Rare Disease Report Staff

FDA will no longer require Genzyme to continue the Risk Evaluation and Mitigation Strategy program.

On Aug. 1, the U.S. Food and Drug Administration (FDA) 

 (alglucosidase alfa) to include patients with infantile-onset Pompe disease, including patients  less than 8 years of age. Until today, Lumizyme was only indicated for persons with late-onset Pompe disease.

Furthermore, THE FDA will no longer require Genzyme to continue the Risk Evaluation and Mitigation Strategy (REMS) known as the Lumizyme ACE (Alglucosidase Alfa Control and Education) Program. 

Pompe disease is a lysosomal storage disease characterized by progressive skeletal muscle weakness and respiratory insufficiency. It is caused by a deficiency in GAA activity, which leads to accumulation of glycogen in tissues affected by the disease (primarily heart and muscle). Persons with late-onset Pompe tend to have a milder form of the condition while those with infantile-onset Pompe usually have more severe symptoms and die at a fairly young age if not treated.

Lumizyme is produced on a large scale (4000L) and until today, indicated only for treating patients with late-onset Pompe disease older than 8 years of age in the United States. Children with infantile-onset Pompe disease were given 

, which is the same drug as Lumizyme but produced on a smaller, and more costly, scale (160L).  The expansion of the label for Lumizyme will likely allow for more efficient production and distribution of the drug as the FDA concluded that the manufacturing of both drugs are comparable and the safety profiles similar.

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Genzyme's Lumizyme Now Indicated for Infantile-Onset Pompe Disease

Caregivers give thoughts on attributes they are looking for in DMD treatment.

It is often suggested that patients of rare disease view the risk/ benefit ratio of a treatment differently than those with more common ailments. If a rare disease is fatal, odds are rare disease patients and caregivers’ will be more willing to take chances on a drug that they feel will improve their life or quality of life.  While that may be true, it is often difficult for regulatory agencies to justify an increased risk for an uncertain benefit if there is no data about the patients/caregivers’ attitudes to justify that decision. 

That is starting to change. The Duchenne muscular dystrophy (DMD) community, led by Parent Project Muscular Dystrophy (PPMD), 

 a survey that quantified caregivers’ thoughts about various attributes they are looking at in a treatment for DMD.  The results are very interesting and should be considered a model for other patient advocacy groups follow.

The survey stemmed after lengthy discussions and meetings with caregivers, advocates, academic researchers, and pharmaceutical drug developers to determine what attributes are most important to the interested parties. The attributes they came up with are listed below.

		Done not change the progression of weakness

New Study Quantifies Duchenne Caregivers' Assessment of Risk vs Reward

FDA updates guidelines to expedite the development and review of new drugs.

 for industry regarding expedited programs for serious conditions. There are four FDA programs intended to expedite the development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening condition. They are: 1) fast track designation, 2) breakthrough therapy designation, 3) accelerated approval, and 4) priority review designation.

Drug to treat a serious disease and fill an unmet medical need.

		Designation may be granted on the basis of preclinical or clinical data

		Process designed to facilitate development and expedite review

		Fast Track designated drugs are eligible for:		

				More frequent interactions with FDA (meetings or written correspondence) during drug development

				Rolling review, whereby companies can submit completed sections of marketing applications for FDA review, rather than waiting until every section is complete

Drug intended to treat a serious or life-threatening disease in which there is currently a treatment available.

FDA Guidance for Expedited Programs For Serious Conditions

	Details of the study that led to recent approval of Genentech’s Gazyva for the treatment of chronic lymphocytic leukemia (CLL) are now available. Goede et al published their 

	The study was a massive undertaking involving 781 patients from 189 treatment centers in 26 countries who were randomly assigned to one of the following treatment groups on a 1:2:2 basis: Leukeran (chlorambucil) alone; Gazyva + Leukeran (obinutuzumab + chlorambucil); or Rituxan + Leukeran (rituximab + chlorambucil) and each patient received treatment for six 28-day cycles.

	What was unique about the patient selection was that all patients had to have a confirmed co-existing condition. Since most CLL patients are older and have coexisting conditions, this design hopefully better reflects real world conditions when treating patients with CLL. Common coexisting conditions included cardiac problems, hypertension, respiratory problems etc. Most patients (82%) had more than three coexisting conditions, and 27% had at least one coexisting condition that was not well controlled at baseline.  The study was also unique in that it compared not just the drug being tested (Gazyva combination) to a standard chemotherapy control (Leukeran alone) but also compared the drug to anoher drug that also targets CD20 (Rituxan combination).

	Median progressive free survival (PFS) in the three treatment groups were:

		26.7 months in the Gazyva + Leukeran group

		16.3 months in the Rituxan + Leukeran group

	Median PFS values for both combination treatment groups were found to be significantly different to the median PFS for the Leureran alone group. In a comparison between the two combination groups, the Gazyva + Leukeren group was statistically superior to the Rituxan + Leukeran group in measurements of response rate and probability of progressive free survival.

	The improvement in efficacy however needs to be balanced with safety.  Percentage of patients with any grade 3 or higher events were higher in the Gazyva comination group [70-73% (Gazyva + Leukeran), 55-56% (Rituxan + Leukeran), and 50% (Leukeran alone)]. However, the percentage of patients who died because of an adverse event was also lower in the Gazyva + Leukeran group (4%) than in the Rituxan + Leukeran and Leukeran alone groups (6% and 9%, respectively).

	In their discussion of the results, the authors noted “Most enrolled patients were older than 70 years of age and had clinically meaningful health problems in addition to CLL. Although elderly patients with coexisting conditions represent the majority of patients with CLL, they have been underrepresented in prior clinical trials…….Our study shows that the combination of an anti-CD20 antibody with chlorambucil results in a better response and prolongation of progression-free survival in these patients.”

	CLL is one of the more common rare cancers afflicting the elderly. CLL symptoms and progression can vary greatly among patients with long periods of stability or even regression. There is currently no cure for CLL but there are numerous treatment options are available to delay progression (eg, Rituxan and Gazyva) but treatment course will be highly dependent on the individual’s health and the disease severity/progression.

	Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. 

. 2014 [Epub ahead of print]. DOI:10.1056/NEJMoa1313984