Following is background information and a Q & A released by the Pharming/Genzyme LLC on important issues concerning clinical trials for enzyme replacement therapy now underway in the Netherlands on acid maltase deficiency, Pompe’s disease.

Background—Pompe Disease

Pompe disease is one of a family of 40 rare diseases known as lysosomal storage disorders. Pompe disease, also known as acid maltase deficiency or glycogen storage disease type II, is caused by complete or partial deficiency of the enzyme alpha -glucosidase and affects an estimated 5,000-1 0,000 people in the Western world. Another well-known example of a lysosomal storage disorder is Gaucher disease, which is caused by deficiency of the enzyme glucocerebrosidase. For Gaucher disease, there is an existing enzyme replacement therapy, in fact the first such therapy for a lysosomal storage disorder.

Clinical forms of Pompe disease vary according to the age of onset and progression of symptoms. The infantile form appears in the first few months after birth and is characterized by a rapid build-up of glycogen in several tissues, severe muscle weakness, and enlargement of the heart and liver. Respiratory and heart complications often lead to an early death in the first or second year of life.

‘The juvenile form usually begins in early childhood and develops more slowly. It is characterized by progressive muscle weakness, with the respiratory muscles being most critically affected. Patients with this form of the disease usually succumb to respiratory failure before the age of 30.

In the adult form of the disease, symptoms may go undetected until the third to fifth decade of life. Glycogen build-up occurs mainly in skeletal muscle, leading to muscular weakness, particularly in the diaphragm, limb girdle and the trunk. Respiratory complications are the main cause of death.

Alpha-glucosidase production

Pharming has pioneered the production of recombinant human proteins isolated from the milk of transgenic animals. This technology allows for efficient production of complex proteins which may be difficult to produce (technically or economically) by other methods. In the particular case of Pompe disease, Pharming has succeeded in producing the enzyme human alpha-glucosidase at high levels in the milk of transgenic rabbits.

The production of human alpha-glucosidase currently takes place at Pharming’s small scale pilot plant in Geel, Belgium. The pilot plant is capable of producing sufficient alpha-glucosidase for clinical trials. In addition, Pharming is constructing a commercial scale plant for commercial production of the enzyme after product approval. The plant’s completion is expected in the year 2000.

In October 1998, a joint venture was established between Pharming Group, N.V. of the Netherlands and Genzyme Corporation, of Cambridge, Massachusetts for the worldwide development and commercialization of human alpha-glucosidase (the joint venture).

The first steps of human alpha-glucosidase development

The safety and efficacy studies for alpha-glucosidase in animals were concluded with positive results. The study showed that regular intravenous injection of the recombinant human alpha-glucosidase appeared to correct the enzyme deficiency and significantly improve tissue morphology with generally few side effects.

Pharming then proceeded to take human alpha-glucosidase into Phase I clinical trials to test the safety and tolerance of the enzyme in human subjects. Participants in this trial were healthy (adult) volunteers. The study was concluded in the summer of 1998 with encouraging results: human alpha-glucosidase was generally safe and well-tolerated.

It is important to note that these are preliminary results. More studies in patients are needed to confirm these findings before an application seeking marketing approval can be submitted to the Regulatory Authorities.

Human alpha-glucosidase in Phase II clinical trials and beyond

As a first step to test recombinant human alpha-glucosidase in Pompe disease patients, a pilot trial will be carried out at Sophia Children’s Hospital in Rotterdam, under the direction of Pharming/Genzyme LLC. The aim of the study is to assess for the first time the safety and early indications of efficacy of the enzyme in patients. It will be a pilot trial with a limited number of infantile (approximately four) and juvenile patients (approximately three). Dr. Ans van der Ploeg at the Sophia Children’s Hospital in Rotterdam is the principal investigator of the current pilot trial.

Data obtained while the pilot study is in progress will be used to design two larger Phase II/III pivotal trials in the US and Europe. Detailed design of these trials can only be done when data from the pilot trial are available. The goal is to have these studies underway in mid1999.

A relatively limited number of patients will be enrolled in the combined trials which is in line with the limited number of Pompe disease patients overall. It is also due to the fact that Pharming’s pilot plant is not equipped to supply more human alpha-glucosidase than the scheduled trials demand, However, as a testimony of the Pharming/Genzyme LLC’s conviction to the success of these trials, the company is currently constructing a commercial scale plant. Therefore, larger amounts will become available, as market demand increases.

Questions and Answers

1. Have the clinical trials started?

Approval for a small pilot study on 4 infants and 3 juvenile patients was recently received in the Netherlands. The study has begun (January 1999) at the Sophia Children’s Hospital in Rotterdam and inclusion of patients has started. Dr. Ans van der Ploeg is the principal investigator. This study is designed to assess safety and give indications of efficacy of recombinant human alpha-glucosidase in this population.

If successful, data obtained while the pilot trial is in progress will be used to design two larger Phase II/III trials in the US and Europe. Detailed design of these trials can only be done when data from the pilot trial are available. Our goal is to initiate the first of these 2 studies in mid-1999.

2. How can I participate in upcoming additional clinical trials?

Once the protocol and sites have been established, your physician should contact the principal investigator at the participating center to determine whether a patient can participate. Your physician should also inform you about the consequences of trial participation, such as potential side effects, additional examinations, prolonged hospital stay and costs.

3. How are patients selected for these clinical trials?

Before starting clinical trials, the principal investigators and participating institutions will be identified. The investigators will follow a predefined protocol with patient inclusion and exclusion criteria that define patient eligibility for trial participation, as well as the number of patients that can be enrolled. Inclusion or exclusion is determined by a selection committee consisting of several physicians including the primary investigator(s) based on the protocol.

4. What are the inclusion/exclusion criteria for the trials?

The protocols for the Phase II/III clinical trials have not been determined to date as they will be dependent on the results of the Phase II pilot trial in the Netherlands.

5. Who are the principal investigators and institutions in the next trials?

The participating physicians and institutions have not been determined yet. Your local patient organization (AMDA in the U.S.) will be informed on all progress toward trial preparation.

6. How will patients from other countries be able to participate in clinical trials performed in the US and/or Europe?

Your physician should contact the principal investigator(s) at the participating center(s) to understand the inclusion and exclusion criteria for the protocol, and to determine whether a patient might be eligible for participation.

7. What are the starting dates for the trials?

The initial, small pilot study taking place in Rotterdam has begun. Our goal is to implement the next trial in mid-to-late 1999.

8. Will therapy be continued for trial patients after completion?

If the product proves efficacious in the trial, our plan is to continue patient treatment under the Pharming/Genzyme LLC until regulatory approval has been obtained.

9. Is it possible to start treatment for patients concurrently with or after completion of the clinical trial?

Construction of a large scale production plant is underway in Belgium. Until that time, product supply is available from a small pilot plant to support the limited patients that are enrolled in the Phase II/III clinical trials. The large scale production plant is scheduled to be operational around mid-2000. Within the framework set by international legislation and the limits to product supply, the Pharming/Genzyme LLC joint venture will evaluate the possibilities for patient treatment concurrently or after completion of the clinical trial.

10. Has the FDA already given the go-ahead in start clinical trials in the US?

Not at this time. Pharming/Genzyme LLC is working to complete the application to perform the clinical trials in the US (i.e.. the IND, Investigational New Drug Application). The FDA will allow us to start clinical trials only after we have finalized the clinical protocol and submitted it to them for review. In Europe, the required approvals to perform clinical trials must also be obtained.

11. When will the product be approved?

The Pharming/Genzyme LLC is committed to working diligently and thoroughly to develop a safe, efficacious product as quickly as possible. As always, timelines may shift depending upon the outcome of the trials, review time by the FDA in the ‘US and the EMEA in Europe, and production capacity at our manufacturing facilities.

After successful completion of the Phase II/III clinical trials in infants, the Pharming/Genzyme joint venture will apply for product approval for this population. Completion of this clinical trial, assessment of results, filing of the application and review by the FDA may take as long as 12-24 months. In Europe, we must complete a Market Authorization Application with the EMEA, the central European regulatory body, to obtain approval in the member states of the European Union.

A second trial in juvenile patients is planned to start later, and the trial will most likely take longer to complete. Thus, the process until approval for treatment of juvenile patients may take until mid-to-late 2001.