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A path to the brain’s secrets

Genetic insights and diagnostic tools are helping scientists navigate toward neurological disease treatments

by Chris Morrison, special to C&EN
September 4, 2017 | A version of this story appeared in Volume 95, Issue 35

A conceptual drawing of a brain.
Credit: Will Ludwig/C&EN/Shutterstock

The brain has an earned reputation as a drug development graveyard. Because researchers lacked both a solid understanding of the root causes of neurological disease and good tools to track disease progression or drug effectiveness, our most complex organ long stymied pharmaceutical companies. Over the past decade, many large pharmaceutical makers significantly pared back neuroscience research, and some exited the space entirely.

In brief

Though genetics has fundamentally changed the pace of drug development for many therapeutic areas, the brain has been slow to reveal its inner workings. A new generation of neuroscience-focused biotech companies is poised to change that paradigm. Armed with genetic information and better tools to diagnose and track disease, these firms are hoping to develop drugs that can be tested in smaller and faster studies. Read on to learn how companies are trying to divide large, heterogeneous neurological diseases into smaller, genetically defined ones.

Those that stayed haven’t yet been rewarded. In Alzheimer’s disease alone, “we’ve had 15 years of nothing but failure,” says Martin Tolar, chief executive officer of Alzheon, a biotech company working on the disorder.

The challenges of fighting Alzheimer’s and other neurological diseases are myriad. The first problem is getting drugs into the brain at all: To reach their targets, molecules must cross the fabled blood-brain barrier—a natural defense evolved to keep them out.

Also, seemingly similar diseases may have disparate genetic underpinnings. There’s typically no process akin to a cancer biopsy, in which a piece of diseased tissue can be poked, prodded, and finally, understood. Lastly, the pace of clinical trials for neurodegenerative diseases, which often need to enroll thousands of patients, can be glacial.

But researchers at a new generation of biotech firms think the brain can be coaxed into giving up its secrets. Armed with genetic insights, therapeutic technologies, and diagnostic tools only dreamt about a decade ago, they are taking a page from more successful corners of the biopharmaceutical world such as oncology. By pulling back a layer of shared symptoms and dividing monolithic diseases into distinct, genetically defined ones, they believe they can design better drugs and test them more quickly.

Along the way, these new biotech companies are also reigniting investor enthusiasm for the notoriously difficult area. According to a recent review by the Biotechnology Innovation Organization, venture capital investment in neurology-focused start-ups more than doubled in 2012–16 compared with the prior five years, to more than $2 billion. That includes the stunning $347 million raised by Denali Therapeutics, a start-up founded in 2015 to tackle neurodegenerative diseases.

One reason for the surge: Neuroscience is finally reaping the benefits of genetic sequencing, a field moving so rapidly that even the skeptics are starting to change their tune about its worth.

In the past decade, “the line has moved from ‘this is never going to work’ to ‘maybe this will work’ to ‘all right, it’s working, but it’s useless and doesn’t mean anything,’ ” says Benjamin Neale, a researcher at Broad Institute of MIT & Harvard. Neale now sees a growing body of genetic knowledge that will accelerate discovery across neuropsychiatric and neurodegenerative diseases.

Biotechs are quickly taking advantage of the mountain of emerging data. Because teasing apart the genetic causes of neurodegenerative diseases requires large population studies, “genetic insights emerging in Alzheimer’s or ALS or Parkinson’s correlate directly with a reduction in cost of sequencing technologies,” says Denali’s CEO, Ryan Watts.

In neurodegenerative diseases, that acceleration has meant going from a handful of genetic risk factors to 30 or 40 in each disease that now point to specific pathways in areas such as lysosomal function or glial cell biology, he says. With that opportunity as a starting point, “we want to work on targets that have the strongest genetic rationale,” Watts says. Denali already has 10 programs in various stages of development.

Those rationales are being honed from genome-wide association studies, which collect and analyze large sets of genetic data to find common variations implicated in disease. Other clues come from sequencing studies that uncover rarer genetic variants where gain or loss of function can cause harm.

“Genetics is a particularly powerful tool kit” for neuropsychiatric and neurodegenerative diseases “because of the inability to directly access the biological systems involved,” Neale says.

Structure of Biogen's SMA treatment Spinraza.
Biogen's Spinraza

Missing generation

The brain’s unique complexity means that even as targeted drugs proliferate in areas such as cancer, infectious disease, and autoimmune disease, new drugs to treat neurological disease are few and far between.

According to a recent analysis of U.S. Food & Drug Administration approval trends by the Swiss venture firm HBM Partners, the central nervous system was the only therapeutic area to see a decline in new drug approvals between 2012 and 2016 compared with the prior five-year period. Moreover, significantly fewer new neuroscience drugs reached the market overall: Just 12 were approved in that time frame, compared with 50 new drugs for oncology, which has particularly benefited from analysis of genetic drivers of disease.

Of those dozen new neuroscience drugs, one offers perhaps the best glimpse of where the field is going.

Spinraza, a nucleic acid drug from Biogen and Ionis Pharmaceuticals, was approved in late 2016 to treat children with spinal muscular atrophy (SMA), a rare and sometimes deadly muscle-wasting disease. By targeting and splicing a specific sequence of RNA, Spinraza increases the production of survival motor neuron protein, thereby preventing the loss of nerve cells that control muscles in kids with SMA.

In clinical trials, the treatment allowed some infants to sit up, crawl, and even walk—milestones that babies with SMA typically never achieve. FDA was so enthusiastic about the drug’s prospects that the agency convinced the developers to evaluate its effectiveness earlier than planned and approved it five months ahead of schedule.

Although the genetic basis of SMA was discovered in the mid-1990s, Spinraza’s approval is an early look at what’s to come as biotech companies’ discovery and development efforts catch up to other early genetic discoveries.

“In the same way oncology went from cytotoxic chemotherapies and running big Phase III studies to see where your drug might work, to targeted therapies, a lot of that is now happening in neurology,” says Paul Bolno, CEO of Wave Life Sciences.

Wave is developing stereopure oligonucleotides targeting specific genetic subsets of neurological disease. Other companies’ oligonucleotides are complex mixtures of stereoisomers, a heterogeneity that Wave believes affects their potency and safety. Wave’s most advanced drug candidates target subsets of people with Huntington’s disease, which is caused by a mutation in the gene for the huntingtin protein. Without treatment, huntingtin protein accumulates in neurons, causing progressive damage and, eventually, death.

In July, Wave began clinical trials for two drugs, each of which targets a specific single nucleotide polymorphism (SNP) on the mutant huntingtin gene transcript. These SNPs are commonly associated with the mutant allele; Wave estimates that two-thirds of people with Huntington’s disease have one or both SNPs.

The cancer playbook

The discoveries underpinning both Biogen’s Spinraza and Wave’s Huntington’s treatments predate the genomics revolution of the past 20 years. Despite the recent explosion of genetic data, industry is still at an early point in translating the genetics of neurological disease to new therapeutic candidates. And although targets are beginning to emerge from genomic studies, so far those discoveries tend to support earlier hypotheses, not generate new ones, Bolno says.

Research institutions like Broad, through its Stanley Center for Psychiatric Research, are working to identify genetic risk factors for psychiatric diseases such as schizophrenia through large-scale studies. The Deciphering Developmental Disorders project, undertaken by the Wellcome Trust Sanger Institute, likewise uses genomic tools to uncover the genetic causes of rare developmental disorders.

Disease-focused philanthropic organizations such as the Michael J. Fox Foundation for Parkinson’s Research and the ALS Therapy Development Institute are exploring new endpoints for clinical trials; collecting genetic, clinical, and behavioral data and biological samples from patients; and working with industry partners to exploit these increasingly large data sets.

Because sequencing can generate so much data relatively inexpensively, researchers feel like they’re on the cusp of understanding much more about diseases such as Parkinson’s and ALS.

“People are realizing what we think of as single diseases are compositions of different causalities,” Bolno says. Equipped with the right tools, drug discovery scientists can also become more efficient. “Because we’re working on a single genetic cause of disease,” companies can run smaller clinical trials that yield better information about whether a drug works, Bolno adds.

The flip side is that molecules with mechanisms of action targeting certain underlying pathologies must be tested in people with those pathologies. That might sound obvious, but clinical trials that enroll the wrong patients have exacerbated neuroscience’s failures. Alzheon’s Tolar points out that people with vascular dementia display similar symptoms as people with Alzheimer’s disease yet would not benefit from the amyloid-targeted drugs developed for Alzheimer’s patients.

Indeed, data from an Eli Lilly & Co. analysis of its failed antiamyloid antibody solanezumab showed that as many as 30% of the patients enrolled in early clinical studies were misdiagnosed as having Alzheimer’s, Tolar says.

New diagnostic tools are helping address that problem. Using positron emission tomography (PET) imaging, which allows researchers to see where their molecules are binding in the brain, or genetically screening people for apolipoprotein E (APOE) status has drastically reduced misdiagnosis in Alzheimer’s studies that target some form of amyloid, he says. Narrowing the population to only those who had two copies of APOE4, the APOE variant most strongly associated with Alzheimer’s, reduced misdiagnosis to 2%.

“Stratification of subpopulations and targeting the right patients, using the cancer playbook—all of this has been incredibly useful” for more recent clinical trials of Alzheimer’s disease drugs, Tolar says. Alzheon will initially study its most advanced drug candidate, ALZ-801, a small molecule that targets toxic amyloid oligomers, in people with two copies of APOE4. The biotech intends to start a Phase II/III study of ALZ-801 in late 2017.

Venture confidence

Investors have put significant money into a new generation of neuroscience-focused biotech firms.

Dec. 2016 BlueRock Therapeutics $225 million Series A Neurodegenerative diseases
May 2015 Denali Therapeutics 217 million Series A Neurodegenerative diseases
Oct. 2015 TauRx Pharmaceuticals 135 million Undisclosed Alzheimer’s disease
June 2016 Denali Therapeutics 130 million Series B Neurodegenerative diseases
Nov. 2016 Biohaven Pharmaceutical 100 million Series A Spinocerebellar ataxia and migraine
Aug. 2015 Ovid Therapeutics 75 million Series B Developmental disorders and pediatric epilepsies
Aug. 2015 Wave Life Sciences 66 million Series B Rare genetic diseases, including Huntington’s and Duchenne muscular dystrophy
Sept. 2015 AveXis 65 million Series D Spinal muscular atrophy
July 2017 E-Scape Bio 63 million Series A Alzheimer’s disease
April 2015 Voyager Therapeutics 60 million Series B Rare diseases of the central nervous system
Feb. 2016 Yumanity Therapeutics 45 million Series A Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS)

Source: Company filings

Old school

As with APOE4, genetic links are almost always uncovered by directly studying a disease. But the drug industry is finding genetic connections between rare and more-common neurological disorders that can also lead to new drugs.

Lysosomal Therapeutics is among several biotech companies developing drugs for a subset of people whose Parkinson’s disease is driven by a mutated form of the gene carrying the recipe for glucocerebrosidase, an enzyme that breaks down certain fats in the lysosome.

The enzyme is a familiar one: The roughly 6,000 people in the U.S. with Gaucher disease have inherited two copies of a mutated glucocerebrosidase (GBA) gene. They experience a harmful—and eventually deadly—accumulation of lipids in the lysosome.

The approval in the 1990s of the first enzyme replacement therapies for the lysosomal storage disease extended the lives for people with Gaucher but also led to a curious discovery. “Clinicians who are all of the sudden treating older Gaucher’s patients started to recognize that the incidence of Parkinson’s disease was unusually high for these patients,” says Lysosomal Therapeutics’ chief scientific officer, Peter Lansbury.

In fact, they’re at a 40-fold elevated risk for the disease—they have roughly a 30% chance of developing Parkinson’s in their lifetimes. Enzyme replacement therapies do not cross the blood-brain barrier, so although they can mitigate the symptoms of Gaucher, they do not stave off the onset of Parkinson’s.

The link between Parkinson’s and Gaucher was discovered in 2004 not by genetics but by real-world observation. Lansbury calls the finding “kind of old-school.”

People who have just one mutated copy of the GBA gene have a roughly 30 to 40% reduction in glucocerebrosidase activity, Lansbury says, and their risk of developing Parkinson’s ranges between twofold and 15-fold greater than usual depending on the specific GBA mutation they harbor.

Lysosomal Therapeutics is developing a small molecule, LTI-291, designed to boost activity of nonmutated (wild-type) glucocerebrosidase in the brain. The goal is to slow Parkinson’s progression, Lansbury says, or even reduce the risk of getting the disease in the first place.

“If we can squeeze 30% more activity out of the wild-type enzyme, based on what we know about the relationship between mutations and rate of progression, it would have a significant effect,” he adds.


Gaucher disease is the most common lysosomal storage disease, so it’s not surprising that the GBA mutation was the first to be also linked to a neurodegenerative disorder, says Kees Been, Lysosomal Therapeutics’ CEO.

GBA mutations are also risk factors for Lewy body dementia, which affects 1.4 million people in the U.S. alone, according to the Lewy Body Dementia Association. Lysosomal Therapeutics has identified other instances in which carrying two copies of a mutation leads to a lysosomal storage disease but carrying only one also confers a higher risk of a particular neurological disease, Been says.

People are realizing what we think of as single diseases are compositions of different causalities
Oaul Bolno, CEO, Wave Life Sciences

Parkinson’s with GBA, as this subset of the disease is known, is particularly fast moving. “This group of patients has rapid cognitive decline; a rapidly progressing, much more severe and debilitating form of the disease; and they’re identifiable by genotyping,” Lansbury says.

Though unfortunate, it makes an ideal situation for development of a targeted therapeutic. Because of this rapid progression, Lyosomal Therapeutics should be able to see an effect by testing LTI-291 in “hundreds of patients for one year, not thousands of patients over multiple years,” Been says, as is more typical of neurodegenerative disease trials.

In January 2017, Allergan paid an undisclosed fee for an option to acquire Lysosomal Therapeutics once its Phase Ib trial for LTI-291 reads out. A clinical study of LTI-291 in healthy volunteers is about to begin, and the data necessary for Allergan to make a decision should be in hand in 2018.

Better biomarkers

One key advantage Lysosomal Therapeutics has over other entrants in the neurodegeneration field is an easy way of seeing whether its drug is doing its job. Boosting the activity of glucocerebrosidase lowers levels of its substrate, glucosylceramide, which can be measured in blood. That kind of built-in biomarker to measure a drug’s engagement with its target is still relatively rare.

Indeed, a challenge in developing drugs for neurological diseases has been understanding whether drug candidates are doing what researchers think they are, says Matthew During, founder and chief scientific officer of Ovid Therapeutics, which has two central nervous system-targeted drugs in midstage trials.

In the absence of a clear-cut biomarker such as reduced quantities of a particular protein, companies are relying on new and better imaging tools to guide their drug development programs.

“If your trial fails, did your drug actually cross the blood-brain barrier and engage your target, and at what level? Now PET ligand enables us to answer those questions,” During says. For one of its two most advanced molecules, TAK-935, a CH24H inhibitor for rare pediatric epileptic encephalopathies, Ovid has identified a plasma biomarker that correlates with the PET signal, giving it a clear picture of whether its drug is active.

Long road

The challenges of developing drugs for psychiatric diseases are amplified by the lack of imaging techniques or blood-based measurements that can indicate whether someone has, for example, schizophrenia, Broad’s Neale points out.

Nevertheless, Neale counsels patience. “Where cancer is today is in no small part due to the genetic revolution that radically altered the landscape of cancer 20 years ago,” he says. The road from genetic insight to new drugs is a long one, and studying cancer has its advantages. For starters, you can take it out of the person and analyze it.

“It’s going to take new biological insights rooted in genetic analysis to really drive us forward to the next level of understanding what is actually going on in neurobiology in any substantive way,” Neale says.

And even as researchers unravel the genetic underpinning of neurodegenerative diseases, they acknowledge other roadblocks. Such diseases tend to progress slowly. Symptoms often don’t show up until years—decades, in the case of Alzheimer’s—after the onset of the disease. That creates a problem for drugs targeting broad and genetically defined populations alike: If a disease is detected years into its progression, even the best drugs may not markedly improve people’s lives.

Denali’s Watts is keenly aware of that limitation. His firm’s development programs are all grounded in genetic insights. But even with the smaller and sometimes shorter trials enabled by genetic subpopulations, the firm is challenged to identify the sensitive tools needed to follow disease progression.

Regardless, he is cheered by the accumulation of genetic insights. “Suddenly you’re seeing pathways defined by human genetics,” Watts says. Technological advancements and reductions in sequencing costs are having an unprecedented impact—one that not long ago seemed out of reach.

As Neale puts it: “Even just five years ago, it was difficult to imagine the real scale of what we would be able to do.”

Chris Morrison is a freelance writer covering the biotech and pharmaceutical industries. He is based in Yardley, Pa.


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