UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
Form
10-K
(Mark
One)
For
the fiscal year ended July 31, 2023
For the Transition Period from [●]
to [●]
Commission
File Number: 001-40101
BRIACELL
THERAPEUTICS CORP.
(Exact
name of registrant as specified in its charter)
(Address of principal executive offices) (Zip Code)
(604)921-1810
(Registrant’s
telephone number, including area code)
Securities
registered pursuant to Section 12(b) of the Act:
Title of each class Trading Symbol Name of each exchange on which registered
Common Shares, no par value BCTX The Nasdaq Stock Market LLC
Securities registered pursuant to Section 12(g) of the Act: None
Indicate
by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate
by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒
Indicate
by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange
Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2)
has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐
Indicate
by check mark whether the registrant has submitted electronically every Interactive Data
File required to be submitted pursuant to Rule 405 of Regulation S-T (§ 232.405 of this chapter) during the preceding
12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒ No ☐
Indicate
by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K (§229.405 of this chapter) is not contained
herein, and will not be contained, to the best of registrant’s knowledge, in definitive proxy or information statements incorporated
by reference in Part III of this Form 10-K or any amendment to this Form 10-K. ☒
If
securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant
included in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate
by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation
received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate
by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or a smaller reporting
company. See the definitions of “large accelerated filer”, “accelerated filer”, “smaller reporting company”,
and “emerging growth company” in Rule 12b-2 of the Exchange Act.
If
an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying
with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate
by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness
of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered
public accounting firm that prepared or issued its audit report. ☐
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes ☐ No ☒
The
aggregate market value of the voting and non-voting common equity held by non-affiliates based on a closing sale price of $7.48 per
share, which was the last sale price of the common shares as of January 31, 2023, the last business day of the registrant’s
most recently completed second fiscal quarter, was $105,163,751.
As
of October 25, 2023, 15,981,726 shares of the registrant’s common shares, no par value per share, were issued and
outstanding.
TABLE
OF CONTENTS
Page
PART I
Item 1 Business 5
Item 1A Risk Factors 31
Item 1B Unresolved Staff Comments 49
Item 2 Properties 49
Item 3 Legal Proceedings 49
Item 4 Mine Safety Disclosures 49
PART II
Item 6 [Reserved] 50
Item 7A Quantitative and Qualitative Disclosures About Market Risk 54
Item 8 Financial Statements and Supplementary Data 54
Item 9A Controls and Procedures 54
Item 9B Other Information 54
Item 9C Disclosure Regarding Foreign Jurisdictions that Prevent Inspections. 54
PART III
Item 10 Directors, Executive Officers, and Corporate Governance 55
Item 11 Executive Compensation 64
Item 14 Principal Accountant Fees and Services 68
PART IV
SIGNATURES 71
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.
● 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. (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 in a pivotal1 Phase 3 study in advanced metastatic breast cancer. BriaCell recently reported
benchmark-beating patient survival and clinical benefit in advanced metastatic breast with median overall survival of 13.5 months in
BriaCell’s advanced metastatic breast cancer patients vs. 6.7-9.8 months for similar patients reported in the literature2.
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 a personalized off-the-shelf immunotherapy, Bria-OTSTM, which provides a platform
technology to develop personalized off-the-shelf immunotherapies for numerous types of cancer, and a soluble CD80 protein therapeutic
which acts both as a stimulator of the immune system as well as an immune checkpoint inhibitor.
Market
It
is estimated by the National Cancer Institute that in 2023, approximately 297,790 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 43,170 are
projected to die in 2023. 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
2,800 new cases of invasive male breast cancer will be diagnosed and approximately 530 men will die from breast cancer in
2023.
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 2022, 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 are living with MBC.2 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
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
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.
The
best response to the Bria-IMTTM monotherapy regimen to date is in patients who matched Bria-IMTTM at one or more HLA
alleles, with higher response rates for patients with 2+ HLA allele matches. If one HLA allele match is found to be sufficient, we
will be able to treat ~50-60% of the patient population, while patients with 2+ HLA matches constitutes ~15-35% of
cases.8 We also saw higher clinical benefit rates for patients with grade I/II tumors. Tumor differentiation in breast
cancer cell lines is often described by their classification as Luminal, Basal A and Basal B subtypes, with Luminal representing
well differentiated tumors, Basal B poorly differentiated tumors, and Basal A an intermediate stage tumor (“moderately”
differentiated).2 Yao and colleagues in 2005 identified a 9-gene signature (AURKB, CENPI, DEPDC1, DEPDC1B, FAM83D, FGD3,
NCAPH, TNFRSF18, FCGR1A) discriminating poorly (grade 3) from moderately (grade 2) differentiated tumors.3 To understand
the place of SV-BR-1-GM in this model, we compared its RNA expression profile with those of three other cell lines representing
Luminal (MCF-7), Basal A (MDA-MB-468) and Basal B (MDA-MB-231), using a 10-gene signature (AURKB, CENPI, DEPDC1, DEPDC1B, FAM83D,
FGD3, NCAPH, DLGAP, KIF2C, VAV3) derived from those by Yao and colleagues. The results, shown in the figure below, demonstrate that
Bria-IMTTM most closely clusters with MDA-MB-468 and as such is considered a grade II “moderately differentiated”
cell line.
Greece:
Results from the EMERGE multicenter retrospective chart review study. BMC Cancer. 2019 Jan 18;19(1):88.
8
Gragert, Loren, Abeer Madbouly, John Freeman, and Martin Maiers. 2013. “Six-Locus High Resolution HLA Haplotype Frequencies
Derived from Mixed-Resolution DNA Typing for the Entire US Donor Registry.” Human Immunology.
2
Neve RM, Chin K, Fridlyand J, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes.
Cancer Cell. 2006;10(6):515-527. Doi:10.1016/j.ccr.2006.10.008)
3
Yao F, Zhang C, Du W, Liu C, Xu Y. Identification of gene-expression signatures and protein markers for breast cancer grading and
staging. PloS One. 2015;10(9). Doi:10.1371/journal.pone.0138213)
Based
on a publication of patients with relapsed breast cancer, we estimate that this will account for ~40% of relapsed metastatic breast
cancer cases (33% grade II and 7% grade I) (Sundquist M, Brudin L, Tejler G. Improved survival in metastatic breast cancer 1985-2016.
Breast. 2017 Feb;31:46-50. Doi: 10.1016/j.breast.2016.10.005. Epub 2016 Nov 2). In patients with relapsed disease, the overall survival
following relapse appears similar for those with grade II and grade III tumors.9
More
recent information comes from 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 Zynyz® with one patient starting on the combination with Keytruda® and crossing-over to the combination
with Zynyz® (22 patients total). In phase II of the study, the Bria-IMTTM regimen is being dosed in combination with Zynyz®
with patients randomized to either receive the Bria-IMTTM regimen first (12 patients) or Zynyz® first (12 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 Zynyz® in phase I, the disease control data is shown below:
■ 12 patients were treated with Bria-IMTTM plus Zynyz®
■ 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 with a CPI has shown a median overall survival (OS) of 13.3 months for patients treated before
2022 and 13.5 months for all patients by the Kaplan Meier method, as shown in the Figure below. For patients treated since 2022, the
median OS has not been reached.
Figure
B. Overall Survival of Patients with Metastatic Breast Cancer treated with the Bria-IMTTM regimen with a CPI.
The market for breast cancer drugs is a multibillion-dollar
market with new drugs being approved on an ongoing basis, indicating the shortage of safe and effective treatments for this deadly disease.
Figure A summarizes current drugs on the market utilized in combination therapy along with their reported market sales, which further
supports market potential for Bria-IMTTM to be used for combination therapy for breast cancer patients.
We
propose the following calculation in order to show the rationale behind the number of patients that we anticipate can be currently treated
by SV-BR-1-GM:
USA – 2022 References
Incidence Growth Rate 0.53%
Therapy Compliance Rate 84% ● Zhao, H.; Lei, X.; Niu, J.; et al. (2021)13.
Expected Launch Date 2026 (BriaIMT) 2029 (BriaOTS) ● Estimated launch date
Peak % Market Share BriaIMT – 10% BriaOTS – 20%; Peak in 5 year ● PMR
Cannibalization 60% ● Management input
% Gross to Net discount -10% ● Internal assumption
9
See note 5, above.
10
Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer
(Dove Med Press). 2019 Apr 10;11:151-164. SEER Cancer Statistics Factsheets: Female Breast Cancer. National Cancer Institute. Bethesda,
MD; American Cancer Society. Breast Cancer Facts & Figures 2017-2018. Atlanta: American Cancer Society, Inc. 2017.
11 Liang TJ, Wang BW, Liu SI, Yeh MH, Chen
YC, Chen JS, Mok KT, Chang HT. Recurrence after skin-sparing mastectomy and immediate transverse rectus abdominis musculocutaneous flap
reconstruction for invasive breast cancer. World J Surg Oncol. 2013 Aug 14;11(1):194. Doi: 10.1186/1477-7819-11-194. PMID: 23945398; PMCID:
PMC3751148.
12 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):2169-2174.
Doi: 10.1093/annonc/mdq220. Epub 2010 Apr 28. PMID: 20427349; PMCID: PMC2962259. .
13 Zhao H, Lei X, Niu J, Zhang N, Duan
Z, Chavez-MacGregor M, Giordano SH. Prescription Patterns, Initiation, and 5-Year Adherence to Adjuvant Hormonal Therapy Among Commercially
Insured Patients With Breast Cancer. JCO Oncol Pract. 2021 Jun;17(6):e794-e808. Doi: 10.1200/OP.20.00248. Epub 2021 Feb 17. PMID: 33596096;
PMCID: PMC8257979.
14
See note 5, above.
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
Licchetta15 Cyclophosphamide and megestrol acetate 29 31 % 7.4 mo 13.4 mo
Leyland-Jones20 Trastuzumab with paclitaxel 32 59 % 12.2 mo
von Minckwitz21 Trastuzumab with capecitabine 78 48.1 % 8.2 mo 25.5 mo
Geyer23 Lapatinib plus capecitabine 163 22 % 8.4 mo
Capecitabine Monotherapy 161 14 % 4.4 mo
Bartsch24 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
Tripathy29 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,29 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.30
15
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.
16
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).
17
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).
18
Gradishar WJ. Taxanes for the treatment of metastatic breast cancer. Breast Cancer (Auckl). 2012;6:159-71.
19
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).
20
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.
21
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.
22
Verma, S. et al. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. N. Engl. J. Med. 367, 1783–1791 (2012).
23
Geyer, C. E. et al. Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer. N. Engl. J. Med. 355, 2733–2743
(2006).
24
Bartsch, R. et al. Capecitabine and Trastuzumab in Heavily Pretreated Metastatic Breast Cancer. J. Clin. Oncol. 25, 3853–3858
(2007).
25
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).
26Cortes 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.
27Kazmi 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.
28O’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.
29Tripathy 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.
30 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).31 This indicates the high unmet need in this patient population which should facilitate
regulatory review of novel therapies such as Bria-IMTTM.
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.32 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.33 An immunogen targeting a carbohydrate antigen, globo-H, was associated with improved
PFS, but only in the subset able to mount antibody responses.34 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.35 Finally, the study of targeted cancer immunotherapies in combination
with other therapies is receiving much attention, particularly combination with checkpoint inhibitors.36
31
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.
32
Mittendorf, E. A.; Peoples, G. E., Injecting Hope—A Review of Breast Cancer Vaccines. Oncology (Williston Park) 2016, 30
(5), 475-81, 485.
33
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.
34
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).
35
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.
36
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”).
Products/Pipeline
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.
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 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
recently announced 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.
In
collaboration with Prevail InfoWorks, Inc. (“InfoWorks”), a Philadelphia, PA based contract research organization,
BriaCell expects 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.
Prevail
Partners, LLC (“Prevail Partners”), an investment fund and affiliate of InfoWorks, has 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. The transaction closed on May 19, 2023.
Recent
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
BriaCell
recently 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.
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
recently 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
months for similar patients reported in the literature.
BriaCell
has achieved proof of concept based on data from a Phase 1/2a study of Bria-IMTTM in advanced breast cancer patients. In essence,
BriaCell has demonstrated disease control and clinical benefit in a high proportion of patients with advanced breast cancer
who have exhausted other therapeutic options. There is also promising data on overall survival as noted above.
Positive
Proof of Concept
Study SVMC #01-026
Study
WRI-GEV-007
Study
BRI-ROL-001
About
Bria-IMTTM
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.
Bria-OTSTM
Using
BriaCell’s novel technology platform and our strong research and development capabilities, BriaCell plans to develop Bria-OTSTM,
a personalized off-the-shelf immunotherapy for breast cancer, and similar immunotherapy cell lines for other cancer indications.
37
Lacher M.D., Bauer G. Fury B., Graeve S., Fledderman E.L., Petrie T.D., Coleal-Bergum D.P., Hackett T., Perotti N.H., Kong Y.Y.,
Kwok W.W., Wagner J.P., Wiseman C.L., and Williams W.V. SV-BR-1-GM, a Clinically Effective GM-CSF- Secreting Breast Cancer Cell Line,
Expresses an Immune Signature and Directly Activates CD4+ T Lymphocytes. Frontiers in Immunology 2018; 9: Article 776.
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.
Current timelines project that the sCD80 may be ready to enter the clinic in early 2025.
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.
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 KBI Biopharma, Inc. (“KBI”) 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.