Losing the Ability to Move
Imagine being out at a park or restaurant and suddenly experiencing a near complete loss of your ability to move. Your spouse, whom you outweigh by 50 lbs, enlists the aid of complete strangers to get you into the car and take you home. Upon arrival, she drags your legs out of the car, pulls you to your feet, and helps you into the house.
A bad dream? No - advanced Parkinson's disease.
Loss of the ability to initiate movement, or akinesia, is one of the most difficult quality of life issues in Parkinson's disease. While it can occur at any time in the progression of the disease, this loss is most common in advanced stages. Patients report being unable to get out of a chair, unable to handle papers at their desk, and being unable to get out of bed in the morning to use the bathroom. These episodes are most commonly associated with the wearing off period just before a scheduled dose of the standard Parkinson's drug, levodopa, but can also be set off by stress, fatigue, or even cold weather. They are commonly they are known as OFF episodes.
I am having troubles with getting my husband out of the car when he is off- he is so frozen he can't move his feet at all - so I have to lift them up, put them in correct position outside the car, and try to drag him up to a standing position---there has to be a better way!!!
-Caretaker comment left on a Parkinson's disease message board.
The very worst times were when I could not get out of bed in the morning to get to the bathroom, or being in a chair and feeling frozen like a statue, wanting to get out of the chair but not being able to, feeling glued to the seat…
-Parkinson's Disease Patient "Jill", YouTube Interview
Parkinson's Disease
Parkinson's disease is a disorder of the mid-brain in which cells responsible for producing dopamine, a key neurotransmitter required for movement, begin to die off. The first symptoms usually involve a mild tremor in a single hand or foot while at rest. Untreated, the disease gradually progresses to parkinsonism, a difficulty in initiating movement and reduced motor coordination. Falling is a major problem, as patients "freeze" in mid-gait. As the disease progresses, treatments become less effective and the patient oscillates between states of hyperkinesia (uncontrolled movements of the arms and legs) and akinesia (inability to initiate movement). In late stage disease, insomnia, dementia, and psychosis may become prominent.
Why Standard Parkinson's Disease Treatment Can't Prevent OFF Episodes
There is no cure for Parkinson's disease. Treatment aims to minimize symptoms. In the early stages of the disease, this can usually be accomplished with relatively innocuous drugs called dopamine agonists. After several years, as the underlying disease progresses, these become less effective and patients are switched to a more powerful drug called levodopa. Levodopa is taken up into the brain by specific transporters where it is converted to dopamine by an enzyme called L-amino acid decarboxylase. It is commonly combined with a second drug called carbidopa that serves to minimize side effects such as nausea. The most commonly used branded levodopa / carbidopa combination is Sinemet.
(click to enlarge)
Most patients will continue to do reasonably well for several years on levodopa therapy, but as their dopamine producing neurons continue to die off, a larger and larger percentage of the dopamine in their brains is derived from levodopa. Each time a dose is taken, dopamine levels in the brain ramp up, peak, and then fall in the hours leading up to the next scheduled dose. As patients become more and more dependent on levodopa, they begin to experience OFF episodes in the period just before their next dose, and hyperkinesia episodes during the periods when the drug level is at its peak.
Taking the next dose early is not a good solution for OFF episodes because a full hour and a half is needed for levodopa's effect to kick in. Furthermore, the early or increased dose reduces the duration and severity of OFF episodes only at the expense of increasing the hyperkinesia period when levodopa levels in the brain are high.
Apomorphine is an Effective Treatment for OFF Periods, but its Subcutaneous Administration is Problematic
One attractive solution to the problem of OFF episodes is the drug apomorphine. Apomorphine acts as a dopamine mimetic, binding to the dopamine receptor and facilitating movement. Unfortunately, it is currently available only as a subcutaneous injection, which is completely impractical for a Parkinson's patient in the midst of an OFF episode to self-administer. This injected form of apomorphine was approved by the U.S. FDA in 2004, and is sold in the United States under the trade name Apokyn.
The Figure below shows the improvement in Unified Parkinson's Disease Rating Scale (UPDRS) motor score obtained by patients as a function of time after injection of Apokyn. Note the attractive complementarity between the response profile of Apokyn and that of levodopa (as Sinemet CR) if dosed simultaneously. Apomorphine levels in the brain peak rapidly, providing rapid restoration of movement. The drug is rapidly cleared from the circulation, falling to below therapeutic levels after a little more than an hour. This is just about the time needed for the response to orally administered Sinemet to kick in (Piccini et al, 2000).
Unfortunately, the subcutaneous administration of Apokyn is quite complicated, and beyond the capability of many patients when experiencing an OFF episode. Patient instructions on the Apokyn website offer a 15 step process, including multiple step procedures for
- Loading the apomorphine cartridge
- Attaching the needle (which cannot be left in place when the pen is stored)
- Priming the pen
- Adjusting the dosage meter
- Disinfecting the injection site
- Performing the injection
- Removing and safely disposing of the single-use needle, and
- Storing the pen
The injections can be performed by a caregiver, but this takes away the patient's independence and increases the burden on the caregiver. The need to change the needle and use an alcohol swab to sterilize the injection site makes the device complex to use away from home. Lastly, many patients are uncomfortable with injections.
Cynapsus' Better Solution: A Sublingual Formulation of Apomorphine
Cynapsus Therapeutics (OTCQX:CYNAF) (V.CTH on the Toronto Venture) is developing APL-130277, a fast-dissolving, fast-acting thin film formulation of apomorphine that can be administered in the mouth. In this route of administration, the drug is absorbed into the bloodstream by diffusing through the tissues of the mouth. The formulation technology for sublingual (SL) drug administration is well developed, and has previously been successfully applied other drugs that undergo rapid first pass metabolism and / or for which rapid absorption into the bloodstream is required. Examples include Abstral® (fentanyl), Suboxone® (buprenorphine/naloxone), Zuplenz® (ondansetron), Saphris® (asenapine), Intermezzo® (zolpidem), and Striant® (testosterone).
Advantages of the sublingual formulation route include rapid uptake into the bloodstream and the opportunity to closely reproduce the pharmacokinetic profile of the injected version of the drug. In April 2011, discussions between Cynapsus and the FDA led to conclusions that the agency would accept for consideration an new drug application (NDA) for APL-130277 provided that Cynapsus can demonstrate apomorphine maximum serum concentration (Cmax) and total amount absorbed (area under the curve, or AUC) that are in the range of 80% to 125% that produced by Apokyn. The Agency further stipulated that the time to peak serum concentration should be in the same range as that specified in the Apokyn label (10 to 60 minutes).
To date, the company has completed two clinical studies with the goal of refining its sublingual formulation and demonstrating the required pharmacokinetic profile. The first of these demonstrated a very similar pharmacokinetic profile to that of Apokyn, except that the company had overestimated the extent of absorption by the sublingual route. The graph below compares the serum levels of apomorphine generated by the first generation sublingual formulation to that generated by Apokyn, with the serum levels for the APL-130277 treated patients multiplied by a factor of about 5x to adjust for under-dosing.
The second trial (CTH102) used a more refined formulation and a higher dose. In this trial, the Cmax, AUC, and Tmax of the 3 mg Apokyn dose was closely reproduced. Based in part of these results, the company began preparations for CTH-103, three dose, active comparator, placebo-controlled, randomized cross-over bioequivalence phase I trial comparing APL277 to subcutaneous apomorphine. The trial will enroll 48 subjects in 3 dose cohorts. Patients within each cohort will receive either APL-130277 or subcutaneous apomorphine in random order. Following a 1 day washout period, they will then cross over to the drug not administered on Day 1.
- Cohort 1 will be administered either 10 mg APL-130277 or 2 mg subcutaneous apomorphine
- Cohort 2 will be administered either 15 mg APL-130277 or 3 mg subcutaneous apomorphine
- Cohort 3 will be administered either 25 mg APL-130277 or 4 mg subcutaneous apomorphine
We expect results from CTH-103 in January 2014. Study endpoints include a complete pharmacokinetic profile with comparisons to subcutaneous apomorphine data, and safety and tolerability. The study is funded by a $0.948 million grant from the Michael J. Fox Foundation (MJFF) and will serve as a "dry run" for the larger pivotal bioequivalence trial, CTH-201, to be performed in 2014. As agreed to with the FDA, Cynapsus will also complete a safety and tolerability study in patients with PD who have not been previously exposed to apomorphine. CTH-301 is planned to be a 3-arm study in 150 patients, with duration of 16-weeks.
Market Potential
Our Full Report contains details of marketing surveys, third party payer surveys, and a large number of comments about Apokyn taken from Parkinson's disease patient online message boards. For the purposes of this article, we summarize these findings briefly as follows:
- Patients describe mixed attitudes toward the injectable Apokyn product. Many call it a "wonder drug", and describe a dramatic improvement in their quality of life associated with its use. Others complain about the difficulty of administration and disliking needles. From patient (and at least one neurologist) comments, the drug seems more effective in some patients than others, and a few experience intolerable side effects such as sudden decrease in blood pressure.
- Physicians queried in a survey contracted by Cynapsus say that they prescribe Apokyn to about 5% of patients. They describe "inconvenience", "difficulty starting therapy", and "injection site reactions" as key barriers preventing more widespread use of the injectable product. On average, they say that they would prescribe a sublingual version to 30% of patients.
- A survey of third party payers commissioned by Cynapsus found that 90% of the responders would reimburse the product within three months of approval by the FDA. Roughly 75% of the responders would reimburse at an average wholesale price equal to the apomorphine injection, with another 50% amenable to a premium price of 25% if the company can show clinical benefit over the injectable product.
Comments on Apokyn Left on Parkinson's Disease Patient Message Boards
Pro
"We can cook food, give him a shot, and in a couple of minutes he can get himself out of his chair and eat dinner."
"It works very quickly and is most helpful when he freezes out in public. It generally works in a matter of minutes"
Con
"The first injection was not well-tolerated. Her blood pressure dropped severely and it took over an hour to get back to normal"
"Have tried the Apokyn Pen and it was a flop as a rescue medicine"
"The medicine works great as a rescue drug but the delivery system is difficult to use"
Revenue Potential
We have looked in detail at the sales opportunity for APL-130277. In the U.S., there are around one million Parkinson's disease patients, about half of who have significant OFF episode issues. According to management's survey of over 500 neurologists and movement disorder specialists, the market breaks down as: ~40% with mild Parkinson's disease (might require 1 SL film per day), ~45% with moderate Parkinson's disease (might require 2 SL films per day), and ~15% with severe Parkinson's disease (might require 3 SL films per day). We estimate 2022 market penetration of 2.5% among patients with mild disease, 5.0% among those with moderate disease, and 6.0% among those with severe disease, for a total of 17.25 sublingual strips per year. Assuming reimbursement at $11.67 per strip (the inflation-adjusted price of Apokyn), we estimate U.S. sales at roughly $200 million. Assuming RoW sales of about one and one-half this amount, we estimate 2022 global sales at $500M.
Valuation
Cynapsus exited the second quarter ended September 30, 2013 with $3.41 million in cash. The company's stated goal is to develop APL-130277 to the point where the U.S. NDA is ready for filing, and then to out-license to a suitable partner for commercialization. To complete this task, the company must complete the CTH-103 pilot study (funded by the Michael J. Fox Foundation) and then conclude the bioequivalence study and follow-up safety study. We estimate the cost to completion at $16 million. With a fully diluted share count of 62.5 million shares and an estimated average price per share for future raises of $0.60, we estimate the share total share count including future dilution at 87 million.
We assume 2022 worldwide sales of $500 million with a royalty rate of 25% and an upfront licensing fee of $40 million. Applying a price-to-royalty multiple of 3x and discounting back at 20% we estimate the fair value of the company's shares at $1.25. This represents tremendous upside from the current price today of only $0.36 per share.
Cynapsus Therapeutics is a little-known, small-cap Canadian pharmaceutical company that has, in our view, a far better solution to a major problem affecting Parkinson's patients. The concept is simple and the path to commercialization has been validated. The stock is cheap, and the risks are relatively low. We like the story and recommend purchase today up to our $1.25 fair-value target.
Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article. (More...)
Additional disclosure: Co-Authored By John Tucker, PhD
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