FDA Authorizes Phase 1 Trial of ImmunityBio’s Novel COVID-19 Vaccine Candidate hAd5; Dual Construct is Designed to Drive Both T Cell and Antibody Immunity

Rhea-AI Summary

ImmunityBio has received FDA approval to initiate a Phase I clinical trial for its hAd5-COVID-19 vaccine, designed to target both the nucleocapsid (N) and spike (S) proteins of SARS-CoV-2. This bivalent vaccine aims to achieve durable T-cell and antibody responses. The trial is set to begin this month at Hoag Hospital, involving adults up to 55 years old. ImmunityBio's innovative approach circumvents limitations of first-generation vaccines by enhancing immune memory and enabling repeated administrations. The company is also developing formulations for alternative routes of administration.

Positive

• FDA authorization for Phase I trial of hAd5-COVID-19 vaccine.
• Targeting both N and S proteins may enhance immune responses.
• Potential for long-term immunity and T cell activation.
• Phase I trial to start this month with 35 participants.
• GMP manufacturing capacity exceeding 100 million doses annually.

Negative

• None.

CULVER CITY, Calif.--(BUSINESS WIRE)--ImmunityBio, Inc., a privately-held immunotherapy company, today announced it has received authorization from the U.S. Food and Drug Administration (FDA) to begin a Phase I clinical trial of hAd5-COVID-19, the company’s novel COVID-19 vaccine candidate that targets both the inner nucleocapsid (N), engineered to activate T cells, and outer spike (S) protein, engineered to activate antibodies against the coronavirus (SARS-CoV-2). These dual constructs (bivalent sequences) of SARS-CoV-2 offer the potential for the hAd5 vaccine to provide recipients with durable, long-term cell-mediated immunity with potent antibody stimulation against both the S and N proteins.

The company anticipates launching a Phase I trial at Irvine, Calif. based Hoag Hospital this month with adult subjects up to age 55.

“While there are a number of vaccine candidates in development, we believe most are limited by their sole focus on antibody responses to the monovalent spike protein, which may be insufficient to activate the full potential of the immune system to fight the coronavirus,” said Dr. Patrick Soon-Shiong, Chairman and CEO of ImmunityBio. “By targeting the nucleocapsid protein on the interior of the virus particle as well as the spike protein on the virus’s surface, we believe this vaccine can stimulate both T-cell-mediated and antibody-mediated immunity to SARS-CoV-2.”

hAd5 Vaccine Seeks to Develop Immune Memory
The hAd5-COVID-19 vaccine candidate is a novel, engineered, second-generation human adenovirus serotype 5 vaccine. Because it delivers both the S and N proteins, the vaccine has the potential to enable recipients to develop immune “memory”, promoting long-lasting immunity to SARS-CoV-2. The N protein has been engineered with a novel signaling domain to enhance T cell activation. The hAd5 vaccine with this Enhanced T cell Signaling Domain (ETSD) has generated potent CD4⁺ and CD8⁺ COVID specific T cell activation recognizing S and N following hAd5 vaccination in pre-clinical studies.

ImmunityBio’s approach differs from first-generation adenoviral platforms, including one based on the chimpanzee adenovirus and the first-generation human adenovirus vaccines being tested in Europe, China, Russia and the United States. All first-generation COVID-19 vaccines in late-stage clinical trials deliver only the monovalent spike protein on the surface of the virus and therefore focus primarily on antibody protection as their primary endpoints.

“Based on our studies in cancer, we recognized that potent T-cell activation can kill the affected cells and requires multiple antigen targets to be maximally activated,” Soon-Shiong said. “Our preclinical studies showed that the N protein was highly immunogenic and generated potent CD4⁺ and CD8⁺ T cells. Furthermore, studies have shown that patients with SARS-CoV infection have long-term T cell memory to the N protein.”

“On the basis of these findings,” continued Soon-Shiong, “we are targeting both the N and S proteins in order to drive T cell response, with the goal of generating B and T cell memory to the COVID-19 antigens, and long-term immunity to the virus.”

hAd5 Vaccine Circumvents Pre-Existing Adenoviral Immunity
Current first-generation adenovirus platforms suffer from the disadvantage of generating neutralizing antibodies which occur after repeated administration, resulting in the attack of the adenovirus vector itself and reduce the effectiveness of the vaccine. ImmunityBio’s hAd5 second generation adenovirus platform has four deletions which overcome pre-existing adenoviral immunity allowing for multiple administrations. This ability to circumvent pre-existing adenoviral immunity has been demonstrated in multiple Phase I / II clinical trials of hAd5 showing tumor specific CD4+ and CD8+ T cells following repeated administrations in the presence of pre-existing adenovirus immunity.^i,ii,iii,iv

ImmunityBio plans to administer the hAd5-COVID-19 vaccine both as a prime and boost to sustain protection against SARS-CoV-2 since multiple re-immunizations using the same vector platform are now possible with the novel hAd5 platform. The company is also pursuing preclinical development for oral, inhalational and intranasal administration to provide mucosal immunity in addition to durable humoral and cell-mediated immunity against COVID-19.

“Given the need for global distribution in both developing and developed countries, the enormous challenge of cold-chain requirements could be mitigated by a room temperature stable formulation of hAd5 that can be administered without the need for needles,” Soon-Shiong said.

COVID-19 Vaccine Program Status:

• IND Clearance for Phase I Clinical Trial Evaluating Oral COVID-19 Vaccine
  The Phase I, open-label, dose-ranging study will be conducted in healthy adults aged 18 to 55 years old. The study’s primary objective is to examine the safety and reactogenicity of two-doses of the vaccine. Additionally, immunogenicity, duration of immune response and occurrence of symptomatic COVID-19 will be measured.
  
• Phase I Trial Design
  35 patients to begin enrollment in October at the following doses of hAd5 S+N:
  • Cohort 1 (n = 10): Prime (Day 1) + Boost (Day 22) at 5 × 10¹⁰ VP per dose
  • Cohort 2 (n = 10): Prime (Day 1) + Boost (Day 22) at 1 × 10¹¹ VP per dose
  • Cohort 3 (n = 15): Prime (Day 1) + Boost (Day 22) at 1 × 10¹¹ VP or 5 x 10¹⁰ VP per dose based on Cohort 1 & 2 results.

• GMP Manufacturing Doses
  GMP dosage formulations have been manufactured in the United States with a drug substance capacity of >100 million doses annually under a joint development agreement with NantKwest, Inc.

• Data from Non-Human Primate (NHP) Study
  Initial results from a non-human primate (NHP) study that is being conducted in collaboration with the Biomedical Advanced Research and Development Authority (BARDA) are encouraging. This NHP study utilizes our GMP final dosage form of hAd5 vaccine in both subcutaneous and oral formulations. Final data relating to seroconversion and generation of neutralizing antibodies together with T cell generation are being compiled for a final study report.

• Data from SARS-CoV-2 Convalescent Serum and T Cells Demonstrating Immune Recall to hAd5-COVID-19 Vaccine
  ImmunityBio is in the process of publishing the study demonstrating that COVID-19 convalescent antibodies and T cells recognize human cell-expressed hAd5 S+N vaccine antigens, with rapid immune T cell recall.

ImmunityBio and NantKwest Joint Collaboration Agreement
Under the terms of a definitive agreement announced on August 24, 2020, ImmunityBio, Inc. and its affiliate NantKwest, Inc. agreed to share equally the costs of development, manufacturing, marketing and commercialization of the products each is developing related to COVID-19, including the hAd5 vaccine candidate. Should a product be commercialized successfully, the companies have agreed to a 60-40 percentage split of net profits, with the larger share going to the company that developed the product. The agreement also details the structure of shared governance of the joint collaboration.

In addition to the vaccine candidate, the agreement currently covers a mesenchymal stem cell therapeutic from NantKwest, whose goal is to reduce the time a critically ill patient spends on a ventilator.

“By working together and combining the novel technologies of the two companies, as well as their resources, we believe we have been able to more rapidly develop products that will address the needs of COVID-19 patients,” said Soon-Shiong, who also serves as Chairman and CEO of NantKwest. “We also will be better able to contribute to the global fight being waged against this deadly pandemic.”

About ImmunityBio
ImmunityBio, Inc. is a late-clinical-stage immunotherapy company developing next-generation therapies that drive immunogenic mechanisms for defeating cancers and infectious diseases. The company’s immunotherapy platform activates both the innate (natural killer cell and macrophage) and adaptive (T cell) immune systems to create long-term “immunological memory.” This novel approach is designed to eliminate the need for high-dose chemotherapy, improve upon the outcomes of current CAR T-cell therapies, and extend beyond checkpoint inhibitors.

ImmunityBio’s platform is based on the foundation of three separate modalities: antibody cytokine fusion proteins, synthetic immunomodulators, and second-generation human adenovirus (hAd5) vaccine technologies.

Anktiva™ (ImmunityBio’s lead cytokine infusion protein) is a novel interleukin-15 (IL-15) superagonist complex and has received Breakthrough Therapy and Fast Track Designations from the U.S. Food and Drug Administration (FDA) for BCG-unresponsive CIS non-muscle invasive bladder cancer (NMIBC). The company is also in Phase 2 or 3 trials for indications such as first- and second-line lung cancer, triple-negative breast cancer, metastatic pancreatic cancer, recurrent glioblastoma, and soft tissue sarcoma in combination with the company’s synthetic immune modulator (aldoxorubicin).

ImmunityBio is also developing therapies, including vaccines, for the prevention and treatment of HIV, influenza, and the coronavirus SARS-CoV-2 with its second-generation human adenovirus (hAd5) vaccine technologies.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include statements concerning or implying that ImmunityBio will be successful in improving the treatment of various diseases, including, but not limited to the novel coronavirus and cancer. Risks and uncertainties related to this endeavor include, but are not limited to, the company’s beliefs regarding the success, cost, and timing of its development activities and clinical trials.

Forward-looking statements are based on management’s current expectations and are subject to various risks and uncertainties that could cause actual results to differ materially and adversely from those expressed or implied by such forward-looking statements. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. These forward-looking statements speak only as of the date hereof, and we disclaim any obligation to update these statements except as may be required by law.

About NantKwest
NantKwest (NASDAQ: NK) is an innovative, clinical-stage, immunotherapy company focused on harnessing the power of the innate immune system to treat cancer and infectious diseases. NantKwest is the leading producer of clinical dose forms of off-the-shelf natural killer (NK) cell therapies. The activated NK cell platform is designed to destroy cancer and virally-infected cells. The safety of these optimized, activated NK cells—as well as their activity against a broad range of cancers—has been tested in phase I clinical trials in Canada and Europe, as well as in multiple phase I and II clinical trials in the United States. By leveraging an integrated and extensive genomics and transcriptomics discovery and development engine, together with a pipeline of multiple, clinical-stage, immuno-oncology programs, NantKwest’s goal is to transform medicine by bringing novel NK cell-based therapies to routine clinical care. NantKwest is a member of the NantWorks ecosystem of companies. For more information, please visit www.nantkwest.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include statements concerning or implying that NantKwest will be successful in improving the treatment of cancer or other critical illnesses, including COVID-19. Risks and uncertainties related to these endeavors include, but are not limited to, obtaining FDA approval of NantKwest’s NK cells and MSC as well as other therapeutics and manufacturing challenges.

Forward-looking statements are based on management’s current expectations and are subject to various risks and uncertainties that could cause actual results to differ materially and adversely from those expressed or implied by such forward-looking statements. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements.

These and other risks regarding NantKwest’s business are described in detail in its Securities and Exchange Commission filings, including in NantKwest’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2020. These forward-looking statements speak only as of the date hereof, and we disclaim any obligation to update these statements except as may be required by law.

ⁱGatti‐Mays, et al. A Phase I Trial Using a Multitargeted Recombinant Adenovirus 5 (CEA/MUC1/Brachyury)‐Based Immunotherapy Vaccine Regimen in Patients with Advanced Cancer. The Oncol, 25: 479-e899. doi:10.1634/theoncologist.2019-0608

ⁱⁱGabitzsch ES, et al. Anti-tumor immunotherapy despite immunity to adenovirus using a novel adenoviral vector Ad5 [E1-, E2b-]-CEA. Cancer Immunol Immunother. 2010 Jul;59(7):1131-5. doi: 10.1007/s00262-010-0847-8. Epub 2010 Apr 2. PMID: 20361185.

ⁱⁱⁱMorse MA, et al. Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients. Cancer Immunol Immunother. 2013 Aug;62(8):1293-301. doi: 10.1007/s00262-013-1400-3. Epub 2013 Apr 30. PMID: 23624851; PMCID: PMC3732790.

^ivOsada T, et al. Optimization of vaccine responses with an E1, E2b and E3-deleted Ad5 vector circumvents pre-existing anti-vector immunity. Cancer Gene Ther. 2009 Sep;16(9):673-82. doi: 10.1038/cgt.2009.17. Epub 2009 Feb 20. PMID: 19229288; PMCID: PMC3800002.