Risks and Rewards of Biologics for the Brain

Living organisms, ranging from human cells to bacteria, are being used to produce new kinds of drugs that are providing promising treatments for some frustrating medical conditions.  These drugs, called “biologics,” rely on the insertion of a DNA sequence into living cells or organisms; the cells then grow and produce a large, often complex, protein using their own natural machinery.  Biologics differ in important ways from the more traditional common forms of drugs, which are smaller, simpler molecules produced from carefully sequenced chemical reactions between inorganic (nonliving) materials.

As scientific “bluebloods,” with their origins in research that earned multiple Nobel Prizes, biologics are particularly exciting to clinical researchers because they hold promise for diseases that have had few effective treatments.  Already, they have become significant for several immunological, inflammatory, and neurological diseases, and the market for them has risen into the tens of billions of dollars.  Despite their promise, however, the development process has also revealed serious (and unexpected) adverse effects, suggesting that caution is warranted. 

Biologics for Multiple Sclerosis

The development of biologics to treat multiple sclerosis is illustrative of both the rewards and the risks of these new drugs. Treatments for disorders affecting the brain represent, so far, only a small portion of biologics developed, but biologics for multiple sclerosis have fundamentally changed clinical treatment of the disease.

Multiple sclerosis is a chronic, recurrent, inflammatory (and presumably autoimmune) disorder that results in injury of the myelin coating of nerve cells in the brain and the central nervous system. When myelin is damaged or destroyed,  the ability of nerves to conduct impulses to and from the brain is disrupted, resulting in highly variable symptoms that may include cognitive changes, difficulty in walking or balance, vision problems, pain, fatigue, and bladder or bowel dysfunction. Multiple sclerosis affects both men and women, often in the prime of their lives, and is one of the leading causes of disability among young women.

Before the first biologic was developed to treat multiple sclerosis, only symptomatic treatment was available, usually anti-inflammatory medications such as steroids. The development of the biologic interferon beta-1b (Betaseron), which was approved in 1993, opened a new class of “immunomodulatory” treatment that could be taken on a regular basis to prevent relapses, slow disease progression, and potentially alter the course of the disease.  Other interferons for multiple sclerosis followed, and the market for biologics for multiple sclerosis is now more than $4 billion per year.

Therapeutic biological products for multiple sclerosis

Therapeutic biologic	2006 sales ($ billions)	Approval date	Company
Interferon beta-1b (Betaseron ® )	1.0 (sales data from 2005)	7/23/1993	Berlex Laboratories
Interferon beta-1a (Avonex ® )	1.7	5/17/1996	Biogen Idec, Inc.
Interferon beta-1a (Rebif ® )	1.5	3/7/2002	Serono Laboratories, Inc.
Natalizumab (Tysabri ® )	< 0.1	11/23/2004	Biogen Idec and Elan Pharmaceuticals

The newest biologic for multiple sclerosis—natalizumab (Tysabri)—highlights the critical issues facing biologics as a whole. Natalizumab is a monoclonal antibody directed against a protein on the surface of white blood cells (immune lymphocytes).  This antibody decreases the lymphocytes’ ability to cross the blood-brain barrier and potentially cause the damaging inflammation of the myelin seen in multiple sclerosis.  The biologic held enormous clinical promise in early trials and fueled the rise in the manufacturer’s stock, which nearly doubled in 2004, culminating when natalizumab received initial FDA approval in November of that year.

At that point, the drug’s performance in clinical trials appeared to be fulfilling its potential.  An interim analysis of one of the major studies showed promising results, and the final results from that trial demonstrated that natalizumab decreased signs of inflammation in the brain by 80 percent (as seen on MRIs), reduced clinical relapses by almost 70 percent, and slowed disease progression by 40 percent.¹  In addition, the medication appeared to be well tolerated, and even before FDA approval, neurology clinics across the country began planning for infusion centers that, it was hoped, would administer the intravenous medication to many of the some 400,000 people in the United States who have multiple sclerosis.

The promise of natalizumab came to a screeching halt, however, with reports of three cases of progressive multifocal leukoencephalopathy (PML), a rare, often fatal, viral infection in the brain that can occur in people with lowered immune responses.  This particular side effect had not been discovered in animal testing, so its appearance was entirely unexpected.  While the reported cases occurred in patients who were taking both natalizumab and other immunosuppressant drugs, Biogen Idec quickly (in February 2005) voluntarily suspended the marketing of natalizumab, precipitating a dive in the company’s stock price.

Now, however, natalizumab has begun a slow climb back to acceptance.  On the basis of a narrower intended use and a strict patient monitoring system to track any new cases of PML, in June 2006 the FDA gave Biogen Idec approval to reintroduce the drug. Carefully chosen people with multiple sclerosis at selected medical centers are receiving the treatment, and the company’s stock price has recovered a small portion of its previous losses.

The price of natalizumab, like that of many biologics, is high.  Patient payments for a single monthly dose of the drug may be $1,000 or more, and health insurance does not always reimburse this.  A 2006 report in the Annals of Neurology highlighted the example of a medical student at the University of California at San Francisco who was recently diagnosed with multiple sclerosis and had a poor response to beta interferon.  Her physician prescribed natalizumab, but her health care plan had not yet approved the medication for coverage—leaving the student at one of the leading medical centers in the country unable to receive the medication.² 

The Genesis of Biologics

The genesis of bioengineered drugs, such as those now available to treat multiple sclerosis, is one of the great success stories in biology and medicine, and in the interplay of those fields with commerce. The speed with which basic scientific discovery was translated into new drugs was remarkably short, less than a decade—about half the time required by most previous new classes of drugs.

Biologics—and the biotechnology companies that create them—have their origins in scientific advances made in the 1970s by researchers who learned how to manipulate genetic material. In 1972, Paul Berg, Ph.D., at Stanford University, first produced recombinant DNA, a form of hybrid DNA created in the laboratory by splicing together segments of DNA from two or more organisms or cells. Soon thereafter, Herbert Boyer, Ph.D., at the University of California, San Francisco, demonstrated the feasibility of inserting foreign DNA into E. coli bacteria.  Georges Kohler, Ph.D., and Cesar Milstein, Ph.D., subsequently discovered enzymes (called restriction endonucleases) that are able to chop up DNA at specific locations, further enabling the splicing together of recombinant DNA molecules.

Together, these discoveries made possible the development in 1982 of the first human recombinant protein, recombinant human insulin. Up to that point, people with diabetes who needed supplemental insulin had to rely on insulin obtained from cows and pigs. While that approach was effective for many people, others had allergic reactions to the foreign protein.  To make recombinant human insulin, the first step was to isolate the human gene (genes are pieces of DNA) for insulin. Next, using restriction endonucleases, the gene for human insulin is inserted (spliced) into a circular piece of DNA from bacteria called a plasmid. The now recombinant plasmid (human insulin gene combined with bacteria genes) is inserted back into bacteria, where it makes many copies of itself as the bacteria divide. The growing numbers of bacteria with the recombinant plasmid produce insulin protein molecules that are gathered and purified into recombinant human insulin.

From this science, the biotechnology industry was born.  Herbert Boyer helped found one of the first biotechnology firms, Genentech, in 1976.  Other firms soon followed, including Amgen in 1980 and Genzyme in 1981. The recombinant DNA technology led not only to recombinant human insulin but also to recombinant factor VIII for hemophilia and recombinant erythropoietin for anemia.  Since the initial production of recombinant proteins from a single human gene, applications of biotechnology have expanded to the formation of monoclonal antibodies, proteins that are directed at a specific target and underlie therapies for breast cancer (for example, trastuzumab, or Herceptin) and rheumatoid arthritis (for example, rituximab, or Rituxan).  According to IMS Health (a company that provides information and analysis for the international pharmaceutical market), because of these scientific advances, the biotechnology industry is now valued at more than $50 billion and is projected to grow to $90 billion by 2009.

Rising Risks…

As the natalizumab example demonstrates, the industry is confronting challenges of both safety and pricing.  The advantage of many of the first biologics, for example human recombinant insulin, is that they are proteins normally found in humans and therefore avoid the allergic reactions that can result from foreign proteins.  But as the field has advanced, so have the technologies employed, and today many commonly prescribed biologics are “chimaeric” proteins derived from spliced DNA from more than one organism (such as humans and mice).  The future will see the production of more chimaeric proteins and also the use of transgenic animals (laboratory animals with some human cells) for manufacturing new products.  These novel therapies carry troublesome risks, especially that of adverse immunological reactions.

Biologics also carry idiosyncratic, sometimes fatal, risks that are impossible to predict.  In 2006, six healthy volunteers in the United Kingdom nearly died after taking a particular monoclonal antibody (TGN1412), originally developed for leukemia and rheumatoid arthritis, in a Phase I trial in a small number of people to assess its safety.  Despite significant investigation, the cause for the serious immune reaction has not been determined. 

Because biologics are based on complex living cells or organisms, they are much more sensitive to changes in the manufacturing process than traditional drugs, which are synthesized through a controlled chemical reaction. Even a slight change in the process can cause a large problem, so biologics receive additional scrutiny from regulatory bodies. Any contaminants from the manufacturing process can produce serious adverse consequences. For example, the subcutaneous administration of a new erythropoietin product (Eprex) to treat anemia was associated with a dangerous fall in the production of oxygen-carrying red blood cells in patients. But the drop in red blood cell production decreased (or completely stopped) after changing from subcutaneous to intravenous administration of the drug.³ According to the manufacturers, the problem occurred after the company started using a different stopper for the syringes used for subcutaneous administration.

Neurologists and psychiatrists are trying to learn from the unanticipated adverse effects of biologics. Many of the immunologically active agents used to treat hepatitis C, cancer, and rheumatoid arthritis, for instance, produce unwanted effects in the brain, ranging from personality change, memory impairment, or mild depression to psychosis, seizures, and movement disorders. Fortunately, these effects are usually only temporary, but their occurrence often limits use of the biologics. Studies to understand the overlap between immunological function and the brain that occurs when these biologics are used may yield important new insights into these brain conditions.

In addition to unanticipated safety risks, producers of patented biologics face commercial risk from the possible introduction of copies.  In the United States, the Hatch-Waxman Act of 1984 allows for the introduction of generic drugs for traditional small-molecule chemical products after a patent expires, if the generic can be shown to be equivalent to the original drug.  However, the act does not cover most biologics, effectively granting many biotechnology firms monopolies without expiration. But competition for biologics appears to be on the horizon.  The European Medicines Agency released a “biosimilar” policy in 2004.  The policy would permit the introduction of similar competitor products after the patent has expired on the initial biologic, if certain laboratory and clinical testing studies are performed.³  In the United States, the Access to Life-Saving Medicine Act, introduced by Congressman Henry Waxman (D-Calif.), would create a regulatory process for approval of “follow-on” (sometimes called “generic”) biologics to compete with innovator biologics after patent expiration.

This issue pits the biotechnology industry—which argues that the manufacturing processes of biologics are much more complicated than those for small-molecule products and thus cannot be safely and precisely replicated—against purchasers of health care, who are looking for relief from rising health care expenses.  At stake is the approximately $10  billion worth of biopharmaceuticals that are projected to lose patent coverage by 2009.³  Resolution of this tension will tax both manufacturers and the Food and Drug Administration (FDA). Because of biologics’ unique nature, companies seeking to develop copies will need to conduct more-extensive clinical testing than is typical in developing non-biologic generics. Such trials are costly and will erode the cost/price advantage on which generics depend.  Likewise, the FDA, which developed its regulatory requirements for biologics during the first 25 years of their availability, will be confronted by patient groups who champion greater access to medications, and to lower-cost ones.

…and Rewards

Biologics also offer enormous rewards for patients and companies.  Because they interact with the body’s own cellular processes, they interfere with the way a disease causes damage, rather than treating the disease’s consequence. The effects of biologics vary from patient to patient and they can be highly targeted.  As molecular genetics advances, increasing numbers of effective biologics are likely to transform treatment by supplying deficient enzymes in certain disorders, for example, Gaucher’s disease, or augmenting the body’s own limited supply of a protein, such as insulin in diabetes.    

While the number of biologics for brain diseases and disorders currently on the market is limited, the pipeline of biologics with applications with neurological applications is robust.

Therefore, many biotechnology firms are attracting the attention of large pharmaceutical companies, which are becoming increasingly dependent on developing, or buying the rights to, and marketing new therapies as their patents on existing products expire.  AstraZeneca’s recent agreement to buy the biotechnology firm MedImmune for $15 billion in cash, a premium more than 50 percent of the stock price, indicates how much the biologics business is valued.

As biologics’ share of the pharmaceutical portion of health care expenses grows, these therapies will continue to draw heightened public interest. Safety and manufacturing concerns, and the demand for generic competition, will likely lead to closer post-marketing surveillance. The challenge will be to continue to reward the development of pioneering therapies, such as new biologics to treat previously untreatable diseases, while addressing their high prices.  A related challenge is to reward these pioneering innovations while exerting pressure on prices of competing products for treating the same disease. This tension is, of course, not unique to biologics, but its resolution is critical because of their especially high costs. 

Issues on the Horizon

Biologics are at the nexus of many of the significant forces at work in medicine: the science, the economics, and the politics.  Because no other effective treatments exist for many neurological conditions, patients and their families are outspoken.  While many neurological disorders are relatively uncommon, drugs to treat them have proven to be commercially attractive, in part because of the high prices manufacturers have been able to charge for new therapies.  Yet there is significant impetus to move faster and to be more productive in discovery and approval of new biologics.

Scientifically, many of the most rapidly advancing areas of neurobiology are likely to create demand for biologics.  While the first applications were in immunology and hormone replacement, new target pathways particularly suitable for biologics are likely to be revealed by research in genetics (especially environmental changes to gene expression), structural biology (the chemical skeleton of nerves, synapses, axons, and receptors), and nerve regeneration and repair.

The economics of biologics will grow more challenging, especially as demand increases.  The financial model of the industry has been built on aggressive pricing of drugs intended for use in a limited number of patients.  Such a model will probably not continue to be viable, as pressure on price from purchasers grows and as indications for biologics extend to more patients.  The consequences are likely to include greater incentives for productivity of the industry, allowing the costs of drug discovery, development, and manufacturing to be lowered.

In many ways, the politics are the most salient issue—and the most interesting.  The vexing issues that surround the field display all the tensions at work between industry and its regulators, on the one hand, and physicians and patients, on the other.  A current example is pressure for early access to new biologics, before FDA approval.

Conventionally, access to any drug that has not yet been approved is restricted to patients who are enrolled in controlled clinical trials. However, many now advocate modifying this restricted access to new treatments that are in development.  One particular remedy, urged by patient advocacy groups, is the patient-sponsored trial, one that is paid for by the patients themselves.  This idea was borrowed from the field of cancer treatment, where it was first used for the treatment of rare tumors, especially in children.  Because of the infrequency of such tumors, the FDA and pharmaceutical companies were generally supportive of this practice and afforded considerable flexibility in obtaining “compassionate use” drugs.  Also, insurers were often willing to offset the cost of such therapy, just as they had done historically for experimental cancer chemotherapy. Neurological patients would like to see the same kind of flexibility available to them.  Several lawsuits currently in the courts argue for a “right to access”; the rulings in this litigation will no doubt have particular bearing on the future of biologics.

From a therapeutic standpoint, the future of biologics appears robust.  Researchers are likely to develop new biologics that address many conditions, often in ways that are tailored to the specific pathology of a disease and to the person taking the drug. But, despite its noble scientific roots, the future of biologics will increasingly be determined by debates in the economic and political spheres.  Like health care as a whole, the field of biologics will have to justify its high prices and demonstrate the economic value of its products.  Because of its cutting edge science, biologics will be at the leading edge of political discussions about the science that should be funded, the types of therapies that will be developed, and the people that will initially have access to them.  Developing innovative resolutions of these debates will require the collective input of patients, physicians, industry, and government.