A frequent question in the clinic is “What’s new in Parkinson’s?” It is a deceptively simple question, because the truth is that there are thousands of researchers around the world working on Parkinson disease (PD), and there is no way to answer the question in anything close to the time of a follow-up appointment in the office. The volume of information is enormous. A quick search for the term “Parkinson disease” in PubMed indicates that in 2017 there were 2,450 articles published in peer-reviewed medical journals. A search going back to 1947 yields 65,022 articles, with the majority in the last decade – a huge and growing database. Navigating that data requires a specialized skill set such as an advanced degree and training in medicine. People with PD who don’t have that degree of training can arm themselves with knowledge by reading articles from MPDN, the Michael J. Fox Foundation, the National Parkinson Foundation, or other reputable sources. Mainers can attend meetings such as the April Parkinson Conference.
The purpose of this article, and the series on pipeline drugs that will follow, is to focus on some of the medications and therapies in development or under trial for the treatment of PD. Search for the information occurred in two main ways. First was review of peer-reviewed medical journal articles describing completed studies. As described in the spring, 2018 MPDN article “the drug development process as outlined by the FDA,” studies proceed through phases prior to FDA approval. Briefly, phase I trials provide information about how drugs work in the body and may be used to find appropriate drug doses and drug tolerance. Phase II trials are designed to give more safety data, refine research questions, develop research methods, and design new phase III protocols. Phase III trials evaluate how effective a treatment is, and monitor for side effects or adverse reactions. After completion of a successful phase III trial a drug may receive FDA approval for a specific disease indication, such as PD, dyskinesias in PD, etc.
If the drug is new, doctors may then begin to write prescriptions after FDA approval, though prescribing physicians are not limited to FDA approved indication.
The second method in the search for information was via ClinicalTrials.gov, a freely accessible database provided by the U.S. National Library of Medicine that, as this article was being written, listed over 268,000 privately and publicly funded studies in the United States and 203 other countries. Every study on the website is assigned a unique number, the ClinicalTrials.gov Identifier, a.k.a. the NCT number, which may be used to search for a particular trial. With the ongoing trials described below NCT numbers are included for the reader because the contents are updated periodically and may give information regarding a more detailed description of the study itself, requirements of the study, participant inclusion versus exclusion criteria, study locations, contact information, and status of the study (recruiting, completed, etc.). It is a very valuable resource for those who want to participate in, or keep up with certain areas of research, and it covers a wide array of worldwide PD investigation. On March 18, 2018 a search for the term “Parkinson disease” for example, produced 1,982 results. Fortunately, searches can be narrowed to contain only certain terms such as the NCT number, study drug, location, age of patient, etc.
As this article begins a series, I will divide into topics, which will include new developments with levodopa (this article), dopamine agonists, drugs already approved for another indication that have value in PD, some interventions that may seem unusual, such as blood transfusions for PD, and other topics.
The accordion pill, a “novel gastroretentive delivery system,” is being developed by Intec Pharma. The drug levodopa is only absorbed in the first part of the small bowel and competes with proteins for absorption, and thus diet may interfere (see the MPDN article “PD and Diet,” winter, 2016/17). Likewise, many people with PD have problems with gastric motility (for eg., the stomach does not empty properly, to be covered later in the this series), constipation, or infection with Helicobacter pylori, all of which may change the rate of absorption of levodopa and negatively affect the window of opportunity for drug absorption. In other words, the drug may not wind up in the right place at the right time for absorption. With immediate release levodopa, the half-life of time that a drug is at its therapeutic concentration in the blood, is only about 90 minutes; whereas the controlled release forms may have a half-life of several hours, though it is variable, and sometimes not well tolerated. This is why some patients reach for liquid levodopa, Rytary, or the DUOPA pump (see article in this issue). A new attempt to address the problem is called the accordion pill because it expands in the GI tract to keep it in a region where dopamine will be absorbed while it slowly releases medication. This approach to treating PD completed a phase II trial of 60 PD patients with doses of 250-500 mg levodopa, given once or twice daily over a 7-21 day period. Per the company’s website (unpublished data) there was a reduction in OFF time and dyskinesias. The baseline characteristics of the patients, including disease severity, were not apparent on the website. The drug will need to complete a phase III trial before FDA approval is sought.
ClinicalTrials.gov lists two current phase III trials testing the accordion pill, though one must have completed the first 27 week trial to enter the second, a 12 month trial:
NCT02605434 is a randomized, double-blind study in adult subjects with fluctuating PD (1). Patients will be given a six week period to establish proper dosing of either carbidopa/levodopa (Sinemet) or the accordion pill (AP-CD/LD) before starting the double-blind maintenance period lasting 13 weeks. In a double-blind study neither the patient nor the evaluator know which treatment is being given in order to eliminate bias. Investigators plan to enroll 328 patients across 96 study sites (including Dartmouth and Boston University), and estimated primary completion is June, 2018. Primarily, they want to measures a change in the percentage of daily OFF time (time medications have worn off and motor symptoms are not controlled) during waking hours. Secondarily, they will measure a change from baseline through study completion in ON time (time medications are working and motor symptoms are improved or controlled) without troublesome dyskinesia during waking hours, a change in the number of total daily levodopa doses, and change in total Unified Parkinson Disease Rating Scale (UPDRS). UPDRS is a standardized tool used by doctors to measure the effects of PD.
NCT02615873 is an open extension trial taking place at 80 study sites that will follow patients who have completed NCT02605434 and evaluate the clinical effect and safety of the accordion pill over 12 months (2).
Subcutaneous (SC) levodopa, ND0612, is a patch/pump system being developed by Neuroderm, and is a delivery system of up to 360 mg levodopa over a 24 hour continuous infusion of a patch/pump (a patch with a small needle placed under the skin, thus subcutaneous). It is designed for moderate to severe PD as an alternative to the Duopa pump or deep brain stimulation. Two phase II studies have shown the drug is safe and tolerable. Reportedly, the phase III studies will begin soon. At this point, Boston will probably be the closest option.
NCT02726386 is an active trial, no longer recruiting, involving 100 advanced PD patients spread over 57 international study sites over a 12 month period (3). The primary outcome of this open-label safety study is to assess the long term safety and tolerability of continuous infusion of ND0612 by recording adverse events, vital signs, and local tolerability of the device and the drug. Estimated study completion date is May, 2018.
NCT02782481, is a phase III, randomized, double-blind, parallel group study of the efficacy, tolerability, and safety of continuous ND0612 in addition to oral levodopa compared to placebo infusion over a 16 week study period (4). The study is multicenter, and intended to include 150 people with PD who experience “motor complications despite optimized anti-PD therapy.” The study is past the estimated completion date, but is listed as still recruiting, though the single recruiting site listed on ClinicalTrials.gov is in Israel.
NCT03462043 was announced in March, 2018 – not yet recruiting at announcement, and is an open-label, randomized, crossover study to assess the relative bioavailability (the proportion of the drug that will enter the circulation, and is thus able to have an effect) of ND0612 (the patch) versus jejunal pump levodopa (an external pump similar to DUOPA) in patients with advanced PD (5). As yet, the only location listed is in Roma, Italy.
NCT02577523 is a multicenter, parallel-group, rater-blinded, randomized phase II clinical study in subjects with advanced PD investigating the efficacy, safety and tolerability of continuous SC infusion of 2 dosing regimens of ND0612H, a solution of carbidopa/levodopa delivered continuous ND0612 infusion, compared to standard oral carbidopa/levodopa (6). Participants will be given the drug for a total of about 2.5 months. Investigators are recruited 38 participants at five international locations, and the study is ongoing, not recruiting.
Inhaled levodopa, CVT-301, (INBRIJA) is a self-administered, inhaled form of levodopa by Acorda Pharmaceuticals. The concept is to avoid the problems with GI tract absorption of levodopa by administering a powder with an inhaler which is absorbed by the lungs, enters the bloodstream, and is carried to the brain. Phase I and II trials were in part funded by the Michael J. Fox Foundation for Parkinson’s Research.
A phase II study evaluated CVT-301, which PD patients self-administered to relieve OFF episodes (times when medications are not working and symptoms are not controlled) (7). Study participants had to have two or more hours per day of OFF time despite oral levodopa four or more times per day. Patients were randomized: 43 to inhaled CVT-301, and 43 to inhaled placebo for 4 weeks. Both groups used inhalers up to 3 times per day for OFF episodes. After two weeks the study-drug dose was increased from 35 to 50 mg. At the end of the fourth week investigators measured the change in UPDRS III score (a measure of the motor signs of PD) from OFF state to the post-dosing scores at 10, 20, 30, and 60 minutes. The treatment effect was evident at 10 minutes and average OFF time changed by close to an hour daily. This might mean that as one was wearing off at the end of dose they used the inhaler to feel ON until the next dose. Typically, this was the case for an average of two 25 minute periods daily. The most frequently reported adverse events among those receiving the drug were dizziness, cough, and nausea, each seen in 3 patients). Investigators concluded that CVT-301 was generally safe and well-tolerated.
The same group next entered a second phase II study which evaluated lung function in patients given a single dose of CVT-301 versus placebo, and in patients who received multiple doses/day over 4 weeks (8). Assessment of pulmonary function (before and three hours after a dose) by spirometry (a portable way to measure lung function) was within normal ranges. The most common side effect was mild-to-moderate cough (21% in the single dose group, 7% in the four week treatment group).
February, 2017 Acorda announced positive phase III clinical trial results for CVT-301 with the SPAN-PD trial (9). SPAN-PD was a phase III, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of CVT-301 compared with placebo in people with PD who experienced motor fluctuations (OFF periods). All took a stable regimen of oral carbidopa/levodopa, and were maintained on other existing PD medications. The study included 339 study participants who were randomized to CVT-301 84 mg, CVT-301 60 mg, or placebo. Participants self-administered treatment up to five times daily for 12 weeks.
At week 12 the change in UPDRS III score compared with placebo was measured at 30 minutes after using the inhaler. SPAN-PD reportedly showed the 84 mg dose resulted in a 9.83 point improvement in the UPDRS III compared with a 5.91 drop for the placebo group. In the 84 mg dose group nausea was reported in 5.3% (2.7% with placebo), cough in 15% (1.8% with placebo), upper respiratory tract infection in 6% (2.7% with placebo). When cough was reported, it was “typically mild and reported once per participant during the course of treatment.” Three of 227 participants receiving CVT-301 discontinued the study due to cough.
Data from the SPAN-PD trial were presented at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) in June 2017.
February 20, 2018 Acorda Therapeutics, Inc. announced that the FDA had accepted for filing its New Drug Application (NDA) for INBRIJA, “an investigational inhaled levodopa treatment for symptoms of OFF periods in people with Parkinson’s disease taking a carbidopa/levodopa regimen” (10). Under the Prescription Drug User Fee Act (PDUFA), the FDA has set a target date of October 5, 2018.
REFERENCES
- https://clinicaltrials.gov/ct2/show/NCT02605434?term=accordion+pill&cond=Parkinson+Disease&rank=1
- https://clinicaltrials.gov/ct2/show/NCT02615873?term=accordion+pill&cond=Parkinson+Disease&rank=2
- NCT02726386 https://clinicaltrials.gov/ct2/show/NCT02726386?term=subcutaneous&cond=Parkinson+Disease&rank=1
- https://clinicaltrials.gov/ct2/show/NCT02782481?term=subcutaneous+levodopa%2C+neuroderm&cond=Parkinson+Disease&rank=2
- https://clinicaltrials.gov/ct2/show/NCT03462043?term=subcutaneous+levodopa%2C+neuroderm&cond=Parkinson+Disease&rank=3
- https://clinicaltrials.gov/ct2/show/NCT02577523?term=subcutaneous+levodopa%2C+neuroderm&cond=Parkinson+Disease&rank=5
- LeWitt, et al. A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson’s disease. Mov Disord. 2016;31(9):1356-65.
- LeWitt, et al. Pulmonary Safety and Tolerability of Inhaled Levodopa (CVT-301) Administered to Patients with Parkinson’s Disease.J Aerosol Med Pulm Drug Deliv. 2017 Nov 21. doi: 10.1089/jamp.2016.1354. [Epub ahead of print] full artice: https://www.liebertpub.com/doi/10.1089/jamp.2016.1354
- http://ir.acorda.com/investors/investor-news/investor-news-details/2017/Acorda-Announces-Positive-Phase-3-Clinical-Trial-Results-for-CVT-301/default.aspx
- http://ir.acorda.com/investors/investor-news/investor-news-details/2018/Acorda-Announces-FDA-Acceptance-of-New-Drug-Application-for-INBRIJA-levodopa-inhalation-powder/default.aspx
