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[Music] it is my pleasure today to welcome our speaker to share her expertise and knowledge about current available ph drugs and new drugs in development dr anna hemnes is an associate professor of pulmonary and critical care medicine and the assistant director of the pulmonary vascular center at vanderbilt university medical center dr hemnes thank you so much for being on with us today thank you so much jill for that kind introduction and it's really an honor to be speaking for uh before this audience today in this virtual format so i'm going to be talking about drug discovery and development today and the first question is what is drug development and discovery well it's the process of discovering and testing a possible new drug and bringing it from the laboratory to patients the goal of this entire process is to bring new therapies to patients that are both safe for the patients to take and also effective for patients in the disease that it's meant to be treating there's all kinds of people who care about this um and they're we call them stakeholders and they include scientists um people in the pharmaceutical industries the fda and of course patients um and everybody has their own important role to play and uh has their own interest in the drug development and discovery um and uh so it makes it a very complex process and it's time consuming and it's costly and somewhat hard to understand so i'm hopeful that we'll debunk some of this today for you so this is an overview of the drug discovery pipeline the first step is is just discovery of the compound itself so most of the time this is the show sort of the average experience of bringing a drug to market in this figure and most the time you have to screen at least 10 000 if not even more compounds to see if they may be effective in um animal models or in cell culture or other what we call preclinical models of diseases and these studies can take a very long time um here is shown on average taking about six and a half years but certainly some are even longer depending on the model system and how and how fast it can be studied and then of those those 10 000 or more compounds are initially screened and then on average about 250 compounds will make it through uh preclinical testing ultimately only about five compounds of those initial ten thousand will make it to clinical studies to ultimately produce one compound and these clinical studies take on average six years we're going to go through a little bit in a sentence in a minute the the phases of studies that occur in these clinical tests um but surprisingly they take a long time so by the time that this is all done you can see in the bottom there's you know about 14 or 15 years that can occur to bring a drug um actually to a consumer from its initial uh study in the lab and so in the clinical phase of testing and we talk about three main phases the first is phase one um in which a drug is tested for the first time in people and the goal of this is to see if the drug is even safe at all in people the second phase is phase two and it includes patients whereas phase one for the most part is focused on healthy volunteers phase two includes patients and tests for safety and efficacy and um efficacy may not be um it may be for instance in pulmonary hypertension it may be um markers of efficacy based on uh right heart catheterization data um as opposed to what is usually used for pivotal trials like six minute walk test um so there it's a smaller study than would be normally a phase three study and is still again looking for safety in that specific disease population and whether there may be any signal for efficacy in that specific disease population and if a drug looks promising at the phase 3 2 level rather then the next step is to do a phase 3 trial and usually this is a much larger group of patients that would be included in phase 2 because at this point you think the drug is likely to be safe and you feel confident in exposing more patients to the drug and this phase 3 trial will compare usually the new compound with standard of care and it further tests in a larger population safety and efficacy now the critical thing is that the drug needs to be efficacious so it has to actually work to improve the disease to pass this final phase 3 process once drugs have passed this phase 3 process and have been able to show safety and efficacy then they can be approved by fda review which is what happens in the in the united states and then the drug can come to consumers and then frequently um we will perform what's called phase four studies where patients are enrolled either in new indications of a study of the drug rather or observational studies to see what happens long-term with drug exposure and these are designed to show the long-term safety and benefit of this compound in this disease specifically so these are the general um phases of of drug discovery um and you can imagine this is um tamp really time-consuming and um takes a lot of um expense and and time like i mentioned so what are the kinds of questions that one can answer through clinical trials well probably the most important thing to answer and the first question is the drug safe in humans because we don't want to give a drug and harm people um so we need to really be careful and define what are the benefits and risks of drug exposure so the first is is it safe and can we tolerate whatever side effects or or potential downsides might occur after administration of the drug so if the drug's safe that's great but nobody wants to take a pill every day that does nothing for them so the next question is how effective is this drug and does the drug improve the disease of interest and each disease will have a specific measure of that improvement frequently in pulmonary arterial hypertension specifically studies will look for efficacy using six minute walk distance so the patient could walk further after drug exposure than they could before drug exposure but sometimes we also look at um staying out of the hospital and surviving longer or not having to escalate from oral therapy for pah to um parenteral things like iv and subcutaneous medications other questions that can be answered through clinical trials is like what's the best method to deliver the drug um is it oral is it inhaled is it iv and what dose is best so a lot of trials will have two different doses of drug and lastly we a couple of other questions we ask is does the drug compare to current standard of care this is particularly important in pulmonary hypertension trials you have to define what the current standard of care is and then see if the drug is beneficial compared to that and then we do start asking ourselves which patients will benefit from um the from this medication and are there a specific group of patients who drive a benefit from this and a specific group of patients who do not who therefore shouldn't be exposed to this drug so these are kind of questions so the goal of drug discovery and development is to bring new treatments to patients that are safe and effective and like i mentioned in the last slide the process is really complex it's time consuming and it's extraordinarily expensive unfortunately so let's talk about how pulmonary arterial hypertension impacts blood flow this slide is a really nice slide of the what we think of as the pathology in the pulmonary arteries of patients with pulmonary arterial hypertension and how they compare to normal so in the far left you can see a healthy pulmonary artery and you can see that there's um names to the things that are in the wall of this pulmonary artery it's like as if it was cut sliced down the middle there's the adventitia the media and the intima and you can see this in cross-section down below and in a normal pulmonary artery they're they're healthy they're flexible and blood flows easily without without any restriction or resistance through this pulmonary artery in panel b which is just to the right of that in mild pulmonary arterial hypertension the artery you can see that the wall of the artery is getting thicker than it was in a healthy pulmonary artery and it limits blood flow and increases resistance but there is still blood able to get through when we look at c uh moderate pulmonary hypertension you can see blood flow is restricted the wall is even thicker than it was before and and you can see in the cross-sectional view in the bottom that it's hard for harder for cells to get through there um and it creates a lot of resistance and then d is uh described as severe pulmonary artery hypertension with plex form lesions and plex form lesions is this sort of outgrowth looking thing that's in the artery at the bottom um and it is really a hallmark of severe pulmonary arterial hypertension oftentimes there's blood clots in there because the blood can't flow normally through there and we think the plexiform lesion may perhaps be some way of of the body's attempt to open up that artery and improve flow um and so these are the this is the pathology that we are really trying to reverse in treating pulmonary arterial hypertension so let's talk about the many pathways that regulate pulmonary hypertension disease progression it's um this is an area of active research uh all over the world and people are trying to understand which pathways um should be targeted there are several that have been described thus far but i'm supposed to say that if i gave this talk in five years we might come up with some other ones that are not here so uh prostacyclin is opens blood vessels and helps them widen and relax nitric oxide this is a very potent signaling molecule that has a very short half-life and um it signals blood vessels to relax like i said endothelin is signaling blood vessels to tighten up when it's high particularly and also to constrict so that it signals the muscles to essentially flex angiogenesis um so this is talking about stimuli that make new blood vessel growth and can be important in pulmonary arterial hypertension growth factors are things that regulate cell growth and enhance or tell cells to turn over more frequently or divide more commonly inflammation is things that promote an immune response like recruiting white blood cells to come to an area and fight off an infection or in this case just to come to the to the blood cell neuro hormonal activation includes signaling for blood vessels to relax or constrict and can regulate blood pressure in the body and the rest of the body not just the pulmonary artery cellular metabolism is really important in pulmonary hypertension um it's how energy is generated for cells and is definitely altered in pulmonary hypertension extracellular matrix is talking about the parts of the vessel wall that are remodeled and cause them to be tight and stiff bmpr2 signaling is really critical to pulmonary arterial hypertension um it is known that patients with heritable pah frequently have mutations in bmpr2 which is a gene and also the signaling in this pathway is altered in almost all forms of pulmonary arterial hypertension and it regulates vascular remodeling and is an area of intense study calcium signaling um is uh regulates blood pressure and also tone of the blood vessel so it regulates how tight the muscle cells around the blood vessel are constricting so the pathways that are currently targeted by pah drugs include the three that you see here prostacyclin endothelin and nitric oxide so nitric oxide we'll talk about first there's uh there are therapies that address this it's clear in pulmonary eternal hypertension that there is too little nitric oxide present in the blood vessel and what nitric oxide does is dilate and open blood vessels in the lungs we call it a vasodilator and there are medications that increase nitric oxide that are um fda approved for pulmonary trial hypertension and these include uh pde5 inhibitors or soluble guanolate cyclase stimulators and you may know these by the names tadalafel sildenafil orbio say watt and you can see the brand names to the right another common problem in pulmonary hypertension is that there's not enough prostacyclin and so that's led to drugs that target this prostacyclin pathway and prostacyclin dilates and opens blood vessels we call it a vasodilator also medications that target this pathway and increase it include prostacyclin analogues um including tree prostanil that can be oral subcutaneous iv or inhaled um celexipag which is an oral prostacyclin receptor agonist ilocrost which is an inhaled form of uh prostacyclin and evaprostinol which is an intravenous form of prostacyclin [Music] and then lastly it we have found that patients with pulmonary trial hypertension have too much endothelin present and um endothelin is a very potent message to blood vessels to constrict and so what these drugs do is essentially try to try to block that signal and they reduce the effects of endothelium we call these endothelin receptor antagonists and you can see there's three that are approved macintentin bostantin and amber santan the current pah therapies i mentioned this a little bit on the last slide can be uh delivered in several different ways so there are oral treatment options um these include all the endothelin receptor antagonists amber santan bosantin and acetantin they also include all the phosphodiesterase type 5 inhibitors sildenafil and tenalophil and then there's now prostacyclin analogues that are available orally including oral true prostanel or selective ip receptor stimulators again targeting the prostacyclin pathway including solexapeg and then in the nitric oxide pathway our soluble guanolate cyclase stimulator rio cigua there's inhaled options for treating pulmonary hypertension and these are both in the prostacyclin pathway and they include ilocrost and inhaled through prostanyl subcutaneous treatment options are the prostate cycle and analog triposterone and then iv treatment options are uh two forms of eeproprostenol the old-fashioned um flowland and then uh the room temperature stable kind that goes by the brand name valatri and then there's also intravenous true prostanel so that's what we have presently in our tool kit for treating pulmonary arterial hypertension but we recognize that we need to continue with drug development and discovery in order to find more effective therapies and so there are many clinical trials presently underway for pulmonary hypertension in fact there's 48 phase 2 trials and 26 phase three clinical trials in progress and you this is not a surprising ratio because as we showed in the earlier slide um many many trials many compounds don't make it out of phase two trials because they don't appear to be safe or effective in in the disease of interest so there's always going to be more phase 2 trials than there are phase 3 trials and the present studies are targeting endothelin prostacyclin and nitric oxide pathways and um they're looking for safety efficacy and dosing long-term treatment combination studies and pediatric studies so they're using drugs that we already know but trying to understand them in different populations that we have not previously studied or that we don't really know like how long treatment with a specific combination of medications may be useful or could these drugs have um utility in treating pediatric pulmonary hypertension so let's talk about some clinical trials that are underway um that are addressing new pathways so there's new biology processes they're under investigation so uh we talked about several different pathways um on our pathways of pulmonary hypertension slide but and as i'm sure you saw many of them were not in fact addressed by the present drugs that we have so inflammation is one of those cellular metabolism is another growth factors uh bmpr2 signaling neuropeptide signaling angiogenesis so all of these are presently under investigation in clinical trials um for pulmonary hypertension and then the other important area of research right now is studies in patients with pulmonary hypertension for um that is not uh pulmonary arterial hypertension so folks that have copd and pulmonary hypertension or significant interstitial lung disease perhaps from scleroderma and pulmonary hypertension sarcoidosis and idiopathic pulmonary fibrosis is also an important area of research with associated pulmonary hypertension so you can see on this slide although the top three prostacyclin endothelin and nitric oxide were have and are presently addressed by our current fda approved drugs there's all these other pathways that um have yet to be addressed and offer hope for new therapies that may um offer more more benefit or more more efficacy in treating pulmonary hypertension now we're going to talk about sort of challenges in ph drug development so um there are real challenges in in the drug development for pulmonary hypertension so the first issue that comes up really commonly is that there's going to be limitations to clinical trial enrollment because the population is small and of course pah in particular is an orphan disease so there's a limited number of folks that can enroll in these trials one of the major solutions that we're using now as a community is newer clinical trial designs and adaptive designs um to address this so that we can really take advantage of people that can and are willing to participate in research to make the most of their uh contribution to the clinical trial the second is that better clinical trial tests are needed um and to sort of clarify this they we need new outcomes for instance or things that we can detect response to therapy so we're hoping to just define in a shorter term if a drug is working in patients so that patients don't have to be in a trial for years and years and years they can be in a trial for a shorter period of time and these clinical tests might be um better measures of improvement in the pulmonary vascular changes that i showed you earlier it could be changes in a biomarker that's in the blood or something like that but that's an active area of research we'd like to have studies that are more predictive in animal models so that we don't have to perform a number of phase one and two clinical trials in particular and drugs that are unlikely to be effective in humans and so we're working in partnership with basic research and patients who are donating various tissues and blood etc to have better pre-clinical models of disease and we really need an improved understanding of pulmonary hypertension biology to target new biol biologic processes for drug discovery and this really is where we're trying to advance pulmonary hypertension research and learn more about pulmonary hypertension biology so understanding really basic mechanisms of how disease starts in people to see if we could impact that or understanding how we can make disease better using novel pathways and these really are sort of some of the most basic experiments and research that we do involving the best preclinical models that we can so you might be sitting there saying gosh this sounds really important i would like to participate and and here are some ways that you might consider participating in drug development the first thing to know is that patients are really crucial for drug discovery and development success um without patients we cannot know if drugs are helping in that population so um i as a researcher and as somebody who cares for patients with pulmonary hypertension i'm so appreciative of all the patients that i have taken care of over the years who have donated their time and ex and you know participated in these trials accepted the risk that's involved in that i think it is really a tremendous gift to give um to all the future people who may unfortunately suffer with this disease um there are a couple of ways that you can participate in research um one is you might be interested in participating in clinical trials so these are like trials of drugs in humans to see if the drug might work and probably the best way to do to see if this is available to you is to talk to your health care team and see if they're offering any studies and if they might be right for you you can also look at an online tool here you can see the website that the pha runs it is a clinical trial finder you can look at some of the um uh registries of clinical trials also so if you go to clinicaltrials.gov which is shown here you can search pulmonary hypertension and see um what trials come up and the inclusion and exclusion criteria are posted there and then um if you're interested in learning more about pulmonary hypertension research and clinical trials there are some really nice pha classroom videos um and the link is shown right there and i think that would be a really great place to start to learn about what's involved in research i think it's also important to recognize though that not all pulmonary hypertension research is just as drug trials there are people myself included who actively used for instance blood samples or tissue samples to study pulmonary hypertension and define what causes disease and to try new interventions so you may be able to qualify for these research studies also um and uh the other option is to enroll in the pha patient registry which helps us understand um what happens to patients across their journey in pulmonary hypertension so there's many ways that you can participate in research that are that are not just simply uh clinical trials if clinical trials um you're not eligible for them or you're uh don't feel comfortable with that then there are there are still mechanisms for you to participate in this and for folks that are family members and caregivers out there um a lot of times healthy volunteers are necessary um for either phase one trials or as comparators for the blood and tissue based studies so you too can can participate and you might be able to talk to the ph clinical team about how that if that's available to you so um to talk again about the pipeline that we have here um you can see that there there were so many many thousands of compounds that were screened only 250 really looked like they might um or were mated to pre-clinical models like in rodent uh models about five compounds made up two clinical trials and then only one uh per that ten thousand made it to fda review um the drugs that we presently have are targeting the nitric oxide prostacyclin and endothelin pathways but there's a number of drugs that are in clinical development that you um could see on the previous slide and i think now will be time for us to move ahead [Music]