EP Vantage Interview - Shire hopes deal points to future of haemophilia care

In earlier this month committing a modest $13m upfront for a number of experimental gene therapy programmes addressing haemophilia A and B from Sangamo BioSciences, UK company Shire is taking what appears to be an interesting and relatively low risk gamble in a field that is crying out for new treatments.

Speaking to EP Vantage, Theresa Heggie, senior vice president of Shire’s Human Genetics Therapy (HGT), says that while looking at treating haemophilia through gene therapy may look like a retrograde step harking back to studies conducted in the 90s, Sangamo’s zinc finger DNA-binding protein (ZFP) technology could represent a new treatment paradigm.

“This is a great possibility to have an opportunity to cure a disease or have a very long lasting treatment,” she says, cautioning that the products have yet to enter the lab.

Shire’s deal with Sangamo will see it receive exclusive worldwide rights to ZFP therapies targeting four genes for blood clotting factors VII, VIII, IX and X. Shire also has the right to develop three other gene targets as part of the collaboration.

However, Sangamo, will remain responsible for all clinical work through to the filing of an IND in the US and a clinical trial application in Europe. Shire in return will reimburse Sangamo for all of its research costs and pay milestones of up to $205 for each successful target.

The bad old days

Previous research using gene therapy was mainly about adding genes, effectively uncoupling the gene from its normal regulatory mechanism, resulting in gene silencing. The technique, which was imprecise, also had the potential to cause cancer or other unwanted side effects through the addition of extra genes.

In contrast Sangamo’s platform technology relies on gene editing and uses its proprietary ZFP nuclease (ZFN) and ZFP transcription factor technology, which can be engineered to recognise specific DNA sequences within a gene.
In tackling haemophilia Sangamo is using the ZFN technique, where by ZFNs pairs bind to a specific DNA sequence causing a double strand break in the DNA. Breaking DNA can trigger a natural process of DNA repair to the cell. Harnessing this repair process can help to achieve a number of clinical outcomes.

Most recent haemophilia research has focused on trying to find long-acting agents to cut down on the number of transfusions patients need. Currently, Biogen Idec and Swedish Orphan Biovitrum are leading the race in this field with their rFVIIIF (Therapeutic focus - Long acting haemophilia agents set to shake things up, July 26, 2011).

But the real breakthrough will be for the company or institute that manages to find and bring to the market a disease modifying treatment, something that Ms Heggie admits will be hard ask. “We have never shied away from challenging or difficult areas, and if there is an important unmet patient need we will go into areas that help meet that patient need.”

Alongside the admirable sentiments the focus on haemophilia also fits into the group’s strategic focus on orphan and hard-to-treat disorders that offer better patent protection, are often given accelerated approval and require small sales forces.

This is something that Ms Heggie acknowledges. “Our grading model includes having relatively small sales organisations and medical organisations that really have a high connection with patient organisations and highly concentrated prescribers,” she says.

Promising results

While talking about sales forces and targeting prescribers is a long way off, Sangamo’s technology has shown interesting results in animal models. In December, the group presented new data showing systemic delivery of ZFNs in adult mice caused them to produce stable and factor IX, as well as appearing to show the treatment had permanently corrected the diseased gene. Although this is a breakthrough, it is hard to know if the effect will successfully translate into humans. It should also be remembered that while the deal with Shire does provide confidence in the core technology, Sangamo has in the past had its failures.

In October, the group reported that SB-509 had not succeeded in its phase IIb trial in diabetic neuropathy. This cast a long shadow over the Sangamo’s technology, which this deal should have helped to shorten.

But there is a long way to go before Shire and Sangamo could see their first haemophilia treatment. However, given the relatively small amounts committed so far by Shire if the programme does fail it will have little material impact.

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