Genetics Fuel Parkinson Pipeline Growth

NeurologyLiveDecember 2018
Volume 1
Issue 2

Growing enthusiasm in the Parkinson disease research community largely centers on advances in understanding the genetic underpinnings of the disease.

In the 200 years since Parkinson disease was first defined as a medical condition, plenty of research has been done, but plenty of questions remain. The biggest one—How can it be stopped?—remains frustratingly unanswered.

Even so, among the scientists and investigators who spend their days seeking a cure, there’s a growing sense that the turning point is just around the corner.

“My impression is that there are more promising potential therapies now than in previous years, and that this is due to an accumulation of research over the past 10 to 20 years that has slowly brought us to the point that we are [at] today,” Rebecca Gilbert, MD, PhD, vice president and chief scientific officer at the American Parkinson Disease Association, told NeurologyLive™.

Therapies now under development have broader, higher aims than the therapies in drug developers’ pipelines several years ago, according to Brian Fiske, PhD, senior vice president of research programs at the Michael J. Fox Foundation for Parkinson’s Research. A decade or so ago, he said, drugs tended to focus on ameliorating the symptoms of Parkinson disease. Those drugs could have a major impact on quality of life but did not necessarily bring the field closer to a cure.

“For us, what is probably most exciting is [that] we’re starting to see trials of drugs that are targeting biological and genetically defined mechanisms that have been linked to Parkinson,” Fiske said. In other words, the therapies in today’s pipeline are aiming for the disease’s fundamental causes.

Scientists and pharmaceutical companies are focused not only on the causes but also more specifically on the disease, according to James Beck, PhD, chief scientific officer and senior vice president of the Parkinson’s Foundation. “Previous efforts to stop Parkinson really focused on issues central to Parkinson, but they were central to many other diseases, as well, like oxidative stress,” he said. “However, I feel the field is entering a time where experimental therapies are targeted to issues that are unique to Parkinson.”

Identifying Genetic Targets

One of the biggest attempts to zero in on Parkinson disease involves looking more closely at genetics. “Personalized medicine is likely going to be an important aspect of the future of Parkinson research,” Beck said.

That shift is good news for patients, because real-world cases have long suggested variability in the disease. “Some people have a lot of tremor; some have none,” Gilbert said. “Some have very severe nonmotor features; some have very few.”

Work is underway to understand the different subtypes, their causes, and whether treatments will vary with subtypes. One variation that is already known involves genetics. About 10% of people with Parkinson disease have a genetic mutation that has been correlated to a much higher risk of developing the disease, Beck said. Several new drug candidates are aimed at tackling those mutations or limiting their effects. “The hope behind these drugs—and currently, it’s just hope—is that they might make a real difference for those with genetic forms of Parkinson and maybe, one day, for those with other forms, too,” he said.

One target of gene-focused Parkinson research is the protein α-synuclein. The process of identifying the protein as an apparent genetic factor took many years and many scientists, according to Beck. “It all began with the work of Roger C. Duvoisin, MD, the [Parkinson’s] Foundation’s first fellow who first identified mutated forms of the protein as the cause of the first genetic forms of Parkinson in 1997,” he said, “to more recent work in 2008 by foundation researchers that discovered α-synuclein might underlie the progression of Parkinson.”

The current scientific thinking suggests that the molecular cause of Parkinson disease is an abnormal buildup of α-synuclein, Gilbert explained. “Research suggests that the α-synuclein molecule can take on different structures and in certain structures can cause other α-synuclein molecules to clump together.”

It is believed that in the small subset of patients with gene-associated Parkinson disease, a genetic variation causes their bodies to produce either too much α-synuclein or an altered form of the protein.

A number of efforts are underway to combat those α-synuclein clumps, known as Lewy bodies. One is a vaccine, PD01A (Affitope; AFFiRiS), which is currently in phase 1b trials and is designed to target α-synuclein. In the phase 1a trial, the therapy proved safe and well tolerated.

Another strategy against α-synuclein is being deployed with NPT200-11, a compound designed to bind to certain regions of α-synuclein to prevent toxicity. According to its developer, Neuropore Therapies, the therapy has been shown to prevent α-synuclein toxicity in the lab and in animal models.1 NPT200-11 is in phase 1 trials.

The furthest along of the α-synuclein-targeting therapies is known as NPT088. In addition to α-synuclein, the therapy targets amyloid-ß and phosphorylated tau and thus is seen as a possible treatment for Alzheimer disease in addition to—or instead of—Parkinson disease. The therapy, which is delivered intravenously to the brain, has been shown in preclinical research to reduce levels of α-synuclein and improve motor function. Results from a phase 1b study are expected in 2019.

Scientists are also working hard to better detect the buildup of α-synucein, Fiske said. “One of the really big pushes right now around α-synuclein…is being able to measure it in people and particularly being able to measure the accumulation in people with the disease— ideally, as early as possible,” he said.

Additionally, a gene therapy that has shown positive results in a mulitdose phase 1b clinical trial is known as VY-AADC01. It uses adeno-associated viral vector serotype 2 (AAV2) to encode the AADC gene, which is involved in the conversion of levodopa to dopamine. Recently reported results showed an increase after 12 months in on-time without troublesome dyskinesia across all doses, varying from 14% to 32%, in 15 patients with Parkinson disease.2

Additional Genetic Targets

A mutation in the LRRK2 gene is believed to be a factor in just 1% to 2% of Parkinson cases. However, in certain ethnic populations, including Ashkenazi Jewish individuals and the North African Arab Berbers, the mutation is present in upward of 40% of Parkinson cases.

In August 2018, Denali Therapeutics announced the results of a phase 1 trial for its LRRK2 inhibitor compound, DNL201.3 The results showed the drug to be safe and well tolerated. The company is planning a phase 1b study for the compound.

Although the population of patients who currently expected to benefit from a drug candidate like DNL201 is relatively small, Gilbert said, the scientific community still has much to learn about the connection between genetic mutations and Parkinson disease. Other patients may have a different, yet-to-be-discovered mutation that could also affect the LRRK2 gene. “What this means is that a medication that affects LRRK2 biology may benefit more broadly than just for those who have the mutation,” she said.

One other genetic avenue being explored relates to the enzyme glucocerebrosidase (GBA). It is believed that about 1 in 10 patients with Parkinson disease in the United States has a GBA gene mutation. Having the mutation does not meant that an individual will develop Parkinson disease—just a small percentage of patients with the mutation do. However, people with the mutation are more likely to be diagnosed compared with the general population. Results of a 2016 study showed that people with the mutation had a 217% higher risk of developing cognitive impairment.4

One trait that makes the GBA gene interesting from a research perspective is the fact that the mutation is also linked to another serious condition—Gaucher disease. A rare but deadly lysosomal storage disorder affecting about 6000 people in the United States, it occurs when patients have 2 copies of the mutation; patients with Parkinson disease have just 1 altered copy.

The link between the 2 conditions offers some hope that a treatment for one disease might lead to a treatment for the other. Lysosomal Therapeutics, Inc, is in the midst of a phase 1b trial for LTI-291, a drug candidate designed to treat GBA-associated Parkinson disease.5

Leveraging Existing Therapies

The parallels between Parkinson and other diseases also create new opportunities for speedy trials. A number of therapies already approved for other conditions are in phase 2 or 3 trials for the treatment of Parkinson disease.

Among them is isradipine, which was approved for the treatment of high blood pressure but may also have a neuroprotective benefit in patients with Parkinson disease. The final results of a phase 3 study of isradipine for Parkinson disease are expected in the winter of 2019.6

Another therapy, exenatide, which was approved more than a decade ago to treat type 2 diabetes, is being evaluated as a treatment to slow the progression of Parkinson disease. Phase 2 results published in 2017 were promising; however, the authors of the study noted that it is not yet clear whether the results were evidence that exenatide actually slowed the underlying progression of the disease or merely produced long-lasting alleviation of symptoms.7

“The important thing to note is that if clinical trials do show that these medications work in Parkinson, they can be transitioned to use in Parkinson much more simply than a medication that is not yet approved,” Gilbert said, “since [adverse] effect profiles are already known, and they are already manufactured and available.”

Of course, not all efforts at repurposing therapies pan out. Study results presented in October at the International Parkinson’s and Movement Disorder Society’s International Congress in Hong Kong showed that a nicotine patch did not slow progression of Parkinson disease.8 Investigators had hoped nicotine might have an effect because epidemiological research has suggested smokers face a significantly lower risk of developing the disease.

Another exciting area of research that Gilbert noted relates to stem cell therapies. She said that investigators have long wondered if stem cells could be used to replace dopamine neurons, the loss of which is believed to be responsible for the motor symptoms of Parkinson disease. The intriguing theory met with a problem: “This is much easier said than done, and in the past, cell-based therapies tested in clinical trials caused unacceptable [adverse] effects such as uncontrollable dyskinesias,” she explained.

Fortunately, stem cell research has grown by leaps and bounds, and now even adult stem cells can be reprogrammed to create stem cells. This raises hopes that dopamine neuron replacement could be on the horizon. A small trial is already underway in Japan.

Still, Gilbert cautioned that the proliferation of stem cell research has also brought a proliferation of often dubious claims. A number of practitioners in the United States and abroad are already marketing stem cell treatments for disease, including Parkinson, often for large sums of money. “None of these treatments are currently FDA approved, and I urge anyone who is interested in stem cell treatment for Parkinson to hold off until he or she is able to join a properly structured clinical trial conducted at an academic medical center,” she said.

The existing model to replace dopamine involves levodopa. Gilbert noted that the current methods of delivering the drug to the brain are problematic for many patients, leading to fluctuations in motor control throughout the day. “One strategy to try [to] prevent these fluctuations is changing how levodopa is given,” she said. “Many new strategies are under investigation, including a continuous infusion pump of levodopa into the subcutaneous tissue of the abdomen, similar to an insulin pump.”

Gilbert also described work being done on a “rescue dose” that could be quickly delivered when a patient loses the ability to move. Acorda Therapeutics has an application before the FDA to market an inhaled form of levodopa; a decision is expected in late 2018 or early 2019.

Although research in recent years has expanded beyond treating symptoms and focused increasingly on the underlying mechanisms, a number of therapies in the pipeline are specific to particular symptoms. Those advances are important, too, Beck said: “Therapies that address symptoms are important for helping people today and have been very important to improving the quality of life of people with Parkinson.”

Among symptom-focused drugs in clinical trials is tropicamide, a solution used in ophthalmology procedures. A completed phase 2 study looked into whether it can alleviate sialorrhea in Parkinson disease. Meanwhile, a phase 2 study is investigating buspirone for the treatment of anxiety in patients with Parkinson disease. Although that therapy is approved for anxiety in the general population, there is some concern that it might have a negative impact on motor function in patients with Parkinson disease. Results are expected in March.

Droxidopa was approved in 2014 to treat orthostatic dizziness, but a 2016 study showed that it can also reduce falls in patients with Parkinson disease.10

More recently, data from a phase 2 trial of SYN-120, which blocks 2 serotonin receptors in the brain, proved inconclusive. Investigators want to know if the therapy can help improve cognition in patients with Parkinson disease. Although the trial data “trended in favor” of the drug versus placebo, the study’s primary end point was not achieved to a statistically significant degree, the drugmaker Acorda Therapeutics reported.10 The company is currently evaluating the data and next steps.

Asked if the development of symptom-focused therapies might also help the larger effort to find a cure or prevention method, Beck said he hoped so but has not yet seen evidence of it: “Unfortunately, efforts to help symptoms have not resulted in any appreciable slowing of Parkinson.”

Collecting Data (and Funding)

Even as new therapies and formulations move through pharmaceutical pipelines, a number of major questions remain. For example, Beck said, the advancement in terms of gene therapies is hampered by this: “The community has a real problem—nobody really knows who has genetic forms of Parkinson.”

The Parkinson’s Foundation is among the groups working to change that. Earlier this year, it launched a Genetic Initiative aimed at offering genetic testing and counseling to patients in order to gain a more robust understanding of the genetic data behind the disease.11 The Michael J. Fox Foundation also has an initiative, Fox Insight.12 The program is an online clinical study asking patients to self-report data about their Parkinson disease experiences. It also partnered with the genetic testing company 23andMe to study the genetics of patients with Parkinson disease. Thus far, more than 26,000 patients have contributed to the study.

“It has really helped develop a better picture of what Parkinson’s is and the diversity of what Parkinson is,” Fiske said. Those data will help in clinical trial designs, but they could also have another impact— attracting more money into the fight to cure the disease.

Fiske said there is a good level of collaboration between his foundation, other Parkinson groups, and the National Institutes of Health. Government funding is also important, he said, but noted that funding levels can shift as political priorities shift, making it difficult to predict trends.

As far as industry goes, the signs are positive. “We’ve seen a lot of increased commitment from companies,” he said.

Drug companies look for things like clearly defined biology, clear unmet need, and clear patient need, Fiske said. As scientists gain ground investigating the mechanisms underlying Parkinson disease, it gets easier to get pharma involved.

Gilbert also noted that some promising research doesn’t involve drugs at all. “There has been mounting evidence over the past number of years that physical activity is beneficial for the motor and nonmotor symptoms of Parkinson and possibly disease-modifying, as well,” she said.

Unlike with drug candidates, she said, there are few adverse effects when it comes to exercise, which provides additional health benefits. The American Parkinson Disease Association recently launched an online training program for fitness professionals and a booklet about exercise for patients.

Edging Closer

As major studies continue to advance, it is not clear what the future of Parkinson disease care will look like, but there is plenty of enthusiasm. When asked which data he most looks forward to seeing in the coming months, Fiske had difficulty deciding but he said he is excited to see what comes from the studies looking into the genetic mechanisms.

“We’re all, as a field, anxiously hopeful, awaiting positive results from those studies,” he said. If those studies produce the kind of data Fiske wants, investigators could be on the precipice of the turning point in the fight against Parkinson disease.

“The holy grail, so to speak, of Parkinson treatment is a neuroprotective agent, or one that prevents, slows down, or cures Parkinson by changing the basic biology of the disease,” Gilbert said.


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3. Denali Therapeutics announces positive clinical results from LRRK2 inhibitor program for Parkinson’s disease [press release] South San Francisco, CA: Denali Therapeutics Inc.; August 1, 2018. investors. Accessed October 18, 2018.

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11. Parkinson’s Foundation announces new genetic initiative connecting Parkinson’s genetic data with clinical care [press release]. Miami, FL, and New York, NY: Parkinson’s Foundation; March 6, 2018. parkinson. org/about-us/Press-Room/Press-Releases/Parkinsons-Foundation-Announces-New-Genetic-Initiative- Connecting-Parkinsons-Genetic-Data-with-Clinical-Care. Accessed October 18, 2018.

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