Item 1A Risk Factors 30
Item 1B Unresolved Staff Comments 51
Item 1C Cybersecurity 51
Item 2 Properties 52
Item 3 Legal Proceedings 52
Item 4 Mine Safety Disclosures 52
PART II
Item 6 [Reserved] 53
Item 7A Quantitative and Qualitative Disclosures About Market Risk 57
Item 8 Financial Statements and Supplementary Data 57
Item 9A Controls and Procedures 57
Item 9B Other Information 57
Item 9C Disclosure Regarding Foreign Jurisdictions that Prevent Inspections. 57
PART III
Item 10 Directors, Executive Officers, and Corporate Governance 58
Item 11 Executive Compensation 67
Item 14 Principal Accountant Fees and Services 73
PART IV
SIGNATURES 78
Forward-Looking
Statements
This
Annual Report on Form 10-K contains forward-looking statements which are made pursuant to the safe harbor provisions of Section 27A of
the Securities Act of 1933, as amended (the “Securities Act”), and Section 21E of the Securities Exchange Act of 1934, as
amended (the “Exchange Act”). These statements may be identified by such forward-looking terminology as “may,”
“should,” “expects,” “intends,” “plans,” “anticipates,” “believes,”
“estimates,” “predicts,” “potential,” “continue” or the negative of these terms or other
comparable terminology. Our forward-looking statements are based on a series of expectations, assumptions, estimates and projections
about our company, are not guarantees of future results or performance and involve substantial risks and uncertainty. We may not actually
achieve the plans, intentions or expectations disclosed in these forward-looking statements. Actual results or events could differ materially
from the plans, intentions and expectations disclosed in these forward-looking statements. Our business and our forward-looking statements
involve substantial known and unknown risks and uncertainties, including the risks in the section titled “Risk Factors”,
that may cause our or our industry’s actual results, levels of activity, performance or achievements to be materially different
from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. In
addition, you are directed to factors discussed in the “Business” section and the “Management’s Discussion
and Analysis of Financial Condition and Results of Operations” section, as well as those discussed elsewhere in this Annual
Report on Form 10-K.
All
of our forward-looking statements are as of the date of this Annual Report on Form 10-K only. In each case, actual results may differ
materially from such forward-looking information. We can give no assurance that such expectations or forward-looking statements will
prove to be correct. An occurrence of, or any material adverse change in, one or more of the risk factors or risks and uncertainties
referred to in this Annual Report on Form 10-K or included in our other public disclosures or our other periodic reports or other documents
or filings filed with or furnished to the U.S. Securities and Exchange Commission (the “SEC”) could materially and adversely
affect our business, prospects, financial condition and results of operations. Except as required by law, we do not undertake or plan
to update or revise any such forward-looking statements to reflect actual results, changes in plans, assumptions, estimates or projections
or other circumstances affecting such forward-looking statements occurring after the date of this Annual Report on Form 10-K, even if
such results, changes or circumstances make it clear that any forward-looking information will not be realized. Any public statements
or disclosures by us following this Annual Report on Form 10-K that modify or impact any of the forward-looking statements contained
in this Annual Report on Form 10-K will be deemed to modify or supersede such statements in this Annual Report on Form 10-K.
This
Annual Report on Form 10-K may include market data and certain industry data and forecasts, which we may obtain from internal company
surveys, market research, consultant surveys, publicly available information, reports of governmental agencies and industry publications,
articles and surveys. Industry surveys, publications, consultant surveys and forecasts generally state that the information contained
therein has been obtained from sources believed to be reliable, but the accuracy and completeness of such information is not guaranteed.
While we believe that such studies, clinical trials and publications are reliable, we have not independently verified market and industry
data from third-party sources.
Risk
Factor Summary
Our
business is subject to significant risks and uncertainties that make an investment in us speculative and risky. Below we summarize what
we believe are the principal risk factors but these risks are not the only ones we face, and you should carefully review and consider
the full discussion of our risk factors in the section titled “Risk Factors”, together with the other information
in this Annual Report on Form 10-K. If any of the following risks actually occurs (or if any of those listed elsewhere in this Annual
Report on Form 10-K occur), our business, reputation, financial condition, results of operations, revenue, and future prospects could
be seriously harmed. Additional risks and uncertainties that we are unaware of, or that we currently believe are not material, may also
become important factors that adversely affect our business.
● There is substantial doubt about our ability to continue as a going concern;
● We are a pre-revenue clinical stage company;
● We are developing novel technologies which may not be effective or safe;
● We have an unproven market for our product candidates;
● We must obtain additional capital to continue our operations;
● We are highly dependent on our key personnel;
PART
I
ITEM
1. BUSINESS
BUSINESS
Overview
of the Company
BriaCell
Therapeutics Corp. (“Briacell” or the “Company”) is a clinical-stage biotechnology company that is developing
novel immunotherapies to transform cancer care. Immunotherapies have come to the forefront in the fight against cancer as they harness
the body’s own immune system to recognize and destroy cancer cells. The Company is currently advancing its Bria-IMTTM targeted
immunotherapy in combination with an immune check point inhibitor (Retifanlimab) in a pivotal1 Phase 3 study in metastatic
breast cancer. Bria-IMTTM is currently under Fast Track Designation by the U.S. Food and Drug Administration (the “FDA”)
intended to accelerate the review process of novel treatments that address unmet medical needs. Positive completion of the pivotal study,
following review by FDA, could lead to full approval of the Bria-IMTTM immune checkpoint inhibitor combination in metastatic breast
cancer. BriaCell reported benchmark-beating patient survival and clinical benefit in metastatic breast cancer with median overall survival
of 13.4 months in BriaCell’s metastatic breast cancer patients vs. 6.7-9.8 months2 for similar patients reported in
the literature in its Phase 2 study of Bria-IMTTM combination study with retifanlimab at the 2023 San Antonio Breast Cancer Symposium.
Additionally, BriaCell reported median overall survival of 15.6 months in Phase 2 Bria-IMTTM study patients treated in
combination with immune checkpoint inhibitor in patients treated with the Phase 3 formulation since 2022 (post-COVID). A completed
Bria-IMTTM Phase 1 combination study with retifanlimab (an anti-PD1 antibody manufactured by Incyte) confirmed tolerability and
early-stage efficacy. BriaCell is also developing personalized off-the-shelf immunotherapies, Bria-OTSTM and Bria-OTS+TM, which
provides a platform technology to develop personalized off-the-shelf immunotherapies for numerous types of cancer. In September 2024,
the Company announced BriaCell has received positive feedback from its Pre-Investigational New Drug Application (Pre-IND) meeting
with FDA for Bria-PROS+TM for prostate cancer.
Market
It
is estimated by the National Cancer Institute Cancer Facts and Figures that in 2024, approximately 310,720 women will be diagnosed with
breast cancer in the United States. That means that every two minutes an American woman is diagnosed with breast cancer and more than
42,250 are projected to die in 2024. Although about 100 times less common than in women, breast cancer also affects men. It is estimated
that the lifetime risk of men getting breast cancer is about 1 in 1,000, and the American Cancer Society estimates that approximately
2,790 new cases of invasive male breast cancer will be diagnosed and approximately 530 men will die from breast cancer in 2024.
According
to the May 2023 “Global Oncology Trends 2023” report by the IQVIA Institute, the global market for cancer drugs (including
immunotherapy drugs) is expected to reach nearly $375 billion by the end of 2027, growing at a compound annual growth rate (“CAGR”)
of 17% between 2023 and 2027, of which about 20% is expected to be immuno-oncology drugs.
1
“Pivotal” is an industry term referring to a Phase 3 clinical study intended to show and confirm the safety and efficacy
of a treatment.
2
Cortes J, et al. Annals of Oncology 2018; Kazmi S, et al. Breast Cancer Res Treat. 2020 Aug 17; O’Shaughnessy J et al. Breast
Cancer Res Treat. 2022; Tripathy D, et al. JAMA Oncol. 2022
About
13% percent of women will be diagnosed with breast cancer at some point during their lifetime. In 2024, over 4 million women were living
with female breast cancer in the United States. Approximately 83% of cases present as invasive breast cancer. Approximately 6% of new
breast cancer diagnoses are Stage IV (metastatic breast cancer (“MBC”), which has already spread to other organs). Twenty
to thirty percent of all women diagnosed with breast cancer will develop MBC. Breast cancer can be subdivided based on receptor status
- the hormone receptors for estrogen (ER) and progesterone (PR), collectively referred to as hormone receptors (HR), and the Her2/neu
growth factor receptor (HER2). Based on the latest SEER statistics, 68% were found to be HR+/HER2−, 10% were triple-negative (HR−/HER2−),
10% were HR+/HER2+, and 4% were HR−/HER2+.1
It
is estimated that over 150,000 women in the US were living with MBC in 20152 and this is projected to increase to over 240,000
by 2030. For those with metastatic disease at diagnosis, their 5-year survival rate is 30%.1 For patients who develop MBC
after initially having localized disease, if they had a good response to treatment (i.e. a disease-free interval of more than 24 months),
their survival rate is similar to that of patients with MBC at initial diagnosis, but if their disease-free interval is less than 24
months, their prognosis is worse.4 We currently propose that Bria-IMT’sTM indication will be for the treatment
of patients with MBC who have no approved alternative therapies available. Similarly, another study showed that the median overall survival
among patients with de novo stage IV MBC was 39.2 months, while for patients with relapsed disease it was 27.2 months.5 Median
progression free survival after first-line therapy is only 9 months and the survival benefit decreases with subsequent lines of therapy.6
One study showed that of 386 patients with MBC, 374 (97%) received first-line therapy, 254 (66%) received second-line therapy,
175 (45%) received third-line therapy, and 105 (27%) received therapy beyond third-line.7 More recent data indicates that
for patients with MBC who have received 2 or more prior lines of therapy, median survival is 5.9-9.8 months.
1
See https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/2022-2024-breast-cancer-fact-figures-acs.pdf
2
Mariotto AB, Etzioni R, Hurlbert M, Penberthy L, Mayer M. Estimation of the Number of Women Living with Metastatic Breast Cancer
in the United States. Cancer Epidemiol Biomarkers Prev. 2017 Jun;26(6):809-815.
3
Breast Cancer Facts & Figures 2017-2018. Atlanta: American Cancer Society, Inc. 2017.
4
Lobbezoo, D. J. A. et al. Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated
with the most favorable outcome. Breast Cancer Res. Treat. 141, 507-514 (2013).
5
Dawood S, Broglio K, Ensor J, Hortobagyi GN, Giordano SH. Survival differences among women with de novo stage IV and relapsed breast
cancer. Ann Oncol. 2010 Nov; 21(11):2169-74.
6
Bonotto M, Gerratana L, Iacono D, Minisini AM, Rihawi K, Fasola G, Puglisi F. Treatment of Metastatic Breast Cancer in a Real-World
Scenario: Is Progression-Free Survival With First Line Predictive of Benefit From Second and Later Lines? Oncologist.
7
Kotsakis A, Ardavanis A, Koumakis G, Samantas E, Psyrri A, Papadimitriou C. Epidemiological characteristics, clinical outcomes
and management patterns of metastatic breast cancer patients in routine clinical care settings of Greece: Results from the EMERGE multicenter
retrospective chart review study. BMC Cancer. 2019 Jan 18;19(1):88.
Figure
A: Overview of current drugs for breast cancer, demonstrating the pattern of novel therapeutic introductions and significant market
uptake. These precedents demonstrate a strong market pull for Bria-IMTTM.
■ $2-5Bil Opportunity in Breast Cancer
■ Up to $25Bil Opportunity across broad indications
*
Worldwide sales figure is based on SEC filings
**
Approved for multiple cancer indications.
References
for figure A:
1.https://pubmed.ncbi.nlm.nih.gov/31235441/
2.https://pubmed.ncbi.nlm.nih.gov/23810467/
3.https://pubmed.ncbi.nlm.nih.gov/25501126/
4.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8676999/
5.https://pubmed.ncbi.nlm.nih.gov/15699478/
6.https://pubmed.ncbi.nlm.nih.gov/18000498/
7.https://pubmed.ncbi.nlm.nih.gov/20124182/
8.https://www.nejm.org/doi/10.1056/NEJMoa1814213?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
9.https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.1095
10.https://pubmed.ncbi.nlm.nih.gov/20421541/
11.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581697/
12.https://aacrjournals.org/clincancerres/article/26/20/5310/82934/A-Phase-II-Study-of-Abemaciclib-in-Patients-with
13.https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70329-7/abstract
14.https://pubmed.ncbi.nlm.nih.gov/20421541/
15.https://pubmed.ncbi.nlm.nih.gov/21172893/
For further information on our lead candidate Bria-IMTTM
clinical development, see “Bria-IMTTM” in the “Production /Pipeline” section.
Competition
Currently
available therapeutic options for breast cancer offer some hope for patients, but there is much room for improvement. Comparable studies
looking primarily at second line or later treatment are shown in Table “A”, below. Evaluating response rates (partial and
complete responses = ORR), progression free survival (“PFS”) and overall survival (“OS”) from clinical trials
in similar subjects with metastatic or recurrent breast cancer indicate that response rates range from 2.7% up to 59%, depending on the
population studied and the intervention (median 24%). PFS ranges from 8 weeks to 12 months (median 5 months) and OS from 6 months to
31 months (median 13 months).
Table
A: Studies evaluating second-line or later treatment options. Data depict an unpredictable response rate to treatment ranging from
6.9-59%, therefore establishing and confirming the opportunity for Bria-IMTTM.
Study Treatment & Design # of Pts ORR PFS/TTP OS
Licchetta1 Cyclophosphamide and megestrol acetate 29 31 % 7.4 mo 13.4 mo
Leyland-Jones6 Trastuzumab with paclitaxel 32 59 % 12.2 mo
von Minckwitz7 Trastuzumab with capecitabine 78 48.1 % 8.2 mo 25.5 mo
Geyer9 Lapatinib plus capecitabine 163 22 % 8.4 mo
Capecitabine Monotherapy 161 14 % 4.4 mo
Bartsch10 Capecitabine and trastuzumab 40 20 % 8 mo 24 mo
alkylating agent 296 7.2 mo
Capecitabine 80 9.3 mo
Treatment of Physicians Choice 233 4 % 2.3 mo 6.7 mo
Tripathy15 Etirinotecan Pegol 92 4.8 % 2.8 mo 7.8 mo
Treatment of Physicians Choice 86 2.7 % 1.9 mo 7.5 mo
MBC
treated with second or higher lines of therapy has a very poor prognosis and few effective therapies that consistently induce long-term
remission,15 which indicates the market demand and clinical need for new and improved therapeutic drugs and treatment options
in order to improve these response outcomes and patient survival rates. Thus, Bria-IMTTM has the potential to induce long-term remission,
especially in combination with immunotherapies. Current treatment of MBC is outlined in Figure “B”, below, which illustrates
different therapeutic treatment options and drugs used upon diagnoses from biopsy and identification of breast cancer biomarkers.16
1 Licchetta A, Correale P, Migali C, Remondo C, Francini E, Pascucci A, Magliocca A, Guarnieri A, Savelli V, Piccolomini A, Carli
AF, Francini G. Oral metronomic chemo-hormonal-therapy of metastatic breast cancer with cyclophosphamide and megestrol acetate. J Chemother.
2010 Jun;22(3):201-4.
2
Harvey, V. et al. Phase III Trial Comparing Three Doses of Docetaxel for Second-Line Treatment of Advanced Breast Cancer. J. Clin.
Oncol. 24, 4963-4970 (2006).
3
Rivera, E. et al. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic
breast cancer. Cancer 112, 1455-1461 (2008).
4
Gradishar WJ. Taxanes for the treatment of metastatic breast cancer. Breast Cancer (Auckl). 2012;6:159-71.
5
Perez, E. A. et al. Efficacy and Safety of Ixabepilone (BMS-247550) in a Phase II Study of Patients With Advanced Breast Cancer
Resistant to an Anthracycline, a Taxane, and Capecitabine. J. Clin. Oncol. 25, 3407-3414 (2007).
6
Leyland-Jones, B. et al. Pharmacokinetics, Safety, and Efficacy of Trastuzumab Administered Every Three Weeks in Combination With
Paclitaxel. J. Clin. Oncol. 21, 3965-3971 (2003). Only 41% of patients had prior systemic chemotherapy.
7
von Minckwitz G et el. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive
breast cancer. Eur J Cancer. 2011 Oct;47(15):2273-81. Prior therapy limited to trastuzamab alone or in combination with a taxane.
8
Verma, S. et al. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. N. Engl. J. Med. 367, 1783-1791 (2012).
9
Geyer, C. E. et al. Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer. N. Engl. J. Med. 355, 2733-2743 (2006).
10
Bartsch, R. et al. Capecitabine and Trastuzumab in Heavily Pretreated Metastatic Breast Cancer. J. Clin. Oncol. 25, 3853-3858 (2007).
11
Blackwell, K. L. et al. Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory
Metastatic Breast Cancer. J. Clin. Oncol. 28, 1124-1130 (2010).
12 Cortes
J, Perez-Garcia J, Levy C, Gómez Pardo P, Bourgeois H, Spazzapan S, Martínez-Jañez N, Chao TC, Espié M,
Nabholtz JM, Gonzàlez Farré X, Beliakouski V, Román García J, Holgado E, Campone M. Open-label
randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer.
Ann Oncol. 2018 Apr 1;29(4):881-887. Doi: 10.1093/annonc/mdy051. PMID: 29481630.
13 Kazmi
S, Chatterjee D, Raju D, Hauser R, Kaufman PA. Overall survival analysis in patients with metastatic breast cancer and liver or lung
metastases treated with eribulin, gemcitabine, or capecitabine. Breast Cancer Res Treat. 2020 Nov;184(2):559-565. Doi:
10.1007/s10549-020-05867-0. Epub 2020 Aug 17. Erratum in: Breast Cancer Res Treat. 2021 Jun;187(2):603. PMID: 32808239; PMCID:
PMC7599186.
14 O’Shaughnessy
J, Brufsky A, Rugo HS, Tolaney SM, Punie K, Sardesai S, Hamilton E, Loirat D, Traina T, Leon-Ferre R, Hurvitz SA, Kalinsky K, Bardia
A, Henry S, Mayer I, Zhu Y, Phan S, Cortés J. Analysis of patients without and with an initial triple-negative breast cancer
diagnosis in the Phase 3 randomized ASCENT study of sacituzumab govitecan in metastatic triple-negative breast cancer. Breast Cancer
Res Treat. 2022 Sep;195(2):127-139. Doi: 10.1007/s10549-022-06602-7. Epub 2022 May 11. PMID: 35545724; PMCID: PMC9374646.
15 Tripathy
D, Tolaney SM, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves C, Dieras V, Müller V, Tagliaferri M, Hannah AL,
Cortés J. ATTAIN: Phase III study of etirinotecan pegol versus treatment of physician’s choice in patients with
metastatic breast cancer and brain metastases. Future Oncol. 2019 Jul;15(19):2211-2225. Doi: 10.2217/fon-2019-0180. Epub 2019 May
10. PMID: 31074641; PMCID: PMC7466911.
16
NCCN Guidelines Version 2.2019, 07/02/2019 © 2019 National Comprehensive Cancer Network (NCCN®).
Figure
B: Current treatment paradigm for metastatic breast cancer including between different treatment strategies and combination therapies
dependent upon biomarker identification and activity within the breast cancer signaling pathway.
Of
patients treated with trastuzumab for MBC, one study showed that 241/331 (72%) progressed within 27 months (32% per year) with median
survival of 13-14 months (CI 10-15 months).1 This indicates the high unmet need in this patient population which should facilitate
regulatory review of novel therapies such as Bria-IMTTM.
There are a number of cancer vaccines
in development for breast cancer, including but not limited to TPIV200 (Marker Therapeutics, Inc.), AE-37 (Antigen Express), and Stimuvax
(Merck KgA). While these development candidates are aimed at a number of different targets, and AE-37 has published data in the HER2 breast
cancer patient population, there is no guarantee that any of these compounds will not in the future be indicated for treatment of low-to-intermediate
HER2 breast cancer patients and become directly competitive with Bria-IMT.
While
there are many biotech companies working to create an effective breast cancer vaccine, a significant gap remains in the effectiveness
and safety of second or higher lines of therapy. The most studied targeted immunotherapy, Neuvax (Galena), a HER2 peptide vaccine, failed
a Phase III trial, but there is encouraging data to support at least three ongoing clinical trials combining trastuzumab with HER2 epitope
immunogens.2 The National Cancer Institute (“NCI”) randomized trial adding PANVAC (a poxviral-based immunogen)
to docetaxel increased the median PFS from 3.9 months to 7.9 months and is to be used as a basis for larger, more sophisticated clinical
trials.3 An immunogen targeting a carbohydrate antigen, globo-H, was associated with improved PFS, but only in the subset
able to mount antibody responses.4 A Johns Hopkins breast cancer trial using a breast cancer cell line transfected with the
gene for GM-CSF has not been positive but, using the same cell line with trastuzumab, 40% of patients enjoyed clinical benefit (CR+PR+stable)
at one year.5 Finally, the study of targeted cancer immunotherapies in combination with other therapies is receiving much
attention, particularly combination with checkpoint inhibitors.6
1 Rossi, V.; Nole, F.; Redana, S.; Adamoli, L.; Martinello, R.; Aurilio, G.; Verri, E.; Sapino, A.; Viale, G.; Aglietta, M.; Montemurro,
F., Clinical outcome in women with HER2-positive de novo or recurring stage IV breast cancer receiving trastuzumab-based therapy. Breast
2014, 23 (1), 44-9.
2
Mittendorf, E. A.; Peoples, G. E., Injecting Hope-A Review of Breast Cancer Vaccines. Oncology (Williston Park) 2016, 30 (5), 475-81,
485.
3
Heery, C. R.; Ibrahim, N. K.; Arlen, P. M.; Mohebtash, M.; Murray, J. L.; Koenig, K.; Madan, R. A.; McMahon, S.; Marte, J. L.;
Steinberg, S. M.; Donahue, R. N.; Grenga, I.; Jochems, C.; Farsaci, B.; Folio, L. R.; Schlom, J.; Gulley, J. L., Docetaxel Alone or in
Combination With a Therapeutic Cancer Vaccine (PANVAC) in Patients With Metastatic Breast Cancer: A Randomized Clinical Trial. JAMA Oncol
2015, 1 (8), 1087-95.
4
Huang, C.; Yu, A.; Tseng, L., Randomized phase II/III trial of active immunotherapy with OPT-822/OPT-821 in patients with metastatic
breast cancer. J Clin Oncol 2016, 34 (15).
5
Chen, G.; Gupta, R.; Petrik, S.; Laiko, M.; Leatherman, J. M.; Asquith, J. M.; Daphtary, M. M.; Garrett-Mayer, E.; Davidson, N.
E.; Hirt, K.; Berg, M.; Uram, J. N.; Dauses, T.; Fetting, J.; Duus, E. M.; Atay-Rosenthal, S.; Ye, X.; Wolff, A. C.; Stearns, V.; Jaffee,
E. M.; Emens, L. A., A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for
HER2+ metastatic breast cancer. Cancer Immunol Res 2014, 2 (10), 949-61.
6
McArthur, H. L.; Page, D. B., Immunotherapy for the treatment of breast cancer: checkpoint blockade, cancer vaccines, and future
directions in combination immunotherapy. Clin Adv Hematol Oncol 2016, 14 (11), 922-933.
There
are several other approaches to developing targeted breast cancer immunotherapies. These include using peptide cocktails, a triple peptide
regimen, recombinant HER2, antigen-pulsed dendritic cells, DNA immunogens, whole cell allogeneic GM-CSF secreting SKBR3 or T47D cells,
an (HLA)-A2/A3-restricted immunogenic peptide derived from the HER2 protein, oxidized mannan-MUC1, and personalized peptide immunogens.
Among
the most promising results in patients with advanced disease have been using whole-cell preparations, particularly if the cells are engineered
to express GM-CSF. We are taking this approach and capitalizing on positive initial results with Bria-IMTTM monotherapy in difficult
to treat patients using a regimen that both limits regulatory T cell activity (using low dose cyclophosphamide pre-treatment) and boosts
the immune response (using post-dose alpha interferon in the inoculation sites). The combination with PD-1 inhibitors is a logical extension
of our findings where 21 of 23 MBC patients had demonstrable PD-L1 expression on the circulating tumor cells (“CTCs”) and/or
circulating cancer-associated macrophage-like cells (“CAMLs”). The overall strategy, once the initial milestones have been
met, to enroll additional patients for product registration, will allow rapid progression of the best therapeutic option to a Biologics
License Application (“BLA”).
Cancer
immunotherapy has become a significant growth area for the biopharmaceutical industry, attracting large pharmaceutical companies as well
as small niche players. Generally, our principal competitors in the cancer immunotherapy market comprise both companies with currently
approved products for various indications, such as manufacturers of approved bispecific antibodies, CAR-T cells, and checkpoint inhibitors,
as well as companies currently engaged in cancer immunotherapy clinical development. The large and medium-size players who have successfully
obtained approval for cancer immunotherapy products include Bristol-Myers Squib Company, Merck & Co., Inc., Genentech, Inc. (a subsidiary
of Roche Holding AG), AstraZeneca PLC, Celgene Corporation, Johnson & Johnson/Janssen Pharmaceuticals, Amgen, Novartis, Acerta Pharmaceuticals
(a subsidiary of AstraZeneca), Juno Therapeutics, Inc. (a subsidiary of Celgene), Kite Pharma, Inc., a wholly-owned subsidiary of Gilead
Sciences, Inc. and Pfizer, Inc./EMD Serono, Inc. Most of these companies, either alone or together with their collaborative partners,
have substantially greater financial resources than does BriaCell.
Companies
developing novel products with similar indications to those we are pursuing are expected to influence our ability to penetrate and maintain
market share. For patients with early stage breast cancer, adjuvant therapy is often given to prevent recurrence and increase the chance
of long-term disease-free survival. Adjuvant therapy for breast cancer can include chemotherapy, hormonal therapy, radiation therapy,
or combinations thereof. In addition, the HER2 targeted drug trastuzumab (HERCEPTIN), alone or in combination with pertuzumab (PERJETA),
both manufactured and marketed by Roche/Genentech, may be given to patients with tumors with high expression of HER2 (IHC 3+), as well
as other novel targets such as MUC1, which may be useful in treating breast cancer. In addition, the FDA approved the first ever immunotherapy
regimen for breast cancer to the Roche/Genentech PD-L1 checkpoint inhibitor atezolizumab (TECENTRIQ), combined with Celgene’s nab-paclitaxel
(ABRAXANE) for TNBC that cannot be removed with surgery and is locally advanced or metastatic.
Many
of our competitors, either alone or with their strategic partners, have substantially greater financial, technical and human resources
than we do, and also have greater experience in obtaining FDA and other regulatory approvals of treatments and commercializing those
treatments. Accordingly, our competitors may be more successful than us in obtaining approval for cancer immunotherapy products and achieving
widespread market acceptance. Our competitors’ treatments may be more effectively marketed and sold than any products we may commercialize,
thus causing limited market share before we can recover the expenses of developing and commercializing of our cancer immunotherapy product
candidate.
Mergers
and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated among a smaller
number of our competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative
arrangements with large and established companies. These activities may lead to consolidated efforts that allow for more rapid development
of cancer immunotherapy product candidates.
These
competitors also compete with us in recruiting and retaining qualified scientific and management personnel, the ability to work with
specific clinical contract organizations due to conflicts of interest, and the conduct of trials in the ability to recruit clinical trial
sites and subjects for our clinical trials.
We
expect any products that we develop and commercialize to compete on the basis of, among other things, efficacy, safety, price and the
availability of reimbursement from government and other third-party payors. Our commercial opportunity could be reduced or eliminated
if our competitors develop and commercialize products that are viewed as safer, more convenient or less expensive than any products that
we may develop. Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval
for our current product candidates or any other future product candidate, which could result in our competitors establishing a strong
market position before we are able to enter the market.
Products/Pipeline
Bria-IMTTM
About Bria-IMTTM
Bria-IMTTM,
BriaCell’s lead candidate, is a whole-cell immunotherapy. Bria-IMTTM in combination with an immune check point inhibitor is
undergoing pivotal Phase 3 clinical testing in patients with advanced MBC patients who have failed prior lines of therapy. The pivotal
Phase 3 combination study is listed on ClinicalTrials.gov as NCT06072612.
Developed
and characterized by a team of dedicated scientists and clinicians, Bria-IMTTM (SV-BR-1-GM) is a targeted immunotherapy being developed
for the treatment of breast cancer. Bria-IMTTM is a genetically engineered human breast cancer cell line with features of immune
cells and clinically applied as a targeted immunotherapy.
In
short, Bria-IMTTM immunotherapy is a genetically engineered human breast cancer cell line derived from a grade II tumor which activates
the immune system to attack and destroy breast cancer tumors.
Mechanism
of Action of Bria-IMTTM
The
mechanism of action of Bria-IMTTM is currently under investigation. It is likely that the expression of certain breast cancer antigens
(proteins expressed in breast cancer cells) in Bria-IMTTM generates strong T cell and potentially antibody responses - resulting
in recognition and destruction of cancerous cells.37
Bria-IMTTM
is designed to secrete GM-CSF, a factor that stimulates components of the immune system. Specifically, GM-CSF activates dendritic cells,
the cells that start immune responses. These activated dendritic cells then activate T cells, a key component of the immune system, to
recognize the tumor cells as foreign, and eliminate them. To amplify this action, we have combined Bria-IMTTM with other immune
system activators including cyclophosphamide (used in low doses to reduce immune suppression), and interferon-α, a cytokine that
further activates the immune system. We believe this approach of simultaneous activation of the immune system via different pathways
will improve the immune system response to attack and destroy cancer cells.
Pivotal
Phase 3 Clinical Study of Bria-IMTTM in Combination with an Immune Check Point Inhibitor in Metastatic Breast Cancer
Bria-IMTTM
is currently under Fast Track Designation by the FDA intended to accelerate the
review process of novel treatments that address unmet medical needs. Positive completion of the pivotal study, following review by the
FDA, could lead to full approval of the Bria-IMTTM immune checkpoint inhibitor combination in advanced metastatic breast cancer.
The
FDA has agreed that improvement in overall survival in the Bria-IMTTM combination arm as compared to the physician’s choice
of treatment arm will be the primary endpoint of the study. The study is expected to enroll 177 patients in the Bria-IMTTM combination
therapy arm and 177 patients in the treatment of physician’s choice arm. To gather additional information on the Bria-IMTTM
regimen alone, 50 patients are expected to be enrolled in this regimen and will be eligible for combination therapy following their initial
post treatment evaluation. The study will have an interim evaluation for efficacy which could result in early completion of the study.
We expect frequent and responsive FDA communication under our Fast Track status during our pivotal Phase 3 study.
The
successful completion of the pivotal study would allow BriaCell to subsequently submit a Biologics License Application and accelerate
the path to commercialization.
BriaCell’s
partnership with New York Cancer & Blood Specialists (“NYCBS”) as clinical site with more than 30 locations and 35 hospital
affiliations throughout Nassau and Suffolk counties, in the Bronx, Manhattan, Queens, Staten Island, and Brooklyn to conduct its pivotal
Phase 3 Study of Bria-IMTTM in Advanced Breast Cancer. Currently the Phase 3 study has 14 locations throughout the USA as
noted in the ClinicalTrials.gov listing https://clinicaltrials.gov/study/NCT06072612.
In
collaboration with Prevail InfoWorks, Inc. (“InfoWorks”), a Philadelphia, PA based contract research organization, BriaCell
continues to recruit additional sites to speed up the patient recruitment process. BriaCell has signed a Master Service and Technology
Agreement (“MSTA”) agreement with InfoWorks to provide clinical services and technologies for BriaCell’s upcoming pivotal
study in advanced metastatic breast cancer. Services include clinical site coordination, project management, clinical monitoring and
pharmacovigilance (safety management) services, and the use of InfoWork’s integrated real-time data analytics platform, The Single
Interface ®, for clinical support and real-time data analysis.
In May 2023, Prevail
Partners, LLC (“Prevail Partners”), an investment fund and affiliate of InfoWorks, purchased 463,408 BriaCell common
shares at a price of $8.63 for gross proceeds of $4 million, representing a 20% premium to the trailing thirty (30) trading day
volume-weighted average price of the common shares of the Company on the Nasdaq Stock Exchange.
Phase
1/2 Clinical Trial of Bria-IMTTM in Combination with Immune Check Point Inhibitors in Advanced Metastatic Breast Cancer
BriaCell
has been conducting a Phase 1/2a clinical trial of Bria-IMTTM, in combination with immune checkpoint inhibitors such as pembrolizumab
(KEYTRUDA®; manufactured by Merck & Co., Inc.) and retifanlimab, an immune checkpoint inhibitor manufactured by Incyte. The
combination study is listed in ClinicalTrials.gov as NCT03328026 under FDA-approved BB-IND 10312 under protocol BRI-ROL-001 at ten clinical
sites throughout the United States.
BriaCell
announced benchmark-beating patient survival and clinical benefit in advanced metastatic breast cancer with median overall survival of
13.5 months in BriaCell’s advanced metastatic breast cancer patients vs. 6.7-9.8 months1 for similar patients reported
in the literature.
The
ongoing study of BRI-ROL-001 combination therapy studies of the Bria-IMTTM regimen with immune checkpoint inhibitors (CPI). In
the ongoing study of BRI-ROL-001, in phase I the Bria-IMTTM regimen was dosed in combination with Keytruda ® in 11 patients
and in 12 patients with retifanlimab, with one patient starting on the combination with
Keytruda® and crossing-over to the combination with retifanlimab (22 patients total). In phase II of the study, the
Bria-IMTTM regimen is being dosed in combination with retifanlimab with patients randomized to either receive the
Bria-IMTTM regimen first (16 patients) or retifanlimab first (16 patients). For the 11 patients treated in combination with
Keytruda® in phase I, the disease control data is shown below:
■ 11 patients were treated with Bria-IMTTM + Keytruda®
■ Tolerability excellent with no dose-limiting toxicities
■ Clinical benefit demonstrated: 1 PR and 3 SD in 8 immune responders
For
the 12 patients treated in combination with retifanlimab in phase I, the disease control data is shown below:
■ 12 patients were treated with Bria-IMTTM plus retifanlimab
■ Tolerability excellent with no dose-limiting toxicities
The
overall survival of the patients for all patients on this study has been evaluated in an ongoing fashion. Since the study was largely
on hold during COVID (2020 and 2021), patients dosed in 2019 and 2020 have been followed for a longer time. Therefore survival data has
been evaluated for patients dosed before 2022 and since 2022. This should be considered in the context of clinical studies in patients
with advanced breast cancer who have failed at least 2 prior regimens. Several recent publications are noted here:
■ Cortes J, et al. Annals of Oncology 2018: Open-label randomized Phase 3 trial
■ Median OS eribulin 9.8 months, gemcitabine 7.2 months, capecitabine 9.1 months
■ Tripathy D, et al. JAMA Oncol. 2022: Phase 3 ATTAIN Randomized Clinical Trial
In
contrast, the Bria-IMTTM regimen, using the Phase 3 formulation, with a CPI has shown a median overall survival (OS) of 13.4
months for all patients by the Kaplan Meier method, as shown in the Figure below. For patients treated since 2022, the median OS was
estimated at 15.6 months.
1Cortes J, et al. Annals of
Oncology 2018; Kazmi S, et al. Breast Cancer Res Treat. 2020 Aug 17; O’Shaughnessy J et al. Breast Cancer Res Treat. 2022; Tripathy
D, et al. JAMA Oncol. 2022
Figure
B. Overall Survival of Patients with Metastatic Breast Cancer treated with the Bria-IMTTM regimen using the Phase 3 formulation
with a CPI.
Letter
of Intent from Weill Cornell Medicine Outlining Plans to Initiate a Phase 2 Clinical Trial of Bria-IMTTM in High-Risk Early-Stage
Triple Negative Breast Cancer
In
August, 2023, BriaCell announced that it has accepted a letter of intent from Dr. Massimo Cristofanilli, Director of Breast Medical Oncology
and Associate Director of Precision Medicine in the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, outlining the parties’
plans and commitment, upon regulatory approval, to initiate a Phase 2 investigator-initiated clinical study to evaluate BriaCell’s
novel immunotherapy, Bria-IMTTM, in combination with a check point inhibitor, in early stage, newly diagnosed, high-risk triple
negative breast cancer patients who have failed to achieve a pathological complete response in the neoadjuvant setting. As of the date
of this filing, the investigative study has not yet commenced, as the Company is focusing on its pivotal Phase 3 study.
Manufacturing
We
do not own or operate manufacturing facilities for the production of our product candidates, nor do we have plans to develop our own
manufacturing operations in the foreseeable future. We currently depend on third-party contract manufacturers for all of our required
raw materials, active pharmaceutical ingredients, and finished product candidate for our clinical trials. We currently employ internal
resources and third-party consultants to manage our manufacturing contractors.
Bria-IMTTM
is currently manufactured under current Good Manufacturing Practices (“cGMP”) pursuant to agreements with UC Davis and with
Fuji, which is located in Thousand Oaks, California.
On
June 11, 2015, the Company entered into an Agreement for Services with The Regents of the University of California, acting for and on
behalf of UC Davis, pursuant to which UC Davis manufactures Bria-IMTTM (previously known as BriaVax) at its GMP facility. The Company
pays UC Davis certain hourly rates depending on the specific services provided by UC Davis in connection with its manufacturing of Bria-IMTTM.
On
July 5, 2022, BriaCell announced that it had entered into a manufacturing service agreement with Waisman Biomanufacturing at the University
of Wisconsin-Madison (“Waisman”), to manufacture Bria-ProsTM, BriaCell’s off-the-shelf personalized immunotherapy
for prostate cancer, for anticipated use in clinical studies. Waisman is a leading contract manufacturing organization with experience
in the manufacturing of cellular therapies for clinical trials. Under the terms of the agreement, Waisman will be responsible for GMP
manufacturing of Bria-ProsTM for anticipated use in clinical studies. Waisman’s expert team will be working closely with BriaCell’s
scientific and product development teams to ensure timely production of Bria-ProsTM in compliance with applicable regulatory requirements
by the FDA.
Pursuant
to the Company’s master services agreement with Fuji, dated May 29, 2023, to manufacture Bria-IMTTM, for anticipated use in
clinical studies including the Phase 3 study. Fuji is a leading contract manufacturing organization with experience in the manufacturing
of cellular therapies for clinical trials. Under the terms of the agreement, Fuji will be responsible for GMP manufacturing of Bria-IMTTM
for anticipated use in clinical studies. Fuji’s expert team will be working closely with BriaCell’s scientific and product
development teams to ensure timely production of Bria-IMTTM in compliance with applicable regulatory requirements by the FDA.
Bria-OTSTM
● Bria-OTSTM: Personalized Off-the-Shelf Immunotherapy
BriaCell
Phase 1/2 Study of Bria-OTSTM, also known as Bria-BRESTM, in metastatic breast cancer is open. The Phase 1/2 clinical study
is listed on ClinicalTrials.gov as NCT06471673.
●
Bucket trial with additional cancer indications planned
●
Enhanced version (Bria-OTS+TM) scheduled to enter the clinic 1H2025 starting with Bria-ProsTM (prostate cancer)
●
We believe Bria-IMTTM is most effective in human leukocyte antigens (HLA) – type matched patients
●
Bria-OTSTM is engineered to express 15 unique HLA types through 4 independent cell lines
●
Provides matched treatment to greater than 99% of patients
●
Simple saliva test provides HLA matched personalized off-the-shelf Bria-OTSTM immunotherapy
●
HLA matched off-the-shelf therapy is faster and less costly than other expensive and complex personalized immunotherapies
●
BriaCell received a Small Business Innovation Research (SBIR) grant from the National Cancer Institute (NCI) to further develop Bria-OTSTM
●
Ongoing collaboration with the NCI to investigate the Bria-OTSTM mechanism action
●
BriaCell has secured numerous US and international patents for Bria-OTSTM
●
Similar immunotherapies are in development for prostate cancer (Bria-ProsTM), lung cancer (Bria-LungTM), and melanoma (Bria-MelTM)
Development
of Additional Immunotherapy Cell Lines
Early
Phase Programs
On
August 4, 2022, BriaCell announced that it has secured an exclusive license from University of Maryland, Baltimore County (“UMBC”) to develop
and commercialize Soluble CD80 (“sCD80”) as a biologic agent for the treatment of cancer. Under the terms of the agreement, BriaCell has
the worldwide rights to develop and commercialize sCD80, while UMBC maintains ownership of the patents. BriaCell will pay royalties to
UMBC upon the commercialization of the product plus patent management costs. The licensing agreement was coordinated by UMBC’s
Office of Technology Development.
The
patents are listed as the following: USPN 8,956,619 B2; USPN 9,650,429 B2; USPN 10,377,810 B2
CD80
is an important co-stimulatory molecule present on antigen-presenting cells and key for activating T cells. CD80 also acts as an immune
checkpoint inhibitor. As noted in the patents, significant data has been generated showing that in animal models sCD80 is capable of
enhancing anti-cancer immune responses and shrinking tumors in model systems. The sCD80 appears to act both as an immune stimulator and
checkpoint inhibitor. This makes it an ideal candidate to combine with BriaCells’s cellular immunotherapy platform.
sCD80 project is temporarily on hold as the Company focused on its pivotal Phase 3 study.
Marketing
and Sales Strategy
The
product will initially be marketed to oncologists who are well-versed in the use of immunotherapy for cancer. Partnering with other pharmaceutical
companies in order to market combinations with a number of drugs is also an option that we intend to pursue. This study will utilize
a frozen formulation which consists of irradiated SV-BR-1-GM cells in viable freezing media. This formulation will permit stockpiling
of immunotherapy so that it can be sent on demand to clinical sites. The eventual goal is to reach all oncologists who treat late-stage
breast cancer, either by direct outreach or by partnering with another company that has an established presence in the oncology space.
Our future commercial strategy
may include the use of strategic partners, distributors, a contract sale force, or the establishment of our own commercial and specialty
sales force, as well as similar strategies for regions and territories outside the United States. We plan to further evaluate these alternatives
as we approach approval for the use of our product candidates for one or more indications.
Other
Commercial Considerations
There
is a high unmet medical need in late-stage breast cancer, providing potential for accelerated approval of Bria-IMTTM. The FDA is
interested in facilitating the availability of novel therapies of patients with unmet medical needs, especially those that can target
the population most likely to respond. In addition, the FDA has granted “Fast Track” status to BriaCell’s lead candidate,
Bria-IMTTM, for the treatment of metastatic breast cancer. These two facts may help facilitate the accelerated approval of Bria-IMTTM.
Production
and Marketing Plan
Bria-IMTTM
cells grow in simple tissue culture media and are irradiated prior to inoculation. Bria-IMTTM manufacturing will be performed by
Contract Manufacturing Organizations. We have been working with FUJIFILM Diosynth Biotechnologies (“Fuji”) and the University
of California, Davis Health System (“UC Davis”) GMP facility, who have developed a frozen formulation where the cells are
grown, harvested and irradiated, followed by cryopreservation in a viable state. The cells are stockpiled and shipped directly to clinical
sites for inoculation. Each lot of Bria-IMTTM is tested for potency (i.e. GM-CSF production), identity (i.e. HER2+ and ER/PR-) and
adventitious agents to rule out contamination with infectious agents. To date, there have been no issues with these tests. Additional
manufacturing facilities have been evaluated and may be enlisted as demand grows.
Marketing
will target oncologists who are well-versed in the use of immunotherapy and especially breast cancer treatment centers. The initial target
will be patients with metastatic or recurrent breast cancer who have failed at least two prior treatment regimens. We plan to develop
the clinical data for Bria-IMTTM and to use this information to reach out to oncologists seeking additional therapeutic options
for their patients. We will include in this effort a physician education campaign targeting the oncologists most likely to treat metastatic
breast cancer. As these physicians become more aware of the data regarding Bria-IMTTM in breast cancer, we will make sure they also
understand how best to use Bria-IMTTM in combination with other therapies that have complementary synergistic mechanisms of action.
This will also come from the clinical studies described above focusing on combination therapy. Partnering with other pharmaceutical companies
in order to market a number of drugs is also an option that we intend to pursue. Our eventual goal is to reach all oncologists who treat
late stage breast cancer, either by direct outreach or by partnering with another company that has an established presence in the oncology
space.
License
Agreements
On
August 4, 2022, BriaCell announced that it has secured an exclusive license from University of Maryland, Baltimore County (UMBC) to develop
and commercialize Soluble CD80 (sCD80) as a biologic agent for the treatment of cancer. Under the terms of the agreement, BriaCell has
the worldwide rights to develop and commercialize sCD80, while UMBC maintains ownership of the patents. BriaCell will pay royalties to
UMBC upon the commercialization of the product plus patent management costs. The licensing agreement was coordinated by UMBC’s
Office of Technology Development.
On
July 24, 2017, the Company entered into a Share Exchange Agreement with its wholly-owned subsidiary, BriaCell Therapeutics Corp., Sapientia,
and all the shareholders of Sapientia. Sapientia, a biotechnology company based in Havertown, PA, is developing novel targeted therapeutics
for multiple indications, including several cancers and fibrotic diseases.
Pursuant