On December 4, 2019 ImmunityBio, a privately held immunotherapy company, reported that it has received Breakthrough Therapy Designation (BTD) from the U.S. Food and Drug Administration (FDA) for its interleukin-15 (IL-15) agonist complex, N-803, in combination with Bacillus Calmette-Guerin (BCG), for the treatment of patients with BCG-unresponsive non-muscle invasive bladder carcinoma in situ (CIS) (Press release, ImmunityBio, DEC 4, 2019, View Source [SID1234551933]).

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This grant of Breakthrough Designation follows on the receipt of Fast Track Designation from the U.S. Food and Drug Administration for N-803 in 2017. The FDA’s Breakthrough Therapy Designation program is designed to expedite the development and review of drugs intended to treat serious conditions and fill unmet medical needs.1 The FDA published guidance in February 2018 to address BCG unresponsive non-muscle invasive bladder cancer (NMIBC), stating that the goal of therapy in patients with BCG-unresponsive NMIBC is to avoid cystectomy.

"We are pleased that the FDA has granted Breakthrough Therapy Designation to N-803 in combination with BCG for the treatment of patients with Non-Muscle Invasive Bladder Cancer with CIS," said Dr. Patrick Soon-Shiong, Chairman and CEO of ImmunityBio. "We look forward to accelerating our work on N-803 to bring greater hope to the thousands of people living with the serious consequences of bladder cancer and to address the unmet need to avoid surgical removal of the bladder in these high-risk patients. Patients who fail current standard of care and who have high risk carcinoma in situ of the bladder are left with a difficult choice of having their bladder removed, a procedure fraught with a clinically significant mortality and morbidity rates. The potential opportunity to avoid this procedure and change the course of this disease with the addition of N-803 is immensely gratifying," he said.

"The favorable safety profile and initial efficacy results from our phase 1 study strongly suggest we may be able to improve the treatment for a disease that has not had non-surgical treatment options for over 30 years," said ImmunityBio Chief Medical Officer, Dr. John Lee.

ImmunityBio’s N-803, an IL-15 Superagonist

The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of the natural killer (NK) and T cells. N-803 is a novel IL-15 superagonist complex consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. N-803 has improved pharmacokinetic properties, longer persistence in lymphoid tissues and enhanced anti-tumor activity compared to native, non-complexed IL-15 in vivo.

N-803 is currently being evaluated for adult patients in two clinical NMIBC trials. QUILT 2.005 is investigating use of N-803 in combination with BCG for patients with BCG-naïve NMIBC; QUILT 3.032 is studying N-803 in combination with BCG in patients with BCG-unresponsive NMIBC.

The Urgent, Unmet Need to Treat NMIBC and Avoid Cystectomy

Bladder cancer has a high incidence worldwide, with 199,922 deaths and an estimated 549,393 new cases in 2018.2 In the United States, bladder cancer is the fourth most commonly diagnosed solid malignancy in men and the twelfth for women; The American Cancer Society estimates 80,470 new cases and 17,670 deaths in 2019.3 Bladder cancers are described based on how far they have invaded into the wall of the bladder. NMIBC occurs when the cancer has not grown into the main muscle layer of the bladder. Approximately 75-85% of all newly diagnosed cases of bladder cancer are non-muscle invasive bladder cancer (NMIBC).4

For the last 30 years, BCG immunotherapy has been the standard for treating NMIBC. However, disease recurrence and progression rates remain unacceptably high. Standard of care recommendations for these patients include lifetime invasive surveillance and rapid treatment of recurrences, creating a substantial financial burden and drastic impact on quality of life. Of those patients who experience recurrence, approximately 30% will progress and succumb to their disease over a 15-year period, and another 50% will undergo radical cystectomy of the bladder in an attempt to control their disease.5

For high-risk NMIBC patients who are BCG-unresponsive with persistent or recurrent disease, treatment guidelines recommend a surgical procedure called radical cystectomy, a surgery to remove the entire bladder that may require removal of other surrounding organs. In men, removal of the prostate may be necessary, and in women, surgeons may also remove the uterus, fallopian tubes, ovaries and cervix, and occasionally a portion of the vagina. Despite the advent of minimally invasive procedures and robotic techniques, the 90-day mortality and morbidity rates in patients who undergo cystectomy remain unacceptably high at 5.1-8.1% and 28-64%, respectively.6 Based on this urgent need, FDA published guidance in February 2018 to address BCG unresponsive non-muscle invasive bladder cancer (NMIBC), stating that the goal of therapy in patients with BCG-unresponsive NMIBC is to avoid cystectomy.