Background

“Biologics” are complex medicines that are reviewed and approved by the U.S. Food & Drug Agency (FDA) under the provisions of the Public Health Service Act (PHSA) for use in the United States. The “biological standard” for approval requires demonstration that a biologic is “pure, potent, and safe” and that its manufacturing facility is designed to assure the product continues to be pure, potent, and safe. The recent passage of the Patient Protection and Affordable Care Act (PPACA) established a foundation for biosimilars to enter the U.S. marketplace. While the PPACA created a general framework, the law also provides FDA authority to establish rules and guidance that will govern the specific requirements and procedures for reviewing and approving biosimilars.

The terms “biosimilars” (also called “follow-on biologics”) refer to products that are intended to copy previously-approved, innovator biologics and are submitted for approval based on similarity to the innovator product. Biosimilars are fundamentally different from small molecule generic drugs, which are virtually identical versions of innovator products and can readily be characterized by comparison of the exact chemical composition to the innovator product. As such, even without clinical trials to show safety and efficacy, generic drugs are usually designated to be “therapeutically equivalent” with the innovator drug and therefore interchangeable under FDA generic regulations. Conversely, while a biosimilar may be similar to an innovator product, it currently cannot be proven to be identical based on the current state of science. Thus, there are unique and inherent characteristics of biologics that must be considered as FDA establishes a regulatory pathway for biosimilars:

• Biologics are manufactured using live cells and biologics, such as monoclonal antibodies manufactured by MedImmune, are larger and more complex than small molecule drugs.
• Biologics are more difficult to characterize using laboratory techniques and have a more complex manufacturing process.
• Every biologic is different – even slight differences between biosimilars and innovator biologics, including their manufacturing processes, can result in meaningful differences in the safety and efficacy profile of the products.

What we believe

We support a regulatory pathway for biosimilars that is based on patient safety, product efficacy and continued incentives for innovator companies to invest in the development of novel, life-changing biologic medicines. We believe a biosimilars pathway should ensure:

• Appropriate rigorous scientific standards and a robust regulatory review process;
• A determination that biosimilars demonstrate the purity, potency and safety of innovator biologics as proven through human clinical trials and post-market surveillance; and
• Implementation of effective innovator regulatory exclusivity and patent enforcement provisions.

Below is a detailed look at our position:

Patient Safety
Because of the complexities of biologics, we believe that patient safety must be paramount when evaluating the approval of biosimilars. The introduction of biosimilars into the marketplace must ensure the current purity, potency, and safety standards established for innovator products by FDA. In addition, because the manufacturing process can have a significant impact on a biologic’s structure and activity, a regulatory pathway should ensure a rigorous inspection and control process for the manufacture of biosimilars that is similar to the innovator product standards

Clinical Trials
We believe that all biosimilars applicants should be required to conduct clinical trials that demonstrate sufficiently similar product safety, efficacy and immunogenicity relative to the innovator product. Non-clinical methods of characterizing complex biotechnology drugs have not matured to the point where they can substitute for clinical studies. Therefore, to ensure patient safety, it is essential for biosimilar sponsors to demonstrate product safety and efficacy by testing their product in adequate and well-controlled clinical studies. Furthermore, immunogenicity testing in human subjects, an integral part of biologics drug development, is critical to help measure potential adverse immune response to the biosimilar product. Immunogenicity has been associated with allergic or anaphylactic reactions, as well as reduction in efficacy or autoimmunity. We believe the FDA should issue molecule-by-molecule guidance for clinical trials required for biosimilars to account for the particular characteristics of the product.

Post-Market Risk Management Programs
We believe that biosimilars, once approved, should have FDA-approved risk management plans to ensure the products are rigorously monitored for post-market safety and immunogenicity. If biosimilars are approved with less clinical data than innovator biologics, the FDA should ensure that longer-term post-marketing outcomes for biosimilars remain similar to those with the innovator product.

Interchangeability/Substitution
We do not support interchangeability between an innovator biologic and a biosimilar product. Current regulations allow small molecule generic drugs to be designated as “therapeutically equivalent” and dispensed interchangeably with innovator products without physician’s knowledge. Because biosimilars are not identical to innovator biologics, they should not be deemed therapeutically equivalent and dispensed interchangeably for innovator biologics absent clinical trials that adequately demonstrate such interchangeability.

Unique Naming and Product Identification
Because biosimilars are similar to innovator biologics (rather than identical), we believe biosimilars should have a unique common name to distinguish themselves for prescribing, dispensing and pharmacovigilance purposes. In the interest of patient safety, it is critical that any adverse events be accurately traced to the actual product administered so that the manufacturer can take immediate remedial actions.

Patent Rights
Strong patent protection is the cornerstone of preserving incentive for biologics innovation, and a biosimilars approval pathway must establish a fair, transparent and effective system for all parties to quickly resolve any patent disputes.

Incentives for Innovation
Because biologics generally have substantial research, development and manufacturing periods and costs, a significant period of non-patent data exclusivity for innovator biologics must be provided to maintain an environment that fosters discovery of new and innovative biotechnology therapies. Although patent protection is important, this alone may be insufficient to protect the substantial investment made by innovators. For example, a biosimilar may be similar enough to an innovator biologic to receive regulatory approval, but different enough to circumvent the innovator’s patents. We support the provisions in PPACA that provides a base 12-year period of data exclusivity for innovator biologics plus an additional 6 months for pediatric studies.

Next Generation Improved Biologics
We support measures that protect investment in improvements to innovator biologics through extension of data exclusivity and intellectual property protections. This will help encourage continued investment and discovery of enhanced versions of previously-approved biologics that are safer, more effective, easier to administer and more capable of meeting patient needs. Modifications such as changes in amino acid sequences involve fundamental changes to a biologic’s molecular structure, and generally require clinical trials to gain regulatory approval. The vital, step-by-step process for advancing these medicines is dependent upon continued incentives for next generation biologics.

Conclusion
As new, innovative biologics and biosimilars enter the marketplace, AstraZeneca and MedImmune believe patient safety and product efficacy are of utmost importance. As a result, we support the development of a regulatory pathway for biosimilars that is based on patient safety, product efficacy and incentives for innovation. We will continue to monitor policy discussions and proposed regulations as the FDA moves forward in establishing a biosimilars pathway, and share our expertise and views where appropriate.

Download POSITION ON BIOSIMILARS (PDF, 34KB)

NIJMEGEN, The Netherlands, January 6, 2009 — MedImmune, the global biologics unit of AstraZeneca, announced today that it has submitted a Marketing Authorisation Application (MAA) for its nasal spray live attenuated influenza vaccine (LAIV), which is now being reviewed by the European Medicines Agency (EMEA). The proposed indication in the MAA is for prevention of seasonal influenza.

The MAA submission for LAIV is based on data from 73 global clinical and U.S. post-marketing studies of more than 141,000 subjects ranging in age from 7 weeks to 97 years and conducted in 38 countries. Study objectives have included clinical safety and tolerability, clinical efficacy and effectiveness, and immunogenicity.

Influenza creates a heavy medical and economic burden on Europe and throughout the world, and we are hopeful that the future availability and product characteristics of this novel nasal spray influenza vaccine will contribute to an increase in vaccination rates and reduce the spread of influenza around the world, said Alex Zukiwski, M.D., executive vice president, clinical affairs and chief medical officer. MedImmune is pleased to submit this application for approval of our nasal spray influenza vaccine in Europe.

About LAIV
Each dose of LAIV is formulated to contain three live attenuated influenza virus strains, which are weakened as to not cause illness: Two Type A influenza strains (A/H1N1 and A/H3N2) and one Type B strain. The vaccine strains are selected annually by the World Health Organization (WHO) based on anticipated circulating influenza strains for the upcoming season. The vaccine is sprayed into the nose, rather than by injection as with other licensed influenza vaccines, where it induces protective immunity.

In the U.S., LAIV is marketed under the trade name FluMist® (Influenza Virus Vaccine Live, Intranasal). It was approved by the U.S. Food and Drug Administration in 2003. The vaccine included in the MAA has not been registered in the European Union (EU) and is not available outside of the United States.

About Influenza
Influenza is the most common vaccine-preventable disease in the developed world. According to WHO estimates, seasonal influenza results in three to five million cases of severe illness and up to half a million deaths globally each year, primarily among the elderly. Rates of infection are highest among children, with school-aged children significantly contributing to spread of disease to their families, communities and high-risk individuals.

Influenza also has socioeconomic consequences related to both direct and indirect health care costs, including hospitalizations, work absence and loss of work productivity when either a caregiver or child is sick with influenza.

In the EU, current guidelines recommend annual influenza vaccination for the elderly as well as those with underlying medical conditions such as chronic heart or lung disease. However, vaccination rates in the recommended groups throughout Europe are estimated to be only 35 percent (Ryan, Vaccine, August 2006).

To date, six EU countries (Finland, Austria, Estonia, Latvia, Slovakia and Slovenia) recommend routinely vaccinating young children against influenza with varying age limits. EU and Member State policymakers continue to evaluate data on the impact of influenza in children to best inform the potential expansion of recommendations.

About MedImmune
MedImmune is a leading innovation-focused biotechnology company whose mission is to provide better medicines to patients, new medical options for physicians and rewarding careers to employees. Dedicated to advancing science and medicine to help people live better lives, the company is focused on infection, oncology, respiratory disease and inflammation, cardiovascular/gastrointestinal disease and neuroscience. Headquartered in Gaithersburg, Maryland, MedImmune has approximately 3,000 employees worldwide and is the wholly owned biologics business for AstraZeneca PLC (LSE: AZN.L, NYSE: AZN). For more information, visit MedImmune’s website at http://www.medimmune.com.

Contacts
Media:
Chris Sampson, +44 (0)207 304 5130 (AstraZeneca)
Sarah Lindgreen, +44 (0)207 304 5033 (AstraZeneca)
Karen Lancaster, +1-301-398-5864 (MedImmune)

“MedImmune is committed to conducting innovative infectious disease research to determine how best to prevent serious illness that can negatively impact pediatric health, especially during this time of year,” said Alexander A. Zukiwski, M.D., executive vice president and chief medical officer. “We believe the data being presented at this meeting will help lead to important new healthcare solutions, and our company is proud to advance our already robust research base to identify the best ways to help protect children.”

MedImmune abstracts to be presented at ICAAC/IDSA on RSV include:

• Respiratory Syncytial Virus Therapy Utilizing Intranasally Delivered Motavizumab, a Monoclonal Antibody Against the Viral Fusion Protein (#V-4145) B. Richter, Tuesday, October 28, 2008, Hall C from 12:15 PM to 1:15 PM

BACKGROUND: A primary cause of pneumonia and bronchiolitis in young children is RSV infection. This preclinical study examined the therapeutic effect of topically administered motavizumab.

• Therapeutic Addition of Motavizumab, a Monoclonal Antibody Against Respiratory Syncytial Virus, Modulates Epithelial Cell Responses to RSV Infection (#V-4146) S. Krishnan, Tuesday, October 28, 2008, Hall C from 12:15 PM to 1:15 PM

BACKGROUND: RSV infection of epithelial cells leads to inflammatory host responses. This preclinical study tested whether motavizumab, a humanized monoclonal antibody against the RSV fusion (F) protein, could modulate epithelial cell immune responses to RSV. Lower and upper airway epithelial cells were infected with RSV and motavizumab or a control antibody was subsequently administered at various points post-infection to evaluate the therapeutic addition.

• Total Healthcare Costs of Preterm Infants with Medically Attended Respiratory Syncytial Virus Lower Respiratory Infection (#K-1429 ) D. Stewart, Sunday, October 26, 2008, Hall C from 12:15 PM to 1:15 PM

BACKGROUND: While RSV lower respiratory infection (LRI) is the most common cause of hospitalization among infants under one year of age, the total healthcare costs of medically attended RSV LRI for babies of this age group is unknown. This retrospective, propensity-matched cohort assessment sought to determine first-year healthcare costs by examining premature infants born over a five-year period who were insured by a national U.S. health plan, including a subgroup analysis of babies born between 33 and 36 weeks gestation.

• In Vitro Mechanism of Action Studies of the RSV-Neutralizing Monoclonal Antibodies Palivizumab and Motavizumab (#V-4146) K. Huang, Tuesday, October 28, 2008, Hall C from 12:15 PM to 1:15 PM

BACKGROUND: Synagis is the only licensed drug product available to help prevent lower respiratory tract RSV infection in premature infants, a leading cause of hospitalizations in this patient population. An affinity-optimized version of Synagis, motavizumab, has been subsequently developed. Since both Synagis and motavizumab bind the RSV fusion (F) protein, which plays a role in virus attachment and mediates the process of virus-cell fusion and cell-to-cell fusion, this study aimed to determine exactly how the drugs neutralize RSV. Four assays were used, which target four distinct steps during virus replication, to identify the mechanism.

• In Vitro and In Vivo Characterization of a Motavizumab-Resistant RSV A Mutant (#V-4148) F. J. Palmer-Hill, Tuesday, October 28, 2008, Hall C from 12:15 PM to 1:15 PM

BACKGROUND: This study investigated the growth characteristics – both in vitro and in vivo – of an RSV mutant that was created in the laboratory and is resistant to neutralization by motavizumab, an affinity-optimized MAb directed against the RSV fusion (F) protein. The F protein of the MAb differs from a wild type RSV F protein, so comparisons were made.

• Characterization of Respiratory Syncytial Virus (RSV)Mutants Resistant to Antibody Neutralization with Novel Amino Acid Changes in the RSV Fusion Protein (#V-4149) N. K. Patel, Tuesday, October 28, 2008, Hall C from 12:15 PM to 1:15 PM

BACKGROUND: Synagis is a MAb approved for the prevention of serious lower respiratory tract RSV infection in premature infants. Motavizumab was developed by affinity optimization of Synagis and is characterized by greater in vitro and in vivo neutralization activity against RSV. Previously, the selection of RSV mutants resistant to Synagis has been reported, characterized by amino acid changes in the RSV fusion (F) protein. This study sought to identify the selection and characterization of additional Synagis MAb-resistant mutants, as well as a novel motavizumab MAb-resistant mutant.

MedImmune abstracts to be presented at ICAAC/IDSA on influenza include:

• Influenza-like Illness and Employee Productivity – Results from the Child and Household Influenza-illness and Employee Function (CHIEF) (#K-4207) M. D. Rousculp, Tuesday, October 28, Room 150B from 2:450 PM to 3:00 PM

BACKGROUND: This prospective cohort study of nearly 2,293 U.S. households evaluated the effect of employee and household member influenza-like illness on worker productivity. The households studied were employees from three large Fortune 500 companies. All households included in the study had at least one child. Households were surveyed monthly throughout the 2007-2008 influenza season to determine the impact of influenza-like illness on employees’ work absenteeism and decreased productivity while on the job.

• Impact of Early and Late Influenza Vaccine Availability on In-Office Vaccination Opportunities (#G1-1208) R. Judelsohn, Sunday October 26, Hall C from 11:15 AM to 12:15 PM

BACKGROUND: The CDC now recommends all children from six months to 18 years of age receive an annual influenza vaccination; however, a key barrier to implementation is the inconvenience to parents and providers around scheduling additional office visits to administer the vaccination. This study examined how many more vaccination opportunities exist if influenza vaccination availability were expanded beyond the typical October-to-December timeframe.

• Benefits Versus Risks of Live Attenuated Influenza Vaccine (LAIV) in Young Children (#G1-1204) G. Oster, Sunday October 26, Hall C from 11:15 AM to 12:15 PM

BACKGROUND: In September 2007, approved use of LAIV in the U.S. was expanded to include children aged 24-59 months but with warning/precautions against use in younger children and children 24-59 months with a history of recurrent wheezing or asthma. Since some latter children may receive LAIV in clinical practice, its risks and benefits versus trivalent influenza vaccine (TIV) in this setting must be considered.

Additional information about the 2008 ICAAC/IDSA conference can be found at http://www.icaacidsa2008.org/.

About Synagis
Synagis(R) (palivizumab) is indicated for the prevention of serious lung infections caused by respiratory syncytial virus (RSV) in children at high risk of RSV disease. Synagis is given as a shot, usually in the thigh muscle, each month during the RSV season. The first dose of Synagis should be given before RSV season begins. Children who develop an RSV infection while receiving Synagis should continue the monthly dosing schedule throughout the season. Synagis has been used in more than one million children in the U.S. since its introduction in 1998.

Synagis should not be used in patients with a history of severe prior reaction to Synagis or its components. Cases of severe allergic reactions such as anaphylaxis and other types of hypersensitivity reactions have been reported with Synagis. These reactions may occur when any dose of Synagis is given, not just the first one. Another serious side effect, which may lead to unusual bruising and/or groups of pinpoint red spots found on the skin, has been reported.

Most common side effects with Synagis may include upper respiratory tract infection, ear infection, fever, and runny nose. In children born with heart problems, Synagis was associated with reports of low blood oxygen levels and abnormal heart rhythms. Side effects, such as, skin reactions around the area where the shot was given (like redness, swelling, warmth, or discomfort) have also been reported.

Please see accompanying full prescribing information at http://www.synagis.com.

About FluMist
FluMist(R) (Influenza Virus Vaccine Live, Intranasal) is a live attenuated influenza virus vaccine indicated for active immunization of individuals two to 49 years of age against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine.

FluMist is contraindicated in individuals with history of hypersensitivity to eggs, egg proteins, gentamicin, gelatin or arginine or with life- threatening reactions to previous influenza vaccinations, and in children and adolescents receiving concomitant aspirin or aspirin-containing therapy.

Do not administer FluMist to children less than two years of age due to an increased risk of hospitalization and wheezing that was observed in clinical trials. FluMist should not be administered to any individual with asthma and to children less than five years of age with recurrent wheezing unless the potential benefit outweighs the potential risk. Do not administer FluMist to individuals with severe asthma or active wheezing.

If Guillain-Barre syndrome has occurred with prior influenza vaccination or if an individual is immunocompromised, the decision to give FluMist should be based on careful consideration of the potential benefits and risks. FluMist should not be administered to individuals with underlying medical conditions predisposing them to wild-type influenza infection complications unless the potential benefit outweighs the potential risk. FluMist should be given to a pregnant woman only if clearly needed.

Most common adverse reactions (occurring in 10 percent or more of individuals receiving FluMist and at a rate at least five percent higher than in those receiving placebo) are runny nose or nasal congestion in recipients of all ages, fever more than 100 degrees F in children two to six years of age, and sore throat in adults.

FluMist may not protect all individuals receiving the vaccine. FluMist is for intranasal administration only.

Please see complete Prescribing Information for FluMist, call 1-877-FLUMIST (1-877-358-6478) or visit http://www.flumist.com/prescribing-information.aspx for additional information.

About MedImmune
MedImmune is a leading innovation-focused biotechnology company whose mission is to provide better medicines to patients, new medical options for physicians and rewarding careers to employees. Dedicated to advancing science and medicine to help people live better lives, the company is focused on infection, oncology, respiratory disease and inflammation, cardiovascular/ gastrointestinal disease and neuroscience. Headquartered in Gaithersburg, Maryland, MedImmune has approximately 3,000 employees worldwide and is the wholly owned biologics business for AstraZeneca plc (LSE: AZN.L, NYSE: AZN). For more information, visit MedImmune’s website at http://www.medimmune.com.

Contacts:
Media: Tor Constantino, 301-398-5801
Investors: Peter Vozzo, 301-398-4358
http://www.medimmune.com