Revised Guidance to the U.S. Gaucher Community: Management of Cerezyme® (imiglucerase for injection) Supply

Temporary Conservation of Cerezyme® Supply to Protect the Most Vulnerable Patients with Gaucher Disease

Prepared by the U.S. Cerezyme® Stakeholders Working Group* (meeting held August 10, 2009)

*The Cerezyme® Stakeholders Working Group (CSWG) includes representatives of the National Gaucher Foundation (NGF), the NGF Medical Advisory Board, the International Collaborative Gaucher Group (ICGG) North American Board of Advisors, and Genzyme Corporation. Please note that some individuals who participated in the CSWG are employees of Genzyme and other individuals or their institutions or organizations receive or have received funding from Genzyme for research, educational activities, and other purposes.

Summary of Revised Guidance*

1. Summary of Revised Guidance*Infants, children, and adolescents (≤18 years old) should continue to receive Cerezyme® without any interruptions.
2. Patients with type 2 (acute neuronopathic) and type 3 (chronic neuronopathic) Gaucher disease should continue to receive Cerezyme® without any interruptions.
3. Adult patients facing imminent life-threatening clinical situations (high risk of death within 3-4 months) without continued Cerezyme® treatment should be considered for the Cerezyme® Emergency Access Program.**
4. All patients receiving Cerezyme® during the period of temporary shortage should be considered for individualized dose reductions, as determined by their physician.**
5. Patients receiving dose reductions or undergoing treatment interruptions should, at minimum, be monitored by obtaining a hemoglobin level, platelet count, and chitotriosidase activity level (if available) at baseline and every 4 – 8 weeks.**
6. Patients receiving dose reductions or undergoing treatment interruptions, if already enrolled, should have clinical data collected and entered into the ICGG Gaucher Registry.*
7. Patients undergoing treatment interruptions may be candidates for clinical trials or treatment protocols using alternative investigational therapies.**.

* In effect through the end of 2009
** Additional information and discussion below

Background

Throughout this temporary period of Cerezyme® shortage, the following fundamental guiding principles have been used to make decisions and formulate recommendations:

1. The most vulnerable patients should be protected from treatment interruptions whenever possible.
2. All countries and regions should participate in an equitable manner proportional to their normal demand.
3. All decisions and recommendations should be made without reference to the commercial or charitable status of patients.

On June 16, 2009, in response to a viral contamination at the Cerezyme® manufacturing plant, Genzyme communicated that the facility was to be shut down and sanitized, causing an interruption in production and a temporary Cerezyme® shortage. On June 24, 2009, the Cerezyme® Stakeholders Working Group (CSWG) issued a Guidance to the Gaucher Community on the Management of Cerezyme® Supply to conserve the supply of Cerezyme® to protect the most vulnerable patients during this period. Additional information on the Cerezyme® shortage is available online at www.genzyme.com/supplyupdate.

The initial Guidance was expected to reduce the use of Cerezyme® to approximately 60% of normal levels. This was based on the assumption that all finished and most Cerezyme® “work-in-process” (WIP) at the time of plant shutdown would become available for distribution, and that the Guidance would be quickly and widely adopted to reduce demand. As these assumptions had some uncertainty, the Guidance noted that the “recommendations may be subject to change if the guidance is not widely adopted or if Cerezyme® production timelines need to be revised.”

At the end of July 2009, based on ordering patterns for Cerezyme® in the U.S., the actual demand for Cerezyme® was greater than 80% of normal demand, significantly more than the 60% level needed to protect the most vulnerable patients from treatment interruptions and avoid a complete “stock-out” of Cerezyme®. Although many physicians and patients altered treatment regimens according to the Guidance recommendations, the complexities of the U.S. health care system did not allow these changes to be realized within the necessary timeframe.

To reduce demand in proportion to the available supply, the CSWG met on July 31, 2009, and defined a narrower group of the most vulnerable patients who should receive uninterrupted Cerezyme® (children ≤18 years old, and type 2 and 3 patients), and reviewed criteria for a Cerezyme® Emergency Access Program (CEAP) that would allow physicians to request Cerezyme® to treat other adult patients who would be in imminent life-threatening clinical situations in the absence of continued Cerezyme®.

In addition, beginning on August 3, 2009, Genzyme put active controls were put in place in the U.S. to limit shipments of Cerezyme® to only those patients who met these revised criteria. These controls have now been implemented globally. At that time, these additional measures were intended to be for the month of August or until further information about the WIP supply became available.

Following the viral contamination, an exhaustive series of additional tests was conducted to determine which portions, if any, of the Cerezyme® WIP material might be suitable for further processing following sanitization of the plant. The results of these tests were reviewed with regulatory authorities, including the FDA. Genzyme determined that approximately 80% of the WIP material should be discarded to minimize any risk that the sanitized plant might be re-contaminated by processing the WIP material, resulting in further delays in the restoration of the Cerezyme® supply needed to meet the normal demand. The remaining 20% of the WIP is being held for further testing and there is no guarantee that it will be processed.

On August 10, 2009, following the decision regarding the WIP material, and its implications for the supply of Cerezyme®, the CSWG was reconvened to formulate this Revised Guidance for the U.S. Gaucher community. It was determined that the revised supply management plan and CEAP initiated on August 3 would need to be in effect through the end of 2009 with the continuing goal of protecting the most vulnerable patients. Even with this plan, the ongoing availability of Cerezyme® cannot be guaranteed.

The manufacturing plant has now completed the sanitization process and the early stages of Cerezyme® production have been successfully restarted. Due to the approximately 120-day production cycle, newly produced Cerezyme® is expected to become available beginning in late November through December 2009, but will not be sufficient to meet demand at that time.

Cerezyme® Emergency Access Program

The objective of the Cerezyme® Emergency Access Program (CEAP) is to provide a mechanism for healthcare providers in the U.S. to request access to Cerezyme® for patients who may face imminent life-threatening clinical situations (high risk of death within 3-4 months) without continued Cerezyme® treatment.

To be eligible for the CEAP, patients must meet one or more of the criteria developed by the CSWG:

Requests for emergency access to Cerezyme® can be submitted by healthcare providers using a standard form (see Appendix). CEAP requests are reviewed according to the above criteria by a multidisciplinary committee including representatives from the Medical Affairs, Patient Advocacy, Patient Safety, and Legal teams at Genzyme. In addition, regular external reporting and ad hoc consultation regarding the CEAP is conducted with physician experts and patient advocacy leaders.

The capacity of the CEAP is dependent upon the limited and finite supply of Cerezyme®, which is also needed to protect the children and patients with types 2 and 3 Gaucher disease. As noted above, Genzyme cannot guarantee availability of Cerezyme® for all eligible patients during the temporary period of shortage.

Dose Conservation

All patients receiving Cerezyme® during the period of temporary shortage, including children, type 2 or 3 patients, and CEAP patients, should be considered for individualized dose reductions, as determined by their physician.

Due to the limited and finite supply of Cerezyme® available during the temporary period of shortage, dose reductions by patients continuing to receive Cerezyme®, when feasible, would help allow for supply to be conserved so that additional patients receive treatment.

Guidance for dose individualization and associated monitoring based on expert consensus has been previously published by the International Collaborative Gaucher Group (ICGG) and may be relevant in this period of temporary Cerezyme® shortage (Genet Med 2005: 7(2): 105-110).

Monitoring

Patients receiving dose reductions or undergoing treatment interruptions should, at minimum, be monitored by obtaining a hemoglobin level, platelet count, and chitotriosidase activity level (if available) at baseline and every 4 – 8 weeks. These recommendations represent a minimal set of tests for assessing disease status.

Because Gaucher disease is a highly heterogeneous and multi-systemic disorder, additional monitoring studies should be conducted as appropriate during the period of temporary Cerezyme® shortage.

Comprehensive annual monitoring, including radiologic assessment of the skeleton, liver, and spleen, should be conducted for all patients as part of routine care. Consensus recommendations for monitoring have been published by international experts in Gaucher disease (Semin Hematol. 2004 Oct;41(4 Suppl 5):15-22; Eur J Pediatr. 2004 Feb;163(2):58-66).

ICGG Gaucher Registry

Physicians who have previously enrolled their patients in the ICGG Gaucher Registry should collect and enter data on these patients into the Registry.

Based on these data, physicians may receive individualized Patient Case Reports, updated on a monthly basis, which provide graphic summaries of patient data to inform individual disease management decisions. Furthermore, because there is limited published data on the clinical effects of dose reductions or treatment interruptions, the collective data from many patients may provide valuable answers to these important unanswered questions through future analyses.

Additional information about the ICGG Gaucher Registry is available online at www.gaucherregistry.com or by telephone at 1-800-745-4447, x15500.

Alternative Investigational Therapies

Patients who are expected to receive prolonged interruption of treatment may be candidates for clinical trials or treatment protocols for alternative investigational therapies.

Genzyme is recruiting patients for two clinical trials of an investigational oral Gaucher treatment, GENZ-112638. The first trial (ENGAGE) is for patients who have not been on treatment with Cerezyme® (http://www.clinicaltrials.gov/ct2/show/NCT00891202). The second trial (ENCORE) is for patients who have received Cerezyme® for three or more years and have clinically stable disease (http://www.clinicaltrials.gov/ct2/show/NCT00943111). Additional information about these trials is available by contacting Genzyme Medical Information (800-745-4447 or medinfo@genzyme.com).

Additionally, in the U.S., the FDA has a mechanism called a "treatment IND" to allow companies to provide expanded access to experimental drugs before they are approved. In certain situations, the FDA will reach out to companies with drugs in clinical development to support the supply of alternative investigational therapies during a shortage of an approved drug for a serious and life-threatening disorder like Gaucher disease.

Genzyme submitted a treatment IND for GENZ-112638 to FDA late in July. A response is expected by the end of August. If the treatment IND is approved by the FDA and the relevant IRBs, patients not eligible for the above-mentioned clinical trials may be able to receive GENZ-112638 if they meet the eligibility criteria in the treatment IND protocol.

Other companies also have investigational drugs for Gaucher disease in development. As a result of the Cerezyme® supply shortage, the FDA has asked these companies, Shire and Protalix, to submit treatment INDs. On August 3 and August 17, 2009, Shire and Protalix, respectively, announced that the FDA had approved their treatment IND protocols. Additional information about these protocols is available online at www.clinicaltrials.gov.

General Guidance

Download form: US Cerezyme® Emergency Access Program (CEAP) Request Form