we have an increase in the dose range from 2x to 12x. And again, the 12x dose is approximately four times what we used in the – as the upper dose in the previous study.
Turning to the opioid-naïve, we have modified the entry criteria there. To some degree, opioid-naïve now is defined as anybody taking either no opioid a day or up to 10 milligrams of oral morphine a day. That’s a standard definition that’s used throughout the industry in these opioid-naïve population studies. We have really expanded the sample size here, because we are expecting a little bit narrower difference in the opioid-naïve population. We want to have more power to be able to pick up that difference. So, the opioid-naïve study is to enroll 740 patients and 444 will be randomized.
Again, we are using a dose range of x to 6x. However, patients cannot randomize at the lowest dose. They must be on the 2x dose to be randomized. Pictorially, the study looks like this for patients who enter the screening phase then they go through a titration phase, which can be as much as four to six weeks. They find an effective dose. They must stay on that dose for two weeks prior to being randomized. They are randomized. They can go to placebo, which is identical film size and appearance or continue on their active treatment being the Buprenorphine. They are followed for the entire 12-week period of time. They received supplemental pseudometaphine in the opioid-naïve study for supplemental hydrocodone, and aspirin in the opioid experienced study up to a limit per day for to maintain for breakthrough pain. We analyzed the differences in pain scores at the end to this point here. That’s the analysis that will be performed.
Now, where are we in the program? Well, both studies are enrolling rapidly as we speak. We expect that both studies will complete either the end of 2013 or the beginning of 2014, and BDSI expects that we will readout one of these studies at least in 2013. All that leads us to an NDA filing date in third quarter of 2014.
And with that, I’ll introduce Dr. Greg Sullivan to address understanding opioid dependence and Buprenorphine treatment.
Dr. Greg Sullivan
Good morning. I am Greg Sullivan. I am an Addiction Physician from Birmingham, Alabama. I was involved in what we call the BNX 201, but now it’s called BUNAVAIL I understand. The new name for the addiction what you just described is the high-dose product.
What I have been asked to do today is to describe some of the findings of the 12-week study that I and many other physicians just completed in 2012. I was first asked to describe this disease space for some of you that are perhaps less for me with it and its conventional treatment so far.
Opioid dependence is, think of this as a spectrum disorder where opioid dependence is the lesser disease and addiction is the more severe disease. And we have all -- perhaps all have some experience with opioids in our life and as soon as you take it, you begin to have tolerance meaning in 2 to 7 days, it works less well, and that’s the very easy thing to have most patients with chronic pain have some form of opioid dependence. Within that same period of time if you abruptly stop taking that you have withdrawn, and then you begin to have, what’s called medication envy within a week or so, where you begin to think about taking it for other things besides the pain you have prescribed it for. That defines opioid dependence and it’s one of the indications for the BNX product.
The other indication is opioid addiction and it is just the continuation of that. And soon you begin to have cravings with continued use, compulsive use, meaning you think about taking doses between doses. You lose control, I mean, you say forget this, I’ll just take two at a time or three at a time, it’s quite common. And then you begin to falling asleep in the doctors’ waiting room or you are buzzed out at your sister’s waiting or things like that, clearly you are hurting yourself with and you have continued use despite harm. That is called the 4 C’s of addiction and that’s what we are treating with this.
Since we started using OPH for what we call non-malignant or non-cancer pain in the late 1970s early 1980s. Sales growth has been 20% per year and unfortunately deaths that followed it. This is the time death stops the chart because of budget cutbacks in 2008 and at that time it was on par with homicides and car accidents with roughly 5 per 100,000 deaths in the U.S. The 2011 rate is 9.6 deaths per 100,000, so it’s doubled in the last four years both for sales and for deaths. That’s in the United States roughly 38,000 people die per year roughly not to fill a smaller jet everyday. So, it’s the number one thing that the government is after to bring this down, it’s the leading cause of death and people under 52 in the U.S.
So what’s the current prevalence well there were 2.6 million opioid users in the U.S. last year roughly the same as cigarette smokers and marijuana experimenters. If you figure that’s 11 million births last year in the U.S. with this new generation Z and 6 million deaths that’s one-third of all the current generation will experiment with opioids during their life time some time one-third. Here are once they are not still a very small part of opioid addiction. But it’s still 1 million users chronically in the U.S. The big gorilla is the prescription opioid pain pills and it was 6.4 million in 2009 that was 12.6 million people of U.S. abuse opioids at some part during the year nearly a quarter of all 18 to 25 year old. Methadone is growing 10% per year and at last year had 100 – 329,000 people in the 1100 methadone clinics in the U.S. This just shows that when the problem changed from IV drug addiction it started in the Vietnam War and actually in the early 2000s it switched to prescription pain pills, but it became official in 2007 when there were more emerging room visits for pain pills and that were for heroin addiction. And now it’s outstripped by nearly 12 fold.
So, the conventional treatment choices so far is the number one treatment for opioid addiction in the United States is incarceration. There is three real big treatments, incarceration is 8 million people that are incarcerated in the U.S. on any given year for the last three. And over 50% of federal prisons and just under 50% of municipal and county prisons are by drug users or for a drug offence. The second most common treatment is what’s called behavioral therapy, which is educating them or stimulating them to try to even realize they have a problem perhaps the most common and most numerous is AA or NA which is Narcotics Anonymous and which has the biggest following. And it has about it’s stated it has a 14% success rate. So, the success rate of behavioral therapy historically has been very low, very low.
The third type of treatment is medication therapy and there are three real treatments in the United States that we can use for medication treatment for opioid addiction. Methadones the classic one that was developed here in the New York by The Rockefeller University in 1974 with that famous study that was controversial at that time they had 20 heroin addicts randomly placed 10 on methadone 10 on placebo. And the 10 on placebo two died and other 8 were incarcerated and the 10 who were put on methadone three found jobs and no one got incarcerated. So, it was convincing enough despite the stigma at the time to get the federal government to approve it nationwide for use of opioid dependence that was 1974 and today there is 329 roughly 329,000 people that go to methadone clinics everyday.
There was a Harrison Act which was the Federal Law back in 1914 when a company called Lilly invented a drug called heroin to treat morphine addiction and they said never again. And so they made a federal law against treating drug addiction as and such – that was called non-medical problem and was a Scientific Law Enforcement. In 2000 there was a federal law called DATA 2000 it was passed and brought it back into the purview of medicine to treat drug addiction back with doctors again made it legal to prescribe narcotics and other drugs to treat it. But there was only very specific you to prescribe the first one in 2010 was approved Suboxone and Buprenorphine in 2002 and it now has 529,000 patients that take it every single day and over 1 million were prescribed last year let’s say also $1.5 billon. It was actually much older drug even before methadone that we used to use called Naltrexone. There is a 100% blocker, it was a – it’s a pill and it was quite effective if you can even get anybody taken, but literally no one would take it. So, it came out in injectable form in 2011 was proof for opioid addiction and it still has relatively small use because no one are subjected enough, but it does block the ability to take opioids for a full month, it’s also $1700 a month.
What’s the different between methadone and Buprenorphine, methadone is – has to be dosed everyday not prescribed. You can’t prescribe methadone for drug addiction, it’s against the law, and you will be arrested, your license taken away, they watch that closely. The methadone for addiction can be dispensed handed out every single day even if it’s snowing or raining or, then you got to come pick it up every single day at methadone clinics throughout the U.S. As I said, there are 1100 clinics. Buprenorphine as long as you complete the eight-hour training and your license, we have DEA licensing our state, if you are a licensed physician you can prescribe Buprenorphine. There is 30,000 providers that can do it. So, almost average 600 and some per state they can write it and that was the goal of 2000 is to provide opioid dependence treatment, wide spread so we can try to curb the massive death rates.
As I said, methadone is highly regulated. It’s also what’s called full covered opioid, which means, methadone is a slow acting, very potent form of any other full power opioid like – even like hydrocodone or morphine or things like that. So, the more methadone you take, the higher you can get, it is very slow acting, so people wouldn’t – it wouldn’t be anyone’s first drug of choice to get high, but unfortunately people don’t understand exactly how slow it acts, and how powerful it is. So, it’s the third leading cause of death overdose death in United States after Oxycodone and Xanax. Interestingly, those are not methadone clinic patients, but rather those doctors that choose to write it off label for pain in U.S. and its highly diverted.
So as I said the difference is Buprenorphine is prescribed by anybody that does the eight hours training and passes the test. There is a DEA license, physician can prescribe it. It has a unique physiology I think Dr. Pergolizzi will try to go over with you, which was that drugs frequently work on receptors. And there is a certain number of receptors about 500,000 in the body that opioids try to bind to, and uniquely to adjust this compound. When it binds it doesn’t bounce like most physiologic chemical, as it binds and grips for 36 hours. So, its unique ability is that it’s A) once you are full you are full, when all your receptors are full, which is a very low dose for the receptor that makes you stop really to get addictive. You can take as much as you want and you just have expensive urine, it just flows out, I mean, there is no place for it to bind. You can also take other drugs like heroin and cocaine and methadone or heroin and methadone, I am sorry, and morphine and there is no place for them to bind. So, you just think it’s a wasted effort.
That’s what we have been talking about with the partial agonist, it fires the receptor about 36%, so you get mental clarity and focus and energy and you are happy about taking the medication 3.5 hours after we take it, but it’s, but that’s all, there is nothing coming after that, no matter how much you take it, but thankfully experiences thought us since 2002 that everybody is pretty happy with 36% stimulus.
So, that was a difference between methadone and Suboxone, methadone and Buprenorphine, what’s the different between Buprenorphine, Suboxone and it was introduced by REC in 2002, and Bunavail the new product by BSI. They were trying to – that we just completed the safety study on. But Suboxone is not absorbed orally, Buprenorphine is a looks like aspirin it’s orange, and if we swallow it doesn’t do any good, it happens all the time in the tablet form. And so people go home and take this and they say I didn’t feel a thing, because A) it is not absorbed and B) if it was absorbed your liver would remove it instantly. It’s good for the liver, The liver likes it. It doesn’t have liver problems. It’s just it doesn’t have your addiction.
So, what you have to do is to take the tablet in oral form and hold it in your mouth for 8 to 10 minutes and it kind of rise around and it tastes better, I mean you’ve got better salivary sweet and savory taste buds, we are not talking about flavor, we are taking about pure taste. So, it never goes away. And it’s a highly bitter taste that’s people just don’t get over. So, that’s all because it’s poorly absorbed. Unfortunately because it’s not observed even when you hold it on your tongue, you only absorb 2 of the 8 milligram tablets or about two in a quarter of the 8 milligram strips of Suboxone, the rest of it goes into your colon and its causes severe constipation. So the improvement in the BNX, their idea was that if we actually have an adhesive that sticks it to the mucosa inside your mouth and it’s a bi-layer strip. So, this side has got the Buprenorphine on it and is struck against your cheek, it really can’t come out and you can’t taste it, it can’t come out and go in your colon constipation and because we are holding it there till all it absorbs, we can use far less amounts. So, it’s about twice as strong as we can use about half as much as Suboxone. And also early on with the tablets and even with film the FDA was real concerned about the fact that we would have (indiscernible) or a mouth ulcer or things occur, because even with the film the normal Suboxone film was not adhesive, it doesn’t stick to the cheek or stick under the tongue it can float around.
And so we are getting sores and ulcerations actually great all these things that occur inside the mouth. So, an important part is once you stick it, it is stuck and it doesn’t go around and cause mouth damage. And the third thing is obviously that the taste which is terrible and about 15% of patients say I’m going to try and help if there is no way I can keep that in my mouth, it’s just that bitter as markedly improved with the BUNAVAIL because it tastes good. Let’s go there is the second layer we talked about this layer going against the cheek inside, the outside layer the one inside your mouth has flavoring and its actually has a pleasant flavor. And since not a since none – since it’s all trapped and going into the cheek, it doesn’t flop down into your colon and cause severe constipation that was the idea.
So, the study started and finished last year and this is all very preliminary for this meeting. There were some needed 200 – we need around 200 patients remember these are heroin addicts and drug addicts and things like that, so it was hard to get 200 patients to show up for all the visits for 12 weeks. We started with 250, around 250 patients and the idea was it is people that have taken Suboxone and has some experience on Suboxone would be changed to BUNAVAIL and see how they will act it and see what their constipation rate was and what it takes preference was.
So, it was an open label study for tolerability, they can take any starting dose they wanted to between 8 milligrams and 32 milligrams. And we were converted to what we believe to be the correct dose of the BUNAVAIL and we were trying to work at those specifics as well during the 12 weeks. So, there is 249 people enrolled 151 were on the Suboxone film and 99 one of the Suboxone tablets, 198 of that completed with the study, 51 discontinued for various reasons it was talked about at the bottom detail, 6%, I am sorry 2% which was six people had significant at ease other than withdrawn, and 14 withdrew consent, which means that I did a significant number of these people. And all I can speak to is what my reasons were, but there were things like they got a job out of town or they were incarcerated or they had other issues with family members had begun, because I had to keep coming in for these visits not daily, but almost daily. So, if there was anything that I have said we ended up they ended up having to with drop and say and just leave.
The other at the bottom was anything from we lost trust in them or it would look like they were maybe experimenting with the pills or with the new film. There is a lot of reasons that especially the drug addiction we are doing research is to take people out of a trial, and we think that they are (indiscernible) for other reasons. This is the 80s we talked about. The drug withdrawal syndrome of 26% was trying to use actually as much cautions that we could use. BDSI wanted to take any of these other symptoms, which are interestingly signs of withdrawal, but are also signs of taking Buprenorphine. So, it’s very difficult to say. I actually had no one say I am having withdrawal I don’t want to stop this drug at all during the study. BDSI, again, under abundance of caution put all these symptoms together and said if they say any of these were encountered as withdrawn. So, 8% have headache, that’s probably the most common, one of the more common side effects was Suboxone to all of these are pretty much the same as Suboxone.
I think the package insert correct me if I am wrong for Suboxone for drug of all symptoms is 35%, is that right. This was the mouth lesions that where is the FDA so much that happens with Suboxone film or Suboxone tablets. And you can see once you stick it to the cheek it’s stuck to cheek it’s not going to cause mouth problem so it doesn’t rater around anymore and doesn’t float around or get stuck on something that incept causing an ischemic lesion or an ulceration or bleeding. Everybody said their mouth did fine, I don’t have anybody that complained to me and these are excellence inspections with each part of the mouth.
This was the big thing BDSI was that after when they develop the film the bi-layer film was they wanted ease-of-use meaning that patients are pretty excited when they go on Suboxone, but as I said we got to say here is you got to say one, two, or three tablets size on aspirin, put them on your tongue and hold them on your tongue, try not to swallow, it’s very bitter. But try it out, this was much simpler where you just take a little dot essentially and stick it to this inside of your cheek. And but you still require some education to teach them how to do that, they got to stick to Buprenorphine inside to the cheek. So as far as ease-of-use goes, over half said it was easy or very easy and a full two-thirds said it wasn’t difficult. As far as flavor goes, the other big thing that they were after with this is remember it’s – Suboxone is very better as another half said it was pleasant or very pleasant and a full two-thirds said it wasn’t bad.
So, this is to show the actual pharmacology of the – how we can limit the amount of Buprenorphine that somebody takes by lowering the dose and by sticking it to the cheek, so not that much makes it to the colon. So, the equivalent of Suboxone is 8 milligrams and as the (indiscernible) is approximately 4 milligrams of BUNAVAIL, and that’s because it’s twice as bio-available, the amount absorbed is the same, which is just to be a good dose for opioid dependence and addiction. And so the amount delivered to the colon cost to patient is three times more with Suboxone film or strips, film or strips or tablets. So, when we started the study, remember everybody was taking Suboxone and 27% complained of constipation. And at the end of the study, there was only 7% remaining, which is a 69% improvement in constipation during the 12-week study. It’s fairly dramatic. So, the BUNAVAIL, what’s previously been called BNX for opioid dependency had a low drop out rate, especially for this treatment group was very well tolerated, and the dosage form was well accepted and it didn’t have any problems with learning how to use it and the resolution of constipation was very significant during the time. Thank you.
Dr. Andrew Finn
Thank you, Dr. Sullivan for that excellent background on the landscape in opioid dependence and a review of the results from our 201 study. Very appreciate it, well done. There are four studies that are the key studies for our NDA program and they are listed on the slide, dose linearity and proportionality study, a bioequivalent study, where we compared our BNX product, and I’ll continue refer to it as BNX, because that’s where I am comfortable right now.
Well, on to Suboxone 8 milligram tablet, a safety study in opioid-dependent patients that Dr. Sullivan just addressed, and then a liquid effect on higher dose PK study that is ongoing right now, third dose being administered on Saturday. So, the one thing, one comment I’ll make on the safety study is that the incidence of drug withdrawal syndrome was 20% approximately on the BNX product below what was reported in the package insert for Suboxone. So, we have done our best to be conservative here and if anything over report rather than get criticized by FDA.
But let me address now the dose linearity and proportionality and the bioequivalent studies. Dose proportionality study was a four-way crossover trial. There were three single film study doses. 1x, 4x and 6x, then there was a single treatment group that received four films of the x dose. So, four treatment groups, everybody randomized and then received all four treatments, and then we have collected the blood samples, 48 hours after each of the doses and calculated the area under the curve for Buprenorphine, the maximum plasma concentration and compared those. 20 healthy subjects participated. The study was done last year.
And we looked at the increased in the area under the curve that is the plasma, Buprenorphine plasma concentration time curve over the entire 48-hour period and extrapolated to infinity. And if you look at that by dose, you can see a linear increase in the exposure to Buprenorphine across the dose range. So, going from a 1x dose to a 6x dose, you have a predictable increase in exposure to Buprenorphine across the dose range study. A similar situation exists for the maximum plasma concentration, again a linear relationship between the doses across the six film dose range with predictable increase in maximum concentration.
Now, turning to the comparison of the single 4x dose and the 4 single x films, it’s a relevant comparison, because you want to know how easily it’s going to be to titrate somebody or to adjust their dose, people may need to take multiple films. We take one film of one size, one film another side to get a precise dose, so they are optimized in terms of their opioid dependence management, and a minimum level of side effect. So, it’s not uncommon to expect that patients what we were taking multiple films. So, what we did in this study was we compared the four film dose with the single film dose that with the same total dose, but they were just administrated differently. So, the test dose is the four film dose and the reference dose here is the single film dose.
I think you can see in the standard bioequivalence parameters, Cmax area under the curve, the four film dose performed almost identically to the single film dose. That’s even more profound when you look at it from the actual level of bioequivalence, where that if you look at the 90% confidence and also around each one of these values, to be bioequivalent, you have to be in the range of 80% to 125% of the referenced product. And I think you will see that all the confidence intervals here are well within the 80% to 125% range, hence bioequivalent between the two doses. And that was what our therapy was based on the work we have done with Buprenorphine alone and with our own (indiscernible) product, this was our expectation and but we needed to confirm that for the FDA purposes and we did. So, we conclude then that there is dose proportionality across the dose range of going from a 1x dose up to 4x in films.
Now, let me turn to the key study for NDA, the bioequivalent study comparing the BNX product with the Suboxone sublingual tablet. This was a large study done in 81 healthy volunteers and they randomly received either the BNX product or the Suboxone sublingual tablet. There were had – there were monitored carefully after each dose so that they did not swallow for as we long as possible after applying the sublingual tablet so, we try to get it optimized the absorption from the sublingual tablet as much as possible to compare us with the market standard.
It was a cross over study so everybody received both doses and in this study we collected both samples out for six days so we want to get a full characterization of the area and the curve so, we collected those samples out for 144 hours after each of the two doses. This was one f the key – this is the key bioequivalent slide right here. Test in this case is to be a next product, reference is the Suboxone tablet. With respect to the maximum plasma concentration, the test product produced a big concentration a 109% of the Suboxone tablet with respect to area on the curve around 95% so, very high bioavailability from the product both in terms of very end of the curve as well as maximum plasma concentrations.
Looking at the right side of the slide, the confidence intervals, the 90% confidence intervals you can see that we are well within the 90% confidence intervals for each of the three critical parameters for concluding bioequivalence. So the outcome from this slide is to Buprenorphine exposure from the BNX product is bioequivalent to the Suboxone 82 milligram sublingual tablet.
These are the results for the Naloxone component of the film and in contrast of the Buprenorphine there is much less Naloxone being absorbed from our product. Now we were not required to be bioequivalent on Naloxone, we can’t be more bioequivalent on Naloxone, we can’t provide more Naloxone than the Suboxone tablet does, less absorption of Naloxone, less Naloxone being absorbed is a positive thing because Naloxone isn’t opioid antagonist that can interfere with the effectiveness of the Buprenorphine. So, the fact that we found less Naloxone being absorbed is a positive thing and I think that helps the overall tolerability of the product and the confidence intervals, none of the confidence intervals except for the maximum plasma concentration even touched the 80 to 125 range followed by FDA.
So in conclusion then, we have bioequivalent of Buprenorphine exposure from the BNX product and significantly less Naloxone being observed from the BNX product. So, what’s that mean in terms of our NDA plan and timeline? Pre-NDA meeting is scheduled for May. We will review all these results with the FDA. Our clinical components are being completed as we speak. As I mentioned, we have one study ongoing that has one more treatment period to complete. It will complete not this weekend, but the following weekend. So, all studies will be done in this month and the entire clinical program will be completely written up by June.
The package insert is already been drafted and the REMS has been proposed for the FDA once we have had their pre-NDA meeting, we will make final modifications to the package insert and the REMS program to satisfy whatever FDA tells us and that will complete in June. The CMC section, the chemistry manufacturing and control section is the last component to complete that will complete in July and the NDA will be submitted immediately thereafter.
So, what are the benefits then of BNX versus the competitor? I think you have heard from Dr. Sullivan. I think you have heard from me some of the key features that have been reflected in the data that I have presented much higher bioavailability allowing much lower doses to be administered, so less potential for adverse events, less drug exposure. The BNX product adheres to the inner cheek within seconds. You don’t have to hold it under your tongue for an extended period of time, concentrate on not swallowing and avoid talking. So, we have a convenience factor that we believe is a substantial advantage over the Suboxone products.
Taste, Dr. Sullivan mentioned to you the taste problems associated with Suboxone product, we have limited exposure to the saliva because of the backing layer and because of the lower doses and a much better taste masking we believe. So, we have better taste masking as an overall benefit for the BNX product over the Suboxone tablet.
With that, I will conclude and turn it to Al Medwar, our Vice President of Marketing and Development to talk about the market opportunity for both BEMA Buprenorphine and BNX.
Thank you very much, Drew and good afternoon everyone. I had been asked to give a quick reminder that after this session, we will have a Q&A and you will have a pad and paper in front of you. If there were any questions you would like to direct to any of the speakers, please go ahead and feel free to write those down at the end of my session, we will collect those and we will start the Q&A session.
So, in the course of the next few minutes, I am going to cover a couple of different points. First, I want to briefly touch upon the opioid dependence and the chronic pain markets, and also talk a little bit about what we believe to be the future potential for each of these individual products, but before I get there, I introduce again BUNAVAIL. And thank you, Dr. Sullivan for already catching on and using the products brand name and we will have to work on Drew a bit to get that used regularly. But it goes without explaining that the brand BUNAVAIL comes from Buprenorphine/Naloxone and you heard repeatedly about the importance and the benefits that come from the higher bioavailability of the product thus BUNAVAIL. And I will say that it’s certainly a lot easier to write BUNAVAIL than it was to write BEMA Buprenorphine/Naloxone all the time.
So, before we go back to BUNAVAIL, I am going to talk for just a few minutes about the chronic pain market. As you know, the market for pain products is extremely significant. Sales are estimated to be in the range of $20 billion according to a study that was done by Decision Resources. The largest proportion as you can see here is the opioids which account for about 40% of the total. On the right hand side, it is projected sales in 2016. And what you see is the market size stays relatively the same as some of the products in certain categories go generic, but what’s of interest is the fact that the opioid category stays still the most significant portion of the market. And if anything it appears that it’s possible that this segment may actually gain in share because of the availability of new agents such as dual-acting opioids like Tapentadol and new agents like Buprenorphine.
So, despite the fact that we know that there has been increased scrutiny over the last couple of years regarding opioids. Opioids are still expected to play an important role in the treatment of chronic pain in the future. So, despite the available options, and Dr. Pergolizzi certainly touched upon this, there is an unmet need for safer analgesic options. There continue to be concerns regarding the cardiovascular and GI risks that are associated with the COX-2 inhibitors and also the effects related to NSAIDs. Both Dr. Sullivan and Dr. Pergolizzi highlighted the escalating problem associated with opioid abuse and addiction. And then finally, there are safety and tolerability issues, safety issues such as respiratory depression and then tolerability issues such as cognitive impairment and constipation which can affect the quality of life of a patient, particularly those individuals who are on chronic therapy.
So, BDSI conducted a marketing research study. It was a quantitative marketing research study. We included over 200 physicians both pain management specialists and primary care physicians who are high prescribers of analgesics. The current prescribing patterns of the participants were compared with the intended future use or the intended future prescribing in an environment where BEMA Buprenorphine was available for prescribing. And what the chart here shows you is the prescription volume that is projected to move or be gained by BEMA Buprenorphine.
Now, as you will see, hydrocodone clearly represents the single product, most likely to be replaced by BEMA Buprenorphine. And an interesting point worth noting, I think 2 million prescriptions lease projected from the research that we did that represents under 1% of hydrocodone use. And if you translate that less than 1% that’s represented here, that in itself is in excess of $300 million in sales. Also you see that there is a cannibalization from the schedule to opioids as well, and if you take those combined that leads to our estimated market opportunity for BEMA Buprenorphine for chronic pain, which is in the range of about $500 million.
Dr. Pergolizzi showed you the analgesic ladder, a bit earlier. This is the WHO’s analgesic ladder. In the findings from our marketing research helped to support how we expect BEMA Buprenorphine to be positioned on the market. Now, you can see the common stepwise approach starting with a non-opioid increasing to the addition or change to an opioid. And as pain either persists or increase moving to one of the schedule two opioids such as OxyContin or morphine.
Here is the area that we believe the product fits. And this fits based on input from physicians and from the marketing research we have conducted. Also its representative of what you saw in the last slide with physicians’ expectation, it would be used in places where typically hydrocodone was used. So, in the NSAID ladder, BEMA Buprenorphine fits in a position following non-opioids such as acetaminophen NSAIDs in patients who either did not get adequate response or in those individuals who had issues with tolerability. You can also see that it stretches a bit beyond that and also goes a bit into delaying the need for schedule to opioids and that’s something Dr. Pergolizzi also made reference to.
Now, as an example, here was sales of Butrans. In 2012, sales of Butrans exceeded $120 million. Now that product is still in its growth phase. It’s an impressive start for a product that we believe despite the novelness of Buprenorphine still has drawbacks due to its formulation. Now we believe with the BEMA formulation physicians will have the opportunity to more effectively titrate to the appropriate dose that the patient needs, it will also offer a much wider dose that will allow for treatment of the patients with varying degrees and higher degrees of pain and we also believe that something that will be well accepted and easy to use for patients.
Now as a matter of fact I am going to add that when we did our marketing research and presented physicians with both the concept of having Buprenorphine in a transdoral patch and in our BEMA technology we had a response in about two to one of those physicians preferred the idea of having it in the BEMA formulation. So, we think it will be well accepted in the market and certainly this is a good start and shows the interest that’s out there in Buprenorphine.
Okay, now we will move over to spend next couple of minutes talking about BUNAVAIL. And I think this has been fairly well covered and everybody recognizes that opioid dependence is a large and growing problem. There are over 2 million people in the U.S. who are dependent on opioids and fortunately there has been an increase in the number of patients seeking treatment given the awareness of opioid deduction less stigma, the availability of Suboxone which has allowed of course patients to be treated in the privacy of physician’s office.
Sales of Suboxone, the market has had one product so far to-date with Buprenorphine and Naloxone of course that’s Suboxone. In 2012 sales of Suboxone as many of you know topped $1.5 billion now it’s an increase of just over 20% in 2012. However, the interesting thing here is the fact that despite the amount of growth there still remains significant opportunity is if you remember from Dr. Sullivan’s slides if you add up the numbers of 2 million or more people with opioid dependence and the 250,000 or so that are believed to be on Buprenorphine that means only a quarter of the population with opioid dependence is currently receiving Buprenorphine which certainly leads an opportunity for the future.
Now how has it been used, you see the same growth in prescriptions in this graph. This is looking at total prescriptions by month originally as everyone knows the that Suboxone tablets were introduced late in 2010. Reckitt Benckiser introduced Suboxone film and Suboxone film has over a short course of time relatively taken over as the dominant form of Buprenorphine that is prescribed. Currently or let’s just as of January of this year 81% of prescriptions dispensed were for Buprenorphine film and the remaining 19% were for Suboxone tablets.
Now the importance here is as many of you know there have been the entry of generic Suboxone tablets. And the movement of this market to the Suboxone film helps in some ways to protect that market. So, how the physicians reacted to the profile of BUNAVAIL according against it’s a marketing research that we have done we talked to over 100 physicians in a quantitative study and physicians were asked about their interest in prescribing BUNAVAIL. And as you will see here the vast majority almost all probably were in excess of 91% of physicians expressed either moderate or high interest in prescribing BUNAVAIL and the output also suggested to us that somewhere between a quarter or a third or possibly more of the share of future use would be in the form of BUNAVAIL.
So, an important question that’s come up now with the availability of generic Suboxone tablets is what does the future for this market look like. I showed you what the market has looked like and looks like currently to-date it’s exclusively Suboxone branded up until this point, it’s a total of $1.5 billion size market and of that as I have mentioned the majority is Suboxone film.
Now with the availability of a generic formulation we believe a couple of things are going to take place. First of all the portion of the market that was previously Suboxone tablets, we expect will follow traditional generic erosion, which is in the ballpark or so of 90%. So, of that remaining less than 20%, we do expect that the majority of that would be converted to a Suboxone generic tablet.
Now, regarding the film, while we recognize that some patients may move to generic tablets we look particularly to those who maybe paying cash, which is in the range of 15-20%, so within our marketing research, we also did some work to get physician and payer perspective regarding the availability of Suboxone generics, and how it might impact their future prescribing. And from that they gave us an estimate of roughly 20% that we are assuming in our modeling is converted to generics. So, what do you end up getting in the future as you get a market that’s split about 60% to 40% branded to generic? And that branded market still stay very significant given that we expect growth rates, the addition of patients to continue in the upcoming years, and if growth continues at its current pace or even a little bit slower it’s entirely likely that with this split the market would still be in the range of roughly $1 billion, and as I mentioned in our marketing research if we conservatively say 25% of the share goes to Bunavail that results in the number of 250 million, which has been our working assumption for what we believe the potential for Bunavail to be on the market.
Now one other important factor, it’s certainly worth making mention here is the audience. We have a product that we believe has strong potential on the market, but it’s also a very appealing product for another reason, one of which is the audience who prescribes the treatments for buprenorphine treatments for opioid dependence is relatively small. There is a total of roughly 5000 physicians who are responsible for 90% of all prescribing. There is a relatively small audience that can be reached with a relatively limited number of sales representatives. Secondly, we already know Buprenorphine is well established and accepted as a treatment for opioid dependence and then there are limited competitors with Bunavail being just a second transmucosal film to the market. So in total that means modest sales and marketing expenditures are needed in this particular category and for that reason BDSI continues to explore its options. We continue to assess both the options of licensing Bunavail while also continuing down the path of assessing a means of commercializing this product on our own, which should we chose to do so.
So finally in conclusion, I would like to thank our excellent panel of speakers, hopefully their presentations had given you good insight into both BEMA buprenorphine and Bunavail, and the opportunity it may provide in the benefits it may provide to patients and their health care providers as well as enhance the future value of BDSI to our shareholders. And with that, I would like to move our question-and-answer Brian will be walking around collecting any of your questions. So, if you could please pass questions down to the end of the row and I will turn things over to Drew Finn to leave the question-and-answer.
Dr. Andrew Finn
Let me just take a moment here and introduce Dr. Genie Bailey who was introduced at the very beginning, which she did not speak. She was one of the top enrollers in our BNX safety study and opioid dependence and addiction specialist in physiatrist practicing in Massachusetts. I’d like to hear this just take a couple of minutes and describe her experience with the BNX film used in her population. The patient perceptions of taste ease-of-use and tolerability, could you take just a minute.
Dr. Genie Bailey
Sure, just to get to a little bit grounded and where I practice. I’m part of a treatment center that’s located in Fall River, Massachusetts and I am on the faculty at Brown, but work out in the third world of Fall River, and we have a very, very high concentration of cheap heroin. So, we have a heroine academic in our area and have for years. So, this was a beginning to do clinical research in opioid addiction was sort of no brain, once I started working there decade ago. We worked with several different kinds of companies we do not research and pharmaceutical research. So, when we approached by this company to provide a different alternative to our clients who are already stable on Suboxone, we had to thing about because we don’t really usually do that. We usually recruit from the community. This was actually taking a patient population that was happy with that they had or was at least doing what was available to them and offering them an alternative to try something different.
We like to go and proceed into involve ourselves from the study and we found that it was really pretty easy to recruit people. People didn’t come to us each week or each month in the Suboxone program complaining about the medication they are receiving. In fact as Dr. Sullivan has said many times, it saves their lives and when it’s been the thing that is helped to rebuild your life and reconnect with your family you don’t really worry so much about how it tends, like it, but you don’t have a lot of options.
So, when we said we got the study, it’s another alternative to same medication is just the different delivery system, which we didn’t really say is a different way of taking it. We have a number of people they jumped to it. So, we actually I think in the screening closed to 35 people and with timing issues and medication enrollment issues, I think we enrolled 25 of those 35 and 23 in my people completed. I think we ended up with like one must visit of the people who completed. So, we got our patients to enroll and we got them to show up and we got them to participate. And overall, people were very happy to at least the most neutral I got was is just as good as what I was doing and I had only one person that was in different and feel like they didn’t like it and they couldn’t really understand why he didn’t like it. He just was just in like the ideas taking something on the inside of his mouth. He preferred of having the tablet.
Generally speaking people found the delivery system easy to use. They found the taste significantly better. They said if it was available tomorrow, they would fight to get it. Unfortunately, my patient pollution is serviced by Massachusetts Medicare and Medicaid. So, it’s unlikely they would be able to get it right out the gate, but either as it may, they would want to be able to use a product. The other thing that did surface over the course of the study was the number of people who found that their constipation issues just went away just weren’t there. So it sort of follows the presentations that you’ve heard earlier, it’s the same story, a little bit more personal touch to what we did.
Dr. Andrew Finn
Thank you, Dr. Bailey. Dr. Sullivan, you were the highest enroller in the BNX-201 study and I’d like for you to comment if you will have a question, it says in the safety study how many patients we’re taking the 4x and 6x doses. So, can you describe what the distribution of patients in your database was for the study?
Dr. Greg Sullivan
The average dose of Suboxone in the United States is 14 milligrams, which is I guess one and three quarters, 8 milligram tablets and that’s the average for our office too. And we have specifically tried to distribute between the 8 milligram, the 16 milligram, the 24 milligram, the 32 milligram, because we were instructed the FDA wanted that. So, we had I guess almost perfect distribution between the four, but whoever asked that question must have wanted to know that I think most people were stick around that 16 milligram mark.
Dr. Andrew Finn
So, we had patients – the dose ranges the approved dose range for Suboxone is 8 to 24 milligram today but FDA asked us to enroll patients that were above 24 milligrams because they are an occasional patients that needs 32 milligrams of Suboxone and so we endeavor to address the FDA’s concern and did include patients that were actually taking more than the recommended dose by FDA and in fact those patients all entered and completed the study has and with the exception of one. So, very hard retention rate at the upper end 32 milligrams as well. I have some questions really on the Buprenorphine its pharmacology and I will turn this to Dr. Pergolizzi. Buprenorphine has ceiling on respiratory depression what causes the LD50.
Dr. Joe Pergolizzi
Right, so those standard type of preclinical model testings will have certain metrics that you’re going look for on the LD50 platforms and so there may be different reasons why you have mortality related to these animals. They could be – could cause any of the reasons I can get you the report if you like.
Dr. Andrew Finn
Another question to me in the BNX randomized withdrawals that it wasn’t or let me correct hear that it’s I think you were talking about the safety study, the BNX safety study how many patients were also Suboxone tablets and how many were also Suboxone films. Interestingly the distribution of patient entries was identical to the marketplace about 65%, 70% of patients came in from the films and about 30%, 35% from the tablets. So, was it completely reflective of the patient population that Al and Dr. Sullivan described? There is another question for me in the fourth component for the BNX clinical program the liquid effect study what we need to show in this study.
This is simply a descriptive study really for package insert labeling. When can you take liquids along with the BNX film, what you need to advice the patients to do either to avoid films or to avoid certain time – type of – I’m sorry avoid a liquid or a certain type of liquid during the period that the film was residing inside the mouth. We have felt to do this study before for FDA, it’s a typical study really just has to do with characterizing your product, so they can write their label properly. So, it’s not a show stopper, it’s just something we have the complete and its on as I said well underway.
So, maybe I can ask Dr. Pergolizzi this question, it’s from the – for the BEMA Buprenorphine program one of the clinical trials favor opioid experienced patients over opioid naive patients in terms of assays sensitivity.
Dr. Joe Pergolizzi
In the regional studies that were presented.
Dr. Andrew Finn
In any study that’s being done on the opioid experienced population why do they favor assays sensitivity over the opioid naive population.
Dr. Joe Pergolizzi
This is really a good question. I think that when we look at the opioid naive patients, usually its issues related to tolerability in the early phase of titration compared to and maintenance. So, adverse events of tolerability compared to the patient who maybe opioid experienced already has some type of a combination of tolerance to those side effects.
Dr. Andrew Finn
Somebody asked for them enrollment update on the ongoing Buprenorphine chronic pain program. I can’t give you any more information, the rest of it’s confidential at this point. We are still – we are forecasting that both studies will complete at the end of this calendar year or the beginning of next year and that at least one of them read out in 2013. The next question is when comparing the BNX versus new film version of Suboxone how does that alter the benefits of lower constipation and improved taste. I think I will ask Dr. Sullivan to respond to that question given that you addressed it already in you representation.
Dr. Greg Sullivan
How does the absorption affected…
Dr. Andrew Finn
How was Suboxone film version you expect any differences in the adverse event profile and then Suboxone film versus the tablet and the benefits that we’re describing for BNX but they still exist in film market.
Dr. Greg Sullivan
The film was developed to try to mimic the tablet absorption, so there is low vial availability of the film and tablet of Suboxone and there is roughly the equal amounts of Buprenorphine to make it to the colon. So, no there is no difference is the short answer. And what was another question on that.
Dr. Andrew Finn
So with respect to the…
Dr. Greg Sullivan
The film and tablet would make any difference I think they would both have the same incidence of constipation.
Dr. Andrew Finn
So, you wouldn’t expect really any differences, but the data we have from patient population that was largely film patients, so indeed they came in with a certain number of them already having constipation at the beginning of the study and very much smaller number at the end of the study. So…
Dr. Greg Sullivan
Now the film studies were done to try to mimic the absorption in the validity of the tablet. So, you think that there will be exactly the same?
Dr. Andrew Finn
Question is about the what the details are regarding the delay between the completion of the studies and the filing of the NDA there is not really a delay it’s a certain amount of time that’s required to prepare a pre-NDA meeting package schedule an NDA meeting with the FDA and then complete the integrated summary of safety across all the studies. So, even though the clinical trials complete the placebo control study is complete, the long-term safety study complete, we have to integrate all the safety data together to present that to the FDA that takes some months to do. So, the combination of those factors is the reason for the delay into the second-half of 2014. There was a question here for Dr. Sirgo, talk about the Endo partnership, change of CEO and impact on the partnership.
Yeah, sure I, first of all it’s good that they made the decision. I think they made a very good choice I think the market accepts that as a very good choice. And the good news I think is that happened sooner than they were predicting it would happen. I can’t speak to how he is going to manage the company going forward, but I think it’s a thoughtful individual. I think he will look at the various business components and make decisions as needed. I think it’s safe to say that the biggest margin business that they have is the branded pharmaceutical business. We’re pretty much their only product in their pipeline. The partnership has been fantastic. I’m sorry to say in many respects what’s happening there at the senior level, but having said that in the working levels and Drew can attach to this it’s been a tremendous partnership. I am sure there is a little anxiety among everybody there is it sorts out, but we weren’t really know it during our interactions with them. We have a great joint development committee that meets once a month project team meetings media – project teams meet every, as Drew pointed out the program is going exceptionally well with enrollment. So, I don’t really think I think it’s going to skip.
Dr. Andrew Finn
Could you comment on their commitment to the pain space?
Yeah, I think again it goes on it goes without saying they are still very strong, very strong presence probably one of the best seen pain sales forces in the business they have had some pressure obviously with Opana and with Lidoderm but it seems to be working through the Opana situation pretty nicely. And again our product is not really that far away from we had hoped to be a successful NDA approval. So, it think they are still committed there at least the price that changes.
Dr. Andrew Finn
I can test it to what Mark said that the cooperation with the Endo project team is tremendous, we’ve got a wonderful large project team we share the responsibilities and divide and conquer. And so we’re all committed to the same goals and working hand in hand to ensure the responsibilities in the – and get the job done. So, it’s been a great partnership to-date. I have a question here for Al if 25% is your conservative assumption of BUNAVAIL market share what are your high end market share estimates?
I mean high end I would love to see it would be 100. But realistically the way we have looked at it is that we did the marketing research with physicians and we have also worked at other products where there are multiple products moving into the marketplace. And generally we tend to see is that a product in our position would generally be somewhere in the range of 25% to 35% market share, so that’s been our working assumption.
Dr. Andrew Finn
And then a follow up what size sales force if we chose to market BUNAVAIL would you need?
Well, we’re in the process of looking at that and doing the work. So, we haven’t defined a number but with 5000 physicians typically if you estimate that a representative can cover effectively 100 to 120 individual physicians in their territories then you’re looking somewhere in the ballpark of 40, 50, 60 or so sales reps and that’s at least our early working assumption that its in that ballpark which in general is a relatively low number especially for a market of this size.
Dr. Andrew Finn
And then a follow on to that what kind of pricing do you expect to have on both products relative to the competitors?
At this point in time we haven’t done the pricing research, so it will be premature to make any statement on that. However, what I will say is that we feel like we have benefits here to the patient and to the healthcare practitioner and that’s we would expect that both of our Buprenorphine products would be priced in a range similar to competitive products.
Dr. Andrew Finn
A question for Dr. Bailey, question has do with the number of patients that are treating – you are treating in your practice if the most approved doctors are approved for Suboxone 99 patient limit or 100 patients, why do you only have 70?
Dr. Genie Bailey
Well, because right now I have others that are involved in research, I have other patients that are on Buprenorphine that are involved in research studies. And I have to keep my slots available for people that are being enrolled in that program and being sent to me. So, it’s logistics I mean it was up to 75 then it goes to 68, then it goes to 72, then it goes to. So, people come in and out. I don’t max it out at 60 that’s just is what was going on the day I wrote the vial. But the other individuals at our clinic are sitting at 87, 88. And I think last week it was 72 for one person. So, we are trying to enroll people as the slots open up, but on anyone day we might have signed a discharge order and we can’t and that’s somebody that instant. So, the FDA requires us to keep a pretty close or we just do anyway at our center a really pretty close tabulation.
Dr. Andrew Finn
So, Dr. Sullivan, do you think the government may due to the 99 patient cap that you have currently based 100 patient cap?
Dr. Greg Sullivan
I think if they change that it will be a vial that you might think in your mind how you would do that, I think the government wants to change it and reduce and eliminate the cap completely so the physicians can treat as many they want. But if you’ve been involved with Suboxone treatment at all you know that for a certain number of the clinics just essentially prescribe it what they call back door step so they essentially writes the prescriptions without any treatment. And they are trying to figure out how to limit that should be people that are board certified in addiction medicines, should it be people that are perhaps some other form of certification such as the new REMS certification after all having doing also. I think they want to I just don’t think happen for at least a year the removal that is.
Dr. Andrew Finn
We have another question regarding what’s going to happen following the Phase III program to the NDA in the BEMA Buprenorphine chronic pain program. Again just to be clear we are completing the pivotal studies at the end of the calendar year the first of 2014 it will take some time to write those studies up. We have to produce an integrated summary of safety across all the studies that have been performed that too takes a significant period of time to integrate all the databases from the trials. We have to present that information to the FDA at a pre-NDA meeting. We have to get agreement on the FDA as to how to complete the NDA all those things just take time. So, it’s you have to request the pre-NDA meeting 60 days in advance. So, there is a time lag between the time you request and the time you are actually going to have the meeting. All those things just add up to several quarters before you can actually submit the NDA.
Was – and the question was the approval of Suboxone film based on demonstrating bioequivalence to both Buprenorphine and Naloxone. And the answer with the question is no. They were to achieve exposure to Buprenorphine that was supposed to be bioequivalent to the tablet, it was not bioequivalent to the tablet. And then Naloxone exposure from the film was substantially greater than you see from the tablet. So, it is not bioequivalent to the tablet, yet it was approved in 2010 I believe.
Why is it different for BNX, why don’t you need to show bioequivalence to Naloxone. They didn’t have to show bioequivalence to Naloxone either in fact their Naloxone exposure was better; it was greater than you see with the Suboxone tablet. FDA – the Naloxone is only included as abuse deterrent feature, it is not included as a therapeutic entity. So, having absorption of Naloxone is not a desired feature, having low absorption of Naloxone is a desired featured that’s what we have in the BNX product it’s lower than you’ll see with Suboxone tablet.
Dr. Pergolizzi, do you believe we need yet another opioid in the market and how do you expect the market to evolve?
Dr. Joe Pergolizzi
Yes. So, I think we need to explore continued options in the form of this would be a repurposed opioid. And so it’s not a new chemical entity, but a new chemical entity would be welcomed as well. Why we need that is because of various variability that exist between patients and to have this particular molecule in this particular delivery system I think will allow us to provide yet another option of proven effectiveness and safety. I think my colleagues have shown a lot of data on addiction and deaths etcetera related to opioids. And a lot of that data, the (indiscernible) data that was out there and there was a lot of discussion about it, but it’s very I think difficult to look at those deaths in isolation of just an opioid alone. A lot of those deaths take place. And again, they are not pain patients per se this is overall deaths related to a diversion too. And they are also related to concomitant use of alcohol and other types of centrally and respiratory depressant agents. So, I think the data was something that we definitely need to look at, but at the same time, I think we have to keep in mind that chronic pain is on the present and that these agents are helpful and effective to get people back into activities of daily living and functionality and quality of life that is needed. So, yes, I think we do another option I think that this particular delivery of a well-established product with reproducible efficacy, effectiveness, and safety as well as a low abuse potential should be very well welcomed in the chronic pain space.
Dr. Andrew Finn
I guess, this is a question to I’d be interested in Al’s view, Dr. Sullivan’s and Dr. Bailey’s views on this, why do you think only, well this is Al’s specific, what do you think only the cash payers will switch to generic?
Well, it’s not necessarily to say just the cash payers would be the ones to convert. They just tend to be those that are a little bit more likely since there is a greater impact on them or greater advantage if they were to convert to a lower-priced generic product. Now, we have done quite a bit of work along with payers to get an understanding of how they may deal with the availability of Suboxone tablets. And the main point that has come across at least to us as if this is a category where they are not looking to take stronghold in managing this particular lower tier which means that different co-pay for the patient. There are programs that can be put in place, for example, I believe that Suboxone film actually has a program where they helped to offset that co-pay, so that there really isn’t much of a difference for the patient between a generic product and a branded product and they can pick the product that is most suited for their needs.
I think another driver is really going to be around what works and what the patient prefers and that really maybe somewhere where either Dr. Bailey or Dr. Sullivan can give their perspective on really how do you feel the interaction will go with your patients upon the availability of mal over generic.
Dr. Genie Bailey
Well, it’s interesting because in Massachusetts we only just within the last few weeks have been able to provide our patients with the Suboxone film through the math Medicaid product. So, people have been converting over at various points beginning January 1 up until even now some were still not providing films. So, we have been using tablets all along. And as I have been shifting and people have been just sort of forced to be shift as they go to the pharmacy to pick up their medication they are not sure what’s going to be in the bag. People have – it’s about 50-50 I mean some people like the films, some people wish they could have their tablets bag. Mostly, it’s around preferring that it does dissolve faster and it fixes and some I missed just what you know.
So, in the transition from tablet to film in that case I mean it’s about 50-50. So, if you are wondering would they go back to generic pill or will mass health sort of forces to go back to generic pill versus film I think that’s up in the air. I think the safety data around pediatric exposure was the other big driving force that we can looked at and couldn’t overlook. The number of pediatric exposure is not all resulting in death, but certainly resulting in hospitalization, ICU, various other medical interventions that were necessary because the children were exposed to the tablets has really been the driving force for the development of the film because the films really have to be able to peel open or cut the foil pack that it’s stored in. So, the risk to pediatric population goes down significantly. If the generic pill is packaged in that same way then you have eliminated the pediatric exposure risk, but if it’s not you are still dealing with the pill bottle versus a fully wrapped container that requires sometimes even scissors to get into it. So, we are (giving) forth for the safety of our patients and their children, so I think for me it is – the equation isn’t quite clear about what we would do generics and what my choices would be frankly. But you have a different population you have a lot more people who have their own insurance plans that give them options.
Unidentified Company Speaker
I think the fact that Buprenorphine has been available for generic for how many years, a lot of years.
Unidentified Company Speaker
Lot of years.
Unidentified Company Speaker
Lot of years, and it has curbing from around 15% of sales, is that right. That speaks to something there is patients don’t ask for generic, insurance companies don’t ask for generic. They go with what works. The conversion other than I guess Massachusetts for probably good reason has pretty much converted to the film for the pediatric exposures and the several pediatric deaths that occurred in 2010 and 2011. And people like the film better they like the film better. So, I think that the Suboxone tablet mark will be eroded by generics if the generics were half way decent remember that generic Subutex was not. And so the journey is still out with regards to these two that are coming out. And the film market I think will be protected for at least a few years until someone comes up with the generic tablet that really works.
Dr. Andrew Finn
So, I have one follow-up question there won’t payers like Medicaid force doctors to switch to generic tablets from Suboxone film?
Unidentified Company Speaker
It’s a little hard to give any precise answer other than to see what may take place here I think there would be instances where there maybe further push to start with the tablet, but I think the ultimate goal is this is a – this can be a deadly condition. And for that reason compliance is really a critical part and some of the differences between the tablet and the film formulations I believe play an important role in compliance. Now we have also gone and looked at some other analogs and tried to look at other market segments where a similar situation occurred and one is one that we are actually very familiar with which is the transmucosal fentanyl market and thinking back to that the original formulation. So, we are talking about opioids, we are talking about transmucosal delivery. There was originally Actiq in the first formulation that was a moderate interest to patients not the perfect means of delivering fentanyl and Cephalon introduced Fentora tablet as a new and improved means of delivering fentanyl. A lot of the same dynamics happened. They have raised the price of Actiq they were very active in their promotion to push as much of the business over to Fentora as they could. And they were relatively successful for a period of time in doing that then the generics came. What happened was Actiq existing Actiq branded product went 90 plus percent generic and Fentora had very, very little impact on it’s use, so ultimately what happened was as even Dr. Sullivan was just saying the product that the branded product they’ve got the generic was eroded while the newer formulation maintained its share actually the share of use of Fentora barely even changed.
Dr. Andrew Finn
You mentioned a point about compliance and I would like to ask Dr. Bailey and Sullivan to comment on compliance with the Suboxone films, have you experienced any problems with compliance in this patient population?
Dr. Greg Sullivan
With drug addiction there is always problems with compliance. I mean that's the disease they were treating. But I think that what you maybe thinking is just the taste or the constipation may have some problems and I think that the statistics were correct around 21% of people just think Suboxone is terrible and will do anything they could to not take it and 30% of patients have severe constipation that limits their ability to take it, so there will be increase compliance on the new products with that have changed that bioavailability completely.
Dr. Andrew Finn
Dr. Bailey, can you add anything to that?
Dr. Genie Bailey
I don’t think, so I don’t really – in my experience with the film right now it’s been so limited. I don’t know I think that originally when the films came out as at least we were told by the representatives that there were going to be sequentially numbered and there was a going to be a bar coding would be able to help to track and make fight against diversion that’s sort of hasn’t rolled out into the pharmacy. And the only way that we can do it is if we have the patients get the film box and come back to the office and have all their films Xerox, so we see the bar codes and we see the numbers ourselves. And that just hasn’t – we just haven’t maneuver operationalized that.
So, I haven’t seen the films really be able to fight diversion as much as I think we had all hoped that they would and maybe still could and whether people divert the films or smoke films more than they snort or do other things with pills, I haven’t heard that there is any difference. I think that this is population that we treat and we work at it. But people could technically be asked to bring back and their open foil tablets and open foiled wrappers and you could have identified that they themselves had in position those films through that month as opposed to pill you can’t do, we do pill counts every time they come, but we know people who come in with pills and are off by two or three and well its at home and the pill counter or I – you do what you can to make sure that they are using the medications as prescribed and you haven’t placed regular pill counts, you haven’t placed random pill counts, you haven’t placed random and regular urine toxicology. But if individuals are going to need to sell it to their neighbor to keep their neighbor from going into withdraw they are going to sell it. And they’re not going to putting themselves in withdrawal, so they are not going to sell more than they need to protect themselves. But if they are not going to watch another addicted individual be sick either, so.
Dr. Andrew Finn
Thank you. I will comment on the track and trace it’s our attention with the BUNAVAIL to have track and trace technology on the film packages. So, we will be able to track down to the film level when they are dispensing where they go through the system. So, we will think that hopefully will be an attractive feature for the prescribers and the healthcare providers. With that I think our time is up now I’ll turn it to Mark to close.
Yes, sorry I know we didn’t get to all the questions here there are a lot of that really, really good ones, we’ll try to get a crossed section of the once that were submitted to is here. We will all be here for a while afterwards, so if we didn’t get to a specific question you want to answer please try to seek us out, we will be happy to do that. Otherwise we really greatly appreciate your attendance here today and I’m hopeful that you walk away you – a little bit more knowledgeable about these two conditions in our products that when you came. So, thank you very much.
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