Candidates: ImmunityBio’s human Adenovirus 5 (hAd5), also known as Ad5-Covid-S/N, a vaccine to protect against SARS-CoV-2; NantKwest’s haNK and ImmunityBio’s N-803 (nogapendekin alfa inbakicept), both therapeutic immunomodulators for patients with mild-to-moderate COVID-19 symptoms; BM-Allo.MSC, NantKwest’s mesenchymal stem cells (MSCs) for severe and critically ill COVID-19 patients on ventilator support
Types: hAd5 (Ad5-Covid-S/N) is a second-generation bivalent, human adenovirus vaccine designed to deliver both Spike (S) and Nucleocapsid (N) DNA, thus generating both antibodies and CD4+ and CD8+ T cell responses, believed to lead to long term cell-mediated immunity—the first such vaccine, according to the companies. The vaccine is based on a second-generation novel, engineered human adenovirus vector with four deletions [E1-, E2b-, E3- deleted], enabling multiple homologous doses, even in patients with adenovirus immunity.
haNK consists of CD-16, off-the-shelf natural killer cells designed to enhance antibody killing of infected cells, given alone or combined with convalescent plasma.
N-803 is an interleukin 15 (IL-15) ‘superagonist’ cytokine designed to stimulate natural killer cells and CD8+ T cells. N-803 has higher activity and is longer lasting than native IL-15, and thus has the potential to overcome low natural killer cell and T-cell count in patients with COVID-19 infections.
BM-Allo-MSC consists of bone marrow-derived MSCs designed to mitigate ‘cytopathic storm.
2021 Status: ImmunityBio on April 8 reported initial data indicating that a single subcutaneous injection of hAd5 in healthy Phase I clinical study participants stimulates the generation of T cells reactive to the spike (S) and nucleocapsid (N) protein antigens delivered by the vaccine. Fourteen to 16 days after the single dose, the mean level of T cells generated in response to the hAd5 S+N T cell vaccine were 10 times higher for N specific T cells. By day 21, both S and N T cell responses achieved levels 10 times higher as compared to pre-vaccination levels. Researchers working with ImmunityBio posted data from the trial April 7 on medRxiv.
ImmunityBio said March 15 that it met the safety requirements for the first 12 participants in its Phase Ib trials of its human adenovirus (hAd5)-based T-cell COVID-19 vaccine in sublingual formulations (NCT04591717) and oral and subcutaneous formulations (NCT04732468). The study’s independent Safety Review Committee recommended the study continue with no modifications to trial design. The trials, which will involve 80 participants, are expected to be fully enrolled in the second quarter, the company said.
Six participants have been dosed in each trial as of March 15. Based on the findings of these trials, the optimal combination of administration route and dose will be determined and entered into the Phase II/III design, ImmunityBio said.
At the recent 2021 Conference on Retroviruses and Opportunistic Infections (CROI), ImmunityBio scientists presented preclinical data from a SARS-CoV-2 challenge study involving subcutaneous and oral immunization, showing hAd5-COVID-19 T-cell vaccine candidate to have been completely protective in non-human primates against high SARS-CoV-2 titer exposures.
ImmunityBio and NantKwest said February 11 that they received FDA authorization to expand a Phase I trial (NCT04591717) of their bivalent hAd5 T-cell COVID-19 vaccine by expanding a currently active multi-cohort trial of the subcutaneous version of the vaccine in order to study the addition of sublingual boosts.
The FDA also authorized a second Phase I trial (NCT04732468) designed to examine the addition of an oral boost to the subcutaneous prime administration. As a result, ImmunityBio and NantKwest will enroll another 105 participants in the U.S. trials of their vaccine candidate.
2020 Status: NantKwest and ImmunityBio—immunotherapy companies led by Patrick Soon-Shiong, MD—said November 10 that its COVID-19 vaccine candidate hAd5 has been administered in a Phase I trial (NCT04591717) with no serious adverse events reported in the low dose cohort. The safety study is ongoing for the high dose cohort. The trial, being conducted at Hoag Hospital in Newport Beach, California, enrolled 20 volunteers across two dose levels and the subject screening for the Phase I expansion cohort is ongoing.
The Phase I, open-label, dose-ranging study is being conducted on 35 participants aged 18-55 years. Volunteers are divided into three groups, each of which receives different doses of the vaccine (5×1010 and 1×1011 viral particles). Participants receive two subcutaneous injections 21 days apart. The study is primarily designed to examine the safety and reactogenicity of two doses of the vaccine. Immunogenicity, duration of immune response, and occurrence of symptomatic COVID-19 will also be assessed.
On August 24, NantKwest and ImmunityBio signed a definitive agreement of undisclosed value to jointly develop, manufacture, market, and commercialize therapeutics and vaccines for combating COVID-19. Two product candidates were covered under the agreement—ImmunityBio’s vaccine, which according to the companies is anticipated to enter into a phase I clinical trial “soon”; and NantKwest’s MSC therapeutic, which is designed to reduce the time a critically ill patient spends on a ventilator.
The companies agreed to share equally the costs incurred after August 21, 2020, of development, manufacturing, marketing, and commercialization of the products each is developing related to COVID-19. 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.
On May 27, NantKwest and ImmunityBio said that ImmunityBio was selected as one of 14 companies to participate in “Operation Warp Speed,” President Donald Trump’s call to develop 300 million doses of vaccine against SARS-CoV-2 by January 2021. Efforts will focus on the development, testing, and large-scale manufacturing of ImmunityBio’s Ad5-Covid-S/N, which is expected to begin clinical trials in June following FDA approval of an IND.
Two GMP-ready manufacturing plants have been readied for COVID-19 vaccine production, with capacity for 100 million doses projected by year-end.
The human adenovirus vector has shown safety in over 125 patients in 13 Phase I and II trials to date, the companies said. They cited clinical studies performed by the National Cancer Institute, which have demonstrated that the novel Ad5 may induce antigen-specific T-cell immunity in patients, even in the presence of pre-existing adenoviral immunity.
The second-generation Ad5 platform, according to the companies, establishes a vector that is immunologically “quiet” or “stealth” as it relates to adenovirus protein production in the host dendritic cell. Unlike first-generation adeno-associated virus vectors, the platform does not produce large amounts of adenoviral fiber leading to high levels of adenoviral-neutralizing antibodies that limit ongoing immune response by diminishing the ability for the vaccine to be produced in the patient—and enables the Ad5 vector to serve both as a prime and a boost treatment, even in patients with pre-existing adenovirus immunity. DNA produced by the adenovirus platform can continuously produce its vaccine antigen for potentially over four months—an advantage, says ImmunityBio, over mRNA vaccines which can only survive a few days in vivo.
The platform has demonstrated the preliminary safety of high doses (up to 15 times the dose anticipated for COVID-19) in Phase I and Phase II studies in immunosuppressed cancer patients, ImmunityBio and NantKwest said.
ImmunityBio also said the FDA has authorized studies on the use of the company’s N-803 to treat patients before the onset of severe disease by potentially activating natural killer cells to mitigate viral replication. ImmunityBio plans to recruit patients for a Phase Ib trial (NCT04385849) designed to assess the safety and immunostimulatory activity of N-803. The randomized, blinded, placebo-controlled study is expected to enroll 30 adults who have tested positive for SARS-CoV-2 and have confirmed mild-to-moderate COVID-19 symptoms. In addition, ImmunityBio said it plans to start Phase I trials in several Los Angeles-area hospitals in June.
As for haNK, NantKwest said it has submitted a pre-IND application to the FDA.
On May 18, the FDA authorized studies on the use of NantKwest’s mesenchymal stem cell treatments to modulate the immune system’s excessive response to COVID-19 infection, thereby potentially reducing the debilitating and sometimes fatal effects of the disease. A planned Phase Ib, randomized, double-blind, placebo-controlled study will evaluate the safety and efficacy of BM-Allo.MSC versus current supporting care in treating patients with severe disease requiring ventilator support.
In the trial, MSCs will be administered to 45 patients in critical care or an ICU setting. The study’s primary objectives include overall safety, and reduced time on a ventilator. The secondary objective is the efficacy of BM-Allo.MSC in reducing the number of days patients require oxygen, duration of hospitalization, and mortality.
Additionally, NantKwest and ImmunityBio have signed a binding term sheet to jointly develop, manufacture, and market therapeutics and vaccines for COVID-19. Each company agreed to contribute their candidates, while both agreed to contribute manufacturing equipment and capabilities. The companies agreed to share equally all costs relating to developing, manufacturing, and marketing of the product candidates globally, while establishing a 60%/40% split of global net profits from the collaboration products, with the majority going to the company contributing the product on which the sales are based. All net profits from sales of combined collaboration products will be shared equally.
In April, the companies said they were in active discussions with the FDA to develop the companies’ multiple treatment and vaccine candidates against COVID-19. The companies submitted IND applications to the FDA for clinical trials of N-803 alone, and a second trial of haNK alone, or haNK combined with convalescent plasma, in patients with mild to moderate COVID-19 infection.
N-803 is being used in clinical trials for other indications and has achieved the FDA’s Breakthrough Therapy Designation from the FDA for the treatment of BCG-unresponsive non-muscle invasive bladder carcinoma in situ (NMIBC-CIS) patients. It has also demonstrated encouraging results in lowering the viral load in SHIV-infected monkeys, as announced last month at the Annual Conference on Retroviruses and Opportunistic Infections (CROI).
NantKwest also said it can grow the MSCs through proprietary isolation and expansion methods, and is using ImmunityBio’s automated, closed system (GMP-in-a-Box) to safely and rapidly grow the cells from a bone marrow cell bank in approximately 7-9 days.
COVID-19: 200 Candidates and Counting
To navigate through the >200 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data.
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: