Part Two Of Three Parts: Parsing Out Parkinson’s
The following key opinion leaders (KOLs) participated in this “virtual roundtable” on new therapeutic approaches in development for Parkinson’s disease.
The truth is, unlike oncology and even the related neurodegenerative disease Alzheimer’s, the Parkinson’s drug-development space still lacks any immediate prospects for disease modification. But new approaches to symptomatic relief have proliferated to fine-tune treatment regimens and exploit various mechanisms to address many other, often dramatic conditions that can affect Parkinson’s patients.
Drug developers are targeting levodopa maintenance — augmenting and stabilizing the level of the neuron-signaling protein, dopamine, in the brain — as well as ancillary conditions, psychological and physical, that can greatly degrade patients’ quality of life and lifespan. Longer-term, researchers are resolving a better picture of the causal mechanisms in Parkinson’s, taking some leads from the works of their colleagues in the Alzheimer’s field on misfolded, aggregated proteins. The top candidate in Parkinson’s is alpha-synuclein, a structural component of neurons in the brain, that appears to follow a prion-like progression of misfolding that parallels advancement of the disease.
Here, in Part Two of our three-part series on new therapeutic mechanisms for neurodegenerative diseases, we compare the views of key scientific opinion leaders working with some of the companies developing new therapeutics for Parkinson’s disease. (See Part One, “Aiming at Alzheimer’s,” in our March 2016 issue, and look for Part Three, “MS: Some Hopes in Sight,” in June.) In our “virtual roundtable,” we stitch together the separate inputs of participants into one comprehensive discussion by a panel of disease experts — KOLs and scientists who are leading some of the most advanced research in their field. This month, we tap the thoughts of three KOLs in the Parkinson’s area: Drs. Irene Litvan of UC San Diego Health Sciences; Cindy Zadikoff, Northwestern University Feinberg School of Medicine; and Robert Hauser, University of South Florida College of Medicine. (See KOLs on page 27.)
Separate cameos of selected companies suggest the range and variety of new-MOA (mechanism of action) and drug development in the Parkinson’s space. As in the other parts of the series, our virtual panel discusses not only the scientific, regulatory, and other practical hurdles that lie before the new approaches, but also the issues that will affect any candidates that ultimately survive the development gauntlet and enter medical practice. Those include the possible use of therapeutic agents with different MOAs in combinations, the methods and authority for configuring combinations, and the challenges of clinical trial design, postmarket regulation, payer pushback, and patient education.
SYMPTOMS OVER CAUSES
Each of the members of our virtual-roundtable panel speaks from multiple perspectives — all of them treat patients, teach students, conduct research, and even run clinical trials. Tackling the first question in the discussion, they deliver useful details about emerging treatments for Parkinson’s disease, including why major disease-modifying therapies may not enter the space for many years.
What are the most promising therapeutic targets/mechanisms for Parkinson’s disease?
LITVAN: One of the most exciting new approaches for potential therapies for Parkinson’s disease comes from our better understanding of how the disease may start and progress, which is based on pathologic and clinical studies. It is being proposed that Parkinson’s disease may start in the GI system and/ or olfactory bulb and following a prionlike progression, spread to the various brain structures. Aggregated, misfolded alpha-synuclein from affected cells acts as a template and converts normally configured alpha-synuclein from normal cells into the misfolded configuration, thereby spreading the disease. If protein misfolding causes disease progression, and aggregated protein leaves the cells when the cells die, then antibodies against the misfolded proteins may be an effective therapy.
ZADIKOFF: We can’t really speak about just one mechanism for Parkinson’s. We have to speak about mechanisms. There may not be a single target that you can attack to address all the symptoms of the disease, particularly both motor and nonmotor. Different people may not get to the same endpoint at the same time, and so where and when in the pathway should we intervene to have a reasonable shot of adjusting the disease course? From a symptomatic standpoint, there are interesting new approaches to dopamine delivery and nondopaminergic pathways in the pipeline. For diseasemodification, the alpha-synuclein approaches are promising. But I hope we learn from the attempts to attack tau in Alzheimer’s disease — it may not be as easy as expected to affect the course of Parkinson’s by attacking misfolded alpha-synuclein.
HAUSER: Alpha-synuclein represents a huge change in our field during the past five to seven years. In the past, we made animal models for Parkinsonian slowness, stiffness, and tremor by killing dopamine neurons with various toxins and testing various agents to see whether they reduced symptoms or limited dopamine neuron loss. But people don’t just get exposed to a dopamine neuron toxin and develop Parkinson’s disease. It is a slowly progressive degenerative disorder.
Lewy bodies, large clumps of protein that occur in essentially all Parkinson’s disease patients, are packed with alpha-synuclein. When we investigated fetal cell transplants as a potential Parkinson’s therapy, two of our patients passed away about 14 years after transplant, and we saw the disease pathology had spread to the transplanted fetal dopamine cells; some of the transplanted cells had developed Lewy bodies. That got people thinking about Parkinson’s disease traveling from neuron to neuron. Investigators also observed what appeared to be alpha-synuclein pathology starting at the bottom of the brain and spreading slowly up toward the top. Today we have gene-based animal models that look a lot like Parkinson’s disease, so now agents are tested in conditions more similar to what happens in the disease.
But there is a lot of skepticism along with the optimism because we’ve been burned time and time again with agents that looked good preclinically and then failed in clinical trials. The lack of appropriate clinical biomarkers may be one reason for that. It is also frustrating we are still no closer to addressing a host of nonmotor symptoms and motor symptoms, including cognition, balance, gait, and speech in a Parkinson’s-specific manner. In late stages of the disease, those symptoms are what most impact quality of life.
EARLY TO SEE, EARLY TO TREAT?
In Part One of this series, KOLs in the Alzheimer’s field stressed the need for early-stage diagnosis and treatment with amyloid-plaque blockers. But, because disease-modifying therapies for Parkinson’s lie much further in the future, our Part Two panel takes a more reserved view.
Is there a need for development of ways to diagnose and treat Parkinson’s patients as early as possible in the disease course, before serious symptoms appear?
ZADIKOFF: Right now, early detection is actually unnecessary outside of research because, even if we detect Parkinson’s early, we cannot treat it any differently. But at some point, the ability to identify this disease early will be necessary in practice, assuming we can learn to address its causes and have a means of disease modification
LITVAN: We need to find biomarkers that could help us diagnose patients at earlier stages, but we now have recently developed diagnostic criteria for prodromal Parkinson’s disease based on age, potential risk factors, and symptoms. The criteria need to be validated, so they can be used to recruit patients at early stages in future therapeutic trials. We may be able to eventually include patients at earlier, preclinical stages when they have genetic markers and imaging with PET or DAT scans showing dopaminergic deficits. It will be ideal to include patients at preclinical stages and prevent progression to prodromal and symptomatic Parkinson’s disease.
HAUSER: One thing Parkinson’s shares with Alzheimer’s disease — by the time physical symptoms appear, 90 percent of patients have decreased sense of smell. Screening tests incorporating smell might be a good way to identify individuals who should receive further testing for Alzheimer’s and Parkinson’s and potentially receive treatment to slow or stop either disease. The other tool we have is the DAT scan to discern whether patients have lost dopaminergic neurons. A DAT scan can also help differentiate between Parkinson’s disease and other movement disorders, such as essential tremor. Identification of individuals with premotor Parkinson’s disease will become critical once we have a proven disease-modifying therapy.
COMBINE TO CONQUER
As with Alzheimer’s and complex diseases in other areas such as AIDS and cancer, the multiple mechanisms involved in Parkinson’s will probably demand combination therapies, presenting similar challenges; our panel agrees.
How likely is it that some future drug therapies, each one hitting a different target, will prove complementary if used in combinations? Could combinations of new drugs pose medical, regulatory, or economic issues for treatment of Parkinson’s?
ZADIKOFF: There are multiple pathways for the cascading effects of Parkinson’s, and different individuals may go down different pathways or the same pathways in different orders, even though they all merge into one in the end. Maybe for one individual, we only have to attack a single pathway to prevent the disease from progressing to that final common end. But maybe once the disease is in motion, we have to attack multiple pathways all at once. For example, not all of the nonmotor symptoms of Parkinson’s are caused by dopamine, so it seems naïve to think addressing only that pathway will resolve all problems.
LITVAN: There are many ways to think about how we might stabilize abnormal proteins or decrease their production or aggregation. Perhaps we will end up having therapies in the future like those in cancer, using more than one mechanism to slow or stop disease progression. There are several mechanisms proposed. Our study, STEADY-PD, is testing whether isradapine can slow disease progression by blocking specific calcium channels in very early Parkinson’s patients. SURE-PD is studying if inosine can do the same by increasing uric acid levels. If these studies are positive, why not combine the two medicines? The idea that we could combine different therapeutic approaches using various mechanisms in the near future is encouraging, but it will be challenging to determine the synergistic effect of combining these different approaches. As there have been so many therapeutic failures, we must be sure that each new drug can slow disease progression on its own before we combine the various successful drugs. There are also a lot of needs in the Parkinson’s area for which drug development needs to happen, such as cognitive deficits or other nonmotor symptoms where only recently therapeutic approaches have been attempted but beneficial drugs are still lacking.
HAUSER: We are still far enough away from having disease-modifying treatments that it is difficult to predict how our health systems will handle combinations of them. We already use drug combinations to manage Parkinson’s symptoms, and they do present challenges in individual patient care, regulation, clinical trials, and reimbursement. Some payers these days refuse to pay for commonly used medications such as trihexyphenidyl, a standard drug for tremor. We are getting more and more denials from payers for approved medications, and it takes a lot of time and effort by doctors and staff to win payer approval. When we have a drug that slows disease progression, I believe third-party payers will be forced to pay for it. But it is up to us to provide convincing evidence that it is in fact disease-modifying.
DOWN TO BUSINESS
Better clinical trial design, regulatory guidance, and collaboration with academic researchers top the panelists’ wish list for industry’s role in the Parkinson’s space.
What does the pharma/biopharma industry need to do to ensure the new treatments reach patients, and soon?
HAUSER: Some companies have been shy about Parkinson’s disease because of the uncertainty in the clinical and regulatory pathways for developing disease-modifying therapies. Everybody knows the pathway for getting a symptomatic medication approved. But what would it take to get a medication approved for slowing disease progression? No one knows the answer, and as an expert community, we don’t really have a consensus on how to sufficiently demonstrate that a medication slows progression.
Before Parkinson’s disease patients start symptomatic therapy, you can monitor clinical signs and symptoms as an index of disease severity. But patients can only go a year or so after diagnosis until they require symptomatic therapy. When symptomatic therapy is introduced, clinical status no longer reflects the underlying disease state. If your putative disease-modifying medication also has a symptomatic effect, you will get a false-positive result. This was the case for the first major trial attempting to show disease modification, DATATOP (Deprenyl and Tocopherol Antioxidative Therapy for Parkinson's disease), which tested selegiline and tocopherol as potential disease-modifying agents. No benefit was seen for tocopherol. However, patients randomized to selegiline went a significantly longer time before they reached a level of disability that required treatment with levodopa. This was initially interpreted as an indication of disease slowing, but we know now that selegiline has a small effect in improving disease symptoms, so the study did not allow a reliable evaluation of disease progression.
One option is to perform disease-modifying studies in early, yet-to-be-treated patients, but then you are unsure if an agent will really delay the important long-term issues such as balance and cognitive decline that are only seen later. Another option is to identify individuals with the disease before motor symptoms appear with the use of olfaction screening and DAT scans, and then determine if it’s possible to delay the onset of classic motor features. Again, the ultimate long-term benefit would remain undetermined from such a study, and it is not clear if we can identify sufficient numbers of such individuals. Another option would be to start studying patients three to five years following diagnosis and monitor them clinically for about five years, possibly in combination with quantitative imaging. We have yet to determine the best design for these trials. At this point, we probably will need a combination of an early and a late study to convincingly demonstrate any disease-modifying benefit. This also explains why there is so much biomarker research under way.
ZADIKOFF: I see academic-industry interaction as a creative polarity. Academic and basic researchers know companies can see the theoretical, mechanistic aspect of drug discovery and development, but we understand companies may test drug candidates empirically at the same time. Empirical action may be necessary when we don’t have all the data, biomarkers, and other tools to measure or define the mechanisms. Still, it is very expensive to go at a challenge like Parkinson’s without good science and ways to measure outcomes accurately. Ultimately, mechanistic understanding and biomarkers will be extremely critical to the success of clinical trials in this field.
Closer collaboration between industry and academics would also be helpful, considering all of the mechanisms and approaches now under discussion. Getting industry and academic researchers and leaders literally to sit together around a big table — I don’t know if that is feasible, but it would certainly help bring things forward. Typical interaction, mainly at conferences, is too random.
LITVAN: One way industry can promote progress in Parkinson’s treatment is to better educate the patients and the general population, so people understand early on when they are having problems that are not normal. If we really want to get new treatments to patients at early stages, we need to diagnose them early. So patients need to recognize and report their first symptoms to their primary physicians, who need to know when to suspect Parkinson’s and refer patients to movement disorder specialists. Education is important because we can improve the quality of life of Parkinson’s patients by treating their symptoms, but education will be even more important once we have treatments that could slow disease progression. Unfortunately, most newly diagnosed Parkinson’s patients have misconceptions about the disease and may see the diagnosis as a death sentence when it is not. In addition to pharmacologic approaches, there are multiple other therapies that can benefit patients with Parkinson’s disease.
HAUSER: We need patients to get involved in clinical trials. Everybody wants better treatments, but we all have to do our parts. Besides physicians, investigators, pharmaceutical companies, and regulators, patients have to do their share, too. It would be very helpful, maybe across all fields and all diseases, if on TV every night we saw the message, “Get involved in clinical trials. This is the way we cure diseases.”
LITVAN: There are many challenges to Parkinson’s drug development, especially for disease-modifying therapies. The scientific challenges include further increasing our understanding of the true mechanisms for aggregation of key proteins in the brain, how the disease spreads, and which disease mechanisms we truly need to target. I believe we’re getting there, and we’re tackling all the different aspects of the disease in some way. So there has been some advancement, and I hope we can capitalize on all that progress and quickly move the new drugs through clinical trials and into the market.
INTERNATIONAL STEM CELL CORPORATION
Entering Phase 1 with a proprietary class of stem cells to replace lost dopamine-producing neurons in Parkinson’s patients
Russell Kern, Chief Scientific Officer: We developed our own class of pluripotent cells, called parthenogenetic stem cells, which are made from unfertilized oocytes. They have the same differentiation and proliferation capabilities as embryonic stem cells, and they can provide immune-matching benefits like iPS [induced pluripotent stem] cells, though to millions of people instead of only one person, the donor. In choosing Parkinson’s as our first therapeutic target, we considered two factors: how many types of cells must be transplanted, and where. Parkinson’s is caused by the death of a single-cell type, dopamine-producing, or dopaminergic neurons, and the course of the disease is well localized in the substantia nigra pars compacta, or midbrain region; transplantation is thus relatively easy, and the stem cells stay in place. Our goal is to treat any stage of the disease. Instead of only replacing the dead neurons, we can replace just a small percentage of neurologic pathology and make the implanted neural cells to prevent other neurons from dying. We started enrollment in a Phase 1 trial in March of this year. [Announced enrollment 3/7/16.] Its design is to treat 12 patients who have had moderate to severe Parkinson’s disease for more than four years. It is basically a dose-escalation study; the primary endpoint is safety, and secondary endpoint is clinical response, at 12 months.
In Phase 3 with an innovative sublingual delivery strip to improve tolerability and duration of a well-known bridging drug for patients in levodopa “off” periods
Anthony Giovinazzo, President & CEO: Our novel and innovative approach is the sublingual delivery method we discovered and developed as opposed to a novel molecular mechanism of action. Apomorphine is the only approved drug in the U.S., Europe, Japan, Australia, and several other countries to treat “off” episodes in Parkinson’s disease — the often long hours between when one levodopa dose wears off and the next one takes effect, when muscle rigidity sets in and other symptoms can resurge. For an idea of the seriousness of this aspect of the disease, I would note that a recent survey of 3,000 patients found that 90 percent suffer off episodes, 65 percent suffer at least 2 hours off daily, and 22 percent experience over 4 daily hours of off time, with some patients experiencing up to 6 hours total per day. It is not a narcotic or a scheduled compound, but a unique small molecule of the dopamine agonist class. Apomorphine is currently only available as a subcutaneous injection, which is inconvenient and uncomfortable because it is highly acidic. Our invention is a sublingual thin film strip, like a breath strip. Under the tongue, it dissolves in a few minutes and also neutralizes the acidity so the free-base drug can travel quickly through the mucosa into the bloodstream. It delivers the same amount of drug as the injection but doubles the duration to 1 to 2 hours. In 2014, we completed a Phase 2 study which demonstrated that our method of delivering the drug apomorphine on a sublingual film strip converts patients from off to fully on, rapidly, consistently, and reliably. We initiated the pivotal Phase 3 efficacy program in June 2015 and the Phase 3 safety study in September 2015.
In Phase 2 with Eltoprazine for treating levadopa-induced dyskinesia; preparing for Phase 1 with MANF (mesencephalic-astrocyte-derived neurotrophic factor), for protecting dopaminergic neurons (and retinal cells) from misfolding and death
Gerald E. Commissiong, President & CEO: We licensed in Eltoprazine, which was originally in Solvay’s pipeline for aggression, but we believe it has great promise for dyskinesia induced in Parkinson’s patients by levodopa therapy. Dyskinesia is a huge unmet need in the symptomatic side of the Parkinson’s space. On the disease-modifying side, in preparation for Phase 1, our neurotrophic factor, MANF, will be several individual products with different dosing regimens and delivery mechanisms, but all around the same fundamental biology. The general mechanism of cell-stress protection has a lot of value because the underlying cause of cell stress might be different between an animal model than what’s actually going on in the human body, but if this growth factor basically helps cells through stress, regardless of what that stress is, then we can still see a functional outcome that may translate from animals to humans. Parkinson’s affects a discrete area of the brain, and the diagnosis is basically a response to drug. It is becoming increasingly simpler to target a specific brain area, and you can get a better sense of the drug’s effects and benefits.
Coming out of preclinicals with high confidence in a disease-modifying small molecule mimetic of a neurotrophic factor to regenerate neurons in patients with Parkinson’s and other neurodegenerative diseases
Leen Kawas, Cofounder, CEO & President: Our technology is noninvasive — it will be an oral pill that passes the blood-brain barrier, and what it will do regionally is regenerate brain cells for neurodegenerative diseases. The ultimate outcome of those diseases is the death of neuron cells and the loss of the connections. At least in animal models, our compound recreates the lost connections by regenerating the brain cells, as well as improving memory, cognition, and ability to learn. We have done all of the preclinical work to support these claims.
Many studies looking at the brains of Parkinson’s and Alzheimer’s patients postmortem have seen huge similarities. There is an overlap between the two diseases. Both kinds of patients at the end stages have cognition decline and marked motor dysfunctions, so the two diseases show similar clinical and pathological phenotypes. They are both degenerative diseases, sharing the same process of degeneration. We are working on a true disease-modifying treatment, and we expect our drug to help any kind of degeneration because it reverses the degenerative process.
Our drug is a small molecule and very inexpensive to manufacture, so it will be an affordable therapy, and we don’t see a reimbursement issue. Our plans for a clinical trial have been supported by the FDA. In a novel clinical trial design, we’re looking at patients, stratification, enrichment, and using a novel biomarker to detect an effective dosing for our drug by measuring function of the targeted brain regions.
Going into Phase 1 to prove its GAIM (general amyloid interaction motif) has universal action against misfolded proteins, including alpha-synuclein in Parkinson’s
Richard Fisher, Ph.D., Chief Scientific Officer: Our lead disease-modifying compound uses GAIM to universally recognize and destroy misfolded proteins, including alphasynuclein, as they assemble. A substantial chunk of Alzheimer’s patients have Parkinson’s pathology, and Parkinson’s patients have Alzheimer’s pathology. These diseases are characterized by multiple misfolded proteins, and one of the exciting aspects of our approach is we can target multiple misfolded proteins simultaneously. Our approach reduced multiple misfolded proteins in mice models; now we want to see whether it does the same in humans. In our Phase 1 trial, we will dose patients for six months, then image to measure two very consistent, well-researched biomarkers, amyloid and tau, to detect any reduction. If the trial is successful, we have proof the mechanism works, and it opens up a lot of possible indications.
CORE PARKINSON’S TREATMENT — BENEFITS WITH RISKS
At the center of the Parkinson’s armamentarium for patients with motor symptoms is the levodopa/carbidopa combination (Sinemet). Levodopa converts to dopamine in the brain to augment the dopamine production curtailed by the progressive death of dopaminergic neurons; carbidopa does not cross the blood-brain barrier but prevents harmful conversion of levodopa to dopamine outside the brain. Still, levodopa maintenance poses a complex set of problems virtually unique and ever-changing in every patient, and much of the drug development in the Parkinson’s space revolves around ways to ameliorate those challenges. Advanced patients suffer frequent “off” periods after one levodopa dose wears off and before another takes effect. Parkinson’s patients may also experience strong physical, physiological, and psychological side effects from the drug itself.
One of the key opinion leaders on our virtual roundtable panel, Dr. Robert Hauser, director, Parkinson's disease and movement disorders at the University of South Florida, gives a practitioner’s account of levodopa maintenance:
The most effective medication for Parkinson’s disease with the fewest side effects, in use since the late 1960s, has been levodopa in combination with carbidopa, sold under various brand names, including Sinemet, and in generic forms. Sinemet only really lasts about 2 1/2 hours in the blood, but in early Parkinson’s disease, when it reaches remaining dopaminergic neurons, it is converted to dopamine, and importantly, stored and then released over time. So neurologists commonly give it on a three-times-a-day schedule, and patients’ slowness and stiffness are much improved throughout the day.
Tremor response to levodopa is a wild card. Tremor may or may not respond to dopamine medication, so that is an unmet need. It would be really nice to have good treatments for Parkinson’s tremor.
As time goes by and people lose more dopaminergic neurons, that dopamine storage and release capacity is diminished. Levodopa may last about 4 hours and then wear off, and slowness and stiffness returns. Then we can move the levodopa doses closer together, which works pretty well for a time, but the levodopa effect keeps shortening, and ultimately, it reflects what’s happening in the blood. It may take 40 minutes for the medication to have an effect, and the benefit may last about 2 1/2 hours, then wear off abruptly.
We can then add symptomatic medications such as the MAO-B [monoamine oxidase B] inhibitors, rasagiline (Azilect), and selegiline (Eldepryl, Zelapar), or dopamine agonists (such as ropninirole [Requip], pramipexole [Mirapex], or rotigotine [Neupro patch]) or COMT [catechol-O-methyl transferase] inhibitors, entacapone (Comtan) or tolcapone (Tasmar). Up to about four levodopa doses per day, plus an MAO-B inhibitor and maybe one other medication works reasonably well, but after that, it gets hard to take more medications more frequently.
One long-acting carbidopa/levodopa, Rytary from Impax Specialty Pharma, came out earlier this year, and it does last longer than the immediate-release form, so it helps some patients. But many still find they need to take Rytary up to five times a day, so we need to do better. Other long-acting levodopa preparations are in development, including Intec Pharmaceuticals’ “accordion pill” — carbidopa/levodopa on a little film that is folded up like an accordion and put in a dissolving tablet. The product is being evaluated as a possible twice-a-day or a three-times-a-day levodopa.
There are two late-stage “bridging therapy” candidates for off periods: inhaled levodopa and sublingual apomorphine, a dopamine agonist. With the inhaled product, the levodopa goes into the lung, is absorbed into the bloodstream, and goes directly to the brain. Phase 2 data suggests the medication starts working in about 15 minutes and may last for about 90 minutes. The sublingual apomorphine could be used in place of the old injectable form, as the injectable form may be uncomfortable for some patients. Cynapsus has the sublingual product in early Phase 2, and it appears to take effect in about 15 minutes and to last about 90 minutes.
The newest levodopa product, already on the market, is a carbidopa-levodopa enteral suspension (CLES, Duopa) pump that moves the medication through the abdominal cavity, through the stomach, and down into the small intestine where it is absorbed. It is highly effective because it can deliver levodopa in a continuous fashion and maintains the response quite well. But it is invasive, and it is a mechanical device, so there is management involved, and you have to carry the pump around. Another promising product a little further back in development is the NeuroDerm pump patch, which delivers levodopa subcutaneously.
It would also be helpful to have a good medication for dyskinesia (impaired voluntary movement). There are two companies that are developing long-acting amantadine formulations. Amantadine (Symmetrel) is available currently in a standard or immediate-release form, and it’s moderately effective for dyskinesia, but can induce confusion or hallucinations, especially in older individuals and those with cognitive deficits. The developers hope a long-acting formulation might avoid some of the peaks of pharmacokinetic activity and thus be better tolerated, but both companies are testing their formulations against placebo rather than standard amantadine, so they won’t really have comparative data. We still have an unmet need for better antidyskinesia medications that would allow us to use levodopa more liberally and prevent one of its worst long-term complications.