The Long Road to Developing a PKU Therapeutic

by Dr. Ray Stevens, Scripps Research Institute, La Jolla, CA

From the Spring/Summer 2007 issue of National PKU News.

As a researcher in the field of PKU and a recipient of funding from the PKU community, I am often asked about the status, timeline, and cost of various PKU research projects. Many of these questions are challenging to answer given the complexities of basic science and drug discovery. But I believe this newsletter is the right forum for educating the PKU community about the drug development process.

Drug Costs/Timelines

Reports on the average cost to develop new drugs vary widely, but some reports indicate that it is between $400 and $800 million. This large amount includes costs incurred because of the rate of failure. It also reflects the high-risk nature of drug development. The numbers also are biased by the expensive development costs at big pharmaceutical firms that are pursuing studies on small molecule (oral) drugs that have very large markets.

More pertinent to PKU are the small biotech companies focused on smaller business markets and protein therapeutics. The costs can be less than noted above, but are still significant.
If one tries to factor in all of the failures along the way and only consider drug development and clinical trials, the cost range is still substantial, from $20 million to more than $100 million.

The time frame is just as broad and can range from 7 years to more than 12 years from start of development to the market, and is largely dependent on the therapeutic area (for example, anti-infectives, cancer, neurological). Whether a big pharmaceutical company or a smaller biotechnology company, the steps the company goes through to create a new drug are the same. They include: gaining understanding of the disease or disorder, evaluating hundreds to thousands of compounds, optimizing potential therapeutic molecules, test tube studies prior to preclinical studies, preclinical studies where animal models are used prior to testing in humans, and then the three (possibly four) phases of FDA-monitored human clinical trials where safety, effectiveness, regimen protocols (i.e., dosage and frequency of treatment), and long term use must be evaluated. Thus it is not surprising that it takes so long and costs so much to develop a new therapeutic.

Cofactor BH4 Drug Discovery

From 1999-2002 there was a great deal of PKU research done by the laboratories of Kure (Japan), Blau (Switzerland), and others on using BH4 (a cofactor for the enzyme deficient in PKU) to help patients with PKU. Because BH4 had previously been used in Japan (for another disorder) and in smaller trials elsewhere, there was a better understanding of the safety and effectiveness of the molecule. However, cost was still a major factor for BH4; a new manufacturing process had to be developed to lower cost of production. Also, further laboratory studies needed to be completed to improve our understanding of the effects of BH4 on PKU.

Importantly, the FDA requires completion of a vigorous series of clinical trials before a drug can be approved for general use. Listed in the table above is a timeline for BH4 (in the form of KuvanTM, or sapropterin dihydrochloride, previously referred to as Phenoptin) clinical development program by BioMarin Pharma-ceutical Inc. You will note the speed of clinical trials relative to what generally happens in drug development, as discussed in the previous section, without any decrease in the safety analysis (which the FDA will not tolerate).

Enzyme Substitution Drug Discovery

In addition to the basic science research that the Steven’s laboratory has been conducting over the past several years to understand who is responsive to BH4 treatment and who is not, our laboratory also has been heavily focused on the development of an enzyme substitution therapeutic for patients with PKU who do not respond to therapy with BH4.
This work has been done in close collaboration with the Scriver laboratory at McGill University and BioMarin Pharmaceutical Inc.

In fall 2006, our research in the Steven’s laboratory took a new direction. Our collaborative basic science research on evaluating the potential for a once- or twice-a-week injectable enzyme therapeutic advanced to the stage that the program is now moving along into preclinical studies at BioMarin.

We also obtained a $2 million dollar grant from the U.S. National Institutes of Health (NIH), as a three-year research grant, to try to convert the injectable therapeutic into an orally available therapeutic. Because of reductions in the NIH budget, we were only awarded 85% of the amount needed to conduct the proposed research. Fortunately, we received an award from the Mid-Atlantic Connection for PKU and Allied Disorders (MACPAD) to cover the 15% shortfall in the NIH award for the first year of funding. We will be requesting a similar amount from the PKU community again this year to compensate for the continued reduction in funding during the second year of the grant.

We believe the potential conversion of an injectable therapeutic to an orally available therapeutic will be beneficial for those individuals with PKU who cannot benefit from BH4 therapy. Not only will this research help individuals with PKU, but it is possible that the methods we are developing to create the oral therapeutic also can be applied to other metabolic disorders currently treated with injectable therapeutics.

However, a number of research hurdles must be overcome (for example, digestive tract degradation of the enzyme therapeutic) before we will know if an orally available classical PKU therapeutic will work. As discussed in previous PKU newsletters, a number of other efforts to develop PKU therapeutics also are ongoing and they will require the same process for approval. Researchers such as Dr. Reuben Matalon, Dr. Joachim Pietz, and Dr. Richard Koch are pursuing research in the large neutral amino acids area (LNAA or NeopheTM) and preliminary results are supportive of additional research. The area of gene therapy for classical PKU also continues; the potential here is enormous and research must continue in this area. However, this is a very long-term effort where a tremendous amount of research by investigators such as Dr. Cary Harding, Dr. Beat Thoney, and Dr. Savio Woo must be completed before the methods are proven to be safe, efficient, and effective.

Summary

Over the past few years, we have made tremendous strides towards development of new PKU treatments. This work will continue at a very aggressive rate, but many years are still in front of us before the goals are completed. The decade 2000 could be termed the “Decade for PKU Discovery and Development.” This has probably been one of the most efficient drug discovery development periods ever observed.

As to a timeline, it is very hard to say due to the tremendous hurdles we must overcome before a molecule has been evaluated and deemed safe and effective. My best answer is that several groups are working their hardest and that in the next 5 to 10 years, I am confident that there will be additional developments in both basic and applied PKU science. Of critical importance has been the partnership between fundraising, patient volunteers, PKU communities, and researchers.

Development Timeline for BioMarin’s KuvanTM

(Kuvan = sapropterin dihydrochloride, a form of BH4)

1999-present Multiple researchers in Japan, Europe, and the U.S. report on the affects to treat PKU with BH4

November 20, 2003 Announces plans to begin clinical trials

February 23, 2004 Initiates clinical program in PKU

July 20, 2004 Reports positive results from a pilot clinical study of BH4 in PKU

August 24, 2004 Files Investigational New Drug Application with FDA for sapropterin dihydrochloride, a form of BH4

December 23, 2004 Initiates Phase 2 clinical trials

April 7, 2005 Initiates Phase 3, double blind, placebo-controlled, multi-center study

January 25, 2006 Receives approval for FDA Fast Track

March 15, 2006 Announces Phase 3 positive efficacy and safety results

January 16, 2007 Announces Phase 3 extension-positive results and efficacy in increasing phenylalanine tolerance

 

Last update: February 2008
National PKU News: www.pkunews.org
E-mail: schuett@pkunews.org