Biomarin (BMRN) is developing PEG-PAL, a follow up to Kuvan, for the treatment of phenylketonuria (PKU). Because it would take too long to go over Kuvan and PKU in detail, we’ll just focus on PEG-PAL for now (see the end of the post for a bit on Kuvan and PKU stratification).

Overview

PEG-PAL is BMRN’s follow up drug for treating PKU. PEG-PAL is a pegylated (PEG) bacterial enzyme called phenylalanine ammonia lyase (PAL). The enzyme is a replacement therapy and is designed to lower elevated phenylalanine (Phe) blood levels to normal levels, something that Kuvan can not do (see end of post). PAL is found in numerous bacterial species, but not in humans. Humans produce a different enzyme called phenylalanine hydroxylase (PAH) and together with cofactor BH4 (which is what Kuvan is), breaks down phenylalanine and keeps blood levels normal.

It’s not practical to simply replace PAH in PKU patients for a few reasons:

1. PAH can only work inside of cells — giving PAH makes it impractical to reduce blood Phe levels;

2. PAH has been shown to have a very short half-life;

To avoid these issues, BMRN, after screening close to 100 bacterial species, chose a mutant version of PAL found in Anabaena variabilis. The bacteria’s version of PAL uptakes Phe and breaks it down into trans-cinnamic acid which is suitable for excretion. BMRN then pegylated the mutant PAL to increase the half life (about 1-4 days in rats, mice and non-human primates) and to mask any potential immunogenicity by the mutant enzyme.

PEG-PAL in Animals

The enzyme has already demonstrated good efficacy in mice with PKU. In a PKU mouse model, mice received weekly PEG-PAL injections x 2 months. Phe levels were measured at Day 3 and Day 7 after each injection. Mice then went 2 months without injections to allow Phe to return to elevated levels and determine sustainability of Phe suppression. After the 2 month enzyme vacation, mice were re-treated for 2 months according to the same schedule. During each of the 2 month treatment periods, Phe levels decreased from 1250 umol/L to less than 250 umol/L after the first week of treatment with a sustainment over the treatment period.

An IND was filed in November 2007 and a Phase 1 study was initiated in May 2008.

Phase 1 Study and Next Steps

Today, BMRN announced it has completed dosing the fifth cohort of patients in its Phase I trial. The study was initially designed to assess safety in seven (7) different dose cohorts with five (5) PKU patients per cohort. The doses were to range from 0.001 mg/kg to 1 mg/kg, however last summer, BMRN announced they had already seen Phe reductions in the lowest cohort and that they would taper off the dose escalation at the fifth cohort (the announcement today).

The patients from the Phase 1 will be allowed to roll over into a Phase 2 study, the design of which should be weekly injections for 8-10 weeks. The study should be initiated by the end of 2Q09 with results mid 2010. The final design is pending.

Risks & Assessments

The biggest risk here is safety and immunogenicity, followed by patient tolerability. The introduction of a foreign, bacterial enzyme into patients poses the potential risk of antibody development. BMRN did not report any issues from its preclinical data, which makes the upcoming Phase 1 data in 2Q pivotal for PEG-PAL’s survival and further advancement. Any type of allergic reactions, local or systemic, will put a damper on things, especially if any side effects are detrimental to the product’s Phe-reducing capabilities.

Regarding adverse reactions, Brian Abrahams from Oppenheimer pushed a bit deeper into the potential reactions on yesterday’s earnings call. Steve Aselage from BMRN commented:

“We have not observed serious adverse reactions in patients who have been treated with PEG-PAL. The events that we have seen are the event that we would be expected to be seen with a product of protein nature, we have not reported any alarming or severe serious adverse reactions to the FDA.”

The overall assessment, not withstanding safety concerns, is that PEG-PAL has the potential to be a disease modifying therapy, able to help PKU patients whose Phe levels are not currently controlled with Kuvan. PEG-PAL has already shown it can reduce >2500 umol/L levels of Phe down to almost undetectable in PKU mice. Kuvan on the other hand can only partially assist with decreasing Phe levels in PKU patients on diet therapy.

Market and Kuvan

Kuvan is BMRN’s oral BH4 (tetrahydrobiopterin) cofactor, 6R-BH4. Though Kuvan has revolutionized the management of PKU patients, it does not work across all patient types. Kuvan only works in patients that are responsive to BH4 and is really only used as add on to diet therapy. Based on the BMRN trials, it can be said that Kuvan works in about 1/3 of patients.

In patients with Classic PKU where Phe levels are greater than 1200 umol/L, Kuvan has only been able to show a 10-15% response rate. Mice dosed with PEG-PAL had Phe levels twice this and the enzyme was able to bring down levels to less than 250 umol/L (normal is 120-360 umol/L).

Kuvan has also only demonstrated about a 50% response rate in Mild PKU where patients must still be on a Phe-restricted diet. Kuvan’s optimal place is in very mild PKU where Phe levels are 180-600, or thereabouts. Even here, Kuvan is still used with diet therapy.

The potential therefore for PEG-PAL is huge as it can offer an across-the-board treatment and liberate patients from Phe-restricted diets.

The downside is that it will be a weekly injection, and more costly.

Kuvan is slated to bring in about $180-200M in 2009 and analysts have estimates of peak sales of about $250-300M+ by 2012-13. Assuming PEG-PAL is priced at about $70-90,000 per year per patient, we can estimate about a $500M product at peak sales (assumption of 6000 patients on therapy, or 1/2 PKU population).

Partnerships and Timelines

Partnered with Merck-Serono ex-U.S. for Kuvan and PEG-PAL. PEG-PAL milestones are $187M

• 2Q09: Results from PEG-PAL Phase I trial

• 2Q09: Initiation of PEG-PAL Phase II trial

• Mid-2010: Results from PEG-PAL Phase II trial

• 2H10: Availability of blood Phe monitor

Stay tuned for more PEG-PAL and BMRN updates…

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