Bioindustry Researchers Take Strides in Preventing Diseases: Developments in Genetic Diagnosis and Therapy

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Johnson & Johnson’s pharmaceutical research arm recently launched a drug-development project that will intercept diseases before patients even realize they’re sick. In the company’s words: “The future of healthcare will increasingly depend on identifying and correctly interpreting the earliest signals of disease susceptibility, preventing or intercepting disease before it even begins.” (1).

The first targets include Alzheimer’s, some forms of cancer, heart disease, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. The company’s Disease Interception Accelerator group will search for genetic variations and other molecular factors that are the root causes of diseases and that can be detected long before clinical symptoms materialize. Other groups will develop treatments that block or halt their initiation or reverse their progress very early in their development. Steve Brozak, president of WBB Securities, estimates that accomplishing these stated goals will cost billions of research dollars and could take decades. But he notes that J&J is one of the few companies that has the money and talent to pull it off (2).

This audacious project heralds the logical culmination of modern molecular medicine. Biochemists unravel the molecular pathways that propel diseases and design precisely targeted drugs to block or control them. Doctors then practice “precision medicine,” prescribing the drugs to patients whose disorders present the targeted pathways. The diagnostic and drug-design tools that make this possible have come of age in the past two decades. They have been widely used in developing effective later-stage treatments and clearly have the potential to identify and take control of factors that launch diseases at the outset. And there is little doubt that successful interventions at a very early stage often will be the best (sometimes the only, and almost always the most cost-effective) way to beat many serious disorders.

Preventive Gene Therapies
The genetic seeds of many disorders are planted at the time of conception and lie dormant inside our bodies for many years before they start morphing into lethal diseases. An array of tumor-suppression and DNA repair genes, for example, protects most of us from cancer for most of our lives.

Hereditary gene variations affect how well genes perform. Some are strongly linked to the development of specific cancers (e.g, breast, skin, or colon cancer) or in some rare cases, a propensity to develop cancer in general. Such genetic variations can be detected fairly easily. “Liquid biopsies” now being developed to detect cancer cells or stray fragments of their DNA in a patient’s blood could provide very early indications of the onset of cancerous growths. Researchers have mastered powerful and flexible methods for selectively adding, deleting, or replacing genes in a live cell’s genome. Such tools can do in weeks what previously required months or years of work using traditional gene-editing tools. And a new family of RNA interference (RNAi) drugs has the potential to regulate gene expression and thus take direct control of genes involved in the earliest stages of disease development (3).

The next step could well be vaccine-like treatments that provide protection before cancers and other disorders start to develop. Researchers are investigating a number of different vectors for reprogramming the genetic code of cells inside a patient’s mature tissues and organs. In early trials, for example, young adults blinded by a rare genetic flaw experienced significant visual improvements soon after a viral vector was used to insert a healthy version of the gene directly into their retinal cells (4). Similar procedures are reportedly being developed to treat cystic fibrosis, brain cancer, and muscular dystrophy.

Preventive gene therapies can provide similar opportunities. Genetic therapies administered early enough to replace pathological variations in gene-repair and tumor-suppression genes could offer many people a significant, lifelong reduction in their risk of succumbing to what is currently the second most common cause of death in the United States. Rare variations in a single gene make some people prone to develop very high levels of cholesterol and suffer heart attacks in their teens. A more common variation in that gene has the opposite effect, and researchers are investigating the possibility of reprogramming cells to replace the harmful versions of that gene with the low-cholesterol version (5).

The human immunodeficiency retrovirus (HIV) pries its way into our immune system cells by latching onto a protein on their surfaces. A recent clinical trial demonstrated the therapeutic potential of genetically engineering a patient’s own immune system stem cells to replace or disable the gene that codes for the HIV-entry protein (6). In the words of senior author Carl H. June, MD (a doctor involved in the trial), “This study shows that we can safely and effectively engineer an HIV patient’s own T cells to mimic a naturally occurring resistance to the virus, infuse those engineered cells, have them persist in the body, and potentially keep viral loads at bay without the use of drugs.”

Hereditary defects in DNA repair genes also are associated with premature aging. Probably the dominant cause of normal aging is the senescence and eventual death of stem cells (the cells that built all our organs and tissues and that continue to lurk inside them, standing by to maintain and repair them throughout most of our lives). Researchers have begun to identify the molecular factors that play a significant role in stem-cell aging and its link to age-related deterioration of various tissues (7). With tools to manipulate the genes that control stem-cell aging now in hand, it is reasonable to foresee a future in which normal aging can be systematically retarded.

Most gene therapies are still in the investigational stages of development, but their feasibility and great promise are no longer in doubt. And no other currently known process has the potential to provide complete cures for the many rare but often deadly disorders caused by hereditary genetic mutations.

Regulatory and Approval Issues
The biggest challenge associated with developing promising genetic therapies will be obtaining approval for preventive drugs by the US Food and Drug Administration (FDA). US federal drug law states that a new drug may be approved only if its efficacy has been established by “substantial evidence” grounded in “adequate and well-controlled” clinical trials (8), which the FDA interprets as requiring studies that demonstrate actual clinical-level benefits. That means conducting trials that can’t be completed any faster than diseases typically progress to the point where they cause clinical symptoms. And those studies will take even longer than that if drugs are designed to intervene before a disease starts to develop. Clinical trials are very expensive, and the clock on drug patents keeps ticking while such studies are conducted.

The Accelerated Approval rule provides the regulatory framework in which the FDA will (in principle though rarely in current practice) allow drugs to be conditionally approved on the basis of subclinical “surrogate endpoints” that the FDA deems to be “reasonably likely” to predict clinical outcomes (9). A manufacturer still must complete studies that last long enough to confirm a drug’s clinical effects, but do so after the drug has been conditionally approved. A drug may be withdrawn from the market if it doesn’t work as expected. But the FDA relies on an ad hoc, opaque, and unpredictable case-by-case analysis when deciding the surrogate endpoint to be used. The agency has largely restricted accelerated approval to HIV/AIDS and cancer drugs.

As a practical matter, accelerated approval may be the only pathway that will draw substantial amounts of private capital into the pursuit of drugs that intervene before a disease has started to develop or early in disease development. Such can be the case for therapies that involve the rarest genetic flaws for which it is impossible to conduct statistically significant conventional drug trials in which half of the patients are treated with a placebo.

A 2006 article in the New England Journal of Medicine attributed the complete absence of drugs that would prevent — rather than just alleviate — the late-stage symptoms of diseases such as Alzheimer’s or osteoarthritis to a drug approval process that “makes it hard, if not impossible” to move the drug through a regulatory approval process before its patent expires (10). “[D]espite considerable advances in our understanding of such diseases, there is no validated and tested path to successful FDA approval of a drug to prevent those conditions. This lack of a clear plan for drug approval adds high regulatory risk to the already high scientific risk of failure.” The authors of a 2011 paper on the application of the FDA’s Accelerated Approval rule to rare diseases reach the same conclusion: Drug developers have encountered significant difficulties because of the “lack of clear qualification criteria for surrogate endpoints” (11).

Finding Solutions
The FDA says its main concern is that surrogate end points are unreliable and that a “substantial risk of adversely affecting the public health” comes into play if a drug is approved on the basis of a surrogate endpoint that does not accurately predict clinical efficacy (12). Many experts in the field, however, have concluded that by collecting large amounts of molecular and clinical data from many patients and analyzing those data with modern statistical tools, companies can accurately identify molecules that play significant roles in the initiation and progression of many diseases. Drug developers and doctors are already successfully using these tools to guide the design of targeted drugs and the way they are prescribed to patients. And the research community continues to launch new studies to unravel the molecular dynamics of diseases from molecular cradle to clinical grave.

Oncology has led the way. Researchers and doctors have set up databases in which they pool and analyze molecular and clinical data collected during patient treatment with approved drugs. Analytical engines map out cancer pathways by comparing large databases of tumor profiles paired with those of healthy cells. This strategy has demonstrated that supercomputers can extract causal pathways from extremely large and complex data sets.

Other researchers have reached the same conclusion. The “overarching goal” of the “Big Mechanism” program recently launched by the Defense Department’s Advanced Research Project Agency (DARPA) is to develop methods to extract “causal models” from large, complex datasets and integrate new research findings “more or less immediately . . . into causal explanatory models of unprecedented completeness and consistency” (13). To test these new technologies, DARPA has chosen to focus initially on “cancer biology with an emphasis on signaling pathways.”

The National Institutes of Health’s Accelerating Medicines Partnership, recently announced a US$230 million, five-year plan to collaborate with 10 big drug companies and eight nonprofit organizations focusing on specific diseases (14). The goal is to unravel the molecular pathways that lead to Alzheimer’s disease, type 2 diabetes, rheumatoid arthritis, and lupus erythematosis as well as to investigate new methods to track a disease’s progress, which could provide early reads about how a drug is affecting that disease. The objective is to “ensure we expedite translation of scientific knowledge into next generation therapies.”

Mikael Dolsten MD, PhD, president of worldwide research and development at Pfizer, emphasized that the Alzheimer’s project will focus on developing a better understanding of the molecular pathways and networks that propel the disease (15). The company will also search for molecular factors in developing drugs that intervene much earlier, intercepting diseases before they become irreversible and untreatable. “It will be critical to have FDA colleagues involved here to get their guidance, how those biomarkers also can be regulatory endpoints,” he added.

Another vote of confidence in accelerated approval and surrogate end points appears in a 2012 report issued by President Obama’s Council of Advisors on Science and Technology (PCAST) (16). The report recommended that the FDA make “full use” of accelerated approval “for all drugs . . . addressing an unmet medical need for a serious or life-threatening illness.” Although there is “some risk” in using surrogate end point to accelerate drug approvals, it is justified by “the opportunities for progress against serious or life-threatening diseases,” while the risk is mitigated by the requirement that conventional trials be completed after a drug is approved.

In April 2014, FDA Commissioner Margaret Hamburg declared that, at least in dealing with drugs that treat chronic conditions, “we don’t [need] to have studies that have to wait for the whole natural history of the disease to unfold to [assess] how something works” (17). Relying more heavily on the expertise and consensus views of outside experts (as the PCAST report also recommends) would help insulate the FDA from the political risk and public criticism that it is likely to face if the agency approves a drug on the basis of a surrogate endpoint but the drug then fails to deliver the clinical effects that were predicted.

A Path Forward
Molecular biology is the foundation of precision medicine and the essential starting point for the most promising currently available tools for developing preventive treatments. It is time for the FDA to fully incorporate our rapidly growing understanding of the molecular dynamics of diseases in the drug-approval process. A drug is “effective” and belongs on the market if it can safely control a molecular pathway that propels one or more diseases. The agency should defer to the consensus views of the scientific community as to which pathways propel which diseases. Doctors should have broad latitude to prescribe targeted drugs accordingly.

Janssen Launches Three New Research Platforms Focused on Redefining Healthcare. Johnson and Johnson: 12 Febuary 2015;

2 Johnson L. Johnson & Johnson Projects Aim to Spot Who’ll Get a Disease. Associated Press 12 February 12 2015;

3 Bender E. The Second Coming of RNAi. The Scientist 1 September 1 2014; www.

4 Cidecyin AV, et al. Human RPE65 Gene Therapy for Leber Congenital Amaurosis: Persistence of Early Visual Improvements and Safety at 1 Year. Hum. Gene Ther. 20(9) 2009: 999–1004.

5 Colen BD. A Shot Against Heart Attacks? Harvard Gazette 10 June 2014; http://

6 Personalized Gene Therapy Locks Out HIV: Paving the Way to Control Virus Without Antiretroviral Drugs. Penn Medicine, 5 March 5, 2014; News_Releases/2014/03/june.

7 Mayo Clinic Researchers Discover that Stem Cell Senescence Drives Aging. Mayo Clinic News Network 15 April 2013. http://newsnetwork.

8 21 US Code §355(d), §505(d) 2. Substantial Evidence. US Government Publishing Office: Washington, DC.

9 CDER, CBER. Guidance for Industry: Expedited Programs for Serious Conditions — Drugs and Biologics. US Food and Drug and Drug Administration: Rockville, MD, May 2014.

10 Alastair JJ, Wood MD. A Proposal for Radical Changes in the Drug-Approval Process. N. Eng. J. Med. 355, 2006: 618–623;

11 Miyamoto BE, Kakkis DE. The Potential Investment Impact of Improved Access to Accelerated Approval on the Development of Treatments for Low Prevalence Rare Diseases. Orphanet J. Rare Diseases 6, 2011: 49; doi:10.1186/1750-1172-6-49.

12 Guidance for Industry and FDA Staff: Qualification Process for Drug Development Tools” CDER/CBER: Rockville, MD, 2014;

13 Big Mechanism. DARPA Information and Innovation Office;

14 NIH, Industry, and Nonprofits Join Forces to Speed Validation of Disease Targets. National Institutes of Health: Bethesda, MD, 14 February 2014;

15 AMP Press Conference audio transcript, 4 February 2014;

16 Report to the President on Propelling Innovation in Drug Discovery, Development, and Evaluation. President’s Council of Advisors on Science and Technology. September 2012;

17 Pittman D. Focus on Chronic Illness Drugs Needed. MEDPAGETODAY 11 April 2014;

Peter Huber is a senior fellow at the Manhattan Institute;

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