Phase 2, Open-Label, Multi-Dose Study of Panhematin in Patients With MDS

The myelodysplastic syndromes (MDS), a diverse group of hematopoietic stem cell (HSC) disorders, are characterized by ineffective hematopoiesis that manifest clinically as anemia, neutropenia, and/or thrombocytopenia. MDS is most frequently observed in the elderly population (median age between 60 and 70 years) and has a male predominance. The incidence of MDS varies from 2.1 to 12.6 cases per 100,000 people per year, with an estimated prevalence of up to 55,000 patients in the United States \[Catenacci, 2005; Williamson, 1994; Aul, 1998; Aul, 2001\]. Patients with MDS most frequently present with symptoms of fatigue, pallor, exertional dyspnea, infection, bleeding or bruising \[Catenacci, 2005\]. MDS can be divided into 2 major subtypes: indolent (or early) MDS, in which pro-apoptotic forces predominate, and aggressive (or advanced) MDS, in which pro-proliferative factors are more common. The only curative therapy for MDS is allogeneic transplantation \[Catenacci, 2005; Thompson, 2005\]. Curative treatments are restricted to younger, healthier individuals with histocompatible-matched donors or those able to undergo intensive chemotherapeutic regimens \[Catenacci, 2005\]. Recently, the FDA approved 3 agents for the treatment of this disease, Vidaza, Dacogen, and revlimid. The latter is approved for a subset of patients with MDS with del 5q abnormality, the former two are more applicable to higher risk disease. Rhu-EPO is currently available to patients with low risk MDS however, if they fail, their options are limited to the agents mentioned above, all of which have significant myelotoxic effects. Effective and less myelosuppressive treatments for low-risk MDS are needed. We are proposing a novel approach for the treatment of patients with low-risk MDS using heme supplementation with Panhematin® (hemin for injection). Panhematin® is an iron-containing metalloporphyrin, indicated for the amelioration of recurrent attacks of acute intermittent porphyria; it acts to limit the hepatic and/or marrow synthesis of porphyrin, presumably, as a result of the inhibition of aminolevulinic acid synthetase (the enzyme which limits the rate of porphyrin/heme biosynthetic pathway) \[Panhematin® Product Prescribing Information\]. There are pre-clinical and clinical data to suggest that heme supplementation with Panhematin® (hematin for injection) has potential as a treatment option for patients with MDS. Preliminary data indicate hemin administration has the potential to stimulate progenitor cell growth, stimulate globin synthesis, and elevate overall hemoglobin levels. Panhematin® has been proven to be well tolerated when used therapeutically in patients with acute intermittent porphyria, and it is anticipated to be well tolerated in this patient population. For this study, selected patients will have low or intermediate 1 risk disease by IPSS, and the standard of care for MDS (supportive therapies) will be administered as needed. Measurement of serum porphyrin levels and Hgb F will be done at baseline and at week 8.