FDA rejected the approval of N-803 for BCG Unresponsive

FDA approved to review resubmitted biologic license application (BLA) of  ImmunityBio's  N-803 in combination  BCG, for the treatment of certain patients with BCG-unresponsive non muscle invasive bladder cancers.

FDA  set a new target action date of April 23, 2024, for the application, so hopefully the new treatment for BCG unresponsive will become available in the first half of 2024.


www.morningstar.com/news/dow-jones/2023102610879/immunitybio-shares-rally-as-fda-accepts-n-803-resubmission


It is a good news for BCG Unresponsive. I was very disappointed when FDA rejected the approval back in May not because of its effectiveness but rather because the contracted 3rd party manufacturer did not meet the requirement for Good Manufacturing Process. There is a class action from investors claiming that ImmunityBio failed to disclose the problem with the contracted manufacturer. So, I was concerned that ImmunityBio might choose bankruptcy and N-803 would not become accessible to patients with BCG Unresponsive. But ImmunityBio was able to secure financing of $400M by debt and equity last month, so I think the company will stay viable. The FDA has set a user fee goal date (PDUFA date) of April 23, 2024, the FDA must complete by April 23, 2024 the review of ImmunityBio's Biological License Agreement(BLA) of N-803. So, we can expect that N-803 will be available by April 23, 2024 granted that FDA approves the new BLA by ImmunityBio. FDA charges $4M for the review if clinical data are involved and $2M if clinical data are not involved.
Incidentally, what ImmunityBio applied to FDA is the combination of N-803 and BCG for BC Unresponsive CIS with or without papillary tumors. N-803 is Natural Killer cells (NK-cells) activator based upon IL-15 (immune signaling molecule). N-803 alone probably did not have enough effectiveness .   Till recently BCG+Interferon alpha 2b were used for BCG Unresponsive. BCG and Interferon alpha 2b were instilled in bladder so it was easier transition for patients to switch from BCG to BCG+Interferon alpha 2b. Merck dropped interferon alpha 2b business so this has become unavailable. I was not happy with MERCK"s sudden withdrawal from Interferon alpha 2b business because MERCK was the only manufacture for it.    Merck instead is now conducting global clinical trial for BCG + immunotherapy drug Pembrolizumab (keytruda) for BCG unresponsive,butPembrolizumab is systemic treatment with systemic side effects.  On the other hand,   N-803 and BCG are instilled to bladder just like BCG+Interferon alha 2b, so it must be easy transition for patients who has been treated with BCG.

This is an example how IL-15 activates idling NK-cells and kill ovarian cancers.

Interstingly,P atrick Soo n-Shiong P  who is the Company’s Founder, Executive Chairman and Global Chief Scientific and Medical Officer in well known figure in medical world as the first surgen to perform pancreatic transplant, entrepreneur to start up several pharmaceutical companies and billionaire who had owned San Diago Tribune till recently and the owner and exectuive chairman of Los Angels Times, and a minority owner of Los Angels Lakers.  He is also an investor and owns investing company Nant Capital.  Nant Capital is the one who bought $200M worth shares from ImmunityBio.   Though the stock price of ImmunityBIo is just above $2 per share, it was over $30 back in eary 2021.  It was when ImmunityBio was developing vaccine for Covid-19, which did not materialize as Moderna and Pfizer became dominant suppliers for mRNA based covid-19 vaccine.   Patrick Soon-Shiong is well versed with pharmaceutical industry with probably every personal connection in the field including FDA, so in this sense,, I feel more confident that N-803 will become available.

On May 11, 2023 Anktiva (N-803) by ImmunityBio  in combination with BCG  for BCG NMIBC was expected to be approved by FDA after its Phase 3 clinical trial had exhibited excellent efficacy with manageable side effects as it was  intravesical treatment.  The clinical trial was for CIS with or without Ta or T1 diseases.  Of 160 participants,  CIS patients have a CR rate of 71% (59/83), with a mediation duration of CR of 24.1 months in responders; 91% avoided cystectomy and 96% 24 month bladder cancer specific progression free survival (defined as progression to MIBC). Papillary patients have a 57% 12 month DFS rate, 48% 24 month DFS rate, and 95% avoided cystectomy.  

According to ASCO report on the result of the clinical trail, Anktiva (N-803) is a mutant IL-15-based immunostimulatory fusion protein complex (IL15RaFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. 

We know BCG treatment invokes various immune cells, both innate immune cells such as neutrophils, Macrophage, NK cells and adopted immune cells such as T-cells. 

The reason why FDA rejected Anktiva (N-803) by ImmunityBio  in combination with BCG in current form is not so much to do with its reported efficacy and side effects but because the 3rd party contracted manufacturer to produce Anktiva(N-803) did not meet the requirement for Good Manufacturing Practice (GMP).   

On the day of the announcement, the stock price became 50% lower.  In August, ImmunityBio was sued class action for ImmunityBio not disclosing issues they were having at the contracted manufacturer.   The stock price of ImmunityBio was $30 in 2021 and now $1.40.  I do not know what had happened.  It was only $3 even before the announcement of FDA's reject back in May.  Why Keytruda was approved for BCG unresponsive back in 2019, A Silicon Valley Bank analysist predicted that Merck will early  $250M/ year  from Keytruda for BCG unresponsive. Keytruda alone for BCG Unresponsive was less than 20% complete response rate at 2 years.    ImmunityBio's Anktiva (N-803) by ImmunityBio  in combination with BCG  for BCG NMIBC showed much higher efficacy than Keytruda alone for BCG unresponsive.  So, I wonder why the stock price of ImmunityBio is so low and was low even the drug was expected to be approved back in April/May. I know a small Canadian pharmaceutical company, Theralase is having a problem of completing Phase 2 clinical trial for Photodynamic Therapy for BCG unresponsive and also    Sesen Bio Pauses Clinical Development for Vicineum in BCG-Unresponsive NMIBC  in 2022.  I have to think that it is very difficult for smaller company to develop  treatment for NMIBC and get approved by FDA.  Meanwhile Merck is conducting world wide Phase 3 clinical trial for BCG + Keytruda.   

Incidentally, according to a pharma site, a rival therapy for BCG-unresponsive NMIBC has however been approved by the FDA. Ferring Pharmaceuticals’ Adstilladrin (nadofaragene firedenovec) gene therapy was cleared last December after priority review, breakthrough therapy and fast-track designations, and is due to be launched in the US later this year. That is good as we have another treatment for BCG unresponsive.  

So, we have Gemcitabine + Docetaxcel,  Adstilladrin for BCG unresponsive now as Merck had dropped Interferon alpha from their business so we cannot have BCG + Interferon for BCG unresponsive anymore.

I as a NMIBC patient sure hope more treatment options become available soon.

pharmaphorum.com/news/fda-rejects-immunitybios-bladder-cancer-drug#:~:text=The%20problem%20lies%20with%20deficiencies,%26%20Exchange%20Commission%20(SEC).