In 2019, the World Health Organization (WHO) estimated that Parkinson’s disease (PD), a brain condition that causes problems with movement and mental health, impacted more than eight million people worldwide, reflecting a doubling in the prevalence of PD in the preceding 25 years.
The first paper implicating mutations in the leucine-rich repeat kinase-2 (LRRK2) gene as a cause of some PD cases was published in 2004. As new drugs enter the clinical trial stage, for PD patients to know whether their illness has a genetic component, could prove especially useful in getting them enrolled into appropriate clinical trials as they arise, which may result in the development and coming to market of drugs that could help with the treatment of their PD.
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According to GlobalData’s Clinical Trials database, three LRRK-related PD patient trials are currently in active stages of development.
Despite the awareness of a connection between LRRK and PD in some patients, past research has shown that genetic testing is not part of the routine evaluation process for PD patients, although 83% of PD patients said they would take a genetic test if it were available.
A 2019 paper indicated that 41% of 178 responding clinicians in the US and Canada had not referred any PD patients for genetic testing in the last year, while more than 80% reported referring fewer than 11 patients over the same period.
Centogene recently published a paper on initial data from its Rostock International Parkinson’s Disease (ROPAD) genetic profiling study (NCT03866603).
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By GlobalDataThe Germany-headquartered biotech’s ROPAD study has been running for almost five years at 100 study sites worldwide. The goal of the study is to characterise the genetics of PD to establish a better understanding of the disease progression, diagnosis, and treatment.
Out of an initial 12,500 patients with PD tested, the data shows that genetic factors – i.e. mutations in LRRK2 or other genes such as Glucosylceramidase Beta 1 (GBA1) – play a role in 15% of PD cases.
Medical Device Network sat down with Centogene’s chief medical and genomic officer Peter Bauer to learn more about the implications of the ROPAD study’s initial findings, and how the data makes a strong case for the need to implement genetic testing into the standard of patient care for PD.
Bauer says that in 2014, California-based biotech Denali Therapeutics had pre-clinical data showing its LRRK2 kinase inhibitor candidate, DNL-151, to be beneficial in animal models. The company wanted to progress into the clinical stage, given its belief that this drug could become the first available on the market that could stop PD progression by effectively turning off a mechanistic driver of neurodegeneration.
However, Denali was looking for 600 PD patients with LRRK2 gene mutations for its trial, but [Denali said] that “we don’t know where they are”, Bauer recounted.
“Denali was sure these patients were out there somewhere, but nobody does genetics with Parkinson’s patients because most do not have a genetic disease.
“With this lack of awareness around the need to prepare for trial-ready populations, Denali hit the ground with potential and didn’t know how to drive its programme.”
Denali came to Centogene for help finding PD patients with potential mutations in protein-encoding gene LRRK2 for enrolment into its since-terminated LIGHTHOUSE (NCT05418673) trial.
The LIGHTHOUSE trial was a study to assess if DNL151 (BIIB122) tablets were safe and could slow the worsening of early-stage PD in participants with specific LRRK2 variants.
With the Denali partnership cemented, Centogene began its ROPAD study, testing PD patients to evaluate whether they had LRRK2 or other gene mutations, in 2018.
Centogene has performed gene profiling using next-generation sequencing (NGS) to determine whether PD patients tested have a genetic mutation.
“A total of more than 15% have been returned a genetic report with a result that is now in their hands to engage in any other genetic trial in Parkinson’s because they know what they are suffering from, or what is the main driver,” says Bauer.
“The relevance of ROPAD is to prepare for clinical programs and have the patients already lined up before the potential new drug is asking for recruitment into clinical trials.”
Bauer adds that having this information is important because it saves a lot of time.
“At Centogene, we think of this as a new era where targeted therapies to stop or to heal Parkinson’s can only be started if we have genetic profiling as a standard of care developed, and effectively the first major finding of the ROPAD study is that this can be done at scale and with an appreciable benefit to those with PD and their families.”
Impact of the ROPAD study
Finding that genes LRRK2 and GBA-1 were a component in 15% of PD patients was not a surprise to Bauer as these mutations have previously been implicated in PD pathology. However, he says that previously there was not a comprehensive picture.
“While you could say that the data only confirms an expectation, what is new is that through ROPAD, patients with Parkinson’s have been systematically offered a genetic test and received a genetic report,” explains Bauer.
“ROPAD has really been designed to enable physicians and their patients to keep this information for their personal record and also to make use of the information for any opportunity in the future, to drive faster treatment development than we have had in the past.”
Bauer adds that there is more added value in the study beyond sponsor Denali’s interest in the data showing 3% of patients with LRRK2 gene variants.
“ROPAD is, therefore, broader and bigger than the initial request, so there’s much more value going forward because we can go back to these profiled patients, the physicians and the Centers of Excellence to now do the next step, such as an additional study, or to activate the patient potential.”
The value of bringing genetic screening to standard PD care
According to Bauer, a neurologist may see ten Parkinson’s outpatients per day, and the clinical symptoms they show all look alike.
As an example, Bauer continues that a neurologist may display some surprise at seeing a Parkinson’s patient who is a little bit younger, with symptoms starting at 55 years of age while most PD patients express symptoms around the age of 65-75 years.
In this case, the neurologist may suspect that Parkinson’s for this relatively younger patient may have a genetic basis.
“But if you don’t do a genetic test, you will never learn,” Bauer says.
Determining early onset PD was another component of the ROPAD study.
“If we have early onset, we see that the return rate of positive results is not 15% like in the overall cohort, but we enrich it for positive genetic findings because this is the high-risk genetic cohort,” says Bauer.
“That’s something where we added value because now you can turn it around and say, okay, for all neurologists out there, if you have Parkinson’s patients that manifest before age 60, you should really consider doing genetics, because there you will find 20% to 25% positive cases, and not only 15% if they are older.
“We have found one item from the clinical descriptor, which is age and onset, that helps us to focus our resources on this population.”
Bauer notes that the other important component in evaluating PD patients is checking whether they have relatives with the disease.
“Many of them will say no, it’s only me, but if there is an uncle or sibling with PD, it will almost double the probability that we find a genetic cause, even if the relative has not been tested. Just having this connection of information is incredibly important to guide the resourcing of genetic testing in the first place,” says Bauer.
“Through this study, we also learned that the genetic profiles that we’ve seen usually trigger some disturbances in biochemical pathways, and while all the details are not yet understood, it also helps us to define the cohort with these genetic forms with a given variant, for example, and determine if is this a mild or a severe variant.
“If this is a mild variant, in the future you could even do the genetic test at 18 years old because the genetics are already there. What you don’t know is whether if you find this marker or if someone will develop Parkinson’s.
“But what you can do is start to build up risk models with the genetic information, maybe with additional biochemical analysis, and say, you’re on a path with a higher risk or lower risk to develop Parkinson’s.”
Bauer adds that for these genetic markers that are the most common – GBA-1 and LRRK2 – usually only around 10% to 20% of those that have the genetic marker will develop PD.
“This tells us that these genetic markers are a strong risk factor. It’s not fate, but it’s very important to learn about,” Bauer says.
In future cases where clinical programmes with drug development are successful, Bauer predicts that it may even become possible to start thinking about preventing people in their 40s and 50s from getting PD with drug support that saves their neurons from developing PD.
“You could ultimately then start to cure PD even before it hit the clinical symptoms, so you would need to do that early enough to be able to establish a preventive medicine paradigm, and that’s completely new,” Bauer says.
“This is a prospect we could never think about in PD before without genetics, because we wouldn’t be able to identify risk profiles in an 18-year-old; now, this is something we can do.”
