With $191 million in startup capital, the genomics startup will draw on existing genetic databases to create personalized medicine therapies for chronic diseases
Why do some people get sick while others do not? That’s what genetic researchers at Maze Therapeutics want to find out. They have developed a new approach to using tools such as CRISPR gene editing to identify and manipulate proteins in genetic code that may be the key to providing personalized protection against specific diseases.
If viable, the results of Maze’s research could mean the development of specific drugs designed to mimic genetic code in a way that is uniquely therapeutic to specific patients. This also would create the need for clinical laboratories to sequence and analyze patients’ DNA to determine whether a patient would be a candidate for any new therapies that come from this line of research.
Based in San Francisco, Maze Therapeutics (Maze) is studying modifier genes—genes that affect the phenotype or physical properties of other genes—and attempting to create drugs that replicate them, reported MIT Technology Review. Maze believes that genetic modifiers could afford a “natural form of protection” against disease.
“If you have a disease-causing gene, and I have the disease-causing gene, why is it that you may be healthy and I may be sick? Are there other genes that come into play that provide a protective effect? Is there a drugging strategy to recover normal phenotype and recover from the illness?” Maze Chief Executive Officer Jason Coloma, PhD, asked in an interview with FierceBiotech.
In 2019, Maze received $191 million in financing from Third Rock Ventures, ARCH Venture Partners, and others, to find ways to translate their findings into personalized medicines, according to a news release. And with the availability of international public genetic databases and CRISPR gene editing, now may be good timing.
“This was the perfect time to get into this space with the tools that were being developed and the amount of data that has been accumulated on the human genetic side,” Charles Homcy, MD, Third Rock Ventures Partner and Maze Scientific Founder, told Forbes, which noted that Maze is tapping existing population-wide genetic databases and large-scale studies, including the United Kingdom’s Biobank and Finland’s Finngen.
To help find genetic modifier drug targets, Maze is accessing CRISPR gene editing capabilities. Jonathan Weissman, PhD, Maze Scientific Founder and Professor of Cellular Molecular Pharmacology at University of California, San Francisco (UCSF), told MIT Technology Review: “You take a cell with a disease-causing gene and then see if you can turn it back to normal. We can do 100,000 experiments at once because each cell is its own experiment.”
“At Maze, we are focused on expanding our understanding of the natural disease protection provided by genetic modifiers through an integrated approach that combines studying natural human genetic variation across the globe and conducting large-scale experiments of gene perturbations,” Charles Homcy, MD (above), Founder and interim CEO of Maze and a partner at Third Rock Ventures, said in a news release. “Through our integrated approach, we believe we will create novel medicines based around those modifiers to treat a number of diseases.” (Photo copyright: Forbes.)
Using CRISPR to Identify the Cause of Disease
One drug research program reportedly progressing at Maze involves developing gene therapy for the neurogenerative disease amyotrophic lateral sclerosis (ALS). The program borrows from previous research conducted by Aaron Gitler, PhD, Professor of Genetics at Stanford University and Maze co-founder, which used CRISPR to find genetic modifiers of ALS. The scientists found that when they removed the protein coding gene TMX2 (Thioredoxin Related Transmembrane Protein 2), the toxicity of proteins building the disease was reduced, reported Chemical and Engineering News.
“We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells,” Gitler and colleagues wrote in Nature Genetics. “Together, our results demonstrate the promise of using CRISPR-Cas9 screens in defining the mechanisms of neurodegenerative diseases.”
“We have the flexibility to think differently. We like to
think of ourselves as part of this new breed of biotech companies,” Coloma told
FierceBiotech.
It’s an exciting time. Clinical laboratories can look
forward to new precision medicine diagnostic tests to detect disease and
monitor the effects of patient therapies. And the research initiatives by Maze
and other genetic companies represent a new approach in the use of genetic code
to create specific drug therapies targeted at specific diseases that work best
for specific patients.
The companion diagnostics that may come from this research would
be a boon to anatomic pathology.
Shifts to new types of facilities where patients are treated provide clinical laboratories and pathology groups with new opportunities to add value to providers and patients
Two important trends have serious implications for the nation’s traditional hospitals. One is the ongoing shift of patient care from inpatient settings to outpatient providers. The other trend is to proactively manage patients so as to avoid the need for hospitalization. Both trends create challenges and opportunities for medical laboratories and anatomic pathology groups.
Thus, it is significant that one advisory group to the federal government on Medicare and health policy recognizes these trends with the recommendations it made to Congress. In June, the Medicare Payment Advisory Commission (MedPAC) released its “Medicare and the Health Care Delivery System” report to Congress. It includes proposals that support healthcare’s shift toward outpatient settings and away from in-hospital care. It also makes two recommendations that impact EDs based on their locations (rural versus urban) and proximity to parent hospitals.
MedPAC believes that shifting money/reimbursement toward different sites of care and for different services improves the ability of providers to be proactive and manage patients in ways that support earlier diagnosis and more active management of conditions—all in ways that help avoid acute events that would otherwise send patients to hospitals.
Thus, for clinical laboratories, the message with MedPAC is that other sites of service would get better reimbursement for the above reasons and would want lab services that support the objectives of their providers. And the recommended enrichment of reimbursement for ambulatory evaluation and similar management services would encourage providers to do a better job of ordering the right test and doing the right thing with the results. This gives labs an opportunity to add value.
Ensuring Access to ED Services in Rural Environments
MedPAC is a nonpartisan legislative branch agency that provides the US Congress with analysis and policy advice on the Medicare program. Most of the points the June report makes pertain to the Medicare program in general. However, chapter two of MedPAC’s report addresses payments to emergency departments specifically, including:
Increasing Medicare payment rates to isolated rural stand-alone EDs; and,
Decreasing payment rates to urban stand-alone EDs located near hospital-based emergency departments.
To ensure rural residents have access to ED services, MedPAC recommends allowing hospitals located more than 35 miles from another ED to convert to stand-alone EDs that would bill under the Outpatient Prospective Payment System (OPPS). Effectively they would become “outpatient-only” hospitals and would receive annual payments to assist with their fixed costs.
In contrast, MedPAC noted an oversupply of emergency services in urban areas, where stand-alone EDs—particularly those affiliated with nearby hospitals—may be shifting services from lower cost urgent care centers and physicians’ offices to higher cost 24/7 stand-alone EDs.
MedPAC reported that outpatient Medicare ED payments increased 72% per beneficiary between 2010 and 2016. A MedPAC press release attributed the growth in off-campus EDs in certain urban locations to “Medicare payment policy [rather] than unmet need for ED services.”
“I think [the MedPAC proposal] is a move in the right direction,” Renee Hsia, MD, MSc, Professor of Emergency Medicine and Institute of Health Policy Studies at the University of California-San Francisco, toldLeaders in Health Care. “We have to understand there are limited resources, and the fixed costs for stand-alone EDs are lower.” Hsia co-authored a report titled, “Don’t Hate the Player; Hate the Game,” published in the Annals of Emergency Medicine. In it she argues that “freestanding EDs will continue to proliferate in areas in which there are few restrictions, potentially creating more supply than demand.” (Photo copyright: University of California San Francisco.)
75% of Freestanding EDs within Six Miles of Hospital EDs
In April, MedPAC published an analysis of five healthcare markets—Charlotte, Cincinnati, Denver, Dallas, and Jacksonville, Fla. In “Using Payment to Ensure Appropriate Access to and Use of Hospital Emergency Department Services,” MedPAC showed that 75% of the freestanding EDs were located within six miles of a hospital emergency room. The average drive time to the nearest hospital was 10.3 minutes.
In that report, MedPAC proposed cutting payment rates 30% for off-campus stand-alone EDs located within six miles of an on-campus hospital emergency room. This proposal means off-campus EDs, which have lower standby costs and typically treat patients with less acute medical problems, would receive Medicare payment rates on par with ED facilities open less than 24/7. If the rate change is enacted, MedPAC estimates Medicare would save between $50 million and $250 million annually.
MedPAC’s recommendation drew the ire of the American Hospital Association (AHA) and other hospital industry stakeholders who believe a payment cut could result in off-campus stand-alone EDs closing. The AHA in March submitted a “comment letter” to MedPAC Executive Director James E. Mathews, PhD, calling the proposal “unfounded and arbitrary.”
“The recommendation is not based on any analysis of Medicare beneficiaries, Medicare costs, or Medicare payments, and would make Medicare’s record underpayment of outpatient departments and hospitals even worse,” Joanna Hiatt Kim, Vice President of Policy at the AHA, told Modern Healthcare. “Even more troubling to us is that [the recommendation] has the potential to reduce patient access to care, particularly in vulnerable communities, following a year in which hospital EDs responded to record-setting natural disasters and flu infections.”
This latest report indicates MedPAC believes shifting reimbursement toward different sites of care and for different services improves the ability of providers to be proactive and manage patients in ways that support earlier diagnosis and active management of conditions.
Medical laboratories and anatomic pathology groups should use this opportunity to create lab services that support these objectives and add value to both providers and patients.
As the public gains awareness of the role clinical laboratories play in modern healthcare, increased engagement and understanding of the technology underlying many of these advances could create risk for labs without transparent reporting protocols to both patients and the public
In recent years, consumers have continually raised the bar in their expectation of quality when they interact with the healthcare system. Not only do patients expect providers—including clinical laboratories and anatomic pathology groups—to improve regularly over time, but the public has even less tolerance for medical errors of any type. Thus, a recent NPR story is one more warning to the medical laboratory profession that it should be devoting resources and effort to improving quality.
Today’s healthcare consumers and patients are more educated about and involved in the care process than ever before. While the exact science and skills may not interest the general public, the technologies underpinning much of the shift toward personalized medicine (AKA, precision medicine) are the same technologies that created the always-connected, digital lifestyles seen around the world.
With this, comes a level of scrutiny and questioning from the public that clinical laboratories or anatomic pathology groups would not have experienced even just a decade ago.
Mounting Scrutiny of Medical Laboratories and Healthcare Professionals
A recent segment on NPR’s “All Things Considered” highlighted this trend and questioned the quality control standards behind many of the procedures powering current testing. The segment also questioned the impact quality control has on the quality of biobanks used to research and create future technologies and tests.
Atul Butte, PhD (above), Director of the Institute of Computation Health Sciences at the University of California-San Francisco, presents an alternate side to Compton and Friedberg’s views in the NPR article. “I am not a believer in garbage-in, garbage out at all,” he said. “I know that no one scientist, no one clinician or pathologist is perfect … But, I’d rather take 10 or 100 so-called mediocre data sets and find out what’s in common, then to take one who says they’re perfect at doing this kind of measurement.” (Photo copyright: Santiago Mejia/San Francisco Chronicle.)
When data and previous research powers much of the innovation taking place across the modern healthcare landscape, the accuracy of said data would seem critical. Yet, without standards in place, there’s not always safeties by which to verify sample integrity and other critical concerns.
Late last year, Dark Daily reported on a study published in PLOS ONE from Radboud University in the Netherlands questioning the accuracy of more than 30,000 published scientific studies that contained misidentified or contaminated cell lines. Guidelines, such as those created for IHR and FISH HER2 testing, provide standards intended to prevent such issues from occurring or detecting them when they do occur.
Quality versus Quantity: A Gamble Worth Taking?
Apart from challenges with healthcare reform and the regulatory landscape surrounding precision medicine, medical laboratories also must struggle with the challenges of gleaning and maintaining useful, accurate information from an ever-growing trove of data produced by analyzers and assays.
Yet, these mediocre datasets include the results of tests that carried a potentially significant impact on patient lives. In the first two weeks of February alone, both the St. Louis Post-Dispatch and The Telegraph published stories related to erroneous testing related to cancer and the potential impact on the clinical laboratories involved and the patients tested.
Increased coverage shows that the world is watching what goes on in medical laboratories, hospitals, and data centers as healthcare continues to evolve. Clinical laboratories must move forward with this in mind or risk pushback and questioning from the public. Transparency regarding standards, and reporting information to patients surrounding testing or concerns, might effectively address this rising trend.
“We are moving faster and faster and faster as this whole precision medicine train is moving down the track,” Tim Allen, MD, Laboratory Director at the University of Texas Medical Branch Department of Laboratory Services, told NPR. “I suspect standardization of these things is going to become a reality much quicker than I would have expected even a few years ago.”
That quality control issues in anatomic pathology are considered newsworthy by no less than NPR is a sign of increased public attention to the quality of lab testing. The story was written to educate the public about the gap that exists in the quality control of anatomic pathology testing. All of this is consistent with the trend for providers to be transparent and report their quality metrics to the public, including patients.
Clinical labs and pathology groups know how advances in targeted therapies and genomics far outpace providers’ and patients’ ability to know how best to use and pay for them.
One fascinating development on the road to precision medicine is that many new cancer drugs now in clinical trials will require a companion genetic test to identify patients with tumors that will respond to a specific therapeutic drug.
This implies more genetic testing of tumors, a prospect that challenges both the Medicare program and private health insurers because they already struggle to cope with the flood of new genetic tests and molecular diagnostic assays. However, even as this genetic testing wave swamps payers, some pharmaceutical companies have cancer drugs for rare types of cancers and these companies would like to see more genetic testing of tumors.
Pathologists and clinical laboratory managers will find this to be precisely the dilemma facing specialty pharma company Loxo Oncology (NASDAQ:LOXO), a biopharmaceutical company located in San Francisco and Stamford, Conn.
Loxo is developing larotrectinib (LOXO-101), a “selective TRK inhibitor.” According to a Loxo press release, Larotrectinib is “a potent, oral, and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRK receptors).” In short, the drug is designed to “directly target TRK, and nothing else, turning off the signaling pathway that allows TRK fusion cancers to grow.”
How to Find Patients for This Cancer Drug
While a powerful, new, targeted cancer drug will be a boon to cancer therapy, it is only intended for a relatively small number of patients. Loxo estimates that between 1,500 and 5,000 cases of cancer are caused by TRK mutations in the United States each year. Conversely, according to the National Cancer Institute, the total number of new cancer diagnoses in the US in 2016 was 1,685,210.
An article in MIT Technology Review on larotrectinib notes, “To find patients, Loxo will need to convince more doctors to order comprehensive tests that screen multiple genes at once, including TRK.” And that is where things get complicated.
“These advanced genetic tests, which can cost $5,000 or more, are offered by companies like Foundation Medicine, Caris Life Sciences, and Cancer Genetics. The problem is, insurers still consider the tests ‘experimental’ and don’t routinely cover them, meaning patients are often stuck picking up the bill,” notes MIT Technology Review.
Data for the graph above comes from theNational Human Genome Research Institute. The graph illustrates the steep decline in cost for whole genome sequencing over the past 17 years. As the cost of genetic testing drops, development of targeted-drug cancer therapies increases. Clinical laboratories and anatomic pathology groups can expect to be performing more such tests in the future. (Graphic copyright: National Human Genome Research Institute/Simple English Wiki.)
To further confuse the market, the National Cancer Institute states that “Insurance coverage of tumor DNA sequencing depends on your insurance provider and the type of cancer you have. Insurance providers typically cover a DNA sequencing test if there is sufficient evidence to support that the test is necessary to guide patient treatment. Tests without sufficient evidence to support their utility may be considered experimental and are likely not covered by insurance.”
Many reliable sources agree. For example, the US National Library of Medicine Genetics Home Reference states, “In many cases, health insurance plans will cover the costs of genetic testing when it is recommended by a person’s doctor.”
That, however, leads to a different conundrum for drug makers such as Loxo: the majority of doctors are not keeping up with the rapid-fire pace of discovery in the realm of genetics and targeted therapies. Some genes like BRCA1 and BRCA2 are familiar enough to doctors that they know how and why they are important. However, most other genes are less known, and critically, less understood by doctors who must also focus on all the other myriad aspects of patient care.
In an article on the Color Genomics $249 Hereditary Cancer Test, which tests for mutations in 30 genes, Timothy Hamill, MD, Professor Emeritus, University of California San Francisco (UCSF) Department of Laboratory Medicine, and former overall director of UCSF’s clinical laboratories, told Wired, “If you talk to docs, they say ‘BRCA, that’s the only thing I’m interested in because I don’t know what to do with the other information.’ Doctors don’t know what to do with it. Patients don’t know what to do with it.”
More Testing Equals More Knowledge
Further complicating the issue, there is an enormous lack of information on how multipanel screenings will affect individuals, public health, and the cost of healthcare in general. Several studies are underway, but they are so new it could be years before any real results become available.
Five years ago, it cost about $20,000 to sequence the whole human genome. Now the average price is $1,500, though there are more and less expensive types of genetic tests. As the cost continues to decline, however, more people will undergo the testing and scientists will learn more about how to identify the best therapy to treat cancers caused by genetic mutations.
Experts concerned people will be unable to judge a true emergency from a minor health concern; patients could be left with a big ER bill if they are wrong
Here’s a groundbreaking way payers are keeping healthcare costs down: Anthem Blue Cross and Blue Shield (BCBS) of Georgia sent letters to its members in May informing them that they will no longer be reimbursed by the insurer for “non-emergency” related services obtained in emergency rooms (ERs).
Pathology groups and medical laboratory leaders, will want to monitor and potentially respond to this important emergency coverage development. Hospital-based medical laboratories receive high volumes of test orders from the ER. Any decline in ER visits from a payer policy like this will have staffing and budget implications for hospital labs.
Medical Groups Warn of Dire Consequences
The new policy garnered national media coverage in addition to local exposure in Georgia, where it went into effect on July 1. BCBS affiliates in New York, Missouri, and Kentucky are considering similar policies as well, noted an article in The Fiscal Times.
“Anthem believes that primary care doctors are in the best position to have a comprehensive view of their patient’s health status and should be the first medical professionals patients see with any non-emergency medical concerns,” Anthem stated in the Fiscal Times article.
In its letter, BCBS of Georgia defines an emergency as a “medical or behavioral health condition of recent onset” that a “prudent layperson” deems health-threatening. However, many symptoms, such as chest pain, can lead to sudden death. How is the average person to know if what they are experiencing will turn out to be angina, a painful but often non-fatal condition, and not a life-threatening embolism?
“Anyone who seeks emergency care suffering from symptoms that appear to be an emergency, such as chest pain, should not be denied coverage if the final diagnosis does not turn out to be an emergency,” the ACEP concluded.
Are Patients Able to Judge Where They Should Go?
Some experts warn that many people might be unable to judge the true nature of their conditions when under stress.
The ACEP and its Missouri Chapter said in a statement that Anthem BCBS lists almost 2,000 diagnoses it considers to be “non-urgent” and not covered in the ER. The professional organization contends, however, that some of the diagnoses on the insurer’s list have the propensity to be medical emergency symptoms as well.
Influenza, which thousands of people die from each year.
However, cold symptoms, sore throat, physical exams, and minor injuries are among the complaints best addressed by walk-in clinics or urgent care centers, BCBS explained in a blog article.
Nevertheless, Debbie Diamond, Public Relations Director for BCBS of Georgia, told The Fiscal Times that a person who mistakes indigestion for chest pain is likely to be covered for ER care (in keeping with prudent layperson guidance).
Distinguishing Between Necessary and Unnecessary ER Visits
It’s not always simple to recognize an emergency from a non-emergency. Even emergency medicine professionals often have difficulty doing so.
Renee Hsia, MD (above), is Professor and Director of Health Policy Studies, Department of Emergency Medicine at the University of California School of Medicine, San Francisco (UCSF). She told the Los Angeles Times that the Blue Cross Blue Shield of Georgia emergency coverage policy is a “well-intentioned policy with dangerous consequences.” (Photo copyright: Angie’s List/Adm Golub.)
“Our findings indicate that either patients or healthcare professionals do entertain a degree of uncertainty that requires further evaluation before diagnosis,” the authors wrote in JAMA.
Where Next? Who’s Next?
Despite the discord over the reduction in non-emergency coverage, more BCBS affiliates may soon adopt the same policy. And what of other large insurers? Might they be watching and considering whether to alter their emergency coverage, as well, to save money?
Thus, clinical laboratories in Georgia hospitals will want to closely monitor their institution’s ER test volume. It could take a while for Blue Cross patients in Georgia to realize that some ER visits (and the clinical laboratory tests associated with them) might not be covered by their insurance. This will happen in instances where their insurer denies claims for services that, in Anthem’s opinion, were better suited for primary care doctors and urgent care centers rather than ERs.
