Theravance Biopharma, Inc. (TBPH) Earnings Call Transcript & Summary

Good morning, and welcome to the Theravance Biopharma KOL event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Theravance website following the conclusion of the event. With that, I'd like to turn the call over to your host, Rick Winningham, Chairman and CEO of Theravance. Please go ahead, Rick.

Thank you, operator, and welcome, everyone, to Theravance's first-ever ampreloxetine dedicated investor event. We're very excited to have you join us, and we believe we've got a terrific agenda to share with you today. Now turning to today's agenda. I'll begin with a background on Theravance ampreloxetine and the exciting opportunity we see for this medicine to make a difference in patients' lives. After that, we'll move forward with a full agenda led by presentations from 2 highly distinguished [indiscernible] disorder specialists, who will discuss the important unmet need in MSA patients with symptomatic neurogenic orthostatic hypotension and the evidence supporting ampreloxetine's potential to address the disease. I'd not always like to thank Dr. Kaufmann and Biaggioni for their participation in this event, but for their many contributions to the field of dysautonomia through the years. It's the dedication of individuals such as these that enable advances in the field of medicine in rare diseases like MSA, that might otherwise not take place on behalf of those loved ones who are affected. I've got a very close relationship to MSA and symptomatic nOH, because my father died from MSA and he had severe symptomatic neurogenic orthostatic hypotension. Contributions that we can make towards this disease can provide terrific benefit for patients, for caregivers and their families. Now before I turn the presentation over to Dr. Kaufmann, I'd like to take a moment to level set for those who are new to the Theravance Biopharma story or who may be reacquainting themselves with our journey. Throughout our company's history, Theravance has maintained a philosophy of building value through the discovery and development of medicines that uniquely address unmet needs. This has led to the approval of 5 medicines thus far, and we hope 6, given the potential we see with ampreloxetine. Today's Theravance is a highly focused organization with 3 compelling pillars of value and a singular culture of determination. Our first, which Theravance discovered, developed and took through FDA approval is YUPELRI. The only nebulized, long-acting muscarinic antagonist therapy or LAMA therapy, approved for the maintenance treatment of COPD. Since LAMAs are considered foundational in the treatment of COPD, YUPELRI represents a unique and valuable option for patients for whom nebulized therapy is appropriate. We continue to identify ways to introduce patients and caregivers to its benefits, whether that's my promoting concomitant use aligned with the updated gold guidelines, or introducing it as an option to patients who may struggle with traditional handheld devices. Our hospital-focused commercial organization has developed a deep understanding of our customers' needs and is executing a highly tailored commercial strategy designed to maximize its overall impact, an approach we plan to utilize for ampreloxetine. Under our co-promotion agreement with Viatris, Theravance and Viatris, both contribute to the overall YUPELRI commercial strategy with profit split 35% to Theravance and 65% to Viatris. Over the past 12 months, YUPELRI net sales have increased 12% overall, and we look forward to continued growth and accelerating profitability for this product going forward. Ampreloxetine, which is the subject of today's presentation represents our next growth opportunity. It offers the potential to be the first medicine to provide durable benefits for thousands of patients suffering from neurogenic orthostatic hypotension as a result of multiple system atrophy. Ampreloxetine was discovered at Theravance and designed to provide the benefits of selective debt inhibition with once-daily dosing in a differentiated safety and tolerability profile. Thus far, it's lived up to its promise in MSA patients, an indication for which we have been granted orphan drug designation by FDA. We're well underway with our registrational study and anticipate disclosing top line results in 2025. Should Ampreloxetine be approved, we plan to execute a highly targeted and data-enabled launch, building off of our success with YUPELRI. Our final asset is our financial strength. We have a strong balance sheet with $100 million in cash and no debt as well as limited cash needs. We potentially stand to realize significant income through future milestones and royalties. In total, these milestones could amount to up to $400 million. As Dr. Kaufmann and Biaggioni will describe more fully, MSA is a terrible incurable disease. And the symptoms of nOH are some of the most debilitating these patients face. MSA is a progressive neurological disorder caused by central nervous system degeneration associated with the abnormal deposition of a protein known as alpha-synuclein. Lesions in the brain lead to autonomic dysfunction and associated inability to regulate important bodily functions, including blood pressure. Patients with MSA experienced significant and persistent blood pressure drops upon standing, a condition known as neurogenic orthostatic hypotension or nOH. Ampreloxetine is designed to mitigate these effects through its actions on norepinephrine, which is a key signaling agent in the autonomic system that is used to regulate blood pressure. It produces a highly physiological effect, which is different from anything indicated to treat nOH today. Unfortunately, there are no effective options for nOH and MSA, which is why we're working so hard to break ampreloxetine to market. MSA is a rare disease. However, an estimated 40,000 Americans suffer from the significant burden of nOH symptoms resulting from MSA and therefore, might -- may benefit from ampreloxetine's treatment. Of course, there are tens of thousands more around the world. As I indicated, the effectiveness of approved therapy for OH is limited with none having demonstrated durable nOH symptom benefits beyond 2 weeks. What's more, the therapies physicians use to treat orthostatic hypotension are limited by side effects and scheduling issues, the most important of which is arguably supine hypertension or dangerously high blood pressure experienced while lying down. Thus far, data generated for ampreloxetine do not indicate that it carries a risk of supine hypertension worsening and its beneficial effects on symptoms have been demonstrated in MSA patients out to 22 weeks. Thus, if we're able to reaffirm ampreloxetine's differentiated profile in CYPRESS, we believe it would bring considerable value to patients, caregivers and payers. We will reserve a more detailed economic discussion for a future date but believe ampreloxetine's impact on the MSA community could be profound. At this point, it's time for you to hear directly from 2 of the world's foremost experts on nOH and MSA who have agreed to share their insights on the nature and management of this condition. Therefore, I'd like to begin by turning the podium over first to Dr. Horacio Kaufmann, a longtime collaborator and leader in dysautonomia research and clinical practice to provide an overview of MSA and nOH. Dr. Kaufmann?

Okay. So thank you, Rick. Good morning. My name is Horacio Kaufmann. I'm a Professor of Neurology at New York University and the Director of the Dysautonomia Center at NYU Langone, also in New York City. My work focuses on the functioning of the autonomic nervous system and the neurological diseases that affect this part of the brain. Today, in the next few minutes, I will be telling you a few facts about multiple system atrophy a debilitating disease, a very debilitating disease that severely impairs the autonomic nervous system that is the involuntary part of the brain and causes neurogenic orthostatic hypotension abbreviated nOH. Unfortunately, none of the drugs currently available for nOH work well in patients with multiple system atrophy or MSA. So there's clearly an urgent need for an effective treatment that can help these patients. So what I want to share with you today is that I believe that now we do have an effective drug for nOH. And I will explain why it is especially effective in patients with MSA. Now let me start by telling you that there is a group of neurological diseases known as synuclein neuropathies. Now the names synuclein neuropathies comes for the fact that these diseases are caused by the abnormal buildup of the [ broadening ] in synuclein that you see the structure of which you see in this slide. Now this protein is present in all neurons. Now it is usually well behaved, but for unknown reasons, sometimes synuclein can become a killer. It actually misfolds, it aggregates in clusters called oligomers and then those oligomers form fibrils and the fibrils then aggregate in what's called Lewy bodies, which are inclusions that are inside the cells, specifically inside the neurons or inside the glial and they are called glial cytoplasmic inclusions. Now the problem is that these inclusions are toxic and essentially kill eventually the neurons or the glial. And that happens not only in the brain, but also in the cerebellum, in the spinal cord and even in the peripheral nerves. Now synucleinopathies, these group of diseases, include Parkinson's disease, includes a form of dementia called dementia with Lewy bodies and also a much more rare disease called multiple system atrophy. Now Parkinson's disease is highly prevalent. There's more than 1 million people in the United States affected with Parkinson's disease and so is the dementia with Lewis bodies with a few hundred thousand patients affected. On the other hand, multiple system atrophy is much less common. It is a rare disease with around 40,000 or 50,000 patients affected in the United States. Now MSA severely impairs autonomic and motor function, is the worst, the most devastating of the synucleinopathies, their average symptom onset is in the 6 decades. That means in the -- usually the first symptoms occur in the 50s. And unfortunately, this occurs within 10 years of diagnosis. So the median survival, as shown here in the slide is around 8 years with very, very severe disability patients usually wheelchair bound within 2 or 3 years of the occurrence of first symptoms. Now in addition to the abnormal synuclein accumulation that causes these diseases that I mentioned, what these 3 diseases, these 3 synucleinopathies have in common, is something called orthostatic hypotension. Now orthostatic hypertension, as shown here in the slide, is a fall in blood pressure -- the slide actually shows the blood pressure in the vertical axis and time in the horizontal axis. So what happens is that when a person stands up, the effect of gravity pulls blood down and then blood pressure in these patients fall because the sympathetic nerves which are the nerves that normally constrict the blood vessels do not -- are not activated properly. So this lack of activation is what causes the fall in blood pressure. Normally, when the these sympathetic nerves are activated, they release norepinephrine. Norepinephrine is the neurotransmitter of these sympathetic neurons. The neurotransmitter is the substance released by the nerve terminals that binds to receptors in the blood vessel surface and makes the smooth muscle that makes the blood vessel wall contract. Now contraction of the smooth muscle decreases the blood vessel diameter and the pressure inside increases, sort of like pressing your fingers on a water hose to make the water go further or go -- take more distance. Now when the release of norepinephrine is impaired, there is not enough base of construction and with standing blood pressure falls. Now this fall in blood pressure is not a trivial problem is a big problem. What this slide shows this cartoon, I wanted to show you in the lower tracing, you see the blood pressure over time. What you see in the upper boxes is the blood flow in the brain. So as you see, when the person is supine, the blood flow in the brain is around 55 centimeters per second, this is the velocity. Upon standing up, when the blood pressure falls, the blood flow in the brain decreases dramatically. And then when the person sits it increases again. Now this fall in blood pressure decreases then the prefusion of the brain, and this lack of blood in the brain produces very, very symptoms. Now the most common symptoms when the blood pressure falls are: trouble concentrating, dizziness, head and neck discomfort, fatigue, weakness, vision problems, the vision gets blurry. Now we can measure or assess these symptoms with a questionnaire. This questionnaire is called the orthostatic hypotension symptom assessment orthostatic hypotension questionnaire. And this questionnaire, as you show here in the slide, has a richter scale, was called richter scale, meaning patients choose the number from 0, which is no symptoms to 10, which is the worst possible symptom. And we have used this questionnaire and validated over the years. And now the Food and Drug Administration, the FDA, in the U.S. accepts this question as an outcome measure for drug approval in clinical trials. And in this questionnaire, the one point change is considered clinically meaningful, meaning if the OHQ decreases one point, the FDA, and of course, us as clinicians, consider that as clinically meaningful, meaning the drug is having the desired effect. Now this problem is orthostatic hypotension or neurogenic orthostatic hypotension. It's called neurogenic because the cause is the abnormality in the neurons in the nerves. This is a very, very common problem in patients with multiple system atrophy. Indeed, as shown in these pie charts here, 80% of the patients with nOH suffered from severe symptoms of neurogenic orthostatic hypotension. And of those that suffer from nOH, from symptoms, 65%, a large amount remain symptomatic despite using all available treatments for this program. Now this is not surprising. And it's not surprising because the available drugs for treating nOH are not particularly good for patients with MSA. For example, Fludrocortisone, which is the most frequently used drug, is not even approved by the Food and Drug Administration for the treatment of nOH, is approved for other indications. The big problem with fludrocortisone is that it causes very severe supine hypertension which, after a while may not even be reversible, you can also cause congestive heart failure and affects the kidneys. Certainly not a drug for chronic use. Midodrine, that is an alpha-adrenergic agonist has been approved many years ago, has a modest efficacy, but most patients, as I mentioned to you before, despite using midodrine, most patients with MSA remain symptomatic. And it requires very short acting and requires at least 3 times a day dosing, which could be a problem, but the biggest problem is that it's not very effective. Finally, droxidopa, which is the second drug together with midodrine that is approval by the FDA for the treatment of nOH. Unfortunately, when we did the mild analysis putting together all the trials that led to the approval of droxidopa, it was not or it is not effective, specifically in patients with MSA. And of course, it also requires a 3x a day dose. Now something fundamental, which is the most important point I would like to make in this talk, if I have one message that I would like you to remember, is that although all patients with synucleinopathies can have in nOH. The side of the lesion causing the reduced norepinephrine release is the cause of this fall in blood pressure, the location, the size of the lesion is different, among these 3 diseases. And the difference is very, very relevant, and you will see why. You see, in the somatic or voluntary nervous system, the gap between the spinal cord and the target organ in the case of the voluntary that is the muscles, that gap is bridged by one neuron. In contrast, in the autonomic nervous system, the gap is bridged by 2 neurons, one neuron leaves the spinal cord and reaches the structure shown in the cartoon here called the ganglia, the sympathetic ganglia and its structure at the side of the core. And in the ganglia, it synapses with the second neuron. Now the second neuron is the one that reaches the target organ and innovates the blood vessel. Now the first neuron is called the preganglionic, meaning before the ganglia, and the second neuron is called the postganglionic. Now the important point is that in patients with Parkinson's disease and dementia with Lewy bodies, the postganglionic neuron is affected whereas in patients -- so meaning the postganglionic neuron, as you see in this -- with this red circle here, that is the neuron that degenerates in patients with Parkinson's disease and dementia with Lewy bodies. In mild contrast, and that's the point I want to transmit to you, in patients with multiple system atrophy, the postganglionic neuron is spare. So it is the preganglionic neuron, the one that degenerates. So although the result is the same in both cases, meaning norepinephrine is not adequately released when the sympathetic pathway is activated because the size of the lesion is very, very different the -- or is opposite. This is crucial when we design a drug. So the drug we are talking about today ampreloxetine works by increasing the amount of norepinephrine in the synaptic play that is in the space between the neuron and the blood vessel. So by the way it can work is when that postganglionic neuron is spare, when it is still adequately functioning, although it's not properly activated. Now the details of how ampreloxetine works is what my colleague, Italo Biaggioni, will tell you in detail in a few minutes, and I believe you will find it quite interesting and is the reason why ampreloxetine is especially tailored and effective in patients with MSA. So thank you very much, and Italo, take it away. Thank you.

Well, thanks, Horacio, for that review and the introduction. I'm Italo Biaggioni. I direct the Autonomic Dysfunction Center at Vanderbilt. We take care of patients with multiple system atrophy and other autonomic disorders. My background is in clinical pharmacology and therefore, our research has focused on developing novel therapies for autonomic disorders. I have been doing this for about 40 years, and I can tell you that I am as excited as it has ever been because of current prospect of developing drugs that will improve the quality of life of our patients. Let's start by reviewing the role of the autonomic nervous system in general and norepinephrine in particular, in our ability to stand up. We take standing up for granted, but it requires a complex set of compensatory mechanisms all designed to maintain average blood pressure. As Dr. Kaufmann mentioned, standing leads to pulling of blood in a lower body, that is sensed by receptors in the neck, that send a signal to the brain so that autonomic pathways will trigger sympathetic activation and increased norepinephrine delivery to the vasculature. This ultimately leads to release of norepinephrine, as I mentioned, from peripheral nerve terminals that produce vessel construction and restore blood pressure. So plasma norepinephrine more or less doubles when we stand out. When these mechanisms are impaired, blood pressure cannot be maintained and patients are unable to stand up because of orthostatic hypotension. This causes great disability in our patients and increases the risk of falls, fainting and trauma. The ultimate cost of orthostatic hypotension is failure to deliver norepinephrine to the blood vessels. In patients with Parkinson disease, dementia, Lewy bodies, or pure autonomic failure, as you can see in the upper half of this slide, the problem is neuro-degeneration of peripheral fibers, and therefore, these patients have very low plasma norepinephrine. In contrast, in patients with multiple system atrophy, the problem is a loss of autonomic pathways in the brain. On the other hand, peripheral norepinephrine pathways are intact and their plasma norepinephrine can be normal, but it cannot be engaged when patients stand up because of the central loss of regulation. If you wish, this is like a car engine running on idle that cannot be lift up when needed. So if there was a way to engage these fibrils in multiple system atrophy that can really improve their condition. So let's take a closer look at these nerve terminals. And we find that they are full of vesicles that are packed with norepinephrine. During sympathetic activation, these vesicles released norepinephrine in to the synapse where alpha receptors are located to induce vaso constructions and increase blood pressure. I would like to highlight how efficient this system is. First, norepinephrine is delivered right where the receptors are located. Second, most of the norepinephrine is uptaken by norepinephrine transporter net to be recycled for the next round of sympathetic activation. And only about 10% of norepinephrine spills over into blood where we measure it as plasma norepinephrine. That means that if we measure, let's say, a 50% increase in plasma norepinephrine, that really means that the concentration on the synapse, the site of action is increased by about 500%. So let's keep that in mind as we review the following slides. In terms of efficiency of this system, third, blocking norepinephrine transporter will result in a higher increase in norepinephrine in the sign-ups. So in summary, this is a highly effective norepinephrine delivery system that we can take advantage of with norepinephrine reuptake blockers like ampreloxetine. But even this nice drawing doesn't make justice in showing us how efficient this system really is. And this electron microscope picture shows how norepinephrine terminals really look like. You can see there's lots of vesicles full of norepinephrine that is being released in this very tight space precisely where the receptors are located. You cannot design a more efficient delivery system and ampreloxetine is the ideal candidate to take advantage of this. And this is precisely what our studies have shown so far. First, ampreloxetine increased plasma norepinephrine in patients with multiple system atrophy by about 60%. If you remember my previous comments, this primarily reflects an increase in synaptic norepinephrine of 600%. Also note that the effect lasted for up to 10 weeks as far as we measure. Second, this translates into an improvement in upper blood pressure of about 60-millimeter of mercury when compared to placebo. As expected, this effect was not seen in patients with Parkinson's disease or pure autonomic failure. If you recall, these patients have lost their peripheral norepinephrine fibrils and therefore, there is nothing for ampreloxetine to engage. So third, ampreloxetine increased upright, but not supine blood pressure. The likely explanation for this effect is an ampreloxetine works best when symptomatic activity is increased on standing. I am particularly excited about these findings because finding a drug that selectively improves our blood pressure is the holy grail for treatment of orthostatic hypotension. Most of these patients already have high blood pressure lying down. And we don't want a drug that will worsen that. And actually, all the approved drugs increase supine blood pressure more than standing blood pressure and therefore, have an FDA Black box warning about worsening of supine hypertension. Finally, ampreloxetine improved symptoms of orthostatic hypotension in multiple system atrophy. This is important because symptom relief is the primary outcome requested by the FDA for drug approval. So in summary, ampreloxetine is a novel and smart approach for the treatment of neurogenic cartoning hypotension in multiple system atrophy. There is a perfect marriage between the mechanism of this in MSA, which is characterized by intact peripheral norepinephrine fibers and the mechanism of action of ampreloxetine that can engage those fibrils to increase their delivery of norepinephrine. That is what the data shows so far that ampreloxetine increased norepinephrine levels, preferentially improved high blood pressures and alleviated symptoms. Again, this is a tailor approach for the treatment of MSA. I want to thank you for your attention. I look forward to the Q&A session. I leave you with Dr. Miller, who will review the drug development program of ampreloxetine as a treatment for orthostatic hypotension. Thank you.

Thank you, Dr. Biaggioni and also to Dr. Kaufmann for your excellent talks on the unique fit ampreloxetine offers in symptomatic nOH and MSA. My name is Aine Miller, and I'm the Head of Development at Theravance Biopharma. Today, I'll cover 3 topics highlighted here. First, I'll cover ampreloxetine's development history which discovered in Theravance labs and describe how it was designed to have particular properties. I'll also review some of the early data we generated, which demonstrates why ampreloxetine's profile is ideal for the population we are currently addressing in the clinic. Second, I'll spend some time reviewing CYPRESS, our registrational study for ampreloxetine in symptomatic nOH in patients with MSA. I will talk why we designed it the way we did and what we learned and applied from our previous clinical studies and why we believe the program is significantly derisked from a clinical perspective. Third, I'll discuss our regulatory plans and time lines, which we believe we've also substantially de-risked. As Dr. Kaufmann and Biaggioni mentioned, ampreloxetine is a selective inhibitor of the norepinephrine transport protein NET, which is found in the presynaptic nerves of the neurovascular junction. Scientists at Theravance specifically designed it to be a selective for net in order to avoid side effects associated with inhibiting other monoamine transport proteins such as serotonin transport protein or SERT. As you will see, the team successfully tailored an excellent profile for ampreloxetine with high potency, a long half life suitable for once-daily dosing and good oral bioavailability. Ampreloxetine is primarily cleared through the liver, which is a desirable attribute in MSA patients since these individuals are not typically diagnosed until their 50s and 60s and may have compromised renal function. Just to expand upon this briefly, we conducted extensive pharmacology work to characterize ampreloxetine's profile in human subjects. Based on preclinical modeling and followed by dose ranging clinical studies, we've chosen a 10-milligram dose of ampreloxetine, which achieves the desired level of target engagement for NET while avoiding appreciable levels of target engagement for SERT. This profile also resulted in excellent tolerability profile, which we have observed for ampreloxetine in our clinical studies to date with a low incidence of side effects that might be associated with SERT blockade. As you've already heard today, nOH is caused by reduced norepinephrine release by the autonomic nervous system upon standing, which in MSA patients results from neurodegeneration in the central nervous system. Scientists at Theravance recognize this unique attribute of MSA pathology and designed the molecule that could offer the requisite net target engagement to boost norepinephrine levels improved blood pressure and vascular perfusion and thereby improve nOH symptoms in these patients. Importantly, 2 attributes of ampreloxetine's [indiscernible] profile went on to be confirmed in the clinic. Firstly, ampreloxetine did indeed increase standing systolic blood pressure and mitigate nOH symptoms, which did not lead to an appreciable change in supine blood pressure. Secondly, ampreloxetine's effects were durable, which is consistent with the hypothesis, but a long-acting NET inhibitor might produce a more stable effect on norepinephrine responsiveness over time, and therefore, a more durable effect on symptoms. Based on our findings in Phase II, we approached the FDA with a Phase III program intended to support ampreloxetine's use in MSA patients, experiencing symptomatic nOH. However, the agency believed ampreloxetine might also benefit other populations suffering from symptomatic nOH, particularly those with Parkinson's disease and pure autonomic failure. Thus, we agreed to enroll a broader population to answer this question. While the results of these initial Phase III studies were negative for the overall broad population, the prespecified analysis we saw in MSA patients was very compelling and consistent with our expectations. Therefore, leading us to design and initiate the pivotal Phase III CYPRESS study, which we are currently conducting. As you can see, our initial Phase III program involves 3 studies. 169, also known as SEQUOIA. 170, also known as REDWOOD and the long-term extension study, also known as OAK. 169 was a traditional placebo-controlled parallel group study where patients with symptomatic nOH due to MSA, Parkinson's or PAF received at our 10 mg ampreloxetine or placebo for 4 weeks. The primary endpoint of this study was OHSA-Item-1, or dizziness lightheadedness at 4 weeks. When we saw the results for 169 and later from 170, it was clear that 4 weeks was not long enough to demonstrate the benefit for ampreloxetine. Most efficacy studies involving NET or SERT inhibitors are usually of a longer duration. Patients completing 169 and De novo patients were eligible to enroll into Study 170, which was our main study assessing the durability of clinical effect of ampreloxetine, compared to placebo for the treatment of symptomatic nOH. As noted here, these complete -- these patients completing 170 then became eligible to participate in the open-label extension study. I'd now like to hone in on our approach and how we designed 170 as well as the findings in greater detail because it bears significantly and why we feel so optimistic about Cypress' potential success. Unlike Study 169, Study 170, used a randomized withdrawal design. By way of background, randomized withdrawal studies are often used to establish long-term effectiveness of investigational therapies with a limited period of exposure to placebo. As you can see, patients in the open-label period of 170 were given 16 weeks of ampreloxetine at 10 mgs, once per day before being randomized to either continue ampreloxetine are switched to placebo for an additional 6 weeks. Before moving on, I'd like to highlight 3 important aspects of the 170 study design. First, knowing that MSA patients were the most likely to respond to ampreloxetine given its mechanism of action and the pathology underlying MSA. Both doctors Kaufmann and Biaggioni so eloquently described, we built an enrollment target of 40% MSA patients into the study protocol. Even though the incidence of MSA is much lower than PD and PAF in the general population. Secondly, we included a perspective by disease analysis in order to evaluate ampreloxetine's effects on these 3 different patient populations experiencing autonomic failure. Third, we employed an enrichment strategy during the open-label period as we have at CYPRESS, in order to identify patients benefiting from ampreloxetine and to optimize the population enrolled in the randomized withdrawal portion of the study. And this is what we saw -- before diving into the details, it's important to know that at the time the 169 study read out, Study 170 was approximately 80% enrolled. At that time, we made a very difficult decision to halt 170 early with only 128 of the planned 154 patients available to be evaluated on the primary end point. While 170 was technically a failed study, I'll draw your attention to the bottom half of the slide. Here, we present the results of the prespecified by disease analysis on the endpoint of OHSA composite score. The same endpoint we are applying as the primary endpoint in CYPRESS. As you have heard earlier today, this core comprise of 6 common symptoms of nOH that can significantly impact patients' quality of life. In the MSA cohort, which consisted of 38 evaluable patients, we saw a clinically meaningful and durable symptom improvement over 22 weeks in MSA patients treated with ampreloxetine. Whereas symptoms worsened towards baseline when ampreloxetine was withdrawn for 6 weeks. This is a clinically meaningful difference of 1.6 points in the OHSA composite score for ampreloxetine treatment over placebo as measured at the end of the randomized withdrawal period. And just as a reminder, midodrine or droxidopa, the therapy is currently approved to treat symptoms of orthostatic hypertension and sometimes used in MSA patients have not demonstrated an impact on symptoms beyond 2 weeks in a double-blind study. Given the unmet need that existed, the FDA did grant droxidopa a conditional accelerated approval based on a very short-term benefit. The FDA went on to request a confirmatory durability study and based on data recently reported on clinicaltrials.gov, droxidopa fail to demonstrate the benefit in the study known as RESTORE. On the next slide, we'll break out ampreloxetine's effect in the MSA cohort by individual components. As you can see from these data, which were taken at the end of the randomized withdrawal period in 170. Ampreloxetine delivers a consistent effect across the most common symptoms associated with autonomic failure. Additionally, ampreloxetine improved activities of daily living that required standing are walking for a short period of time. This is important for 2 reasons. First, should CYPRESS be successful and subject, of course, to regulatory review, ampreloxetine would be the only therapy indicated to treat a broad range of nOH symptoms. Midodrine is not indicated to treat symptoms, but to raise broker pressure, while droxidopa is indicated for its short-term ability to improve dizziness and lightheadedness only. Secondly, given nOH symptoms are not just limited to dizziness and instead in MSA, it presents with multiple symptoms, which our OHSA composite endpoint is capturing. This should improve the odds a successful outcome if ampreloxetine is delivering a benefit to patients. So we've talked a bit about the durability of ampreloxetine and what it has delivered. But here is what it looks like in graphical form. As you can see to the right MSA patients remaining on ampreloxetine therapy during the random most withdrawal period, maintain the symptom benefits they experienced while participating in the open-label portion of the study. In contrast, patients administered placebo experienced a clinically meaningful worsening of the OHSA composite score. In addition to this, you will see there is a plateauing of effect during the open-label portion of the study at week 12. And as a reminder, the OHSA is an 11-point ordinate scale with 0 representing no symptoms and 10 representing the worst possible symptoms of nOH. As I'll discuss when we get to CYPRESS, this experience helped informed and we believe, improve our pivotal study design and our odds of a successful come. As you can appreciate, despite not reaching our objectives in Study 170, we emerged undeterred in our pursuit to make ampreloxetine available to many MSA patients without an effective treatment option for their nOH. In the summer of 2022, we scheduled a Type C meeting with senior leadership within the cardiorenal division of FDA and discuss both our findings and proposed development plan moving forward. Importantly, the agency agreed that the results of our prespecified by disease analysis in M&A could be used as supportive data for a registrational filing, provided we confirmed ampreloxetine's benefits in one additional Phase III study using the same randomized withdrawal design as 170. In addition, they agreed that the OHSA composite score could be used as the primary endpoint of the study rather than OHSA Item 1. So this is our Cypress design. We kept the randomized withdrawal design used in 170 with which we saw the compelling benefit in MSA patients, and we powered the study to be able to have approximately 60 patients complete all 8 weeks of the randomized withdrawal period, this contemplates drawbacks or discontinuations of which we expect a few. For example, [indiscernible] are failure to meet our enrichment criteria. As a reminder, we achieved a nominally significant benefit on the OHSA composite in Study 170 with only 38 MSA patients. As a reminder from our earlier discussion, the majority of patients in Study 170 reached maximal effect of ampreloxetine on symptom improvement by week 12. Thus, we shortened the open-label period for CYPRESS and the enrichment time point was moved to week 8. We added an additional 2 weeks to the randomized withdrawal period to maximize the treatment difference between placebo and ampreloxetine and CYPRESS. It is our hope that the increasing benefit seen over placebo in Study 170 can be replicated and improved upon over the additional 2 weeks we have built into the design of CYPRESS. And then finally, in keeping with our discussions with FDA and our findings in 170, we went on to choose the OHSA composite score as the primary end points of the study. Before transitioning to the regulatory portion of my presentation, I'd like to discuss how we are operationalizing CYPRESS because we believe this is also a key factor in determining the study's potential for success. Below on the lower left, we've taken a number of steps to streamline the CYPRESS experience based on learnings from our initial Phase III program. Building on the Study 170, which was conducted when the pandemic was still restricting care, we incorporated ways in which patients could participate in CYPRESS remotely into our program. We've aimed to reduce patient burden, which can complicate the study's implementation or deter aside some patients from participating. Now moving to site selection. We've returned to many of the high-quality sites that participated in Studies 169 and 170, which supports the idea that we can look forward to a result that is consistent with our 170 experience. However, we augmented the initial approach with identifying additional sites with the potential to deliver similarly high quality results. Our study is global. We have sites now activated on 4 continents. If you move to the lower left-hand corner of the slide, one of the aspects of CYPRESS that sets us apart is the fact that we are managing the study directly rather than using a traditional CRO model. We have worked to identify sites with high standards for clinical conduct investigators who understand the complexities of managing nOH and MSA and patients who best fit the criteria of the CYPRESS study. We are developing a close working relationship with many centers of excellence that should be caring for a majority of patients in the future. As with our previous program, we are using an enrollment steering committee to ensure patients approved to participate in the study meet the enrollment criteria we have established and most importantly, that an MSA diagnosis is confirmed. A diagnosis of MSA is somewhat complicated and demands a degree of specialization. Finally, I draw your attention to the lower left quadrant of the slide. Against this backdrop, we remain on track to meet our enrollment objectives and are bringing to CYPRESS an additional level of engagement. We've been working closely with the MSA community, including key advocacy groups for several years now. We have leveraged these relationships through traditional outreach and novel AI-driven strategies in order to keep our time lines. Most importantly, based on study metrics we are seeing in CYPRESS, they are consistent with both Study 170 and our internal models. As you know, the FDA requires that sponsors provide substantial evidence of the drug's effectiveness in order to be approved. One option for demonstrating substantial evidence is the use of a single well-controlled trial supplemented by confirmatory evidence in line with guidance provided by the FDA. This is often a pathway utilized for investigational therapies in development for rare orphan diseases. As I mentioned previously, we met with FDA in 2022 and agreed upon an approach where a positive CYPRESS results, supported by our findings in Study 170 would serve a substantial evidence of ampreloxetine's effectiveness and support a filing for full approval. At that meeting and in subsequent interactions, the agency also expressed a desire to confirm the clinical utility of the OH symptom assessment and to establish thresholds for what would constitute a clinically meaningful improvement in the OHSA. At last year's American Autonomic Society meeting, we presented initial findings on this very topic. Specifically, we conducted what is known as an anchor-based analysis on Studies 169 and 170 in order to determine whether the OHSA composite score anchored 2 patients impressions of clinical severity change. As part of this analysis, we also determined the minimum threshold for improvement or worsening on the OHSA composite score that would be considered clinically meaningful. Our analysis demonstrated that the OHSA composite was indeed an appropriate measure of clinical status and that changes on the order of one point, either improving or worsening were clinically meaningful to patients. These results are consistent with the initial validation studies for the OHSA questionnaire and compare favorably to the 1.6 point benefit we saw in the MSA cohort in Study 170. Moving on, I'll briefly comment on the clinical safety and tolerability information we've collected thus far. To date, we've dosed over 800 individuals with ampreloxetine from Phase I through to the end of our initial Phase III program. Importantly, we've had over 200 patients suffering from nOH exposed to ampreloxetine with over 100 exposed for greater than 6 months and 60 patients for year or more. [indiscernible] development ampreloxetine has demonstrated an excellent tolerability and safety profile with a low side effect burden. No obvious on or off target effects clearly attributed to its use, a low dropout rate for issues of safety or tolerability and no signal for worsening of supine hypertension. Of course, safety data from the CYPRESS study will further supplement the safety database. To finish, I'm going to walk through our regulatory plans and how we are planning for an expedited NDA filing post-CYPRESS data readout. Based beyond our alignment on the design of CYPRESS, we've also held extensive interactions with the FDA on other elements of the registrational package for ampreloxetine. Specifically, we believe we have alignment on all elements of the regulatory package that would satisfy the agency's requirements and have completed the vast majority of this work. This includes nonclinical, pharmacology and toxicology clinical pharmacology and CMC. We have already proactively begun authoring an NDA for ampreloxetine, leveraging the Theravance's experience with our successful YUPELRI NDA filing and approval. We are working diligently this year to complete authoring for the majority of completed work so that we are in a position to efficiently incorporate the results from CYPRESS once available and finalize the application. We continue to expect to complete enrollment in the open-label portion of CYPRESS in the second half of the year and for top line data to be available in 2025. Once we have those data, we will quickly move to submit our application and plan to request a priority review from FDA. Given these timelines, we have already begun initial commercialization preparations for ampreloxetine which now segues nicely to run this presentation around the exciting commercial opportunity that exists for ampreloxetine. Over to you, Rhonda.

Thanks, Aine. My name is Rhonda Farnum, and I lead the commercial and medical affairs functions at Theravance Biopharma. I'm thrilled to be part of today's presentation to share our initial perspective on the significant market opportunity for ampreloxetine. And I will begin by reflecting on the current market limitations impacting MSA care and how we will approach commercialization planning for ampreloxetine's entry into the market. Over the last hour, we have heard from both Dr. Biaggioni and Dr. Kaufmann about the devastating impact MSA has on patients and their caregivers and how underserved this community is by the current nOH treatment options. Unfortunately, none of the available options work well in MSA patients with nOH. As a result, there is an urgent need for an effective treatment that can help these patients. A majority of MSA patients have nOH and the symptoms associated with this condition are disabling, leading to increases in patients' risk of falling and associated injuries, cost of care and declining quality of life. And despite receiving treatment with currently available therapies, approximately 65% of MSA patients remain symptomatic, reinforcing the notion that these options do not work well. Therefore, a new treatment solution that can provide a clinically meaningful option and improve the quality of life for these patients is desperately needed. Given ampreloxetine smart and selective design we believe it may be that solution for MSA patients. As Aine reimbursed earlier, the CYPRESS study design presents an unparalleled approach to treating nOH by addressing a wide range of symptoms and thereby potentially improving the quality of life for MSA patients. With this background, I am going to focus the rest of the presentation on our initial evaluation of the unmet need in the market and how ampreloxetine may transform care for the MSA community. Now I would like to take a few moments to describe our view of the patient opportunity for ampreloxetine. A new analysis of real-world claims data supports a prevalence estimate of roughly 50,000 individuals with MSA in the United States, which also was referenced by Dr. Kaufman earlier in the presentation. Based on this figure and the high incidence of nOH in these patients, we believe the addressable population for ampreloxetine is approximately 40,000 patients suffering from symptomatic nOH in the U.S. positioned to treat MSA, primarily autonomic and movement disorder specialists are located in centers of excellence, which results in a fairly concentrated target market. There is an established treatment paradigm and guidelines and specialists already appreciate the signs and symptoms of nOH. These marketplace dynamics latest to believe that addressing this patient population presents a focused and very manageable opportunity for the Theravance team. Finally, as has been emphasized throughout today's presentation, MSA patients have limited options and current orthostatic hypotension therapies do not deliver. As discussed, neither midodrine nor droxidopa had successful Phase III confirmatory trials, yet remain on the market in part because of the high unmet need in this space. This leaves a clear path for ampreloxetine to differentiate in and likely grow this market opportunity and deliver a clinically meaningful option to patients. To ensure that the path is defined for success, we will continue to enhance our understanding of the patient journey and marketplace dynamics through ongoing research and MSA community engagement. While our focus today is to discuss the opportunity in the U.S., ultimately, our goal is to make ampreloxetine available worldwide. As you can see on this slide, in European and Asian countries, including the EU5, Japan and China, the number of addressable MSA patients with symptomatic nOH is several fold larger than it is in the U.S. And in some territories, the range of therapeutic options is even more limited. Therefore, we will continue to pursue a partnership opportunity for ampreloxetine to Rest of World strategy with the intention of providing a clinically meaningful option for nOH to MSA patients worldwide. Next, we have a view derived from a new analysis of a patient-level claims database. We estimate only 1/3 of MSA patients are treated with orthostatic hypotension therapies. And of these patients, the majority received midodrine and agonists, which, as you heard earlier, does not work well in this patient population and many MSA patients are not responsive to this mechanism of action. Notably, only 12% of treated patients received droxidopa, the only FDA-approved therapy indicated for nOH patients. This reiterates the fact that droxidopa does not work well in the MSA patient population and is not a preferred treatment option. We believe it's minimal adoption in the MSA population demonstrates that droxidopa is not an appropriate comparator for ampreloxetine's market potential. With so few options to manage nOH, it is clear that there remains a high unmet need in this rare disease space. To further our understanding, we have been engaging with MSA advocacy groups, patients and their caregivers. They further reiterate this need and are actively seeking new therapies to better manage their condition. Along with physicians to see nOH's devastating impact and the dangerous effects on patients' quality of life, these physicians express an urgency to protect patients from the mini burdens of this disease, like injuries from frequent falling and physical deconditioning, which can contribute significantly to impacting quality of life. In addition to understanding how MSA patients are treated, we have also assessed where they are being treated. From our initial analysis, the treatment landscape is fairly concentrated. As you can see here, we have already identified the 31 MSA centers of excellence recognized by leading advocacy organizations, Mission MSA and Cure PSP. Many of our CYPRESS clinical trial sites are at these centers. We have also identified 250 high-volume accounts, which include both hospitals and/or specialty clinics and 90 high-volume specialists comprised of both neurologists and cardiologists. So we understand where patients and prescribers are, and we continue to hone our efforts over time to inform a focused and efficient launch deployment. As we develop our commercialization strategy, we are confident we can implement a targeted approach similar to other rare disease launches. We believe Theravance is uniquely positioned to bring this new treatment option to patients, caregivers and health care providers, based on our strong foundation of experience, which includes years of studying ampreloxetine in nOH and our understanding of the market. We plan to also leverage our clinical trial experience in key MSA centers and with opinion leaders to build out our go-to-market strategy. As we continue to develop our commercialization plans for ampreloxetine, we are also monitoring general trends and launch strategies in the orphan drug market. Here, I would like to highlight a recent report by an investment bank that studied 63 rare disease drugs launched in the U.S. over the last 3 years. The report identified 5 key factors listed here on the left that had the greatest impact on a drug's launch opportunity. On the right, the study also reported the average launch prices for 52 chronic therapies included in the analysis. Across these 8 therapeutic areas, the average price was approximately $380,000 per year. The important takeaway here is to appreciate the opportunity from which we will continue to learn from other orphan drug launches and draw out how best to deliver value to small underserved patient populations. Moving to my last slide. Our objective today was to share insights from the early stages of our commercialization journey. As we gain a deeper understanding of the market, we plan to communicate more detailed information and plans at future forums. As you can tell from our initial findings, we are extremely excited by the opportunity to deliver a therapy that can make a difference in the lives of MSA patients and their caregivers. We are busy setting our vision for Launch Excellence and are assembling our imperatives around 3 simple things: design, build and transform. Starting with the architecture of our approach, we will capitalize on a detailed understanding of nOH MSA's unique needs to create a targeted launch strategy. This approach will borrow from our established infrastructure and proven capabilities in navigating large academic centers in the U.S. hospital market, which are driving YUPELRI adoption in the specialty respiratory market today. We also recognize the importance of educating and raising awareness of MSAs unmet needs and the equally important understanding of ampreloxetine's potential differentiation from the standard of care to ensure rapid adoption at launch. Borrowing from a deep market understanding, we will further build upon existing functional capabilities with targeted and innovative approaches that will best serve the needs of a rare disease launch, such as AI-driven omnichannel communications and in-depth patient engagement that will help inform an access focused distribution strategy with meaningful patient support programs. Leveraging these types of strategies in addition to our demonstrated success with YUPELRI in the U.S. hospital marketplace, we believe we can efficiently build upon our existing infrastructure while seeking a partnership for ampreloxetine's rest of world strategy. Lastly, tying back to Theravance's core purpose of delivering medicines that make a difference, the potential opportunity to ampreloxetine could offer as the first durable effective solution for nOH patients is significant, with a clear objective of solving for the high unmet needs of MSA patients and their care team, we are moving forward with focus and momentum around the ampreloxetine launch and we view this opportunity as Theravance's next chapter of growth. With that, I will end the presentation and turn it back over to Rick to share his closing remarks, and then we will open it up for Q&A. Rick?

Thank you, Rhonda. And now we can go to the Q&A. Operator?

[Operator Instructions] The first question comes from Marc Frahm at Cowen.

Thanks everybody for putting together today's session. Maybe for the physicians, just can you maybe explain some of the underlying kind of biology that's going on that leads to not just the fairly rapid change in norepinephrine levels and blood pressure but then kind of taking what appears to be kind of several months to kind of fully resolve or fully impact all of the symptoms on the push of scale. And then in your care, and maybe this is also for the company, just within that scale, what do you view as kind of the most impactful to patients and the biggest unmet need for the patients? Is it really the full breadth of the scale or are there particular symptoms within there that you think are particularly important to show the effect on?

Sure. Thanks, Mark. Let's go to Italo first and then Horacio for the first section, and then we'll come back on the second part of the question.

So if I heard correctly, the question was whether how long does it take for symptoms to improve with ampreloxetine? I hope that was the question, if I understood correctly. And you can see effects from the first dose. There's an acute improvement in upright blood pressure, and that results in improvement in symptoms. The reason we're focusing more long term is because there is no treatment so far that has shown durable effects. Droxidopa was 2 weeks where the data we have for ampreloxetine is 22 weeks. So I think that's a big breakthrough in terms of durability of effects. In terms of the disease itself, multiple system atrophy, it's a progressive neurodegenerative disorder that unfortunately progresses relatively quickly in about 6 to 8 years. And perhaps Horacio Kaufmann, might want to explore more of that. Horacio, you're on mute so if you could...

Horacio, you are on mute? So if you could...

Yes. Thanks, Italo. I think one of the -- I mean, there were a few issues on the question. Again, if I understood, you wanted to know how long it takes for all the autonomic symptoms to develop. Was that the case, Marc? Was that?

It was more -- it seems that you have a fairly rapid impact norepinephrine levels and then also a pretty rapid impact on blood pressure. But the kind of the impact on symptoms seems to be a bit more delayed and take not days, but maybe a few months to really reach its maximum, can you just kind of explain that disconnect.

Okay. But you're talking about the effect of ampreloxetine or...

Correct. yes. Yes, the drug effect.

I mean it's quite interesting that, as Italo mentioned, the effect on blood pressure many times is quite acute. However, it seems to take a few weeks to get the maximum point. We believe that this has to do with the pharmacology of the drug that is longer acting and it's not just an acute effect, although the acute effect is obvious. The whole improvement takes many times a few weeks. I believe that's part of the pharmacology of the drug. Again, we'll -- this is what the clinical trials show. Going to, if I understood, Marc, your other question, what are the most relevant features of the scale? Was that the question? You see Item 1, which is the dizziness, lightheadedness is perhaps the most obvious but there's no doubt that the reason why we included the other items on the scale, this OHQ is because the whole impact of nOH on the patient is not just the dizziness or lightheadedness. We believe it's a much better tool, a much better assessment of the effect of the drug for these disease to use the whole scale. And that's the reason and the FDA agree with us that it is the whole OHQ, what is the first part, the one that is the symptom assessment, the one that better represents the problems that the patient experience and the impact of ampreloxetine on the improvement. I don't know if I answer fully your question, Marc.

Yes, that was very helpful.

The next question comes from Douglas Tsao at H.C. Wainwright.

I'm just curious for the 2 physicians that they can offer some perspectives in terms of what percent of the overall MSA population would be appropriate for treatment with ampreloxetine if was approved. And generally, at what point in terms of the patient diagnosis or the patient journey, would treatment for their nOH be needed or desirable?

Horacio, will you start and then we go to Italo.

Yes. Thanks for the question. It's quite interesting that nOH very frequently is the first symptom of patients with multiple system atrophy. In fact, many patients have nOH many times quite severe, even before they have any noticeable motor symptoms. So many times, this is even something that occurs months or even a year before other symptoms. So it's very early on. It's very disabling and it affects at least 80% of the patients. In the surveys is 80 or -- my feeling is that it's a little higher, in my practice, it's a little higher. I would say that almost every patient with MSA, in fact, almost every patient with MSA has nOH. Now it is symptomatic, meaning it produces significant symptoms in at least 80% of them. So it's -- there's no doubt and it's one of the criteria for diagnosis. So there's no doubt that this is highly prevalent. On the other hand, it appears to me, that's my clinical opinion that perhaps ampreloxetine should be the first line of treatment in these patients, and it should be pretty early on in the journey of the disease. You see in a few years, patients are severely disabled. So as clinicians, it's very important, the first few years of the disease when still quality of life can be significantly improved. And when in nOH is perhaps one of the most dramatic disabling symptoms is to treat early and powerfully with a drug that is effective and that has -- that appears to be quite safe. So again, we believe, or I believe, that this would be -- patients should receive the drug early on. And I would say that almost 80% of the patients with MSA could or should receive these treatments.

Italo, anything to add to Horacio's comments?

So, no, I think that was perfect. I have nothing really to add. I think most patients will need and should benefit from treatment.

Very good. Doug, does that answer your question?

That's very helpful. And I guess, how do you think about what this means in terms of a patient's sort of disease progression? Or are there other sort of secondary benefits for an MSA patient when you treat your nOH with ampreloxetine potentially?

Italo, you want to start?

Yes. Unfortunately, I don't believe that it will affect progression of disease. It will improve quality of life, which is for us, a very important part of the treatment of these patients. And it will avoid fall. And if patients are not able to stand up and they get decondition, the orthostatic hypotension just gets worse. So in that way, it will improve the quality of life for these patients and will avoid progression of the orthostatic hypotension. Unfortunately, I don't think it will improve the -- or reduce the progression of disease. Horacio?

I think you answered perfectly, Italo. I would emphasize what Italo says and remind you of this vicious cycle that occurs. You see patients will have motor problems but initially, the motor problems are not that severe. So the orthostatic hypotension not only makes them very difficult to stand up and walk it accelerates the deconditioning. So this vicious cycle that lack of treatment of nOH will make patients even more unable to work or move and that in itself versus the orthostatic hypotension. So no doubt that as far as we know, the drug doesn't change the biology of the progression of the neurodegeneration but by slowing the inability to walk in a way, it prolongs the time that the patient is able to do physical activities. So it doesn't slow the biological progression but it allows the patient to remain active for a longer period of time. So it slows the worsening that the orthostatic hypotension causes in the rest of the motor symptoms.

And I guess just a quick follow-up. I mean how significant is that deconditioning effect that you spoke of, Dr. Kaufmann?

Dramatic, dramatic. I mean we are all aware of the dramatic effect of exercise. And one of the biggest problems we face is that exercise may worsen orthostatic hypotension. So patients stop moving, stop having physical activity, and that worsens their motor ability dramatically. So by allowing them to keep moving, we really can slow that effect, that vicious cycle of deconditioning. You see that the conditioning is not just the physiologic effect that lack of activity has on muscles, it's the fear of falling, it's -- look, almost everybody has -- may have had the experience of fainting, right? This sensation when you stand up very quickly and you get lightheaded, the sensation you are going to faint. Now imagine if you have that sensation because normally in any of us, that occurs for a few seconds and disappears. In these patients, imagine what it is that each time they stand up, they get this feeling that they are going to faint. So that fear of fainting, fear of falling causes even more deconditioning. If you can treat that, you have done a big service to the patient and his ability to move.

Yes. Operator let's go to the next question.

The next question comes from David Risinger at Leerink.

And yes, I wanted to add my thanks for you hosting this session. It's super helpful and thank you to the 2 KOLs. So I wanted to start with a couple of questions on the patients. So what is a typical patient profile? What do they look like? Are they obese? Are they skinny and how variable do they appear? I'm just trying to get a sense for that. And I'm also curious about the variability of patient comorbidities in a small trial.

Italo, maybe you can comment, then we'll go to Horacio, and then we'll talk just a bit about CYPRESS and what we do to control quality of the study.

So these patients, the sad thing is that they can be otherwise pretty healthy. The loss of autonomic function means that you also not only have low blood pressure standing but tend to have high blood pressure lying down. And when other worse -- you can envision a patient with Parkinson, the worst Parkinson you've ever seen, that will be like what a late disease MSA patient looks like. But they're not particularly obese. I don't have the -- I don't think they have more comorbidities than the rest of us. And most of them, especially the patients that are enrolled in our studies, are otherwise relatively healthy and we can improve them -- their quality of life because of the orthostatic hypotension. I don't know, Horacio, you want to comment on that?

You answered -- there's no predilection on body mass index. You have them in all flavors that are like the profile of the U.S. population, they are thin or obese, they are all types. Now usually, the -- you see average age at onset in all our studies is 55, 56 years old. So these are young people. And they are younger -- usually younger than patients with Parkinson's disease. So they have usually -- as Italo mentioned, they have lease comorbidities. Many times, these are -- or most of the times, these are relatively healthy patients and again, younger than those with Parkinson's disease and many of them I would say most of them that I see in the clinic, they are still working. They're still actively working. They are not retired. Again, the typical patient is the 54- or 55-year-old guy or man or women that starts with lightheadedness or dizziness on standing, some increased frequency urinating that they believe is age-related, sometimes sexual dysfunction. And following that, some mild difficulty walking all with balance that somebody may notice, all their speech becomes a little slower. That's the typical and otherwise healthy. That's the typical profile.

So just to add to that, I think in looking at our -- the CYPRESS program, Aine, you just may want to touch on a point that you made during your comments on the purpose of the Enrollment Steering Committee.