Category Archives: Gene Medicine

CRANBURY, N.J., March 02, 2020 (GLOBE NEWSWIRE) -- Amicus Therapeutics (Nasdaq: FOLD), a global, patient-dedicated biotechnology company focused on discovering, developing and delivering novel medicines for rare diseases, today announced financial results for the full-year ended December 31, 2019. The Company also summarized recent program updates and reiterated its full-year 2020 guidance.

Corporate Highlights for Full-Year 2019 and Year-to-Date 2020

2020 Key Strategic Priorities

John F. Crowley, Chairman and Chief Executive Officer of Amicus Therapeutics, Inc. stated, Amicus has made great strides in our continued evolution as a leading global rare disease biotechnology company. We are on track and well-capitalized to achieve all our 2020 key strategic priorities including our global Fabry launch, Pompe late-stage development program, and gene therapy pipeline. With a very successful, commercial product in Fabry disease, a late stage program with Breakthrough Therapy Designation in late onset Pompe disease and 14 gene therapy programs for rare diseases in development, including two in the clinic, we are now, strongly positioned to achieve our vision of delivering groundbreaking new medicines and hopefully one day cures for people living with rare metabolic diseases.

Full-Year 2019 Financial Results

2020 Financial Guidance

Anticipated 2020 Milestones by Program

Amicus previously announced 2020 program milestones in early January 2020. All anticipated milestones remain on track as follows:

Galafold (migalastat) Oral Precision Medicine for Fabry Disease

AT-GAA for Pompe Disease

Gene Therapy Portfolio

Conference Call and WebcastAmicus Therapeutics will host a conference call and audio webcast today, March 2, 2020, at 8:30 a.m. ET to discuss the full-year 2019 financial results and corporate updates. Interested participants and investors may access the conference call by dialing 877-303-5859 (U.S./Canada) or 678-224-7784 (international), conference ID: 2782337.

A live audio webcast can also be accessed via the Investors section of the Amicus Therapeutics corporate website at http://ir.amicusrx.com/, and will be archived for 30 days. Web participants are encouraged to register on the website 15 minutes prior to the start of the call. A replay of the call will be available for seven days beginning at 11:30 a.m. ET on March 2, 2020. Access numbers for this replay are 855-859-2056 (U.S./Canada) and 404-537-3406 (international); conference ID: 2782337.

About GalafoldGalafold(migalastat) 123 mg capsules is an oral pharmacological chaperone of alpha-Galactosidase A (alpha-Gal A) for the treatment of Fabry disease in adults who have amenableGLAvariants. In these patients, Galafold works by stabilizing the bodys own dysfunctional enzyme so that it can clear the accumulation of disease substrate. Globally, Amicus Therapeutics estimates that approximately 35 to 50 percent of Fabry patients may have amenableGLAvariants, though amenability rates within this range vary by geography. Galafold is approved in over 40 countries around the world, including the U.S., EU, U.K, Japan and others.

U.S. Indications and UsageGalafold is indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based oninvitroassay data.

This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

U.S. Important Safety Information

Adverse ReactionsThe most common adverse reactions reported with Galafold (10%) were headache, nasopharyngitis, urinary tract infection, nausea and pyrexia.

Use in Specific PopulationsThere is insufficient clinical data on Galafold use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Advise women of the potential risk to a fetus.

It is not known if Galafold is present in human milk. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Galafold and any potential adverse effects on the breastfed child from Galafold or from the underlying maternal condition.

Galafold is not recommended for use in patients with severe renal impairment or end-stage renal disease requiring dialysis.

The safety and effectiveness of Galafold have not been established in pediatric patients.

To report Suspected Adverse Reactions, contact Amicus Therapeutics at 1-877-4AMICUS or FDA at1-800-FDA-1088 orwww.fda.gov/medwatch.

For additional information about Galafold, including the full U.S. Prescribing Information, please visithttps://www.amicusrx.com/pi/Galafold.pdf.

E.U. and U.K. Important Safety InformationTreatment with Galafold should be initiated and supervised by specialists experienced in the diagnosis and treatment of Fabry disease. Galafold is not recommended for use in patients with a nonamenable mutation.

For further important safety information for Galafold, including posology and method of administration, special warnings, drug interactions and adverse drug reactions, please see the European SmPC for Galafold available from the EMA website at http://www.ema.europa.eu.

About Amicus Therapeutics Amicus Therapeutics (Nasdaq: FOLD) is a global, patient-dedicated biotechnology company focused on discovering, developing and delivering novel high-quality medicines for people living with rare metabolic diseases. With extraordinary patient focus, Amicus Therapeutics is committed to advancing and expanding a robust pipeline of cutting-edge, first- or best-in-class medicines for rare metabolic diseases. For more information please visit the companys website at http://www.amicusrx.com, and follow on Twitter and LinkedIn.

Non-GAAP Financial Measures In addition to financial information prepared in accordance with U.S. GAAP, this press release also contains adjusted financial measures that we believe provide investors and management with supplemental information relating to operating performance and trends that facilitate comparisons between periods and with respect to projected information. These adjusted financial measures are non-GAAP measures and should be considered in addition to, but not as a substitute for, the information prepared in accordance with U.S. GAAP. We typically exclude certain GAAP items that management does not believe affect our basic operations and that do not meet the GAAP definition of unusual or non-recurring items. Other companies may define these measures in different ways. Full reconciliations of GAAP results to the comparable non-GAAP measures for the reported periods appear in the financial tables section of this press release. When we provide our expectation for non-GAAP operating expenses on a forward-looking basis, a reconciliation of the differences between the non-GAAP expectation and the corresponding GAAP measure generally is not available without unreasonable effort due to potentially high variability, complexity and low visibility as to the items that would be excluded from the GAAP measure in the relevant future period, such as unusual gains or losses. The variability of the excluded items may have a significant, and potentially unpredictable, impact on our future GAAP results.

Forward-Looking StatementsThis press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 relating to preclinical and clinical development of our product candidates, the timing and reporting of results from preclinical studies and clinical trials, the prospects and timing of the potential regulatory approval of our product candidates, commercialization plans, manufacturing and supply plans, financing plans, and the projected revenues and cash position for the Company. The inclusion of forward-looking statements should not be regarded as a representation by us that any of our plans will be achieved. Any or all of the forward-looking statements in this press release may turn out to be wrong and can be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. For example, with respect to statements regarding the goals, progress, timing, and outcomes of discussions with regulatory authorities, and in particular the potential goals, progress, timing, and results of preclinical studies and clinical trials, actual results may differ materially from those set forth in this release due to the risks and uncertainties inherent in our business, including, without limitation: the potential that results of clinical or preclinical studies indicate that the product candidates are unsafe or ineffective; the potential that it may be difficult to enroll patients in our clinical trials; the potential that regulatory authorities, including the FDA, EMA, and PMDA, may not grant or may delay approval for our product candidates; the potential that we may not be successful in commercializing Galafold in Europe, Japan, the US and other geographies or our other product candidates if and when approved; the potential that preclinical and clinical studies could be delayed because we identify serious side effects or other safety issues; the potential that we may not be able to manufacture or supply sufficient clinical or commercial products; and the potential that we will need additional funding to complete all of our studies and manufacturing. Further, the results of earlier preclinical studies and/or clinical trials may not be predictive of future results. With respect to statements regarding projections of the Company's revenue and cash position, actual results may differ based on market factors and the Company's ability to execute its operational and budget plans. In addition, all forward-looking statements are subject to other risks detailed in our Annual Report on Form 10-K for the year ended December 31, 2019 to be filed today. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, and we undertake no obligation to revise or update this news release to reflect events or circumstances after the date hereof.

CONTACTS:

Investors:Andrew FaughnanDirector, Investor Relationsafaughnan@amicusrx.com(609) 662-3809

Media:Christopher ByrneExecutive Director, Corporate Communicationscbyrne@amicusrx.com(609) 662-2798

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TABLE 1

Amicus Therapeutics,Inc.Consolidated Statements of Operations(in thousands, except share and per share amounts)

TABLE 2

Amicus Therapeutics,Inc.Consolidated Balance Sheets(in thousands, except share and per share amounts)

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Amicus Therapeutics,Inc.Reconciliation of Non-GAAP Financial Measures(in thousands)

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Amicus Therapeutics Announces Full-Year 2019 Financial Results and 2020 Corporate Updates - BioSpace

This letter to the editor was submitted by Max Blankfeld, the chief operating officer of Gene By Gene/FamilyTree DNA, regarding an article published by The Ticker's science section about the company sharing genetic data to law enforcement.

FamilyTreeDNA does not share genetic data with law enforcement. It is also true that FamilyTreeDNA does allow law enforcement to submit crime-scene DNA to its matching database.

The fact that both statements are true has confounded the media, resulting in incorrect and misleading reporting, as was the case with The Ticker Science article titled, "Is Testing Your Ancestry Safe?" FamilyTreeDNA matching database does not share genetic data with any third party, including law enforcement.

The DNA matching process is completely automated and the only information shared between DNA matches for customers who consent to participate in the matching process is a public profile information controlled by the customer and the estimated relationship between matches based on the number of shared centimorgans.

FamilyTreeDNA does not share, sell or barter the genetic data of its customers with any third party.

In the year 2000, FamilyTreeDNA, the pioneer of the Direct-to-Consumer genetic testing, started offering a service that allows people to find relatives and ancestral origins.

This was geared towards genealogists, who after encountering a roadblock with their traditional genealogical tools, resorted to the matching tool that we developed, which allows two individuals to see if they have enough DNA in common to claim a close relationship.

The success of this initiative not only led other companies to follow suit, but other groups of people started using it: adoptees who wanted to find biological relatives and ancestral origins, sperm- donor children who wanted to find half-siblings and more recently, law enforcement, who wanted to see if, through genetic matches to crime scene DNA, they could get hints that would lead them to the potential criminal or to identifying a victim.

In the cases of murder or sexual assault, DNA matches provide an investigative lead for law enforcement to follow, enabling the identification of suspected perpetrators faster than ever before.

In none of the above cases is the FamilyTreeDNA database searched or searchable.

Each individual that tests with us has a password-protected page where they can only see those whose DNA has a minimum level of matching. When we realized that law enforcement was using this tool, FamilyTreeDNA could have simply turned a blind eye or been subject to subpoenas.

Instead, we created a process for oversight through formal registration and submission of crime-scene samples. In conjunction with law enforcement and with the supervision of a Citizens Panel composed of representatives of our customers and a professor of bioethics at the Baylor College of Medicine, we developed the Law Enforcement Guide, which is publicly available at https://www.familytreedna.com/legal/law- enforcement-guide.

In the past week, law enforcements use of FamilyTreeDNAs matching database has led to a serial murder confession in Clearfield, Utah and the release of a man who spent the last twenty years in a California jail for a crime he did not commit.

In the 20 years since the inception of FamilyTreeDNA, we are proud to have helped thousands of customers find long lost relatives.

Now, we are proud of fulfilling a public safety role in helping identify perpetrators of heinous crimes like rape and murder, identification of their victims and the exoneration of the falsely accused and imprisoned.

Excerpt from:
A letter to the editor genetic data and law enforcement bias - The Ticker

I love working with people, says Allison Werner-Lin of the School of Social Policy & Practice (SP2). Werner-Lins office overlooking Locust Walk is homey and lamp-lit, with student gifts sharing space with scholarly tomes. This is just one of her workspaces, however. Recently returned from sabbatical, Werner-Lin has been working with the National Cancer Institute (NCI), as well as out of her home in upstate New York, which doubles as a private practice for families seeking bereavement therapy. The divide between academia and clinical practice suits her. I feel like I have one foot in each world and in a very positive way, Werner-Lin says.

Werner-Lin has extensive clinical and research experience and uses both to inform her work, which centers on heritable cancers. She began her academic work studying young adults with mutations in genes associated with breast and ovarian cancer, BRCA1 and BRCA2. Recently, her work with the NCI has branched out to the study of Li-Fraumeni syndrome (LFS). Patients with LFS have a mutation in a tumor-suppression gene, resulting in a high incidence of cancer starting in childhood, and 50% of LFS patients develop cancer by age 40. Both patient populations make life-altering decisions based upon their family histories and medical diagnoses.

Dr. Werner-Lins groundbreaking research merges science with social work at the intersection of qualitative health research, the structure and evolution of genes, hereditary cancer, and how it impacts individuals and families at various stages of life, says SP2 Dean Sara Sally Bachman. Each day, Allison is pushing the frontiers of genomic study and oncological social work while also mentoring other social change agents who will undoubtedly make a difference locally, nationally, and internationally.

For more than a decade, Werner-Lin has worked in the Clinical Genetics Branch of the Division of Cancer Epidemiology and Genetics of the NCI organizing the human side of research. Patients come annually to the NCI to receive full-body MRI cancer screenings and participate in data collection that covers everything from cancer history to family communication to risk management. Werner-Lin mentors an interdisciplinary team of predoctoral and postdoctoral fellows to explore how these families understand and cope with genetic information. Her work is used to train providers in delivering holistic medical and psychological care.

We talk with families about their experiences communicating cancer-risk information with loved ones, making reproductive decisions, and managing the endless cycle of screening, Werner-Lin says. She has seen patterns in how families share cancer-risk information and seek support, noting that information travels based on relationship patterns and emotional closeness, not necessarily degree of risk.

People with LFS have limited options for cancer prevention, and expectations for a cancer diagnosis and early death are common. Were seeing a lot of physical loss, where amputations and other changes in physical function are common consequences of treatment.

Many of the people Werner-Lin speaks with are looking at different pathways to parenthood or are choosing not to have children at all, she says. Grief becomes a chronic part of their lives, and those kinds of sustained of losses can connect individuals in and across families.

Former SP2 graduate student Catherine Wilsnack is a Cancer Research Training Award Fellow at the NCI, doing qualitative research as part of Werner-Lins team. Wilsnack first met Werner-Lin while in her second year at SP2 and calls the encounter transformative. Werner-Lin is a phenomenal mentor in every way, says Wilsnack, who earned her masters in social work (MSW) in 2019. She always goes above and beyond for her students. I would not be where I am today if it were not for her and her guidance, so I just feel extremely lucky.

Now in midcareer, Werner-Lin is taking the time to mentor younger generations. There are so many opportunities to focus on other peoples career development without such a bounded focus on my own professional needs, she says, crediting her own mentors with the ability to achieve professional success.

At Penn, Werner-Lin is involved in the Cancer Moonshot initiative led by Katherine Nathanson and Steve Joffe, an effort designed to accelerate cancer research aimed at prevention, detection, and treatment. Werner-Lins aspect of the project, based at the Abramson Cancer Center at Penn Medicine, involves issues surrounding genetic testing in people aged 18 through 40. Susan Domchek, executive director of the Basser Center for BRCA, says, Allisons work in terms of the psychosocial implications of having a BRCA mutationhow an individual can come to terms with that and how that information gets disseminated between familieshas been extremely helpful. She has a deep expertise on helping families navigate these situations.

Approximately 1 in 400 people carry mutated breast cancer genes, though mutations are more common in certain groups of people. The gene mutations are passed in an autosomal dominant pattern, meaning each parent with a mutation has a 50% chance of passing it on. Children of a BRCA-positive parent can pursue genetic testing to learn if they carry the mutation, adding pressure to family planning.

Werner-Lin was one of these children. Her mother has a BRCA1 mutation. She recovered from colon cancer when Werner-Lin was in college and is currently in remission from a rare ovarian cancer. When I was 23 and was thinking about having kids, I couldnt figure out how to do it, Werner-Lin says. I started talking to people, talking to other women, and that became my dissertation.

This curiosity and compassion led Werner-Lin to operate a private therapy practice out of her home, where she exclusively sees children and young adults with a deceased parent. People often dont see how therapy is connected to the genetics part of my work, but for me they are inseparable, Werner-Lin says. In my cancer work, parents often die young, leaving small children. Frequently, the children of cancer patients conflate their parents lives with their own, not seeing options, degrees of freedom, or technological innovation.

Working together with an MSW student, Werner-Lin does whole family-therapy, from diagnosis to end-of-life, through the grieving process. She helps to facilitate goodbyes, talks about legacy building, and makes the concept of death more concrete for young people.

The language adults use to talk about death is often confusing and shrouded in existential concepts, Werner-Lin says, citing references to angels or going to a better place. Young kids dont necessarily understand time or geography, she says. If were in New York, and Mommy went to the other side, is that a better place?

Instead, she says, we talk about the brain being a light switch, and once you turn it off you cant turn it on again. We talk about how the heart stops beating and the eyes stop seeing. These practical realities are important, Werner-Lin says. Kids need to understand the way the world is predictable, especially when people they love and need can fall off the earth at any moment.

Now back on campus, Werner-Lin is focusing on teaching and engaging with her graduate students. Acting in service to her patients, her students, and her colleagues is a core part of Werner-Lins brand of academia. If you tell her that you want to do something, Wilsnack says, she will go out of her way to help.

See the article here:
Working on 'the human side' of heritable cancers - Penn: Office of University Communications

High costs, data management issues and recruitment problems are some of the main challenges for personalised medicine in clinical development. Credit: US Air Force/Kemberly Groue Genome sequencing costs are falling fast, opening the playing field for developing highly personalised drug candidates. Personalised medicine in the 21st century offers the promise of therapies customised based on the study of what truly makes us unique: our DNA.

The importance of the individual has been widely established in medicine since time immemorial. The well-worn adage that physicians should treat the patient, not the disease has been around since the 19th century, and the awareness of that message is far older than that. Even Hippocrates, the father of Western medicine who treated patients in the fifth century BC, stressed the importance of treating each patient as an individual.

For the sweet [medicines] do not benefit everyone, nor do the astringent ones, nor are all patients able to drink the same things, Hippocrates wrote.

Hippocrates might have tailored his rudimentary treatments based on the patients age, physique and other easily observable factors, but personalised medicine in the 21st century offers the promise of therapies customised based on the study of what truly makes us unique: our DNA.

Advancements in genomics, proteomics, data analysis and other fields both medical and technical are gradually facilitating the development of laser-focused drugs, as well as the ability to predict peoples personal risk factors for particular diseases and how individual responses to various treatments might differ.

After years of anticipation, there is now evidence that governments around the world have clocked the importance of personalised medicine and are driving efforts to the build the genetic data sets and biobanks that are required to push the science forward. Former US President Barack Obama launched the Precision Medicine Initiative to great fanfare in 2015; the scheme has since evolved into the All of Us research programme, which aims to gather health data from more than a million US volunteer-citizens to unlock new insights.

In the UK, the 100,000 Genomes Project reached its goal of sequencing 100,000 whole genomes from 85,000 NHS patients with cancer or rare diseases. Genomics England has noted that so far, analysis of this data has revealed actionable findings in around one in four rare disease patients, while about 50% of cancer cases suggest the potential for a therapy or clinical trial.

You can match a blood transfusion to a blood type that was an important discovery, said Obama at the launch of the Precision Medicines Initiative, summarising the broad appeal of personalised therapies and diagnostics. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature?

The stage might be set for personalised healthcare to dramatically transform public health, but few in the medical field would deny that the world is hardly ready yet. Transitioning from the traditional one-cure-fits-all treatment model to new processes that leverage patients genetics, lifestyles and environmental risk factors is an immense task that presents challenges in both the laboratory and the clinic.

Oncology is, by a landslide, the field that has been most impacted by developments in precision medicine; around 90% of the top-marketed precision treatments approved in 2018 were cancer therapies, while other therapeutic areas have lagged far behind. The majority of approved precision medicines in oncology achieve something of a halfway house between the old way and the new they fall short of being tailored to a specific individual, but they allow for more detailed stratification of patients by the oncogenic mutations of their tumours, which may be driving cancer cell survival and growth.

Common examples of these mutations are HER-2 in certain breast and stomach cancers, BRAF in melanoma and EGFR in lung cancer. High expression of these proteins at cancer sites can be targeted by precision treatments, such as Roches monoclonal antibody Herceptin (trastuzumab) for HER-2, Genentechs BRAF inhibitor Zelboraf (vemurafenib), and Roches EGFR inhibitor Tagrisso (osimertinib). Regulators such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are also increasingly approving tumour-agnostic treatments the first and most famous of which is Mercks immunotherapy Keytruda (pembrolizumab) which target specific biomarkers regardless of tumour location.

But despite the availability of a growing menu of personalised cancer treatments, actually matching patients up to the right therapy can be difficult. According to a survey of US acute care organisations conducted by Definitive Healthcare and published in December 2019, just over 20% had established precision medicine programmes. Investment in genomic testing is vital to quickly get patients on the best treatment course, but financial and operational barriers remain.

The foremost among these is the cost associated with genomic sequencing and the use of companion diagnostic devices, cited by 28% of Definitive Healthcares respondents as the biggest challenge for already-established precision medicine schemes. Lack of expertise is another obstacle, as many physicians may struggle to accurately interpret test results without specialist assistance another major cost driver for clinics and hospital departments trying to build pathology teams that are up-to-date with the newest tests. A 2018 survey of 160 oncologists by Cardinal Health found that 60% of physicians who dont use genomic tests avoid them because of the difficulty of interpreting the data.

In clinical research and development, too, there are growing pains associated with moving the pharmaceutical pipeline towards drugs targeting smaller patient sub-groups. Again, cost is a central issue companion diagnostics dont come cheap, finding and validating biomarkers to guide targeted therapies is a lengthy task, and analysing vast amounts of data often requires new teams with specialised knowledge.

The expense of incorporating a host of new processes into innovative trial designs not to mention the cost of manufacturing cell and gene therapies obviously has an impact on the list price of personalised drugs that win approval. This is most clearly seen in the eye-watering prices of some of the worlds first truly individualised cancer treatments, chimeric antigen receptor T-cell (CAR-T) therapies.

Treatments such as Novartiss Kymriah and Gileads Yescarta remove T-cells from the patients blood, modify them to target tumour cell antigens and then infuse them back into the blood stream. These therapies have achieved impressive results in rare and advanced cancers, but cost upwards of $400,000 per patient, limiting their reimbursement options among both private and public payers. Promising advances in CAR-T manufacturing and potential off-the-shelf T-cell production could help bring these costs down in the years to come, but for now the problem remains.

As for the broader clinical trial eco-system, these studies have been historically set up to assess a drug candidates safety and efficacy in an increasingly large segment of the patient population, building evidence towards the regulatory approval process. Bringing a personalised medicine through the clinical development process is a new paradigm in a number of ways; as well as the aforementioned cost drivers, there can be an extra enrolment burden to identify and recruit patients this is already a common cause of trial failure, but its all the more difficult when youre looking to access a small patient sub-group with the appropriate biological profile.

The difficulty of providing sufficient evidence of safety and efficacy can also present issues where current regulations struggle to accommodate new innovations in personalised medicine. Smaller trial designs present statistical problems in terms of understanding a drugs definitive risk-benefit profile, and while some personalised applications can be discovered as part of larger trials that fail to meet their endpoints outside of a select patient group with particular biomarkers, many current regulations dont accept post hoc analysis and would require an entirely new trial.

Personalised medicine developers desire better guidance on how best to design a successful clinical trial for a personalised therapy, because absent guidance, they risk presenting suboptimal evidence regarding stratification options, reads a 2017 study on personalised medicine barriers, published in the Journal of Law and Biosciences. Designing clinical trials for differently responding subgroups (for example, biomarker-positive and biomarker-negative groups) requires additional time and resources. Companies are reluctant to make this investment without a commensurate increase in the certainty of regulatory approval.

The increasing use of surrogate endpoints, conditional approvals and real-world data is helping to address these issues, but theyre not yet an ideal solution. Conditional approvals rely on very careful post-marketing observation and analysis, while the value of surrogate endpoints has been questioned, adding to the tension between accelerating approvals and ensuring patient safety.

The ultimate benefits of creating more personalised treatments are clear, and their advantages for human health could, in the long-term, be matched by their economic returns. After all, quickly treating patients with the right therapy for them or, even better, using knowledge of a patients genetic risk profile to prevent illness in the first place would be a huge financial gain for overburdened health systems.

Todays costs are gradually falling, as NIH data on DNA sequencing costs demonstrate. But there is still a long way to go before we can wave goodbye to the blanket drug development that has dominated modern pharma for decades, even in the advanced field of oncology, let alone other therapeutic areas. Only a sustained and holistic push from regulators, drug developers, clinicians, governments and others will be enough to bring us over the line.

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Precision medicine in 2020: what barriers remain for drug developers? - pharmaceutical-technology.com

Human health and biomedical science have been transformed in tandem over the past two centuries. From around 1850 to 1920, better nutrition and prevention of epidemic infections were the main contributors to massive improvements in life expectancy and reductions in infant and maternal mortality. These challenges have now receded for much of the world. Chronic diseases have become the principal threats to a healthy lifespan, and in the past half century we have seen a second wave of improved health, above all from enormous gains in control of cardiovascular diseases and cancer. Whereas the increase in life expectancy in the industrialized world from about 50 years in 1900 to nearly 70 years in 1950 is well-known, the addition of nearly a decade in life expectancy since 1970 is far less appreciated. But a rich body of theoretical and practical experience on what drove this more recent wave of success yields a clear set of principles that are securely established as foundational concepts in biomedical and related sciences.

What does transformational progress in reducing the burden of chronic disease look like and how did it happen? What can it tell us about the most promising pathways for future population-wide advances in health?

About two-thirds of all deaths in the United States and most industrialized countries are caused by cardiovascular disease (CVD) or cancer. Although the burden and character of both these disease categories have evolved dramatically in recent decades, for CVD the magnitude of the reduction in incidence (occurrence of new cases, both fatal or nonfatal), prevalence (proportion of the population living with a chronic condition), and death toll in the past 60 years is not widely appreciated. Mortality rates from coronary heart disease (CHD), the most common form of CVD, in the United States peaked in 1968, and have declined by 2%-3% every year since, until the past two years. The total reduction, after adjusting for changes in the age structure of the population, is now over 75%. Though CVD of course remains common, there are at least six hundred thousand fewer CVD deaths per year in the United States as result of this decline, and the total number of deaths averted since 1968 is on the order of twenty million. This unprecedented success in reducing the burden of the leading cause of death in industrialized countries was achieved not by any single intervention, but through advances along multiple pathways: the development of a clear understanding of the etiologic process; determined efforts to create public awareness, especially about the role of diet and physical activity; successful policy interventions to promote such things as low-fat dairy products and removal of trans fats from food items; introduction of safe, cheap, and effective medications to treat causal risk factors such as high cholesterol and blood pressure; and improved treatment of acute cases and advanced disease of the coronary arteries. Rapid declines in mortality from stroke, the other component of CVD, have been even larger than the declines from CHD, and are continuing as well.

Although the magnitude is considerably smaller, progress has now been made in lowering cancer death rates. Age-adjusted total cancer mortalityhas declined over 30%in the past 25 years in the United States. Reduction in tobacco use is the most important factor, and for men accounts for 40%-50% of the overall decline in all cancer deaths. Male smoking prevalence rates have dropped from 65% to 20% in the past 70 years. Lung cancer mortality has declined 50% in men since 1991; colon cancer deaths fell by 50% for both sexes; breast cancer deaths in women are now 40% lower. Cervical cancer death rates have declined by 60% since 1975, and prostate cancer mortality has declined by more than 50% since 1994.

Cancer, of course, is a composite of a wide range of tumors, each with distinct causes, natural histories, and challenges to prevention, detection, and treatment. Nonetheless, the main drivers can be identified. The great decline in smoking is responsible for reductions in lung cancer in both sexes and for fewer deaths from laryngeal and likely bladder cancer. Widespread adoption of technologies that permit early diagnosis (for breast and prostate cancer) or detection of premalignant states (cervix and colon) appear to have been the largest contributors to the reductions in mortality of these cancers, but improved surgical techniques and treatment options have probably played a role as well.

Thus modern biomedicine, especially the component focused on prevention, has brought transformational change not only to infectious diseases but to chronic diseases that less than five decades ago posed hopeless challenges. In the course of this transformation, we have accumulated a rich knowledge base of what research, what tools, and what implementation strategies work in reducing the burden of disease and death.

Throughout most of this remarkable period of improved public health, the field of genetics functioned within well-defined subdisciplines in such diverse areas as selective breeding of animals and improvement of crop yields, statistical modeling of heredity, and experimental work to understand monogenic disorders. One of the most significant accomplishments early on in genetics was the clear demonstration that most common or complex traits were highly polygenicthat is, they resulted from the combined small effects of many genes. Characterization of the double helix structure of DNA in 1953 and parsing how genes are expressed in terms of molecular function ushered in a new era of intense focus on the molecular pathways that shape the growth and maturation of the organism. In the 1980s the advent of faster, more efficient gene sequencing technology ignited an explosion of new research opportunities, and eventually the transformation of genetics, a reasonably discrete scientific discipline, into genomics, a vastly more open-ended project with its sights set on establishing a precise, mechanistic description of the fundamental rules of biologynot only of intergenerational transfer of information via germline DNA, the traditional focus of genetic research, but of the causal sequence underlying virtually all disease processes. The launching pad for this new era was the Human Genome Project, led in its first phase by James Watson, codiscoverer of the double helix. At a projected cost of $3 billion, only the federal government, primarily the National Institutes of Health, could afford such a large and focused endeavor.

This massive project encouraged people in the genomics community to see themselves as transformational actors in all forms of medical research, and to promise equally transformative benefits for health. As NIH proclaims in its mission statement the goal of NIH research is to acquire new knowledge to help prevent, detect, diagnose, and treat disease and disability. Genomics became key to that mission. In June 2000, at the ceremony hosted by President Bill Clinton announcing the completion of the Human Genome Project, the world was offered the hope that genome science will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases. Twenty years on, the scale of investment, the dynamism within the field, and the far-reaching claims for transformational impact on health and medicine have only accelerated.

Genomics has further matured since 2000, and broadened into an open-ended pursuit spanning domains from how cells regulate metabolic activity to the impact of all environmental exposures that individuals encounter over their lifetime. As a consequence, an enormous growth in resources devoted to research, training, technology development, and implementation, including a substantial de facto reallocation of resources that had been used in traditional biomedical disciplines, has been directed to genomics-oriented biomedicine. NIH, with its $39 billion annual budget, has aggressively promoted this agenda, and currently invests roughly half its resources in genomics-related research. In parallel, NIH spends less and less on research into prevention and public health. In pursuit of the goal to make genomics the basis for a new era of precision medicine, NIH Director Francis Collins has launched the All of Us research program, with a goal of recruiting one million Americans to have their whole genome sequenced, at a total cost of about $1 billion. NIH continues to advance an undiminished message of promise for this science, as Collins declared in May 2018: We would expect to see more effective prevention of many diseases, fewer diagnoses of serious illness, and an extension in health span. Genomics science is now being offered as the foundation for a population-based medicine of the future.

We thus appear to be in the early stages of a decisive transition between the multifaceted approach that has yielded such progress over the past two centuries, and the emerging new model driven by genomic sciences and captured by the term precision medicine. What, then, should we expect from genomics and personalized medicine in meeting the enormous chronic health challenges that remain, such as diabetes, dementia, arthritis, renal failureand, of course, CVD and cancer? And what about the huge challenges presented by violence and suicide? Based on well-established principles, drawn from the history of biomedicine and public health, are the promissory notes issued by genomics likely to be cashed for value? Does the evidence of success from the first two decades of the genomics era justify the original and continued predictions of transformational progress in population health?

The current undeniable crisis within the health care delivery system notwithstanding, we now stand on a massive edifice of technology and basic biology. We can muster a vast array of effective pharmacologic agents, transplant many solid organs, and perform extraordinarily complex surgical procedures; we can detect and treat many conditions in their earliest stages; we have developed many ways of preventing disease before it starts, especially with the weapons of social policy. At the core of these advances lies a set of principles about what causes disease and how large-scale population-level improvements are achieved.

In the middle of the nineteenth century, the great German pathologist and public health advocate Rudolf Virchow declared mass disease means society is out of joint. A more contemporary framing of that principle would emphasize that like the rest of the animal and plant kingdom, humans long evolutionary lineage has left us well adapted to life on this planet. As a corollary, the vast majority of health risk, certainly more than 90%, is derived from deleterious environmental exposure over our life course, not information encoded in our DNA. Human genetic adaptability is no match for newly emerging threats to health, as the history of epidemics shows. When a new agent appears on the scene, whether cholera, a new flu virus variant, cigarette smoking, or a huge increase in animal fat consumption, the human genome is unable to prevent the premature deaths of millions of humans. In other words, the human genome does not express itself as a dominant or primary cause of mass disease.

Occasionally, evolutionary forces have conferred new protective adaptations to region-specific epidemicsthe role of sickle-cell disease and thalassemia in reducing risk of severe malaria among some African populations is the paradigmatic example here. But the genetic repertoire of our species leaves us susceptible to many noxious exposures that vary with time and place too rapidly for evolutionary forces to react to. Mass disease with a global scopeillnesses that occur in at least 5%-10% of the worlds populationalmost always occur because of widespread insults that arise external to the organism, whether it be the sanitary conditions in medieval cities that gave rise to plague, or the conditions of trench warfare that contributed to the 1918 flu pandemic. Mass diseases are products of the societies in which we live.

In earlier periods, both insufficient total calories and inadequate sources of specific nutrients were the primary drivers of risk. In the modern era, all too often excessive exposure to substances that are inhaled, ingested, or absorbed through the skin are the fundamental causes of common disease. The transformational events in our progress against chronic disease have been driven by mitigation of those exposures through a familiar litany of interventions such as vaccination, improved diet, and altered behavior. What we have learned about disease, medicine, and population health over the past two centuries tells us that the primary domain of interest for disease prevention consists of external factors, which are products of sick societies, rather than heritable factors that modify individual-level risk. From this perspective, the prediction that precision genomic medicine will lead to population-wide health demands a sharp break from the source of such benefits in the past.

The introduction of genomics into the mainstream of biomedical research violates another historical precedent. Though technology has clearly played a key role in helping build the current medical armamentariumfrom imaging to clinical chemistry to drug developmentwith rare exception those technological advances emerged from focused research on a disease challenge (vaccines), had self-evident utility at the moment of discovery (the Roentgenogram), or were imported from outside the medical enterprise (lasers, fiber optics). Scientific advances that have led to improved health have nearly always been the result of research that matched technologies to specific human health problems and their clinical solution.

The grand theory of human molecular genetics is that the gene is a code that needs only to be deciphered in order to solve the problem of human disease. This theory arose in the 1950s simultaneously with, and reinforced by, the development of modern computer science, with coding of programs at its root. A few decades later, as we have noted, genomics developed as a laboratory-based technology, erupting into widespread use with the development of rapid and accurate sequencing methods. Only then was genomics injected into mainstream biomedicine, and retrofitted to address problems beyond its inherent scope. As applied to clinical medicine, DNA sequencing technology is first and foremost a tool to study germline errors in the code, preeminently Mendelian (single-gene) traits. The ethos of genetic determinism, and the irresistible allure of technological solutions, have opened the door for the adoption of genomics for the study of conditions where it has no or minimal relevancenamely most, if not all, human diseases. Sequencing (and the rapid acceleration of its throughput) was quickly promoted as a tool for gene mapping, and thereby attracted much broader research interest. The current wave of large-scale gene-mapping projects has been justified through an appeal to genetic determinismmore causal knowledge self-evidently must lead to solutions. This new causal knowledge would come, in ways we could not foresee, from as-yet-unexplored domains.

When tested, however, these hypotheses have not, to date, been adequately verified. Likewise, the effect of individual genetic variants being sought have been grossly overestimated, in clear contradiction of the established theory of the supposed polygenic inheritance of complex traits. The outcome was almost preordainedgenomic theory emerged without feedback from the clinical or any other empirical setting, and it advanced and captured increasing swaths of biomedical science without evidence of improved population-wide medical advance. Indeed, the more we learn about the genome, the more distant it seems to be from a role as a causative agent in most widespread diseases. We have every reason to believe that the same will be true for those diseases where the etiology remains obscure.

Beyond an appeal to principles, we now have the accumulated experience of some 25 years of genomic research, with a few projects reaching back as far as the 1970s. Anything approaching a broad summary of this rapidly evolving science is clearly beyond our scope here. However, an empirical basis for our concerns is required, and several conclusions have now achieved general consensus in the academic community. First, however, it is necessary to reaffirm what no one disputesthat adequate support for all branches of science is an essential investment in the infrastructure of modern society. Nor can those investments be limited to science that promises near-term benefits. For genomics at the present, this trade-off was articulated by former National Cancer Institute director Harold Varmuss sentiment that genomics is a way to do science, not medicine. Second, the advent of genomic technology has already generated a huge array of new tools beyond DNA sequencing that have transformed many lab sciences, and advanced public health, for example contributing crucially to our understanding of the spread of viruses in epidemics and the evolution of drug resistance in microorganisms, to new diagnostic assays, and to immunotherapy for cancer.

Major changes in population health, and extension of healthy years of life, however, belong to a dimension far removed from these incremental, niche advances, as beneficial as they are for many patients.

Enthusiasm for genomics and precision medicine builds on expectations for major scientific and medical progress in at least five major areas.

1. Enabling disease prediction.Although thousands of familial, genetic syndromes had been catalogued in the pre-genomic era, it is now possible to define the DNA sequence variations in great detail, and early success with cystic fibrosis, the so-called BRCA complex related to breast cancer, and Huntingtons disease offered the promise of much wider translational success for genomics. As noted, however, for most diseases the impacts for specific genetic factors are small, and studies of unprecedented size were required. Many of these have now been completedat enormous cost, needless to sayand a robust literature exists for common disorders such as CHD, diabetes, hypertension, obesity, and other metabolic traits.

Focusing on two pressing public health concerns of the moment, CHD and diabetes, we have conclusive evidence regarding risk prediction from DNA markers. Collectively representing cohorts of almost half a million patients, four major studies have now published virtually identical results. As is well known, the odds of dying from CHD is driven by four major risk factors: elevated cholesterol, cigarette smoking, high blood pressure, and diabetes. After accounting for these easily measured traits, DNA markers offer trivial additional information, perhaps identifying 2%-3% of individuals who might be reclassified as low or high risk. The sole response to this information would be adjustment of the dose of a cholesterol-reducing statin at a younger age. Roughly 80%-90% of the risk of the common adult form of diabetes, type 2 diabetes, can be determined from body mass index (BMI; a simple ratio of height to weight), and randomized trials have shown that in almost half of patients type 2 diabetes can be prevented, and indeed normal glucose control restored, with weight loss. Regular fitness activity and cessation of smoking also modify risk. The very large studies already completed demonstrate that virtually no additive predictive information can be derived from more genome-wide searches for additional risk variants. Similar knowledge has emerged for hypertension, stroke, dementia, and numerous other conditions.

Genetic prediction of cancers similarly struggles with predictors that are too weak in most cases to be useful in clinical practice. For example, in a very large European database in which the average lifetime risk of breast cancer is 5.1%, the risk for women in the top 5% of gene scores is 12%, and in the bottom 25% it was 2.4%. These results have no impact on clinical practice: preemptive invasive procedures cannot be justified for a group of women whose likelihood of not getting breast cancer is 88%, and 2.4% risk is still too high to abandon screening.

2.Providing critical new insights into molecular pathways.The rise of genomics has encouraged the view that once the DNA mutations underlying a trait have been identified, no matter how small, downstream metabolic consequences would be revealed and, along with them, targets for clinical intervention. Efforts to define cell-based pathways using molecular technology have in fact met with some success. We now know, for example, much more about immune function, control of fetal hemoglobin, and lipid regulatory mechanisms, in large part through application of genetic and molecular technology. However, most metabolic networks are so intricate, redundant, and multidimensional that following Ariadnes thread is mere childs play compared with an attempt to move from identifying a mutation to tracing that mutation to a specific physiological outcome. Complexity involved in inference from genotype to organism has been evident for years. In sickle cell anemia, for example, an apparently simple genetic changethe single nucleotide substitution of adenine for thymine in the hemoglobin geneproduces strokes, pulmonary hemorrhage, painful bony crises, and enhanced susceptibility to the pneumococcus bacteria. The linkage of genetic change to clinical manifestation is sufficiently complex that six decades after the underlying molecular basis of the disorder was discovered, we still have no specific therapy for the condition.

A technique that will knock out altogether the action of a gene almost invariably does not lead to the expected observable consequence in the organism, and there is as yet little evidence that genome-wide association studies that statistically link multiple genetic sites to risk markers for diseases are leading to significant improvement in understanding pathophysiologic processes. The rare successes that have been achieved (for example, identification of an allelic variant in the genetic locus PCSK9 that influences cholesterol metabolism) are still being derived from study populations where the link between risk and genetics (for example, in high-risk families) was already long-established. Living organisms are simply too complex to yield up a set of fundamental laws, and instead reveal more and more intricate processes and networks that wriggle and squirm across time and space, refusing to cast a fixed image.

3. Isolating genetic mutations that predispose patients to severe adverse drug reactions.Pharmaceutical agents are essentially foreign bodies, as far as our species is concerned, that evolution has never been called on to protect us from. It should be unsurprising, then, that many drugs have side effects, as well as some variation in absorption, metabolism, or effect depending on the individual. Genetic predisposition therefore can play a role in modulating person-level response. Some important successes have been achieved, especially in the identification of people at risk for severe adverse reactions. Early in the experience of so-called pharmacogenomic testing, variation in the efficacy of drugs used to prevent blood clots was identified. The added value of characterizing the relevant genes has now been studied in clinical trials. The most important examples are warfarin and clopidogrel, drugs that inhibit clotting by modifying platelet function. Both have significant side effects. Clopidogrel requires further metabolic conversion in the liver to make the active compound, and person-level variation in enzyme function produces the genetic effect. The original molecule was reformulated to avoid this variability in response; the most recent agent to become available, ticagrelor, avoids the between-person variability seen with clopidogrel, and thereby obviates the need for gene testing. Clearly drug companies have great incentive to market their drugs to the widest possible sales base to maximize profits, and want to avoid the step of gene testing if possible. Additional new drugsthe so-called non-vitamin K oral anticoagulantsare now showing promise for patients experiencing serious side effects from warfarin, further limiting the role of gene testing for that drug.

Current use of the new anticoagulants, however, requires conventional assays of platelet function. This return to traditional practiceomitting gene prediction and measuring the physiologic variables that are the direct target of the treatment (e.g., serum lipids, blood pressure, blood sugar)reaffirms our assertion that decision-making for individual patients will continue to be based on biochemical or other basic parameters. The complexities along the pathway from gene to physiologic outcomes are almost always influenced by too many other factors for us to be able to make clinically useful decisions from genetic information.

For other classes of common drugs, even these modest successes have rarely been seen. For example, a very extensive, long-running NIH-funded project on medications used for high blood pressure resulted in genetic scores that at best predicted 1-2 mmHg difference in response between individuals after testing; as above, they merely confirmed that direct measurement of blood pressure after you prescribe the drug will remain the basis of clinical practice. A vast array of other minor findings has been reported, but over time the scenarios we outline here have been repeated: either new agents replaced drugs that required gene testing (including a drug for hepatitis C), or the genetic effect was trivial. Pharmacogenomics overall has therefore not lived up to early expectations. Additional efforts face a stiff challenge to success, for reasons that should now be familiar: links between genomic makeup and patient response to drugs are too complex to have much clinical value, and actual measurement of physiological end points are almost always more informative.

4. Identifying targets for new drugs.At the very earliest stages of the genomic revolution, the pharmaceutical industry and innumerable start-up companies invested heavily in the search for novel targets that could be identified through DNA association studies. Though some new agents discovered from genetic research are in clinical trials (for example, a protein inhibitor for elevated triglycerides and an RNAi blocker for fatty liver disease), these efforts have yielded surprisingly little. In fact, a crisis has emerged with a drastic reduction in new drugs coming to market in the past two decades. An important exception relates to drugs influencing immune response, including autoimmune diseases. And there may well be drugs in the pharmaceutical pipeline based on genomic research that could yet translate into useful products.

5. Unlocking at long last the secrets of cancer, which after all, according to the current dominant theory, is a genetic disorder.Despite years of intense, well-funded research, progress toward effective treatment, let alone cure, of most cancers remains an elusive goal. To oversimplify the general proposition, harmful DNA mutations at least at some stage may drive the growth of tumor cells, and ultimately the metastases that prove fatal. Identifying driver mutations and blocking their effects could thus possibly offer cures. Unfortunately, the results across all these hope-filled propositions have, in sum, been dismal. From a historical perspective genomics is a young science, and the unexpected will occur with time. However, for some hypotheses, accumulating research is asymptotically approaching a null result.

The dominant theory in cancer biology remains gene-centric: either somatic mutations, occurring in the absence of known external cause, allow a clone of cells to escape from normal control of cell replication and death, or pathologic mutations in some less-defined way act at the earliest stages to drive growth and metastasis of tumor cells. Whereas it is incontrovertible that carcinogenic agents of diverse types, including viruses, ionizing radiation, and aromatic hydrocarbons, do cause pathologic mutations, a vigorous debate continues within oncology as to whether this is actually the process that triggers and sustains cancer development. For example, recent work demonstrates that normal tissue adjoining tumors harbors the same mutations as the tumors themselves; conversely, tumors transplanted from one model organism to another usually do not survive. In other words, the mutations themselves are clearly not the sole actors, or perhaps not even the causal driver, of tumor growth. Thus, a complementary field theory has been proposed that emphasizes tissue-level factors, particularly cell-to-cell communication. Recent experimental evidence now conclusively shows that at least some of these abnormal functional states, which cannot be explained in terms of mutations, must exist for tumors to propagate locally and, more importantly, to metastasize. Though this brief summary hardly does justice to a complex, rapidly evolving field, we hope it begins to communicate why large-scale sequencing projects of tumors have not delineated clear causal pathways, and more importantly why agents developed to block driver mutations have usually not met expectations, or, if they succeed, seem to act through entirely unexpected and independent mechanisms.

Despite these unresolved questions, substantial success has been achieved with several classes of new antitumor drugs. The drug imatinib mesylate, marketed as Gleevec, has been widely celebrated in this regard. Although it is the sole example in current use of target-selective therapy, it has led to lasting remission for some two thousand patients in the United States per year with chronic leukemia, without the debilitating side effects of chemotherapy. But Gleevecs success may be (and so far has been) hard to repeat: it works on a specific causal chromosomal abnormality of the sort that is uncommon in most cancers. Moreover, life-long therapy is required at an approximate average cost of $1 million per patient.

Biomarker-driven molecular research, leading to development of antibodies on the cell surface of individual tumors, has also met with substantial success. For example, a panel of genetic tests for individual tumors that allows better matches for drug therapy has entered the clinical arena. Immunotherapy, an important example of the transition from molecular research to translationespecially the so-called check point inhibitorscan specifically target solid tumors in about 15% of patients, although these are not genetic targets. An increasing, but small, proportion of patients with melanomas have attained durable long-term remission with a combination of new genetic/immunotherapies.

But the central theory of cancer as a genetic disorder, with its corollary that the ability to identify unique driver mutations will lead to therapies that can block their action, has not been verified. Instead, it has become a piece of a much more complex puzzle. Whereas any research toward safe, effective antitumor drugs is of enormous value, when entered onto the balance sheet of factors that account for the 30% decline in cancer rates achieved in the past several decades, the contribution of new curative agents developed through molecular techniques to improvements in health on a scale measurable in population-level statistics remains, at best, somewhere in the range of 2% or less. New knowledge will increase this contribution, yet predictions of a truly transformative role for treatment of advanced cancer lack empirical justification. Most invasive solid tumors have remained stubbornly resistant to curative or durable palliative therapy. At the same time, two new immunizing agents against viruses established to cause cancer in the past few decadesthe human papilloma virus that causes cervical cancer, and the hepatitis B virus that underlies most cases of hepatocellular carcinomapromise, if widely used, to virtually eradicate these two cancers without regard to genomic variability, potentially saving more than a million lives a year worldwide.

Many observers will no doubt find this account overly pessimistic. Numerous success stories have been omitted. The advances enabled by the advent of genomic technology are far-reaching and of great scientific importance. Whole subdisciplines, from human evolutionary history to epidemic surveillance and vaccine preparation for conditions such as Ebola and influenza, have indeed been transformed. But a key distinction is that these advances are due to the power of genomics when applied toagentsof human disease, not to the diseasehost. Many infectious organisms must take advantage of molecular targets on the surface of cells or be targets for killer white cells. Thus an understanding of species-specific susceptibility to bacteria or virusesfor example, pneumococcus or Ebolacan be very informative in vaccine preparation. Distinguishing molecular signatures of pathogens within a species has made outbreak investigation much more precise. Buthumangenomics and precision medicine have not transformed human health. Nor, in our view, is there a basis from which to argue that they will do socertainly not in any foreseeable future.

Meanwhile, the opportunity costs are enormous. To help bring them into focus, we offer a somber, indeed heart-breaking story that has played out in one of the oldestand thereby most matureexperiments to employ genomics as a tool to improve human health. The Pima Indians of the Sonoran Desert in central Arizona were deprived of irrigation water from the Gila River around 1900 when it was diverted upstream by commercial farmers. Isolated, and confronted with famine, they became dependent on food subsidies from the US Department of Agriculture, and adopted a diet low in nutritional value but high in calories. In the following decades an epidemic of obesity of unprecedented magnitude swept the reservation. The prevalence of type 2 diabetes rose to 50%, and even adolescents with the disease have now required dialysis for renal failure. In the 1970s, NIH established a research institute in nearby Phoenix to search for the unique genetic factors that predisposed the Pima to this crippling disease and use this knowledge to cure or prevent the disease. Despite five decades of research no important genetic mutations were identified, and the sum of available evidence showed that those susceptibility loci that could be isolated were no different, and no more common, in the Pima than in the majority US population.

The depths of the intellectual poverty of this long-running experiment can be summarized by the following quotation, posted as a research advance by the Phoenix group on the website of the director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2016: In a prospective study conducted between 1965 and 2007, NIDDK investigators followed children from Arizonas Gila River Indian Community for development of type 2 diabetes. They found that BMI and impaired glucose tolerance were strong predictors of type 2 diabetes, but other components of the metabolic syndrome were not. It should be noted here that the scientific observations highlighted in this advance was known to the Ayurvedic medical tradition in India in the fifth century BCE, and was certainly common knowledge in the modern era by the seventeenth century. Yet even today this genomic research continues along the line explored for so many years among Pima populations. The rationale for an NIDDK project started in 2015 states: When it comes to kidney disease years of exposure to diabetes may change the way the body reads its DNA, increasing the risk of kidney disease being exposed to high blood sugars or high blood pressure may cause people who have a genetic susceptibility to have kidney disease in the future.

About 10 years ago the Gila community broke off collaboration with NIDDK and mounted its own preventive campaigns based on weight control and increasing physical activity. The risk of hyperbole notwithstanding, this unhappy saga ranks with the Tuskegee Experiment as another egregious project where the natural history of a fatal illness in a vulnerable population was allowed to run its course, under the careful observation of government-funded scientists, in pursuit of a narrow, unjustified hypothesis, built on notions of genetic determinism and race-based susceptibility, while available preventive or curative alternative interventions were ignored or actively shunned.

We wonder if the story of the Gila River Indian Community, writ large, will be the outcome of the headlong rush toward precision medicine across the entire spectrum of biomedicine. In the cancer realm, for example, consider that fatty liver from obesity is now becoming a major cause of liver cancer in some countriesyet another widespread example of sick societies. Or pancreatic cancer, whose etiology has been an enigma, and for which early detection and effective treatment remain elusive goalsyet very recent evidence suggests fungal infection from the gut could play a major role. A similar causal pathway emerged between the Helicobacter pylori bacterium and stomach cancer, and treatment of this type of bacteria has had an important impact on peptic ulcer disease, and may yet influence the risk of stomach cancer. Preventive interventions for more cancers are almost certainly possible. The search for environmental causes of cancer proceeds apace, but the effort remains modest compared with the work expended on searching for genomic correlates. We have learned the importance of radiation, microorganisms, toxic chemicals, and lifestyle factors such as obesity, and (for breast cancer) age at first birth, but we still have much to learn about the nongenetic causes of cancer. Implementation of modalities to prevent and detect premalignant lesionsas with colonoscopycould achieve much less costly and more rapid downturns in cancer mortality than are likely to result from the long road to curative therapies derived from molecular research, which are often applied near the end-stage of disease.

Progress is also being observed in two other significant chronic disease challenges. There is a growing awareness that vascular disease has been underappreciated as a cause of dementia, and improving heart health is now accompanied by a welcome decline in incidence of dementia in the elderly. Type 2 diabetes is a major global threat to health, moving rapidly to nonindustrialized countries. As noted, whereas obesity accounts for 70%-80% of risk, and reversing the obesity epidemic has thus far proven difficult, type 2 diabetes incidence rates appear to have leveled off or declined in many countries. Randomized trials have demonstrated that weight loss of as little as 15 pounds can lead to a 40% reduction in onset of type 2 diabetes in high-risk patients, and return 40% of patients with recent onset of the disease to nondiabetic status. Policy to influence food production and sales, as well as eating patterns, is in its infancy and can boast only modest success, but that is clearly the only solution to the challenge of obesity and type 2 diabetes. It goes without saying that the opioid epidemic in the United States, which has cost 770,000 lives since 1999 and reduced overall life expectancy, is a poster child of a social disease whose amelioration will not be driven by precision genomic medicine.

We do not believe genomics and precision medicine will transform biomedicine and population health. Though the history of science will have the final word on this era, we believe that large segments of the biomedical community, supported by tens of billions of public dollars, are in effect headed down the wrong road, if not into a cul-de-sac. To understand this assertion, it is essential to recognize the distinction between transformational change and widespread niche advances. The concern that we have addressed here lies singularly with population health, with benefits accruing to millions. Scientific understanding of both the reasons for enormous gains in population-wide health, and the origins of disease, are being largely displaced by a reductionist, technology- and theory- (and career- and profit-) driven approach to health and medicine that remains largely unproven (and wildly expensive). Of course we want to explore and pursue many new research avenues, but the powerful legacy of genetic determinism and the devotion to technological solutions have narrowed the scope of research aimed at improving population health, and thus narrowed and reduced the benefits that biomedical science could and should be providing, right now.

Ironically, two decades into the genomics revolution life expectancy in the United States has declined for three consecutive years, the reduction in cardiovascular disease rates has leveled off, and a surge of opioid deaths has devastated many communities. These adverse events have no direct relationship to genomics or precision medicine, but just as clearly we have not observed the promised bonus of more effective prevention of many diseases, fewer diagnoses of serious illness, and an extension in health span. We could, of course, be accused of making a grossly premature judgment. Two decades is a reasonable interval, however, in which at a minimum to demonstrate proof-of-concept, and we see no evidence of that modest milestone having been reached. More to the point, we argue that genes as a cause and precision medicine as the cure violate basic precepts of health and medicine. Biomedical science should be reoriented and reprioritized to expand its scope in accord with what we actually know about health and disease, and to expand the benefits of science for all.

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'Headed down the wrong road': The quest for precision medicine distracts us from what already works - Genetic Literacy Project

CRISPR Therapeutics (NASDAQ:CRSP) has done very well for itself, with the company's stock almost doubling in 2019 as optimism surrounding its gene-editing technology continues to grow. Considering how much of a game-changer gene-editing technology can be for patients with incurable conditions, it makes sense that people are excited.

While shares have tumbled over the past couple of months, this might be a good thing for investors looking to buy this promising stock at a cheaper price. If you're on the fence about CRISPR or are looking for a stock with great upside potential, here are a few reasons why CRISPR looks like a good pick in 2020.

Image source: Getty Images.

CRISPR is arguably the top name in the relatively young gene-editing market right now. The company currently has nine drug candidates, with four either having begun clinical testing or close to starting.

CRISPR's flagship candidate is CTX001, a drug that targets sickle cell disease and transfusion-dependent beta-thalassemia (TBT). Patients with either of these conditions have malformed red blood cells that struggle to deliver oxygen throughout the body. Approximately 300,000 infants are born with sickle cell disease each year, with another 60,000 born annually with TBT.At present, there are no treatments for either condition.

The other three noteworthy candidates in CRISPR's pipeline are CTX110, CTX120, and CTX130. These drug candidates are a type of new cancer-immunology treatment known as a chimeric antigen receptor T cell (CAR-T) therapy. These types of treatments involve modifying a patient's immune cells in a lab to make them better at killing cancer cells. While it's traditionally quite expensive, CRISPR's technology could possibly make these new CAR-T therapies cheaper than the competition.

While the drug is still in early clinical testing, CRISPR reported some success with CTX001 back in November when it announced that two patients had been treated successfully with the drug. The two patients, one diagnosed with sickle cell disease and the other with TBT, managed to eliminate all of their symptoms following a single CTX001 infusion.

In the case of TBT, the number of required blood transfusions dropped to zero, while the sickle cell disease patient experienced zero occlusive crises (blood vessel blockages that occur due to the abnormal shape of the patient's blood vessels).

CRISPR has confirmed that it will be providing more data for both CTX001 and its cancer immunotherapies sometime this year. That means that investors can look forward to further potential catalysts in 2020, likely toward the latter half of the year.

In general, investors shouldn't take too much stock in the financial figures of early-stage biotechstocks unless there's something really alarming going on (like not having enough cash). Revenue figures change dramatically once a drug receives approval, and companies tend to report significant losses until drug candidates reach late clinical stages.

However, CRISPR's situation is different. In its recently released fourth-quarter financial results, the company reported an impressive $77 million in revenue, a substantial improvement from the mere $100,000 seen last year. Annual revenue for 2019 came in at $289.6 million in comparison to 2018's $3.1 million.

While this virtually all comes from CRISPR's collaboration agreement with Vertex Pharmaceuticals, the important point is that CRISPR is now reporting a profit. Net income for the fourth quarter came in at $30.5 million, whereas last year the company saw a net loss of $47.6 million.

Data source: YCharts, CRISPR Therapeutics.

No other notable gene-editing stock out there is reporting a profit right now. Even if CRISPR ends up dipping into a net loss again in subsequent quarters, the fact that the company managed to report a positive net income this early on in its drug development program is impressive.

Given how young the gene-editing industry is and how experimental this technology can be, positive clinical results in this field can have a positive effect on all stocks in the sector. When Intellia Therapeuticspresented new data regarding two of its drug-editing programs earlier in February, shares of all gene-editing stocks -- including CRISPR -- shot up, despite the fact that they are all competitors.

While this might seem strange at first, it makes sense given how young this industry is. Further clinical proof that gene-editing drugs work, no matter where it comes from, is good for the entire sector. A rising tide lifts all ships, and CRISPR investors also should look out for potential catalysts from other gene-editing companies, which could act as an indirect catalyst for CRISPR's stock.

Intellia, Editas Medicine, and Sangamo Therapeuticsare all working on sickle cell disease and transfusion-dependent beta-thalassemia treatments of their own. Positive developments from their treatments could have a spillover effect on CRISPR's stock. Editas stated recently that it expects to file an Investigational New Drug (IND) application for EDIT-301, its sickle cell drug, by the end of 2020.

The answer is yes, it definitely can. CRISPR Therapeutics has plenty of good things going for it, and there is a lot of long-term enthusiasm surrounding both the company and the industry. While shares of CRISPR have fallen a fair bit over the past couple of months -- down 14% since the start of 2020-- so have other gene-editing stocks. As such, it doesn't seem to be as much of a problem with CRISPR in particular as it is a sector-wide phenomenon. Since there's no real news that appears to be behind this decline, I wouldn't worry about it too much.

Instead, now looks like a good time to buy gene-editing stocks, because they're trading at a bit of a discount. Back in November, Oppenheimer analyst Silvan Turkcan issued a price target of $80 for CRISPR Therapeutics, suggesting at least a 57.1% upside to the stock based on current prices. That seems very reasonable, and I wouldn't be surprised if CRISPR does much better than that in 2020.

However, CRISPR still remains a high-risk investment given the fact it's an early-stage biotech stock. If you want to buy shares right now, keep your position on the smaller side. Never risk too much of your portfolio on a single stock, no matter how promising it might seem.

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Can CRISPR Therapeutics Double Your Money in 2020? - The Motley Fool