New FDA Orphan Drugs: MGA031, KBPA101, TLF Oral Solution

Yael Waknine

October 17, 2006

October 17, 2006 — The US Food and Drug Administration (FDA) has approved orphan drug status for a humanized Fc-engineered anti-CD3 monoclonal antibody hOKT3-gamma-1 (Ala-Ala) in the treatment of recent-onset type 1 diabetes mellitus; a fully human monoclonal antibody for the treatment of nosocomial pneumonia caused by serotype O11 Pseudomonas aeruginosa; and an oral solution formulation of talactoferrin alfa for the treatment of renal cell carcinoma.


Orphan Drug Ala-Ala (MGA031) for Recent-Onset Type 1 Diabetes Mellitus

On October 10, the FDA approved orphan drug status for a humanized, Fc-engineered anti-CD3 monoclonal antibody hOKT3-gamma-1, also known as Ala-Ala ( MGA031, made by MacroGenics, Inc), in the treatment of recent-onset type 1 diabetes mellitus (T1DM).

According to a company news release, approximately 1 in every 400 to 500 children and adolescents develop T1DM, which is caused by a T lymphocyte–dependent autoimmune attack on pancreatic beta cells. In the absence of a cure or halting of disease progress, patients with the disease are subject to life-long intensive insulin replacement therapy and risks for heart and kidney disease, hypertension, blindness, and other complications.


Ala-Ala is a human monoclonal antibody that binds to an epitope of the CD3-epsilon chain expressed on mature T cells, interfering with autoimmune mechanisms that lead to destruction of pancreatic islet cells in T1DM patients. Engineered Fc regions allow it to bind with high selectivity to these regions.

According to the news release, clinical trials have demonstrated the agent's potential ability to slow progression of the disease and improve health and quality of life for affected patients. In one study, 2-year follow-up data from 21 patients showed that a single course of Ala-Ala within 6 weeks of diagnosis yielded improved C-peptide responses after a mixed meal tolerance test; reduced hemoglobin A1c levels; and lower insulin requirements compared with the control group.

The company anticipates initiating a phase 2/3 trial of Ala-Ala for the treatment of T1DM during the fourth quarter of 2006; additional potential indications include other autoimmune diseases such as psoriatic arthritis and multiple sclerosis.


Orphan Drug KBPA101 for Nosocomial Pseudomonas Pneumonia

On October 3, the FDA granted orphan drug status for a human monoclonal antibody ( KBPA101 , made by Kenta Biotech, Ltd) in the treatment of nosocomial pneumonia caused by serotype O11 Pseudomonas aeruginosa.

Nosocomial pneumonia caused by P aeruginosa can be life-threatening, particularly in mechanically ventilated patients; the mortality rate can be as high as 40%. Moreover, the microorganism shows a high intrinsic resistance to antibiotics and an ability to acquire adaptive resistance during a single course of therapy.

According to a company news release, KBPA101 binds to P aeruginosa bacteria and kills it in a manner independent from the microbiological sensitivity of antibiotics. In animal models, a single dose of the agent yielded rapid clearance of Pseudomonas lung infections caused by a lethal bacterial challenge.

KBPA101 previously was granted orphan drug designation from the European Commission in July 2006.


Orphan Drug Talactoferrin Alfa (TLF) Oral Solution for Renal Cell Carcinoma

On October 12, the FDA approved orphan drug status for an oral formulation of talactoferrin alfa ( TLF oral solution, made by Agennix, Inc) in the treatment of renal cell carcinoma (RCC).

According to a company news release, RCC is the most common type of kidney cancer, accounting for approximately 90% of kidney tumors and occurring with an incidence rate of 39,000 cases per year. The current standard of care for nonmetastatic RCC is nephrectomy followed by observation. Treatment options for metastatic cancer may include chemotherapy, cytokine therapy, targeted therapy, and/or radiation.

Oral TLF is a unique recombinant form of human lactoferrin that binds to enterocytes lining the upper gastrointestinal tract, thereby initiating an immunostimulatory cascade in gut-associated lymphoid tissue that results in the activation of both innate and adaptive immunity, including recruitment and activation of dendritic cells, NK-T cells, and CD8+ lymphocytes. This is followed by systemic immunostimulation, the activation of tumor-draining lymph nodes, and infiltration of distant tumors by immune cells, which results in their destruction.

Results from 2 phase 1/2 clinical trials in patients with advanced or metastatic cancers who had received oral TLF as second- or third-line monotherapy (patients with RCC = 9 of 51) showed that 100% of RCC patients experienced tumor shrinkage or reduction of growth rate ( P < .05). Four patients remained progression-free for more than 6 months, with 2 patients receiving therapy for more than 2 years.

One patient who had previously progressed on treatment with a 4-drug chemotherapy and immunotherapy regimen achieved a confirmed durable partial response with 71% tumor shrinkage at 22 months compared with baseline, as evaluated using Response Evaluation Criteria in Solid Tumors ( RECIST; approximately 92% by World Health Organization response criteria).

Although the median progression-free survival has not been reached, the current rate of 4.5 months is significantly higher than that expected from the literature (7.3 months vs 2.5 months). In addition, the 14-week progression-free survival rate (100%) was much higher than the expected rate of 20% (P < .0001). In clinical trials of this and other indications (such as non–small cell lung cancer), oral TLF appeared to be safe and well tolerated. No significant drug-related adverse events were reported.


According to the news release, oral TLF is currently in phase 2 clinical trials for RCC. In addition, fast track designation was recently granted by the FDA for the use of oral TLF as first-line therapy for non–small cell lung cancer, and for topical TLF gel in diabetic foot ulcers.

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