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Perspective interview - Nicola Longo (PEG-PAL)

Perspective interview - Nicola Longo (PEG-PAL)

2014 PKU Perspectives Nicola Longo

Prof Nicola Longo discusses the potential of PEG-PAL therapy

Work to evaluate clinically the use of pegylated recombinant phenylalanine ammonia lyase (PEG-PAL) as a potential therapy for PKU is ongoing, and Prof Longo provided an update on the Phase III clinical study, looking at this novel enzyme substitution therapy. He was speaking at the 2014 Annual Multidisciplinary European PKU Symposium.

Prof Longo1 is both a physician and a research scientist. He sees patients with various metabolic disorders, including PKU from the State of Utah but also the neighboring states of Idaho, Wyoming and Nevada. He leads the Division of Medical Genetics at the University of Utah in Salt Lake City (USA). Over recent years, his work to develop PEG-PAL as a therapy for PKU has attracted interest from around the world.

What is PEG-PAL

We asked what makes PEG-PAL different from sapropterin, the only drug so far to be licensed for use with PKU patients

'Sapropterin is a very nice therapy because in those patients who are responsive, their high blood-Phe levels are reduced to more acceptable levels,' the professor said. 'However, not all patients are responsive, as this is dependent on their phenylalanine hydroxylase (PAH) genotype.

'Also, even with responsive patients, the levels do not reduce to the level we would consider normal in a person without PKU. Enzyme substitution therapies such as PEG-PAL are promising because they are not dependent on a specific genotype and this greatly widens the number of people who may be amenable to the therapy. The second difference is that sapropterin is an oral medication and PEG-PAL is an injectable one. Obviously it is usually easier to take an oral medication.

'A third difference is that a PKU patient taking sapropterin will synthesize Tyr from Phe, as a product of the transformation of Phe. With PEG-PAL there is no generation of Tyr so we might need to supplement Tyr for patients treated with the enzyme.'

To substitute or to replace

This raises the question, why substitute? Why not synthesize PAH? ‘In theory we could just give PAH back to patients, Prof Longo explained. ‘We don’t do this because it is a formidable task to synthesize PAH and to make it active. Bacteria make enzymes by different mechanisms to humans and we really don’t understand how to achieve the necessary supramolecular structure or how to involve the cofactor which stabilizes the enzyme.

Does the use of a non-human enzyme pose an increased risk of triggering an immune response, we wondered.

Prof Longo explained: ‘Because PEG-PAL is an enzyme derived from bacteria we have to expect a degree of immune response, but there are similar enzymes in humans like histidine ammonia lyase (HAL) which have some degree of homology. The principle of using foreign proteins to reduce the level of some chemical in the body has also been proven previously. Pegloticase for example, licensed for the treatment of gout is a pegylated bacterial enzyme. While every patient with PKU will respond to PEG-PAL we still do not know the degree to which the immune response of a patient taking the therapy will be an issue

'How tolerable will it be to patients? How will the patient’s immune response limit the action of the enzyme? We hope, through the Phase III study to learn how patients adapt to the administration of the foreign protein over time. We know from other cases that the human body can develop tolerance to the administration of foreign proteins over time but we don’t yet know whether this will be the case with PEG-PAL. We might find that we have to match PEG-PAL to patients according to their immune reaction, just as we have to match sapropterin to the patient’s PAH genotype.'

Genotype or immunotype

If PEG-PAL is effective will this mean we no longer need to take the patient’s PAH genotype into account, we asked.

'Actually, the severity of the PAH deficiency may well have an effect on how PEG-PAL is administered.' Prof Longo explained. 'I think a combination of this, along with the nature of the patient’s immune response to the enzyme, will determine how often they need to inject, once a day or perhaps once a week, and how they will respond. The Phase III study should allow us to understand this better. Because the study only started recently we have nothing to report at present other than to say that enrolment has been outstanding and we don’t see this presenting an obstacle to completing the study.'

Assessing the unassessable

PEG-PAL is currently being investigated for safety and efficacy with regard to controlling blood-Phe levels. But, how important is it going to be to the lives of patients? The extent of the effect of reduced blood-Phe on the executive function of adult patients is much harder to quantify and the value of aggressively controlling blood-Phe levels in adults is still debated.

'I think that overall there is an agreement that early in life, low-levels are recommended,' Prof Longo said. ‘But, there is more disagreement over what to do with older patients with PKU and yes, a lot of the disagreement comes from the fact that we haven’t had a system so far to determine what happens in adult patients when their blood-Phe levels are lowered. I think this is an area where PEG-PAL may help because it could decrease Phe level in patients with PKU who are not compliant with the diet.

Professor Longo pointed out that: ‘If we can demonstrate an effect of lowering the Phe level on executive function or on other adult intellectual functioning in such patients then we would have data to show that even in adults a reduction in Phe level is beneficial.

'We will need to develop better tests of executive function that are less affected by confounding factors, like inattention, stress and mood. The tests will also need to be simple to use and not inconvenient for the patients or the physicians so that they can be repeated often. This is a challenge but something that we must continue to work on with our psychologist colleagues.'

Beyond PEG-PAL

Despite the promise of PEG-PAL, and his hopes that it will prove to be a useful therapy for PKU patients Prof Longo looks forward to a future where it isn’t necessary at all. 'The disadvantage of the available interventions and most of those under development, including PEG-PAL, is that they are just therapies. They need to be continued for the whole of the patient’s lifetime.

'The ideal situation would be to develop a cure for the disease.  What do I mean, a cure? An enzyme is missing in the liver: let us try to find a way to place the enzyme back in the liver. People have attempted gene therapy for this condition; in animal models it works very well but it is not yet ready for humans. For the future, I hope that we will be able to do gene correction in the liver of patients with PKU, so once the correction is done the patient will not need diet and will be able to just have a normal diet, a normal life, like everybody else.'


1 - Prof Nicola Longo (Division of Medical Genetics, University of Utah, Salt Lake City, Utah, USA)