Antiviral InteliStrat Inc.

Based on VLP (virus-like particle) technology, consisting in proprietary matrix protein forming 3D structure nanoparticle, designed to carry RSV fusion protein "F" (post-fusion stable conformation) on its surface to elicit specific immune response;

Developed as vaccine for infants via maternal immunization (ResVax™), for older adults (60+ years) and for pediatrics (6 months to 5 years) (designated RSV F vaccine);

Modifications have been introduced to ensure that the recombinant viral F-protein in the vaccine is properly folded and more stable than the native (pre-fusion) F protein in the viral envelope;

Formulated with aluminum phosphate as adjuvant

Ref.: Sponsor's website; Gilbert BE et al., Vaccine. 2018 Dec 18;36(52):8069-8078 (www.ncbi.nlm.nih.gov/pubmed/30389195)

Administration by injection

Ref.: Sponsor's website

In preclinical studies, mice were injected twice with 10 µg/dose of VLPs with and without adjuvant, and compared to inoculation of inactivated or live RSV virions, or placebo:

• Highest titer of neutralizing antibodies was obtained with VLPs/adjuvant group
• VLPs induced antibody titers higher than those obtained with live RSV or inactivated RSV
• VLPs induced strong cell-mediated immune responses with activation of CD8+ cytotoxic T-cells against viral F protein
• VLP-inoculated mice had reduced amounts of RSV in their lungs after challenge with live virus

Ref.: Sponsor's website; Smith G et al., PLoS One. 2012;7(11):e50852 (www.ncbi.nlm.nih.gov/pubmed/23226404); Raghunandan R et al., Vaccine. 2014 Nov 12;32(48):6485-92 (www.ncbi.nlm.nih.gov/pubmed/25269094)

On Apr. 2, 2013, Novavax announced top-line results of Phase II dose-ranging clinical trial (NCT01704365) conducted in in women of childbearing age:

• Trial was a randomized, blinded, placebo-controlled study evaluating safety and immunogenicity of two-dose levels (60 µg and 90 µg) of nanoparticle vaccine with and without aluminum phosphate (alum) as adjuvant, in 330 women of childbearing age
• Vaccine was administered IM as either 1 or 2 injections of vaccine or placebo, at study day 0 and day 28, with safety and immunogenicity evaluated over a period of 6 months and 4 months, respectively
• Vaccine was well-tolerated and without any vaccine-related SAEs, with only transient mild to moderate injection site pain, more frequent in adjuvanted vaccine recipients, and mild to moderate headache, fatigue and muscle ache
• IgG antibodies to viral F protein in serum rose 6 to16-fold across both 60 and 90 μg doses, with adjuvant enhancing immune response
• More specifically, peak geometric mean titers of anti-F IgG in the two-dose alum groups ranged from 12,000-14,000 representing a 13 to 16-fold rise, compared to a 6 to10-fold rise in the non-alum groups; minimal increases were observed by increasing the doses (60 to 90 μg)
• Peak geometric mean RSV A neutralizing antibodies in the alum groups ranged from 9.5-10.5 log2, representing a 3.1 to 3.8-fold rise
• Neutralizing antibody responses were seen with both doses and with similar magnitude following first or second vaccinations

On Aug. 10, 2015, Novavax announced top-line results from Phase II study conducted in older adults (60 years of age or older):

• Phase II trial initiated in Oct. 2014 was randomized, observer-blinded, placebo-controlled study done with 1600 older adults in US during 2014-2015 RSV season, who received 135 µg dose of vaccine w/o adjuvant
• Among subjects receiving vaccine (N=759), there were 21 cases of symptomatic RSV infection, compared to 38 cases in placebo group (N=771), representing 43.9% efficacy
• Among subjects receiving vaccine, there were 19 cases of RSV-associated lower respiratory tract infections, compared to 36 cases in placebo group, representing 46.4% efficacy (p=0.03)
• Among subjects receiving vaccine, there was a durable 4.8-fold increase in anti-F IgG response (vs. day 0) at days 14, 28 and 56, with immune response observed in over 93% of subjects; Antibody titers peaked at day 14 post-vaccination, plateaued at day 28 and remained at elevated levels through day 56 (last measurement)
• Safety profile in vaccine group was nearly identical to that of placebo group

On Sep. 29, 2015, Novavax announced top-line data from ongoing Phase II trial NCT02247726:

• Trial was randomized, blinded, placebo-controlled study in which 50 healthy pregnant women in their third trimester were randomized to receive either placebo or 120 µg of RSV F Vaccine adjuvanted with 0.4 mg of aluminum phosphate
• Subjects were followed through remainder of their pregnancies, delivery and for an additional 180 days postpartum to assess safety and immunogenicity as measured by serum RSV anti-F IgG, microneutralizing, and Palivizumab-competing antibody titers; Upon delivery, umbilical cord blood samples were obtained to determine titers of RSV Palivizumab-competing antibody, anti-F IgG, and microneutralizing titers in newborns, and additional serum samples from the infant participants were obtained over the following 6-month period to provide preliminary estimate of half-life of vaccine-induced maternal antibodies
• Women in vaccinated group demonstrated a geometric mean 14-fold rise in anti-F IgG, 29-fold rise in Palivizumab-competing antibody, and 2-fold rise in microneutralization titers, while women who received placebo demonstrated no significant change in their antibody levels
• At delivery, geometric mean anti-F IgG antibody titer in immunized women was 7,244 Elisa Units and on average, the infants' antibody titer equaled 100% of the mothers' anti-F IgG antibody titer; The geometric mean Palivizumab-competing antibody titer was 212 µg/mL in immunized mothers and the average Palivizumab-competing antibody transfer within the mother-infant pairs was 90%
• Geometric mean microneutralizing antibody titers in immunized mothers were 759 and 481 µg/mL for RSV/A and RSV/B respectively, and average microneutralizing antibody transfer within mother-infant pairs was 90% for RSV/A and 100% for RSV/B
• Estimated half-lives of infant Palivizumab-competing antibody, anti-F IgG, RSV/A and RSV/B microneutralizing antibodies, based on data through day 60, were 41, 30, 36 and 34 days, respectively

On Sept. 15, 2016, Novavax announced topline data from Phase III Resolve™ clinical trial of its RSV F Vaccine in older adults:

• Phase III Resolve™ trial was a randomized, observer-blinded, placebo-controlled trial that enrolled 11,856 older adults (60 years of age and older)
• Primary objective was efficacy in prevention of moderate-to-severe RSV-associated lower respiratory tract disease, and secondary objective was efficacy of the vaccine in reducing incidence of all symptomatic respiratory disease due to RSV
• Results in regards of Primary objective: among 5935 individuals who received the placebo, 26 (0.44%) showed moderate-to-severe RSV-associated lower respiratory tract disease, compared to 28 out of 5921 individuals (0.47%) who received the vaccine; Vaccine efficacy was evaluated as -7.9% (CI: -84, 37); p=0.78, not significant
• Results in regards of Secondary objective: among 5935 individuals who received the placebo, 117 (1.97%) showed symptomatic respiratory disease due to RSV, compared to 102 out of 5921 individuals (1.72%) who received the vaccine; Vaccine efficacy was evaluated as 12.6% (CI: -14, 33); p=0.32, not significant
• Vaccine was well tolerated

On Jul. 24, 2017, Novavax announced topline data from its Phase II safety and immunogenicity trial NCT03026348 (E205) of the RSV-F Vaccine in older adults:

• Objective of the Phase II randomized, observer-blinded, placebo-controlled trial was to assess safety and immunogenicity of one and two-dose regimens of the RSV-F Vaccine, with and without aluminum phosphate or Novavax’ proprietary Matrix-M™ adjuvant, in 300 older adults who were enrolled and vaccinated outside of the RSV season to best assess immunogenicity of the treatment arms
• Immunogenicity outcomes indicate both aluminum phosphate and Matrix-M adjuvants significantly increased the magnitude, duration and quality of the immune response relative to a control of 135 µg dose of the RSV-F antigen alone (the formulation used in the prior Phase III older adults efficacy study)
• Similarly, two-dose regimens significantly increased immune responses and suggests two doses of the RSV-F Vaccine with adjuvant may augment durability of the immune response to the vaccine
• According to the sponsor, the data strongly support the inclusion of adjuvanted formulations of the RSV-F Vaccine in future older adult trials
• All formulations and regimens were safe and well-tolerated

Ref.: Glenn GM et al., Vaccine. 2013 Jan 7;31(3):524-32 (www.ncbi.nlm.nih.gov/pubmed/23153449); Glenn GM et al., J Infect Dis. 2016 Feb 1;213(3):411-22 (www.ncbi.nlm.nih.gov/pubmed/26259809); August A et al., Vaccine. 2017 Jun 27;35(30):3749-3759 (www.ncbi.nlm.nih.gov/pubmed/28579233); Fries L et al., Immun Ageing. 2017 Apr 12;14:8 (www.ncbi.nlm.nih.gov/pubmed/28413427)

Preliminary data from Phase III study (Prepare™) were announced via Press Release on Feb. 28, 2019:

• In the trial, efficacy of ResVax against the primary and two secondary endpoints in per-protocol infants with RSV lower respiratory tract infection (LRTI) through 90 days of life was evaluated as being:

    39% against medically significant RSV LRTI (97.5%CI, -1% to 64%)
    44% against RSV LRTI hospitalizations (95%CI, 20% to 62%)
    48% against RSV LRTI with severe hypoxemia (95%CI, -8% to 75%)

• Pre-specified exploratory analyses of these same vaccine efficacy endpoints, which included additional data ascertained from hospitalization records, were:

    41% against medically significant RSV LRTI (95%CI, 16% to 58%)
    42% against RSV LRTI hospitalizations (95%CI, 17% to 59%)
    60% against RSV LRTI with severe hypoxemia (95%CI, 32% to 76%)

• While the study did not meet the pre-specified success criterion for the primary clinical endpoint of this trial, the sponsor believed that ResVax did protect infants from some of the most serious consequences of RSV infection, including RSV LRTI hospitalizations and RSV LRTI with severe hypoxemia;
  According to the sponsor, ResVax was associated with the following positive findings:
• Reduction in all-cause LRTI hospitalizations (25%) and all-cause LRTI severe hypoxemia (39%) in infants observed through the first 180 days of life
• Mothers vaccinated from 28 up to < 33 weeks of pregnancy, showed vaccine efficacy rates against RSV LRTI hospitalization of 53% and severe RSV hypoxemia of 70% through the first 90 days of their infants’ lives, compared with 26% and 44% for mothers vaccinated >= 33 weeks of pregnancy
• Over 90% of RSV LRTI hospitalizations and RSV LRTI severe hypoxemia in the placebo group occurred in the first 90 days of life
• 99% of vaccinated mothers had measurable antibody responses to the vaccine, with >=100% transplacental transfer for all antibody types measured
• ResVax appeared safe in mothers and their infants through 180 days post-delivery

Ref.: Press Release dated Feb. 28, 2019 (ir.novavax.com/news-releases/news-release-details/novavax-announces-topline-results-phase-3-preparetm-trial)