| Drug Name |
MYHIBBIN™ (mycophenolate mofetil) |
| Active Ingredient |
mycophenolate mofetil |
| Date of Approval |
5/1/24 |
| Manufacturer |
Azurity Pharmaceuticals, Inc |
| Approval Pathways and Indications |
Indication: MYHIBBIN™ is an antimetabolite immunosuppressant indicated for the prophylaxis of organ rejection in adult and pediatric recipients 3 months of age and older of allogeneic kidney, heart or liver transplants, in combination with other immunosuppressants.
Approval Pathway: NDA |
| Therapeutic Class |
Immunosuppressant Agent |
| Formulation |
Oral Suspension |
| MoA |
Mycophenolate mofetil (MMF) is absorbed following oral administration and hydrolyzed to mycophenolic acid (MPA), the active metabolite. MPA is a selective uncompetitive inhibitor of the two isoforms (type I and type II) of inosine monophosphate dehydrogenase (IMPDH) leading to inhibition of the de novo pathway of guanosine nucleotide synthesis and blocks DNA synthesis. The mechanism of action of MPA is multifaceted and includes effects on cellular checkpoints responsible for metabolic programming of lymphocytes. MPA shifts transcriptional activities in lymphocytes from a proliferative state to catabolic processes. In vitro studies suggest that MPA modulates transcriptional activities in human CD4+ T-lymphocytes by suppressing the Akt/mTOR and STAT5 pathways that are relevant to metabolism and survival, leading to an anergic state of T-cells whereby the cells become less responsive to antigenic stimulation. Additionally, MPA enhanced the expression of negative co-stimulators such as CD70, PD-1, CTLA-4, and transcription factor FoxP3 as well as decreased the expression of positive co-stimulators CD27 and CD28.
MPA decreases proliferative responses of T- and B-lymphocytes to both mitogenic and allo-antigenic stimulation, antibody responses, as well as the production of cytokines from lymphocytes and monocytes such as GM-CSF, IFN-Ɣ, IL-17, and TNF-α. Additionally, MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection.
Overall, the effect of MPA is cytostatic and reversible. |
| Dosing and Administration |
Oral Suspension: 200 mg/mL mycophenolate mofetil
Adults:
• Kidney Transplant: 1 g orally twice daily
• Heart Transplant: 1.5 g orally twice daily
• Liver Transplant: 1.5 g orally twice daily
Pediatrics:
• Kidney Transplant: 600 mg/m2 orally twice daily, up to maximum of 2 g daily
• Heart Transplant: 600 mg/m2 orally twice daily (starting dose) up to a maximum of 900 mg/m2 twice daily (maximum daily dose of 3 g or 15 mL of oral suspension)
• Liver Transplant: 600 mg/m2 orally twice daily (starting dose) up to a maximum of 900 mg/m2 twice daily (maximum daily dose of 3 g or 15 mL of oral suspension) |
| Administered by self or by HCP |
Administered by self |
| Place in Therapy |
MYHIBBIN™ is the only FDA-approved ready-to-use oral liquid formulation of mycophenolate mofetil. MYHIBBIN™'s ready-to-use formulation provides patients, pharmacists, and caregivers an alternative to other mycophenolate dosage forms.
In 2023, there were more than 46,000 transplants in the United States, an 8.7% increase over 2022, according to the Health Resources and Service Administration, which is part of the Department of Health & Human Services.
MYHIBBIN™ is indicated to prevent organ rejection in adult and pediatric recipients 3 months of age and older of allogeneic kidney, heart, or liver transplants, in combination with other immunosuppressants.
While a new formulation may be useful, the severe adverse effects and warnings associated with this drug would significantly affect its place in therapy, limiting the usefulness based on patient population. Mycophenolate mofetil oral suspension contains a boxed warning for embryofetal toxicity, malignancies, and serious infections.The use of this medication during pregnancy is associated with increased risks of pregnancy loss and congenital malformations; it should be avoided if safer treatment options are available. The drug has also been associated with an increased risk in the development of lymphoma and other skin malignancies. |
| Expected Market Launch Date |
Second quarter of 2024 |
| New Molecular Entity (NME) or Existing Formulation |
Existing Formulation |
| Expected Cost |
Unavailable |
| Product Discontinuation |
N/A |
| Clinical Trials |
Several clinical trials contributed to the FDA approval process. For kidney transplants, a pooled analysis of three phase III, randomized, double-blind, multicenter clinical trials conducted across the United States, Canada, Europe, and Australia involved a total of 1493 patients. These trials compared MMF in twice-daily doses of 1.0 g or 1.5 g (MMF 2 g or 3 g) with placebo (PLA) or azathioprine (AZA). The primary efficacy endpoint in these trials was biopsy-proven rejection or treatment failure at 6 months. The pooled analysis focused on various outcomes at 1 year, including graft loss, patient death, incidence and treatment of rejection episodes, and graft function (serum creatinine).
At the 1-year mark, the graft survival rate was 90.4% and 89.2% in the MMF 2 g and 3 g groups, respectively, compared with 87.6% in the PLA/AZA group. This difference was not statistically significant. However, MMF significantly reduced the incidence of rejection episodes: 40.8% for PLA/AZA patients versus 19.8% and 16.5% for the MMF 2 g and MMF 3 g groups, respectively. Renal function was consistently better for both MMF treatment groups at 3, 6, and 12 months.
In heart transplant data from a double-blind, randomized, active-controlled trial, patients were randomized at the time of transplant to receive either MMF (1,500 mg twice a day, N = 327) or AZA (1.5 to 3 mg/kg in 4 daily doses, N = 323) in addition to cyclosporine and corticosteroids. A total of 289 patients in each group received the study drug. For the co-primary endpoint, 53 of 289 (18.3%) AZA-treated patients either died or received another transplant compared with 34 of 289 (11.8%) MMF-treated patients (p < 0.01). Time to re-transplantation or patient death was significantly shorter for AZA- than MMF-treated patients (p = 0.029).
Liver transplant data were evaluated from a double-blind, randomized, comparative, parallel-group, multicenter study of primary hepatic transplant recipients. A total of 565 participants received either mycophenolate mofetil 1.5 g twice daily (n = 278) or azathioprine 1 mg/kg/day to 2 mg/kg/day plus cyclosporine and corticosteroids (n=287). The incidence of biopsy-proven and treated rejection censoring for graft loss was 40.0% in the AZA group versus 31.0% in the MMF group (P < 0.06). |
| Sources |
Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R, Alderman E, Valantine H, Dureau G, Mancini D, Mamelok R, Gordon R, Wang W, Mehra M, Constanzo MR, Hummel M, Johnson J; Mycophenolate Mofetil Cardiac Study Investigators. Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. J Heart Lung Transplant. 2005 May;24(5):517-25. doi: 10.1016/j.healun.2005.02.002. PMID: 15896747.
Got. (2024, May 6). Azurity Pharmaceuticals, Inc.. announces FDA approval of MYHIBBINTM (Mycophenolate Mofetil oral suspension). Azurity Pharmaceuticals. https://azurity.com/azurity-pharmaceuticals-inc-announces-fda-approval-of-myhibbin-mycophenolate-mofetil-oral-suspension/
Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L, Barker C. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups. Transplantation. 1997 Jan 15;63(1):39-47. doi: 10.1097/00007890-199701150-00008. Erratum in: Transplantation 1997 Feb 27;63(4):618. PMID: 9000658.
Wiesner R, Rabkin J, Klintmalm G, McDiarmid S, Langnas A, Punch J, McMaster P, Kalayoglu M, Levy G, Freeman R, Bismuth H, Neuhaus P, Mamelok R, Wang W. A randomized double-blind comparative study of mycophenolate mofetil and azathioprine in combination with cyclosporine and corticosteroids in primary liver transplant recipients. Liver Transpl. 2001 May;7(5):442-50. doi: 10.1053/jlts.2001.23356. PMID: 11349266. |