The expiration of GlaxoSmithKline’s patent on AZT last month may be a watershed moment in the history of HIV therapy. Certainly not as great as the development of the first retroviral drug effective at controlling the virus, but maybe an important sign of things to come, both in treatment and research.

    On Sept. 19, FDA approved four different generic versions of Retrovir (zidovudine), known as AZT, manufactured by three different companies, for use in the United States.

    Although Retrovir was a comparatively low seller in 2004-thirteenth in the retroviral class, according to IMS Health-its patent expiration may create ripples in the market as well as incentives for research.

    Peter Young, president Young & Partners a specialized investment-banking firm, believes that HIV drugs losing their patents could drive innovation by creating financial incentives to develop cutting-edge therapies that dramatically improve treatment in order to get ahead of the generic alternatives.

    “It might end up being a very good thing because there is room for improvement to the extent that if people have patented new drugs that are very effective, they will be able to make money,” he said.

    In fact, most retroviral cocktails are re-combinations of familiar compounds, including AZT. When enough of these cocktails come off patent, they may create a useful lineup of generic drugs for patients who seek an alternative to high-priced branded therapies.

    “There is room for improvement in HIV/AIDS drugs,” Young said.

    The loss of revenues from Retrovir will not hurt GSK very much, however. Their AZT-containing cocktail Combivir was the top selling drug in market in 2004. It generated $3.1 billion dollars last year, in comparison to $36 million by Retrovir, according to IMS Health. GSK also has the fifth most profitable retroviral, Trizivir, which made $400 million. Trizivir also contains AZT.

    “The affect on GSK is going to be very modest,” Young said.

    He indicated that the vast number of HIV drugs available mean that one drug going off patent is not going to cause large drops in price throughout the market.

    “It’s not like other categories, like cholesterol, where three or four dominate,” he said.

    Generic AZT availability will help low-income people who must obtain the drugs through discount programs, usually sponsored by the government. Some advocacy groups, such as the AIDS Healthcare Foundation, have criticized GSK for extending AZT’s patent life through fixed-dose cocktail drugs Combivir and Trizivir.

    Manufactured by two Indian companies-Ranbaxy Laboratories Limited and Aurobindo Pharma LTD-and a subsidiary of Boehringer Ingelheim, Roxane Laboratories, the newly approved generics were already tentatively approved for use in developing countries under the President’s Emergency Plan for AIDS Relief.

    FDA claims these approvals indicate that drugs purchased under PEPFAR will be available to Americans when the patents on the brand versions expire.

    Right now there are eight tentatively approved PEPFAR products, according to FDA spokeswoman Karen Mahoney.

Articles

A look at what the advent of generic antiretroviral drugs could mean for the industry.

Generic AZT Hits the United States

A new therapy for patients with too much iron in their systems, Exjade (deferasirox), received positive reviews from FDA’s Blood Products Advisory Committee on September 29. If approved, Exjade would be the first oral drug available in the United States to help patients eliminate excess iron. 

    An alternative to an older drug that is administered over many hours through a needle under the skin. Exjade is eagerly anticipated by specialist physicians and patients with blood disorders.

    Exjade won unanimous committee support even though its trials did not demonstrate “non-inferiority” to Desferal (deferoxamine), the only other drug available in the United States. Novartis manufactures both drugs.

The company claimed that Exjade is just as effective as Desferal but that the doses of the new drug for patients in the trials were too low. Exjade performed as well as its predecessor among a smaller subset of trial patients who were given higher doses, according to Novartis’ presentation to the committee.

Iron chelation therapy is an unusual treatment designed to help patients with too much iron in their blood and livers. In most cases it does not treat a disease. Iron overload is usually a byproduct of prolonging a patient’s life with blood transfusions, explained Bryan Mackenzie, an assistant professor of cellular and molecular physiology at the University of Cincinnati.

    Most patients in the Exjade trials suffered from thalassemia major, a genetic blood disorder that decreases people’s ability to make all of the components of hemoglobin, the part of the red blood cell that transports oxygen throughout the body. Iron is an essential part of hemoglobin and is necessary for binding oxygen. 

    As a result of low hemoglobin, thalassemia patients need regular blood transfusions, said Kenneth Bridges an assistant professor at Harvard Medical School and doctor at Brigham and Women’s Hospital. 

    The transfusions add hemoglobin, Bridges explained. But because patients already have the iron-component of hemoglobin, the additional iron in the transfused blood creates a toxic build-up in their organs, especially the liver, heart and pancreas.

    “The overload of iron is a byproduct of medical advances,” Bridges said.

    Thalassemia patients’ bodies also absorb more than the normal amount of iron from food, Mackenzie explained, enhancing the overabundance. Their bodies are trying to generate more red blood cells in response to the lack of hemoglobin. As a result, they increase the uptake of iron in the intestines.

    Although iron is necessary for normal functioning, it is difficult for the body to get rid of excess, according to Thomas Coates, an associate research professor at the Los Angeles Children’s Hospital. Most people lose about 1 milligram of iron each day through their intestines and menstrual blood, Coates said. The body recycles the rest.

    “The body has no mechanism to protect itself when it exceeds its ability to eliminate iron,” he explained.

Iron chelation drugs bind excess iron, and take it with them when they are eliminated from he body as waste. The existing therapy, Desferal, uses a large water-soluble molecule to bind iron. Water-solubility allows it to be eliminated from the body easily, Mackenzie said. But it also makes it difficult for the drug pass through the water-repellant membranes surrounding a cell, which it must do to reach the iron. 

    Because of its structure, it is absorbed into the intestines too slowly for oral ingestion to be effective. And it passes through cell membranes so slowly that it must be administered over 10 to 12 hours, usually via a needle pumping the drug under the skin while the patient sleeps, Coates said.

But Exjade has a lower molecular weight and is fat soluble, which helps it pass through cell membranes to reach iron, according to Novartis spokeswoman Kim Fox. 

    “It’s a completely different chemical entity from Desferal,” she said, noting that Ciba-Geigy, which merged with Sandoz to form Novartis in 1996, began the research on the delivery technology.

    This change in structure allows the drug to be delivered orally once a day and absorbed in the intestines, Coates explained. Eighteen of his patients participated in clinical trials for Exjade.

    “It really has changed a lot of lives,” he said. “This is a huge thing.”

    Coates and Bridges both noted that compliance can be a problem for patients on Desferal because of the time commitment and discomfort of taking the drug.

    Even though Exjade does not bind iron better than Desferal, the improvement in patients’ quality of life would be a major benefit, Mackenzie said. He noted that bad compliance can lead to heart damage and the need for cardiac drugs later in life.

Although Exjade was primarily tested on patients with thalassemia, it is also indicated for others who need frequent transfusions. Patients with sickle cell disease and hemochromatosis, a hereditary disease in which the body absorbs too much iron from food, also need iron chelation therapy, Mackenzie said. It could also be used after transfusions following bone-marrow transplants, Bridges added.

Experts are thrilled about the development of a new iron chelation drug that could be taken orally, changing the lives of patients who need chronic blood transfusions.

Blood Advisory Committee Recommends Exjade by Novartis

A new drug designed to defend cells against the toxins produced by anthrax won Human Genome Systems a government contract worth at least $1.8 million last month. The company will supply the department of Health and Human Services with a sample of its drug, ABthrax (raxibacumab), for testing. The government then has a year to decide whether to purchase up to 100,000 doses of the drug under the BioShield Act, which would trigger the second phase of the contract.

    Current antibiotic treatments seek to kill anthrax bacteria that germinate from inhaled spores before they reach the lymph nodes and spread infection. To supplement antibiotics, the new drug aims to prevent a later phase of infection, when toxins produced by anthrax bacteria enter cells and kill them, explained Jerry Parrott, Human Genome Sciences spokesman. 

When anthrax spores are inhaled, macrophages (immune scavanger cells in the lungs) ingest the spores. Inside these cells, the dormant spores become active, sometimes called “vegetative,”  bacteria, said Stephen Morse a professor of epidemiology at Columbia University and director of the school’s Center for Public Health Preparedness. The macrophage transports the germinating spore to the nearest lymph node, where it leaves the macrophage as an active bacteria and begins producing the toxin that kills cells. 

    Anthrax toxin is composed of three proteins, explained John Young a professor of infectious disease at the Salk Institute. One of these, called protective antigen (PA), binds to one of two anthrax receptors on the cell surface, and begins a process that brings the other two proteins into the cell interior, where they fatally disrupt cell functioning. 

    After PA binds to the receptor, an enzyme called furin cuts PA, Young said, forming a seven-part ring that will eventually transport toxic proteins into the cell. The other proteins that make up anthrax toxin, edema factor and lethal factor, attach to the ring. This complex enters the cell by merging with an endosome, a bubble-like cell structure whose membrane separates its contents from the rest of cell. 

    This interior of an endosome is acidic, which drives a reaction that turns the PA ring into a pore in the membrane of the endosome, Young explained. The edema factor and lethal factor move through the pore into the interior of the cell, where they disrupt normal functioning and eventually kill the cell.

ABthrax works by binding PA outside of the cell and blocking it from attaching to the anthrax receptors, Parrott explained. Because PA does not bind to the anthrax receptors,  ABthrax prevents the reactions that allow lethal factor and edema factor to enter and kill the cell.

    PA is the most common target of the latest approach to fighting anthrax infection, said Young, who is a co-founder of PharmAthene Inc., another company developing an anthrax treatment, PharmAthene and  Medarex Inc., another biotech, are developing Valortim, a drug that binds PA to a second receptor, which prevents if from ushering edema factor and lethal factor into the cell. 

If the government decides to go forward with phase two of the contract with Human Genome Sciences, the company will have to conduct an additional safety study and scale up its manufacturing process, Parrott said. Until then, the company is taking no action, Parrott said, since the government is the largest, if not the only, customer for the drug, 

    Days before the contract for ABthrax was awarded to Human Genome Sciences, a similar deal was made with Cangene Corp., according to company spokeswoman Jean Compton. The Canadian company manufactures Anthrax Immune Globulin, an injection of concentrated, purified anthrax antibodies distilled from the plasma of people who have received the anthrax vaccine and developed antibodies naturally. 

    AIG is a type of treatment known as a “hyperimmune.” It can be administered after or just before exposure and provide the recipient with the necessary antibodies to fight anthrax infection for approximately three weeks, Compton said. But it does not enable patients to develop antibodies on their own, like a traditional vaccine would.

ABthrax takes advantage of new knowledge about anthrax to fight the bacteria’s lethal toxin.

Pharmaceutical Executive-10-11-2005

Generic AZT Hits the United States

Blood Advisory Committee Recommends Exjade by Novartis

Human Genome Sciences Awarded Contract for Anthrax Drug