AlphaVax Product Overview

A primary focus at AlphaVax is the commercial potential of its alphavaccine vector technology in cancer immunotherapy, and the development of immunotherapeutic alphavaccines for the treatment of cancer is an  area in which AlphaVax seeks a leading position in new treatment modalities.

AlphaVax has successfully optimized the alphavaccine technology, developed a strategic intellectual property portfolio, and a robust, scalable manufacturing process, and has advanced seven alphavaccine candidates into ten completed human clinical trials. The vaccine vector platform has demonstrated a favorable safety profile while eliciting the desired vaccine-specific immune responses.

Our vaccine development team successfully brought together its collective experience in process development, analytical methods, regulatory affairs, compliance, technology transfer, and manufacturing.

In addition, the technology is commercially available in vaccines for the veterinary market - based upon our RNA particle technology - and include products for PEDv, swine epidemic diarrhea, influenza, and rotavirus. Most of the development of veterinary and companion animalvaccines is today conducted by Merck's Animal Health's subsidiary, Intervet.

Pipeline

■ Completed  |  ■ In planning/Underway 

Program Pre-clinical GMP Phase I or I/II Phase II
Cancer Immunotherapy
CEA(gastrointestinal cancers)
Her2 (breast cancer)
TRP2 (melanoma)
VRP adjuvant technology
PSMA (prostate cancer) ✔ ✔ ✔ ○
Program Pre-clinical GMP Phase I or I/II Phase II
Infectious Disease
CMV
HIV - monovalent
HIV - multivalent
Influenza - young adults, elderly
Pandemic Influenza - H1B & H5
RSV
HSV-2
SARS
Program Pre-clinical GMP Phase I or I/II Phase II
Biodefence
Botulinum Toxin
VEE/EEE/WEE
Filovirus
Smallpox

AlphaVax Cancer Treatments

Summary of Leading Programs

The commercial potential of its alphavaccine system in cancer immunotherapy is one of AlphaVax's primary areas of focus. Promising safety and immunogenicity results from the Company's first batch of Phase I clinical studies included four different alphavaccines,
Clinical testing of the Company's RNA particle alphavaccines for the immunotherapeutic treatments of colon cancer and breast cancer has produced encouraging safety and immunogenicity results, as well as signals related to survival and the breaking of tolerance.

Our alphavaccine for treating CEA expressing colon cancer indicated that (i) the vaccine was able to "break self-tolerance" and (ii) led to a trend for enhanced survival in patients in a high-dose cohort -- with measurable T cell responses.
Evaluation of the CEA alphavaccine in earlier stage III colon cancer patients elicited clinically relevant CEA-specific immune responses of greater magnitude and frequency than those measured in the Stage IV patients. Positive T-cell responses and antibodies against CEA have been seen.
The summary data showed a 5-year survival rate of 17% in Stage IV cancer and 100% in Stage III, with a relapse-free rate in the latter group of 75%. CEA-specific humoral immunity was seen in all patients. The CD8+ effector memory T cell to Treg ratio was also raised.

AlphaVax's HER2 alphavaccine for breast cancer patients with HER2-expressing tumors led to the induction of HER2-specific immunity and the enhancement of systemic immunity.

In collaboration with Memorial Sloan-Kettering Cancer Center (MSK), studies identified a potent therapeutic VRP vaccine encoding the melanoma differentiation antigen TRP-2. Treatment with this TRP2 VRP vaccine demonstrated durable anti-tumor effects. It was noted, from comparative studies in the murine model, that the RNA particle alphavaccine platform appeared to be superior to all others previously tested. A combination of immunomodulatory monoclonal antibodies and our vaccine candidate pointed to an increase in both immunogenicity and efficacy.

AlphaVax Clinical Experience

Infectious Disease

Introduction

AlphaVax has advanced various alphavaccines into a range of Phase I / II clinical trials. The vaccine candidates were split almost equally between cancer and those tested as anti-infectives in Phase I trials. Cumulatively these trials enrolled over 500 subjects, and the results demonstrated a favorable safety profile for our RNA particle vaccine platform -- all candidate vaccines have been shown to be very well tolerated, with only mild to moderate local reactogenicity; and no safety issues have been observed. From the immunogenicity assessments conducted for CMV, influenza and HIV, measurable immune responses, humoral, cellular or both, have been observed in all trial subjects who received two or three inoculations of the highest dosage level tested. AlphaVax’s RNA particle has a role to play in viral diseases, such as pandemic and seasonal influenza, respiratory syncytial virus, and varicella zoster.

In addition, the results from the initial cancer immunotherapy trial suggest that our alphavaccine vector can break tolerance to a tumor-associated antigen; appears to impact positively survival; and should be clinically useful for immunotherapy in the setting of tumor-induced immunosuppression.

Vaccine for Cytomegalovirus (CMV)

AlphaVax designed its CMV alphavaccine RNA particle candidate to express three different CMV proteins (trial AVX601). Two proteins, pp65 and I E1, are the principal targets for cellular immune responses in CMV seropositive individuals, and a third, glycoprotein gB, is the principal target for neutralizing antibody responses. Humoral and cellular mechanisms shadowed the conferred protective immunity. – a balanced immune response to all three proteins being observed. 

Clinical Results 

The two component alphavaccine (AVX601) expressing CMV gB or a pp65/IE1 fusion protein was evaluated and shown to be wel- tolerated, with mild to moderate local reactogenicity, minimal systemic reactogenicity, and no clinically important changes in laboratory parameters. 

All vaccine recipients developed ex vivo, direct IFN-gamma ELISPOT responses to CMV antigens. 

AVX601 vaccine induced neutralizing antibodies to CMV in all recipients of high dose vaccine.

CMV antigen-specific CD4 + and CD8 + effector T cells producing multiple cytokines in response to CMV peptide stimulation were induced in all immunized subjects. CD8 + T cells stimulated with pp65 produced the highest percentage of cytokine-positive cells. CD4 + T cells exhibited responses representing all of the possible 7 cytokine profiles. Polyfunctional T cells were detectable and were present 6 months after the third dose of vaccine.

Vaccines for Influenza

Preclinical Results

Alphavaccines expressing influenza hemagglutinin (HA) have been shown to protect mice, chickens and ferrets against influenza challenge, including strains of the highly virulent, potentially pandemic H5N1 avian strain in chickens. In mice, the immunogenicity of an alphavaccine expressing HA from influenza A/Vietnam/1203/2004 (H5N 1) virus is significantly greater than the immunogenicity of an H5 recombinant protein from the same virus strain. The immunogenicity of an alphavaccine expressing the HA from the swine-origin 2009 H1N1 influenza virus induces HI antibody levels exceeding those required for protection in mice, pigs, and nonhuman primates.

​CEA-expressing cancer (eg, colon cancer)

- breaking tolerance & enhanced survival potential
- CEA antibody responses​

In collaboration with Duke University Medical Center and with support from NCI, a Phase I / II study (open-label, dose-escalation study) was conducted to evaluate the safety and immunogenicity of carcinoembryonic antigen (CEA (6D)) - expressing virus-like replicon particle (VRP) vaccine (AVX701) in patients with CEA-expressing malignancies. The subjects with advanced or metastatic (Stage IV) CEA-expressing malignancies were treated with one of three escalating doses or CEA-expressing VRP. in thesis subjects, AVX701 was administered by intramuscular (IM) injections every 3 weeks for a minimum of four immunizations, with additional doses of patient's without progressive disease every 3 months.

A total of 28 subjects were treated in the dose-ranging part of the study and no safety or toxicity issues were identified, confirming the favorable safety profile of this intervention seen in other studies (Morse et al. 2010 JCI). Following repeated administration, AVX701 was shown to be effective in eliciting CEA-specific T-cell and antibody responses even in the presence of anti-vector neutralizing antibodies and elevated Treg levels. The study results suggested that patients with CEA-specific T-cell responses exhibited longer overall survival.

A study enrolling patients with Stage III cancer was subsequently initiated and closed to new participants in 2017. Patients (12) were administered the candidate vaccine intramuscularly every three weeks for four administrations. VRP-CEA-activated CEA-specific antibodies with above-baseline titers were seen in all. The titer in Stage IV, of 80 rose to almost 500 in Stage III patients. A median follow-up of 60 months showed that all were alive, and three patients showed recurrent disease. The antitumor immune response was demonstrated by a reduction in Tregs and an increase in the antigen-specific effector T-cell.

Clinical Results – Seasonal Influenza Vaccine 

A vaccine expressing the H3 HA gene (a Wyoming H3N2 strain of influenza virus) led to the efficient - humoral and cellular response - and persistent stimulation of both antibody and T cell responses, in both the young and the elderly. Those with pre-vaccination influenza antibody titers that were unprotective were altered to a protective level. A rapid and dose-dependent T cell response was also observed and remained significantly elevated; and was boosted by a second immunization.

Vaccine for HIV-1 ​

Clinical Results

Two clinical trials (HVTN 040 and HVTN 059) conducted under BB-IND 10171 in the United States and southern Africa, evaluated the safety and immunogenicity of a candidate vaccine. No serious safety concerns were identified. 

HVTN 059 was a randomized, placebo-controlled, double-blind trial that evaluated safety and immunogenicity in healthy, HIV-1 uninfected adults. The immunogenicity results demonstrated a dose-dependent anti-Gag antibody response. After three doses of vaccine, the antibody response in the active vaccine recipients showed a response rate of 100% at the 10 8 IU dosage level (and 80% at the 10 7 IU dosage level). There was also a dose-related cellular immune response. 

Cancer Immunotherapy

Our alphavaccine vector system is unusually well-suited for tumor immunotherapy because of its ability to generate a comprehensive immune response with both antibodies and T cells that specifically target tumor-associated antigens, combined with the ability to sustain immunologic activity over repeated use -- despite the presence of an immune response to the vector. Our immunotherapeutic vaccine for colon cancer had been predicated upon those studies that  demonstrated that tolerance to self-antigen was broken in mice transgenic for carcinoembryonic antigen (CEA) by alphavaccines expressing CEA. 

CEA-expressing cancer (e.g., colon cancer)

- breaking tolerance & enhanced survival potential
- CEA antibody responses

A Phase I / II study was conducted to evaluate the safety and immunogenicity of carcinoembryonic antigen (CEA (6D)) - expressing virus-like replicon particle (VRP) vaccine (AVX701) in patients with advanced or metastatic (Stage IV) CEA-expressing malignancies. 

Following repeated administration, our sRNA vaccine was shown to be effective in eliciting both CEA -specific T cell as well as antibody response: even in the presence of anti-vector neutralizing antibodies and elevated Treg levels. Results suggested that patients with CEA-specific T cell responses exhibited longer overall survival.

A separate study in Stage III cancer led to VRP-CEA activated CEA-specific antibodies with above-baseline titers. The titer, in Stage IV, of 80 rose to almost 500 in Stage III patients. The anti-tumor immune response was demonstrated by a reduction in Tregs, and an increase in the antigen-specific effector T cells. A median follow-up of 60 months showed that all were alive - three patients showing recurrent disease.

​​​​​​HER2-expressing cancer (breast cancer)

- positive T-cell responses

A study of patients with advanced or metastatic breast cancer (all of whom had HER2-expressing malignancy) showed that our RNA particle vaccine candidate produced a clinical benefit by increasing HER2-specific memory CD8 T cells. The vaccine had anti-tumor effects; and the expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased progression-free survival. A Phase II clinical trial comparing this vaccine candidate against pembrolizumab and against a combination of the latter two showed both a cellular and systemic immune benefit.