On April 30, 2013, Raptor Pharmaceuticals' (RPTP) cysteamine bitartrate delayed release (RP103, Procysbi™) will be up for approval for the treatment of nephropathic cystinosis. RP103 is a reformulation of cysteamine bitartrate (Cystagon®) which allows dosing every 12 hours as opposed to every six hours with Cystagon. Why is this change in regimen important?

Cystinosis: disease background and treatment

Nephropathic cystinosis is an inherited (autosomal recessive) lysosomal storage disorder caused by defective transport of the amino acid cystine out of lysosomes. The stored cystine is poorly soluble and crystallizes within the lysosomes of many cell types, leading to widespread tissue and organ damage. In North America, the incidence of infantile nephropathic cystinosis is 1 case per 100,000-200,000 live births; an estimated 400 individuals in the United States have cystinosis. Approximately 15 new cases of cystinosis are diagnosed each year in the United States.

In the past, the treatment of cystinosis

Tivozanib is an oral inhibitor of vascular endothelial growth factor (VEGF), and inhibits all three VEGF receptors. AVEO Pharmaceuticals (AVEO) submitted an NDA in September 2012, based on results of the global Phase III TIVO-1 trial, a randomized superiority-designed pivotal trial evaluating the efficacy and safety of tivozanib compared to sorafenib (Nexavar®) in 517 patients with advanced renal cell carcinoma ((RCC)) who had no prior treatment with a systemic therapy, as well as data from 17 clinical studies involving over 1,000 subjects who received tivozanib.

The primary endpoint for the Phase III trial was progression free survival or PFS. Improvement in PFS determined by investigators was 5.1 months (14.7 vs. 9.6), while an independent assessment showed only 2.8 months (11.9 vs. 9.1, p = 0.042). This difference between unblinded (investigator) and presumably blinded (independent) evaluation of PFS demonstrates one of its weaknesses as an endpoint.

Following approval of Alexza's (ALXA) ADASUVE (loxapine for inhalation) for the treatment of adult agitated patients with schizophrenia or bipolar disorder, it may be time to address two of the issues that have arisen, concerning ADASUVE and the STACCATO device that is used for drug delivery, and their implications for Alexza. The STACCATO device is designed to vaporize a drug for inhalation without thermal degradation.

There is no evidence that the STACCATO device itself presents a risk of pulmonary toxicity

While this concern appears to have somewhat dissipated, there were reports that there were risks of pulmonary toxicity related to the device itself. These initial concerns might have been related to the unfortunate use of the word placebo, suggesting the vaporizing of an inert substance. However, ALXA clarified with the FDA that the "The placebo device is the same device as the active device without

Hemispherx Biopharma's (HEB) rintatolimod (trade name Ampligen) will be reviewed by an FDA Advisory Committee on December 20, 2012 for the treatment of chronic fatigue syndrome (CFS). Because the etiology of CFS is unknown, such a review presents unusual regulatory and scientific challenges, though of course drugs are approved for conditions whose pathophysiology is incompletely understood, such as the common headache.

Rintatolimod/Ampligen

Rintatolimod (poly I:poly C12U),is an experimental immunomodulatory double stranded RNA. Rintatolimod was first synthesized in the 1970s and has been proposed as a treatment for illnesses such as CFS, HIV, hepatitis B, hepatitis C, and cancers, including renal cell cancer and metastatic malignant melanoma. The biological properties of rintatolimod are conveyed by a unique naturally occurring receptor on the cell surface called "TLR-3." Toll-like receptors or "TLRs" such as TLR-3 serve as "pattern recognition" receptors in the early detection of pathogens and the establishment of early

Dynavax's (DVAX) HEPLISAV had an FDA Advisory Committee on November 15, 2012. The Advisory Committee voted 13 to one that HEPLISAV data adequately demonstrated immunogenicity. Additionally, the Committee voted eight to five with one abstention that there were insufficient data to adequately support the safety of HEPLISAV. To follow-up on the safety issues discussed in the recent review performed by Theodore Cohen, I would like to make the following comments:

Safety database is comparable to Engerix-B's

The number of patients in the safety database for HEPLISAV (n = 4425) is comparable to the database that supported the approval of Engerix-B (GSK) (n =5071).

No significant differences in safety between HEPLISAV and Engerix-B

As the FDA briefing documents state:

The overall safety evaluation across studies did not reveal significant imbalances in rates of clinically important adverse events. No significant differences in ANA titers, ANCA or anti-dsDNA levels were