Jazz Pharmaceuticals plc (JAZZ) Earnings Call Transcript & Summary

Good afternoon, everyone. Welcome to our session with Jazz. It's my pleasure to be hosting the Jazz team with Bruce Cozadd, who is the Chairman and CEO of the company; along with his R&D leadership team. We've got Robert Iannone, who is the Head of Research and Development; Phil Jochelson who's the Head of Neuroscience Development and Joshua Stadelmann, who's the Vice President of neuropsychiatry. Perhaps I would request Bruce to kick us off with a few opening remarks, and we can take it from there. Before I let you start, Bruce, just for the audience, if you have any questions along the way that you'd like me to ask, please feel free to send it over in the chart. With that, Bruce?

Great, Ami, and thank you for having us today. It's nice to be able to dive into 1 area of our pipeline with a little more specification. Before we get going, I do want to note that no forward-looking statements, and those are obviously subject to risk factors. So please do see our SEC filings for a description of those. I'll also probably refer to non-GAAP financial measures, and our website has a full reconciliation to GAAP. So if we can go to Slide 5. So in January, we introduced Vision 2025, which includes 3 components central to our ongoing growth, commercial, pipeline and operational excellence. And the focus today is obviously on the second component pipeline. We've been making significant investments in our pipeline and people to drive innovation, advanced novel therapies for patients in need and deliver sustainable growth and enhanced value. Certainly, our acquisition of GW last year provided an important new therapy Epidiolex to our commercial portfolio, and most germane to today's discussion, bolster our R&D pipeline and capabilities through the addition of the nabiximols program to our late-stage pipeline, and the GW cannabinoid platform, which has the potential to generate multiple development opportunities. And just as importantly, many talented colleagues have joined our R&D team, providing expertise in the development of cannabis-based therapies. Next slide. As you know already, we're focused on 2 primary therapeutic areas, neuroscience and oncology, and we're very excited about some of our near-term opportunities outlined on this slide. We initiated 5 clinical trials in the second half of 2021, including trials for all 3 programs we're discussing today. nabiximols, suvecaltamide, previously referred to as JZP385, and JZP150. And we're expecting the first data readout from our nabiximols program in the first half of this year, which Dr. Steinerman will discuss in more detail. He is a Board-certified neurologist and neuro psychiatrists who joined our team through the GW acquisition. I have to say, Dr. Steinerman is also a boomeranger, having been part of the JAZZ R&D organization prior to working on the [ NivicSmals ] program at GW. So we're excited to have him back. That was an easy $7 billion to spend to get you back, Joshua. Before working in industry, Joshua served as an investigator for multiple CNS clinical trials and led clinical research and educational programs in academic neurology. So let me hand it over to you, Dr. Steinerman.

Thank you, Bruce. If we go to the next slide, I'd like to emphasize that spasticity is an important clinical phenomenon. It's often underappreciated and underrecognized. Spasticity manifests in multiple neurological conditions. And the initial focus for the nabiximols research program has been on MS multiple sclerosis spasticity, where we have the most data and experience as well as global regulatory approvals. It is important to highlight objective manifestations of spasticity such as increased muscle tone, muscle spasms and increased muscle reflexes. The mechanism of spasticity is depicted in the figure. Normally, there's descending motor neurons, which regulate the stretch reflex between the spinal cord and the periphery via inhibition. In the presence of MS lesions, the result of the disinhibition is a hyperexcitable stretch reflex, an abnormally increased muscle activity. It's also critical to emphasize the subjective patient experience of spasticity. Patients often describe muscle stiffness, tightness, spasms, pain, difficulty moving. This is often focused on the lower extremities affecting ambulation and can also impact sleep and quality of life. I'd like to elaborate on a few anecdotes to make the spasticity phenomenon more relatable. Most people are familiar with muscle spasms as an example, which can be sudden and painful. Imagine ongoing unpredictable spasms in multiple muscle groups, possibly awaking you from sleep. One individual we engage as part of our patient-centered research efforts told us that it was like his body was encased in steel bands and that he's in constant fight with his own body. If we go to the next slide, please. I'd like to describe nabiximols as a product and the mechanism by which it exerts its antispasticity effect. Nabiximols is a botanical product derived from specialty bread cultivated cannabis plants. Among its hundreds of chemical constituents are over 120 cannabinoids as well as terpene, steriles, triglycerides and other noncannabinoid constituents. Nabiximols modulates the endocannabinoid system, which consists of endogenous cannabinoids, molecules that are made by the body, cannabinoid receptors including but not limited to CB1 and CB2 receptors, in addition to transporters and enzymes would regulate the levels of the endocannabinoids. The figure is a simplified depiction of how elements of the endocannabinoid system regulate neurotransmission specifically. It's important to realize that the endocannabinoid system also maintains homeostatic functions in multiple other cell types and physiological systems. And while the precise mechanisms by which nabiximols exerts its antispecificity effect remain to be fully elucidated, and animal models of MS and spasticity, nabiximols reduced limb stiffness, improved function and modulated excitatory inhibitory balance and the endocannabinoid signaling. Two phytocannabinoids, which resemble the endogenous endocannabinoids that are plant-derived are most abundant in nabiximols. THC acts at CB1 and CB2 receptors. CBD modulates THC activity in CB1 receptors in addition to other pharmacologic targets. Coadministration of THC, CBD, and the numerous other botanical constituents produces complex pharmacological interactions and thus, the entirety of the drug substance is considered active. If we advance to the next slide, I'd like to highlight that nabiximols has been approved globally in 29 countries based on prior clinical trials. Those trials focused on the patient-reported outcome measuring their experience of spasticity. And based on our discussions with FDA, we have developed complementary trials with additional measures that include muscle tone and muscle spasm frequency as the primary endpoints. We now have an ongoing clinical trial program with 3 studies providing multiple shots on goal to support our future NDA in the United States. Collectively, these MS trials have the potential to provide a compelling body of evidence and we'll learn from each of these trials. The first trial, which is smaller and shorter relative to the other 2 is evaluating the effects of nabiximols compared to placebo on a clinical measure of muscle tone in the lower limbs. It is a Modified Ashworth Scale endpoint referred to as the lower limb muscle tone 6. The LLMT-6 is the average of 6 individual Ashworth Muscle groups, namely the knee flexors, the knee extensors and the plantar flexors on both right and left side to the body. Data is estimated in the first half of '22. If the results from this first trial are positive, there is the potential for an NDA submission to FDA in 2022. The second study, the most recently initiated of the 3 studies will evaluate the effects of nabiximols compared to placebo on the LLMT-6 endpoint as well. It includes approximately 190 participants with MS, and data is estimated in late 2022. The third study is designed to demonstrate the efficacy of nabiximols compared to placebo in reducing muscle spasms in MS spasticity. It is a 12-week parallel group study with a sample size of approximately 450 participants and data is estimated in early 2023. Wrapping up on the next slide, I would like to emphasize that nabiximols can address a significant opportunity and unmet need for patients in the United States. Spasticity occurs in up to 84% of MS spasticity patients and approximately 1/3 of those who experience spasticity live with uncontrolled symptoms. A significant proportion of MS patients have tried cannabis unregulated or unapproved cannabis products to self-medicate. And current treatments, which are available by prescription are falling short of patient and health care provider expectations. Surveys have shown that patients and physicians are dissatisfied with available medications that there are limitations, both with regard to tolerability and with regard to inadequate efficacy and highlight the need to develop alternative therapeutic agents with novel mechanisms of action and different safety profiles to provide symptomatic relief for these individuals. Thank you very much for your attention.

Thank you, Joshua. Just a reminder for the audience, we are going to take Q&A from the audience on each topic at the end of the slide presentation for each. So I've received something -- some questions on nabiximols, I'm going to combine it for the question I had. Joshua, just with regards to the first study that's going to read out in the first half of the year with 52 patients. If I compare it to one of the studies that was conducted in Europe, this was conducted in the Czech Republic and Austria, and it showed a positive readout on the Modified Ashworth Scale subscore by muscle group, which is the closest end point I could find to the LLMT-6. How do you think about translating data from there into either the first study or the second study that's going to read out with the LLMT-6 score data primary endpoint because the European study was enriched for patients that were responding to nabiximols in Part A of the study, plus it was a much larger study in terms of just the patient's size. I think they started with about 191 patients. So help us put in context, what does it mean for the readout for the U.S. trials and set our expectations right for what we should expect from each of the 2 readouts?

Thank you, Ami. Happy to address the question on the LLMT-6 end point. You referenced our previous trials, we've actually done extensive post-hoc analyses of the previous trials compared to what you have seen in the original publications. We have confidence based on both trials that we conducted and published that included the Ashford endpoint that support efficacy on the Modified Ashworth as well as the specific 6 muscle groups that are highlighted from the Ashworth in the LLMT-6. So the LLMT-6 shows a signal in those prior trials and also is highly clinically relevant to the lower limb in the muscle in the MS patients.

Can you explain why there's a difference in the way the trials have been designed in terms of Part A, Part B, where you screen for patients that respond to nabiximols in Part A, and then you measure the endpoint in Part B. And we do not see that in the U.S. trials. Why is that?

Two of the previous positive trials on the NRS were indeed enriched trials, which featured a 4-week run-in period to identify responders. Although these trials are not enriched in that way, they are enriched in the sense that the patients will have elevated Ashworth scores in the lower limbs in -- as a part of the inclusion criteria. So they are set up to have an effect specifically in patients who have demonstrated increased muscle tone at baseline.

Got it. Okay. Okay, that's very helpful. Just with regards to the U.S. studies that are studying spasm frequency, and that's one of them, you've listed as a third study in the earlier slide. That endpoint was hit by one of the European studies. But that study also involved in enrichment. Do you expect -- are you changing the enrollment criteria in a similar way in this U.S. study as well, if you could help us understand that?

Exactly, Ami. I could address it almost in the same way that we addressed the discussion on muscle tone, but I'll elaborate. Both trials, which were the 604 trial and [ SABAN ] trials have been published, but post-hoc analysis show efficacy on both muscle tone and muscle spasm in both of those trials. We published some of these proceedings and are working on a manuscript. What I would like to say is exactly the same point that although we don't have an enrichment for muscle spasm responders, we do recruit for people who have elevated frequency of muscle spasm to baseline, so we anticipate to find a benefit in those patients.

Got it. And maybe one last question that came in from the audience. Can you just address the powering of the first trial and perhaps the second one as well, the 52 patients and the 190 patients trial?

Joshua, I can take that if you don't mind. Yes. So thanks for the question, Ami. We have not disclosed details on the powering specifically. But what I can say is those 2 "sister studies" were intended to have an opportunity with a smaller study in parallel to a larger study that were similarly designed so that the larger study, we think would be fully powered to the effect size that would be meaningful and support an FDA approval. The idea of running the smaller study in parallel was twofold. If we see an effect that's large enough even in that smaller sample size, which is possible, less likely, but possible, then we could use those data to begin a dialogue with the FDA and potentially support a submission. Certainly, even in the absence of that, the other trial continues, and we may have had some learnings from that trial that overall would impact the more chances of success.

Okay. That's very helpful, Rob. Perhaps we could move to JZP385 here.

Great. Thank you very much. So here on Slide 13, I'd like to start by saying that we at Jazz believe there is a significant opportunity to improve the treatment of movement disorders. And the Jazz pipeline reflects this with suvecaltamide and the nabiximols program. Essential tremor is very common with 11 million prevalence in the U.S. and European markets. ET is characterized by an involuntary rhythmic tremor that is not a symptom of another neurological disorder or drug-induced side effect. The characteristic to-and-fro movements, which are called oscillations, of at least 1 part of the body due to involuntary rhythmic muscle movements can occur 1 to 12 times per second. It was commonly affecting the hands and arms, but also they had even the voice and the lower limbs. As you know, essential tremor can be highly debilitating with significant effects on a patient's quality of life and activities of daily living, such as eating, drinking, dressing, shaving and writing. This can result in feelings of embarrassment, can be associated with cognitive deficits, anxiety, social phobia, depression and sleep disturbance. There is a very high unmet medical need with up to half of patients not responding to either propranolol or primidone and over half of the patients, reportedly discontinuing medications either due to lack of efficacy or to the side effects. And in fact, there has not been an FDA-approved therapy in more than 50 years. So moving to Slide 14. Suvecaltamide is a highly selective T-type calcium inhibitor, a modulator of T-type calcium channels, which play a role in the brain's management of muscle movement. The differentiated mechanism of action has the potential to improve tremor in patients who have not responded to current treatments. T-type calcium channels help to regulate in nerves, nerve cells balance of calcium ions, acting as a gatekeeper to help ions enter and leave the cell membrane. In the left figure, we see the normal state. Normal Cav3 expression activity, balanced channel opening and inactivation and normal firing and communication. If there is an increased activation of these channels, the volume of calcium ions crossing the membrane increases and becomes unbalanced, which contributes to irregular burst of nerve signaling -- in irregular burst of nerve signal. In the middle figure is the pathological state, abnormal neuronal firing, disregulated neuronal communication and excessive rhythmicity. In essential tremor, increased activation of T-type calcium channels in 2 of the brain's movement managing nerve networks results in excessive rhythmic signals that promote a patients recurring involuntary muscle movements, known as tremors. Importantly, suvecaltamide preferentially binds to a specific confirmation of the channel to reduce and stabilize activity. This preferential binding to a specific confirmation of the channel blocks neuronal transmission only when under conditions of hyperexcitability, and differs from the nonstate dependent T-type calcium blockers. In the right figure, we see channels after introduction of suvecaltamide, reduced channel activity, stabilized firing and communication and normalized network oscillations. The high selectivity of suvecaltamide, along with its lack of effects on other types of ion channels, makes suvecaltamide promising candidate for the treatment of essential tremor. Suvecaltamide is the first medicine to be developed for essential tremor, specifically to address the overactivation of calcium channels. And on to Slide 15. This illustrates the design of the ongoing Phase IIb study of suvecaltamide in central tremor, which is a double-blind, placebo-controlled trial in patients with moderate to severe disability associated with their tremor, who will receive once-daily oral doses of either 10, 20 or 30 milligrams of suvecaltamide or placebo for 12 weeks. All participants randomized to the active arms will start at a dose of 5 milligrams each day and undergo a fixed titration to the randomized fixed dose level. The key endpoints are focused both on functional improvement and improvements in quality of life. Based on results from the T-CALM proof-of-concept study and also FDA feedback, the primary endpoint is a composite of the Essential Tremor Rating Assessment Scale also known as TETRAS and is composed of items from 2 subscales, first, the TETRAS activities of daily living, which includes measures such as feeding with a spoon, drinking from a glass, hygiene, pouring liquid, using keys, et cetera. And also the TETRAS performance scale, which includes measures of handwriting and drawing using the Archimedes spiral that we showed earlier. So thank you for your attention, and I'm happy to take questions.

Thank you, Rob. Can you talk about some of the data that was generated in the prior study? And maybe help us think about the endpoint evaluated in that study and what you're going to evaluate in the Phase IIb? And maybe put it in context for what does the FDA want to see or do we have clarity on what the FDA would like to see as an endpoint in essential tremor?

Yes. Thank you for that, Ami. So as you know, the T-CALM study was a proof-of-concept study. It was a randomized, well-designed trial. And in that study, we looked at several different endpoints among them, the TETRAS rating scale and different aspects of it. So we have the opportunity to see the effects across different endpoints, including TETRAS and also patient-reported outcomes. And have had extensive consultation with the FDA around what would be the most appropriate primary endpoint, also building in additional secondary such as patient and physician-reported outcomes. So based on those interactions, as I mentioned in my presentation, we selected the composite, drawing elements from both the activities of daily living, but also the performance rating scale.

Got it. Can you help us understand from a clinically meaningful perspective, what type of a change in the composite outcome score you would be looking to see to really sort of have the drug pass muster in terms of demonstrating efficacy?

We haven't disclosed details of the analysis plan to the level of what effect size are we powered to, for example. However, as I mentioned, we did draw on the T-CALM study. We know the effect size that we were observing there. We gained important information around the patient population in order to define that population relative to antitrust criteria around severity, for example. And in discussions with the FDA, designed the study and powered that study to an effect that we and the FDA agreed will be clinically meaningful.

Okay. Can you talk to the severity of patients that will be enrolled in the Phase IIb?

Yes. So again, we won't disclose the exact criteria. But as mentioned, we drew on data from the T-CALM study to get a sense of patients who would be benefiting most. And there is a minimum criteria of severity required for inclusion in the program. And often, these are patients who not only have enough of a disability to be able to pick that up in the trial that we've designed but have also been on other therapies that are clearly refractory to it in many cases.

And roughly to put it in context, what percent of the total patient population that you described would that address?

If I had a specific number to that. But as I mentioned in the opening comments, it's a highly, highly prevalent disease. And I would say a significant portion of those patients have some symptoms that are really traveling to them. And so if you interact with patients who are suffering from a essential tremor, you can see that tremor in the hand may make it very challenging to do simple things like drink coffee from a cup or right with a pen or a pencil. And so it's those kinds of -- that kind of severity that we'd be looking to address, which I think is fairly common.

Yes. And as you can probably guess, Ami, this can actually be career limiting for people in different professions, a surgeon, a musician, for some people, this is the difference between being able to earn their living or enjoy their art or not. So really impactful on quality of life.

And just to add to that, I have been emphasizing that we have clarity from FDA and from the T-CALM study on the primary endpoint, but important to note that we have secondary endpoints, especially around global impression scale. So asking patients how they're doing. And I think that, that will ultimately add to the primary endpoint in terms of what we're observing clinically meaningful to patients. And that will ultimately support the approval.

Okay. I think if I'm not mistaken, the study that Cavion did evaluated 10-milligram dose b.i.d. Is that correct?

That's right. And as you may know, we took that -- we created a new formulation that would be suitable for once daily dosing, we evaluated that in healthy volunteers. And therefore, bringing forward the once-daily formulation, which we think is a real advantage to patients. And we've selected 10, 20 and 30 milligrams. So 20 is roughly the equivalent of 10 twice a day from the T-CALM study, we're then bracketing that with higher and lower doses. And importantly, we think that once nightly -- once daily formulation can help us to do a better, more precise titration and ultimately manage the tolerability there.

I have some limited data in front of me here. I believe that the earlier study had about 19% dizziness rate. I'm not sure what grade those were. If you could comment on that and also the discontinuation rate in the earlier trial and how you've sort of considered that in the study?

Yes. So as you know, although there was a 19% rate of dizziness, the manuscript reflects that only 2 of those patients actually discontinued due to the dizziness, giving you a sense of, overall, the more significant dizziness AEs. And generally speaking, I'd say the drug was well tolerated, and we learned from that trial around the importance of carefully it's slowly titrated to that maximum dose. We think that using the extended formulation that we have to minimize the Cmax reaching a twice daily dose will recur twice and to a higher level, will actually facilitate a smoother titration with fewer side effects. So we've tried to address it further in the Phase III as well.

So 2 discontinued due to dizziness. And my rough estimate is there were about 8 patients who discontinued in the study? I'm seeing about 17% discontinuation rate. So what were the other common causes of discontinuation?

I'd have to go back to give you a precise answer, and I'm happy to do that. But again, generally, what I would emphasize there is that we think that many of these things can be managed through more careful titration and may ultimately be lessened through the new formulation that we have, and we'll minimize those pre concentrations throughout the day.

Okay. All right. Thanks, Rob. I think it's time to move to JZP150. Phil?

Okay. Thank you, Ami. I'm excited to present our 150 program to you. As we know, JZP150 is a mobile highly selective inhibitor. And the initial development is focused on PTSD. PTSD, as you know, results from exposure to actual or threatened death, serious injury or sexual violence. And that is one of the key diagnostic criteria for the DSM-5, using the DSM-5 tastification system. It represents a global public health problem that is associated with significant morbidity and mortality. For example, up to 40% of patients with PTSD also may have substance use disorders. In addition, up to 30% of these patients made suicidal ideation and it's a highly prevalent condition affecting up to 8% of adults during the lifetime. Importantly, there's been no newly approved pharmacotherapy in almost 2 decades. The 2 approved therapies are both SSRIs, so share similar mechanism of action and have the mutations with respect to the efficacy and/or safety. Key highlights from our program in addition to initiating the Phase II study at the end of last year is we were granted fast track designation by FDA. And this underscores FDA's recognition that this is a severe disease and unmet need. It has a differentiated mechanism of action, [indiscernible] is it potent and selective for FAAH but also has irreversible binding. And this has the potential to provide a prolonged pharmacological effect as a result of that differentiating feature and also allows us to give a once-a-day oral administration product. Importantly, it also has the potential to impact the pathophysiology and the symptoms of PTSD. And we have a publication, a recent publication that demonstrated the benefit on the fear extinction -- improving fear extinction learning and reducing stress reactivity in an experimental model of PTSD in healthy volunteers. I won't spend a lot more time on the significant unmet need because I think I've touched on that. But I do want to emphasize that the pharmacology of this drug does lend itself to development opportunities beyond PTSD. Can we move to the next slide? So in this slide, I'm going to cover the PTSD pathophysiology and the rationale for treatment with JZP150. We're going to focus on the top panel and then the left -- far left side. And what we have here is at the bottom of that figure is the postsynaptic neuron and the top is the presynaptic terminal. And in between that space is what we call the synaptic cleft. AEA is an endogenous or an endocannabinoid. It's an endogenously produced substance undermined. And it is produced in the postsynaptic neuron and then released into the postsynaptic cleft where it binds and activates the CB1 receptors, which ultimately results in the release of important neurotransmitters such as glutamine and GABA. FAAH is the enzyme that actually results in the metabolism of AEA. When one has a traumatic event with stress and anxiety exposure, what happens is you get a hyperactivation or overactivation of FAAH. And as a result of that overactivation of FAAH, there's less AEA production. And this has been shown in both preclinical and clinical models that AEA reduction is apparent in these conditions. As a result of that low AEA levels, you get less activation of the CB1 receptor and which subsequently results in the lower release of the important neurotransmitters. And this can translate not only to symptoms of anxiety, but as the impaired extension of emotional memory. So moving to the bottom panel, with the JZP150, which inhibits FAAH, we can increase AEA levels, we can restore the CB1 receptor signaling and this has the potential to reduce anxiety, improve fear extinction learning and improve sleep. With respect to the top 2, the reducing anxiety, and improve the extension, I'll refer you backwards to that recent publication in the Journal of Biological Psychiatry in that experimental model of healthy volunteers. It was very effective not only in increasing anandamide levels tenfold relative to the placebo group. This was a randomized placebo-controlled study, but also showed reductions in stress reactivity can improve fear extinction learning. Fear extension learning is essential to the treatment of PTSD and interventions, which enhance fear extension learnings such as prolonged exposure to therapy, have been shown to be efficacious in patients with PTSD. So having a pharmacological drug, which also has the potential to further improve that fear extension learning would be very complementary to existing practice where they use other interventions to do that. Moving on to the next slide. We have an ongoing Phase II study, which we initiated, as you know, at the end of last year. This is a randomized placebo-controlled study in 270 patients with DSM-5 diagnosed PTSD, patients will be randomized to either receive placebo, a low dose of JZP150 at 0.3 milligrams once daily or a high dose of JZP150 4 milligrams administered 1 daily and it will be a 12-week double-blind treatment period. The primary endpoint for the study is the CAPS-5, also the -- known as the -- more expanded name for that is the Clinician-Administered PTSD scale total symptoms severity score, we will look at the change from baseline to week 12. CAPS-5 is considered the gold standard assessment of PTSD symptoms and is certainly recognized not only by clinicians, but also by the PTSD National Center and also in consultation with the FDA, we have agreement on that as the primary endpoint for this program. It's a 30-item structured interview, which looks at the severity, intensity, frequency of PTSD symptoms across various symptom clusters as well as the impact on social and occupational functioning. Items that scored from 0 to 4, high scores indicate greater severity of symptoms. The top line data from the study is expected around the end of 2023. In the interest of time, I'll end there and be happy to take any questions and appreciate your attention.

Thank you, Phil. Maybe a couple of quick questions in the time we have. Since the asset was acquired in October 2020, what work has been done on the formulation or the dosing of the study? And how did you pick these 2 doses for the study?

Great. Excellent. Well, I think there's a number of accomplishments that we had over -- in a relatively short period of time. In approximately a year, we were able to have -- get our arms around and learning around PTSD as a disease and work with many key opinion leaders in the area. We were able to put together a protocol that we, in consultation with the FDA, designed what we think is an appropriate protocol with the appropriate endpoint. We achieved Fast Track designation and it's -- if you think about that, that will happen within approximately a year and then initiated the Phase II study. So I think it speaks to the operational excellence, I think that we strive towards Jazz and it's another example of that. With respect to the dose selection, there was a fair amount of legacy data. It was a pet that we inherited from Pfizer, which include pet receptor occupancy study. And we also have biomarkers both the ability to inhibit 5% FAAH inhibition as well as the AEA response to that. And we had that multiple doses ranging from 0.3 all the way to 4 milligrams. And we were able to triangulate that as well as look at some of the clinical data that had previously been generated around safety and tolerability. So we think we feel comfortable that we book ended the dose range. The 0.3 we're expecting to be on the minimally effective side, but we did want to characterize that in 4 milligrams as what's been studied in the cannabis use disorder study, was also studied in osteoarthritis study And also was studied in that healthy volunteer experimental model of PTSD looking at fear extension learning.

Okay. Maybe I'll end with one last question maybe for Bruce. Bruce, when you started this discussion, you highlighted 5 novel assets that you're targeting that could come to market by the end of the decade. Are these 3 out of the 5? And which are the other 2? And perhaps also, how much are you dependent on business development for your 2025 vision? Probably 2 questions in 1.

Your specialty, Ami. First of all, I just want to end by thanking you again for the opportunity to dig into these 3 programs a little bit in more depth than we usually can in our broader presentations. These certainly are 3 of the programs that we're very excited about, but there are only 3 of many programs we're excited about across neuroscience and across oncology. Over the past few years, we've added about 18 new programs to our pipeline, and we will continue to be active on the corp dev side to broaden out our commitment to innovation in neuroscience and oncology. So I do expect that to continue. We've been busy. We'll stay busy. We've got great cash flow. As you know, you see us rapidly delever from 4.9x when we closed the deal in May of last year to 4.1 at the end of last year. And our target to be below 3.5x leverage by the end of 2022 does leave us room even in this year to continue to be active. So expect that, that strategy will continue. We're also excited to have novel programs emerging from our CombiPlex program and/or GW cannabinoid program. So the combination of our internal productivity and continuing to access external innovation makes us confident that we can hit or beat that target of 5 novel compounds coming to market this decade beyond the ones that we've already launched.

That's a lot. You're all keeping very busy. But this was a productive discussion. We learned about some assets that we don't really usually get that much in detail into. So I thank everybody and the team for taking out time to participate today, and thanks to all our listeners as well.

Thanks, everyone.

Okay. Thanks. Have a good day.