Commercial Opportunities
Commercial Opportunities
Today, the current drug lV busulfan is approved for the pretreatment of stem cell transplants for CML patients in the United States. However, it is reported that there is substantial “off-label” use in other disease conditions, especially AML. After our drug Bulanta ™ is approved in the USA for CML, we plan to investigate the use of Bulanta ™ in these other disease conditions:
Current Uses of IV Busulfan
Acute Myeloid Leukemia (AML)
CRISPR
Sickle Cell Anemia
Thalassemia
Acute Lymphocytic Leukemia (ALL)
Multiple Myeloma (MM)
Aplastic Anemia
Chronic Myeloid Leukemia (CML)
Neuroblastoma
Myelodysplastic Leukemia (MDS)
Hodgkin's Lymphoma (HL)
Non-Hodgkin's Lymphoma (NHL)
Market Size
Estimates of the market for busulfan range from $225 million to more than $1 billion today. According to the largest manufacturer of busulfan, the worldwide market for the busulfan active ingredient is more than 22 kilograms, which translates to more than a $300 million market.
We believe Bulanta ™ has the potential to substantially replace the current IV busulfan products due to the removal of the solvent DMA.
The stem cell transplant market is growing by 6% per year. The largest producer of the active pharmaceutical ingredient (API) stated busulfan sales are increasing 5 to 10 percent per year.
Regulatory Strategy
GreenJay intends to submit for regulatory approval for its lead drug, Bulanta ™, through the 505(b)(2) regulatory pathway for CML. GreenJay has conducted a pre-IND meeting with the FDA that has provided guidance relating to our development plan.
The 505(b)(2) New Drug Application (NDA) is a streamlined process in which the applicant relies on one or more investigations conducted by a company other than the applicant and for which the applicant has not obtained right of reference. The 505(b)(2) pathway enables investigators and/or manufacturers
to apply for approval without the need to repeat all the drug development work performed for an innovator drug.
To show comparability with the marketed IV busulfan products, GreenJay intends to conduct PK studies in rodents.
Other IV busulfan products
Currently, IV busulfan is sold by Otsuka (Busulfex) and nine generic manufacturers. All of these products contain DMA as an excipient. GreenJay believes that an IV busulfan without DMA could supplant a substantial portion of sales.
Bulanta offer significant safety and compatibility benefits compared to other formulations of busulfan. Below are references to DMA in current busulfan IV formulations currently marketed:
Mentions of DMA in IV Busulfan Package Insert
2.2 Preparation and Administration Precautions
Busulfan injection is incompatible with polycarbonate. Do not use any infusion components (syringes, filter needles, intravenous tubing, etc.) containing polycarbonate with busulfan injection.
Use an administration set with minimal residual hold-up volume (2 mL to 5 mL) for product administration.
5.4 Embryo-fetal Toxicity
Busulfan can cause fetal harm when administered to a pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits. The solvent, DMA, may also cause fetal harm when administered to a pregnant woman based on findings in animals. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and after treatment with busulfan [see Use in Specific Populations (8.1), (8.3)].
8.1 Pregnancy
Risk Summary
Busulfan can cause fetal harm when administered to a pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits following administration during organogenesis. The solvent, DMA, may also cause fetal harm when administered to a pregnant woman.In rats, DMA doses of approximately 40% of the daily dose of DMA in the busulfan dose on a mg/m2 basis given during organogenesis caused significant developmental anomalies (see Data). There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
Animal Data
Following administration during organogenesis in animals, busulfan caused malformations andanomalies, including significant alterations in the musculoskeletal system, body weight gain,and size. In pregnant rats, busulfan produced sterility in both male and female offspring due to the absence of germinal cells in the testes and ovaries. The solvent, N,N-dimethylacetamide (DMA), administered to rats at doses of 400 mg/kg/day (about 40% of the daily dose of DMA in the busulfan dose on a mg/m2 basis) during organogenesis caused significant developmentalanomalies. The most striking abnormalities included anasarca, cleft palate, vertebral anomalies,rib anomalies, and serious anomalies of the vessels of the heart.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Busulfan is a mutagen and a clastogen. In in vitro tests it caused mutations in Salmonella typhimurium and Drosophila melanogaster. Chromosomal aberrations induced by busulfan have been reported in vivo (rats, mice, hamsters, and humans) and in vitro (rodent and human cells). The intravenous administration of busulfan (48 mg/kg given as biweekly doses of 12 mg/kg, or 30% of the total busulfan dose on a mg/m2 basis) has been shown to increase the incidence of thymic and ovarian tumors in mice.
Busulfan depleted oocytes of female rats and induced sterility in male rats and hamsters. The solvent DMA may also impair fertility. A DMA daily dose of 0.45 g/kg/day given to rats for nine days (equivalent to 44% of the daily dose of DMA contained in the recommended dose of busulfan on a mg/m2 basis) significantly decreased spermatogenesis in rats. A single subcutaneous dose of 2.2 g/kg (27% of the total DMA dose contained in busulfan on a mg/m2 basis) four days after insemination terminated pregnancy in 100% of tested hamsters see Use in Specific Populations (8.3)].