Operating ReviewHuman Genetic Therapies

Human Genetics Therapies (Shire HGT)

Shire's new HGT team, the former TKT, specializes in discovering, developing and commercializing protein therapeutics primarily for the treatment of genetic diseases. This business extends Shire's reach by strengthening its portfolio and pipeline with a range of new therapeutic possibilities for patients suffering with genetic diseases.

'By adding the proprietary protein technologies of TKT to the proven commercialization knowhow of Shire, we've generated an entity worth far more than the sum of its parts,' says David Pendergast, Shire HGT's Executive Vice President and General Manager. 'Together, we've signalled our intention to continue growing as market leaders in serving specialist physicians and their patients.'

TKT, acquired in 2005, is an excellent strategic fit for Shire, adds Dr Pendergast, former executive vice president and chief operating officer of TKT who has 33 years of pharmaceutical industry experience. 'Both Shire and TKT leverage relationships with highly specialized physicians and focus on the development of products that offer a strong benefit-to-risk ratio. Both also care enormously for the patients and families that are ultimately served by our product lines.'

Shire HGT provides specific disease area expertise, a high-quality product portfolio and a low-risk, well-balanced development pipeline with one marketed product and two attractive late-stage products directed at genetic diseases. In addition, protein replacement therapy provides a good platform for further expansion through research and product in-licensing. Shire HGT's approach to product development is to use protein therapies to replace lost biological function resulting from a malfunctioning or missing gene in affected patients. It does not conduct high-risk discovery research and protein replacement therapies generally benefit from fast development timelines. These drugs have a high success rate in reaching the market and normally benefit from long lifecycles once marketed due to orphan drug status exclusivity (seven years in the US and ten years in the EU) and robust patent protection.

back to topback to top

High-potential market

Dr Pendergast notes that the evolution of the biotechnology sciences has allowed for the engineering of proteins and producing them in large quantities. Combined with the discovery of inherent and engineered means of delivering proteins to cells throughout the body, this provides great potential to address a number of serious diseases previously not approachable with drug therapies. 'The number of these diseases is large since there is the potential for a single gene mutation to occur with any birth and we have had centuries of evolution for these problems to develop.' At this time protein replacement therapy is often the only treatment for these patients.

Shire HGT employs slightly more than 500 individuals worldwide and has a presence in those countries which reimburse protein therapies for genetic diseases and where patient populations warrant a presence. Based in Cambridge, Massachusetts the team is at work on a number of exciting scientific and medical fronts.

'We use several technologies including gene activation, fusion proteins, and standard transfections,' explains Dr Pendergast. 'Our approach for glycoproteins is to use human cells either employing gene activation or standard methods. This approach yields a truly human molecule in both the amino acid sequence and the carbohydrate structure thereby making the therapy highly active and less immunogenic.

Dr Pendergast notes that genetic disease research is less risky than traditional pharmaceutical research. 'The diseases and their causes are well known, the treatment path clear, and if we get good animal model data, the likelihood of a late stage project failure is low.'

Shire HGT works on genetic diseases with serious mortality and morbidity effects on patients that are amenable to protein replacement therapy. One large category is Lysosomal Storage Diseases (LSDs) resulting from the body's inability to produce a specific enzyme designed to metabolize different waste products. These products build up in the lysosomes of cells over time resulting in the engorgement of cell lysosomes, cell stress and death followed by tissue distress and organ failure. LSDs can interfere with the central nervous system in ways that can often have a distressing physical effect. Often named for the physician that first described them clinically, these conditions are today known as Fabry Disease, Hunter Syndrome, and Gaucher Disease, among others. Shire HGT also has early research programs in a number of non-LSD genetic diseases.

back to topback to top

A strong pipeline

Shire HGT has one approved product and two late-stage clinical development candidates with rapid development time lines:

  • REPLAGAL: an enzyme replacement therapy currently approved and marketed to treat patients with Fabry Disease LSD that affects 8-10,000 patients in countries likely to reimburse for the treatment. Symptoms usually begin during childhood or adolescence and include burning sensations in the hands that get worse with exercise and hot weather and small, raised reddish-purple blemishes on the skin. Lipid storage may lead to impaired arterial circulation and increased risk of heart attack or stroke. The heart may also become enlarged and the kidneys often become progressively involved resulting in ESRD. REPLAGAL is approved in 34 countries outside of the US where ease of administration (one fifth the volume infusion of the competing product) and a broader label have helped to establish REPLAGAL's competitive position. It is estimated the current market is $190 million in Western Europe;
  • ELAPRASE: An enzyme replacement therapy in registration since December 2005 for the treatment of Hunter Syndrome. The product has gained fast track status in the US and Shire hopes it will be launched in mid-2006. Shire also submitted a MAA to the EMEA for idursulfase and the subsequent review is expected to take 12 months. Hunter Syndrome, also known as Mucupolysaccharidosis II (MPS II) is a rare, life threatening genetic disorder caused by a lack of the enzyme iduronate- 2-sulfatase. Symptoms include hernias, frequent ear infections, enlarged livers and spleens, reduced respiratory capability, joint malformations, short stature and cardiac problems. A number of patients will also suffer significant CNS damage. The market is estimated at $300 million worldwide; and
  • GA-GCB: A gene activated glucocerebrosidase which recently completed Phase 2 studies for the treatment of Gaucher Disease, a genetic disorder caused by deficiency of the enzyme. This deficiency causes a fatty substance to accumulate in certain body tissues such as the spleen, liver, and bone marrow. An individual affected by Gaucher Disease might exhibit one or several of these symptoms: enlarged liver and/or spleen, anemia, fatigue, easy bruising, impaired blood clotting, bone pain, and fractures. The total worldwide estimated market is more than $840 million.

Shire HGT's key products - REPLAGAL, ELAPRASE and GA-GCB - are manufactured through a proprietary process derived from human cell lines, an advanced technology compared to conventional method of using Chinese hamster ovary lines. Currently relying on a combination of internal manufacturing and external manufacturing/filling partners to produce its products, the unit is in the early stages of planning for expanded manufacturing capability.

back to topback to top

A focused team

Since the acquisition of TKT by Shire Dr Pendergast has overseen a complex transition and built a business and management team that is focused on protein therapies for genetic diseases and is organized around four critical business processes: discovery, development, supply and sales. 'We are well positioned for success because we have a culture that is very committed, focused, team oriented, open, science based and data driven.' His favorite parts of the job are developing therapies that help patients and working with bright people to solve problems. 'Our team has a broad range of experiences and expertise from very large pharma to folks that started with TKT over 15 years ago. They all have proven track records and the team works well together. We have good technologies and a clear mission.'

Dr Pendergast says that Shire will help Shire HGT make the most out of its science and technology allowing an increase in the number of projects it can now undertake and allowing all of the fruits of that research to be marketed internally. 'Shire's corporate infrastructure, financial support, business development expertise and ability to market products targeted at larger patient populations will ensure that Shire HGT's innovative protein platform reaches the greatest number of patients in the least amount of time and make a real difference in people's lives.'

back to topback to top

Human Genetic Therapies
Human Genetic Therapies
Human Genetic Therapies

'We have unparalleled technology to develop treatment for genetic diseases and I am very proud to be part of the team that is making these therapies possible!'

David Whiteman
Principal Medical Director, Shire HGT

'I'm very excited about our ability to 'truly' make a difference in patients' lives.'

Andrew Komjathy
Vice President, Commercial Operations

'Breakthrough products and exceptional staff make Shire a great place to work!'

Jerry Justin
Senior Director Manufacturing Operations, Shire HGT

Human Genetic Therapies

'We are committed to accelerating the development of protein therapeutics for genetic disorders.'

Yas Saotome