Table of Contents As filed with the Securities and Exchange Commission on March 19, 2018. Registration No. 333-223414 UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 Amendment No. 1 to FORM S-1 REGISTRATION STATEMENT Under The Securities Act of 1933 UNUM THERAPEUTICS INC. (Exact name of registrant as specified in its charter) Delaware 2834 46-5308248 (State or other jurisdiction of incorporation or organization) (Primary Standard Industrial Classification Code Number) (I.R.S. Employer Identification Number) 200 Cambridge Park Drive, Suite 3100 Cambridge, Massachusetts 02140 (617) 945-5576 (Address, including zip code, and telephone number, including area code, of registrant’s principal executive offices) Charles Wilson Chief Executive Officer Unum Therapeutics Inc. 200 Cambridge Park Drive, Suite 3100 Cambridge, Massachusetts 02140 (617) 945-5576 (Name, address, including zip code, and telephone number, including area code, of agent for service) Copies to: Kingsley L. Taft, Esq. Danielle Lauzon, Esq. Caitlin L. Murray, Esq. Goodwin Procter LLP 100 Northern Avenue Boston, Massachusetts 02210 (617) 570-1000 Christiana Stamoulis President and Chief Financial Officer Unum Therapeutics Inc. 200 Cambridge Park Drive, Suite 3100 Cambridge, Massachusetts 02140 (617) 945-5576 Patrick O’Brien, Esq. Ropes & Gray LLP Prudential Tower 800 Boylston Street Boston, Massachusetts 02199 (617) 951-7000 Approximate date of commencement of proposed sale to the public: As soon as practicable after the effective date of this registration statement. If any of the securities being registered on this Form are to be offered on a delayed or continuous basis pursuant to Rule 415 under the Securities Act of 1933, as amended, check the following box. ☐ If this Form is filed to register additional securities for an offering pursuant to Rule 462(b) under the Securities Act, please check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering. ☐ If this Form is a post-effective amendment filed pursuant to Rule 462(c) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering. ☐ If this Form is a post-effective amendment filed pursuant to Rule 462(d) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering. ☐ Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company or an emerging growth 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. Large Accelerated Filer ☐ Accelerated Filer ☐ Non-Accelerated Filer ☒ (Do not check if a smaller reporting company) Smaller Reporting Company ☐ Emerging Growth Company ☒ 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 to Section 7(a)(2)(B) of the Securities Act. ☒ CALCULATION OF REGISTRATION FEE Title of Each Class of Securities to be Registered Amount to be Registered(1) Proposed Maximum Offering Price per Share(2) Proposed Maximum Aggregate Offering Price(2) Amount of Registration Fee(3)(4) Common Stock, par value $0.001 per share 6,635,500 $14.00 $92,897,000 $11,566 (1) Includes 865,500 shares that the underwriters have an option to purchase. (2) Estimated solely for the purpose of computing the amount of the registration fee pursuant to Rule 457(a) under the Securities Act of 1933, as amended. (3) Calculated pursuant to Rule 457(a) under the Securities Act of 1933, as amended, based on an estimate of the proposed maximum aggregate offering price. (4) $10,739 of this registration fee was previously paid by the Registrant in connection with the filing of its Registration Statement on Form S-1 on March 2, 2018. The registrant hereby amends this registration statement on such date or dates as may be necessary to delay its effective date until the registrant shall file a further amendment that specifically states that this registration statement shall thereafter become effective in accordance with Section 8(a) of the Securities Act of 1933, as amended, or until this registration statement shall become effective on such date as the Commission, acting pursuant to said Section 8(a), may determine.
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As filed with the Securities and Exchange Commission on March 19,
2018. Registration No. 333-223414
UNITED STATES
Amendment No. 1
to FORM S-1
REGISTRATION STATEMENT Under
The Securities Act of 1933
UNUM THERAPEUTICS INC. (Exact name of registrant as specified in
its charter)
Delaware 2834 46-5308248 (State or other jurisdiction of
incorporation or organization) (Primary Standard Industrial
Classification Code Number)
(I.R.S. Employer Identification Number)
(617) 945-5576 (Address, including zip code, and telephone number,
including area code, of registrant’s principal executive
offices)
Charles Wilson
200 Cambridge Park Drive, Suite 3100 Cambridge, Massachusetts
02140
(617) 945-5576 (Name, address, including zip code, and telephone
number, including area code, of agent for service)
Copies to:
Caitlin L. Murray, Esq. Goodwin Procter LLP 100 Northern
Avenue
Boston, Massachusetts 02210 (617) 570-1000
Christiana Stamoulis President and Chief Financial Officer
Unum Therapeutics Inc. 200 Cambridge Park Drive, Suite 3100
Cambridge, Massachusetts 02140 (617) 945-5576
Patrick O’Brien, Esq. Ropes & Gray LLP Prudential Tower
800 Boylston Street Boston, Massachusetts 02199
(617) 951-7000
Approximate date of commencement of proposed sale to the public: As
soon as practicable after the effective date of this registration
statement.
If any of the securities being registered on this Form are to be
offered on a delayed or continuous basis pursuant to Rule 415 under
the Securities Act of 1933, as amended, check the following box. If
this Form is filed to register additional securities for an
offering pursuant to Rule 462(b) under the Securities Act, please
check the following box and list the Securities Act registration
statement number
of the earlier effective registration statement for the same
offering. If this Form is a post-effective amendment filed pursuant
to Rule 462(c) under the Securities Act, check the following box
and list the Securities Act registration statement number of the
earlier effective
registration statement for the same offering. If this Form is a
post-effective amendment filed pursuant to Rule 462(d) under the
Securities Act, check the following box and list the Securities Act
registration statement number of the earlier effective
registration statement for the same offering. Indicate by check
mark whether the registrant is a large accelerated filer, an
accelerated filer, a non-accelerated filer, a smaller reporting
company or an emerging growth 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.
Large Accelerated Filer Accelerated Filer Non-Accelerated Filer (Do
not check if a smaller reporting company) Smaller Reporting
Company
Emerging Growth Company 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
to Section 7(a)(2)(B) of the Securities Act.
CALCULATION OF REGISTRATION FEE
Amount to be Registered(1)
Proposed Maximum Aggregate Offering Price(2)
Amount of Registration Fee(3)(4)
Common Stock, par value $0.001 per share 6,635,500 $14.00
$92,897,000 $11,566
(1) Includes 865,500 shares that the underwriters have an option to
purchase. (2) Estimated solely for the purpose of computing the
amount of the registration fee pursuant to Rule 457(a) under the
Securities Act of 1933, as amended. (3) Calculated pursuant to Rule
457(a) under the Securities Act of 1933, as amended, based on an
estimate of the proposed maximum aggregate offering price. (4)
$10,739 of this registration fee was previously paid by the
Registrant in connection with the filing of its Registration
Statement on Form S-1 on March 2, 2018.
The registrant hereby amends this registration statement on such
date or dates as may be necessary to delay its effective date until
the registrant shall file a further amendment that specifically
states that this registration statement shall thereafter become
effective in accordance with Section 8(a) of the Securities Act of
1933, as amended, or until this registration statement shall become
effective on such date as the Commission, acting pursuant to said
Section 8(a), may determine.
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The information in this preliminary prospectus is not complete and
may be changed. These securities may not be sold until the
registration statement filed with the Securities and Exchange
Commission is effective. This preliminary prospectus is not an
offer to sell nor does it seek an offer to buy these securities in
any jurisdiction where the offer or sale is not permitted.
PRELIMINARY PROSPECTUS (Subject to Completion) Dated March 19,
2018
5,770,000 Shares
Common Stock
Unum Therapeutics Inc. is offering 5,770,000 shares of its common
stock. This is our initial public offering and no public market
exists for our common stock. We anticipate that the initial public
offering price per share of our common stock will be between $12.00
and $14.00.
We have applied to list our common stock on The Nasdaq Global
Market under the symbol “UNUM.”
We are an “emerging growth company” as that term is used in the
Jumpstart Our Business Startups Act of 2012 (JOBS Act), and, as
such, we have elected to comply with certain reduced public company
reporting requirements for this prospectus and future filings. See
“Prospectus Summary—Implications of Being an Emerging Growth
Company.”
Investing in our common stock involves risks. See “Risk Factors”
beginning on page 12.
Price to Public
Underwriting Discounts and
Inc. (Before Expenses)
Per Share $ $ $ Total $ $ $ (1) See “Underwriters” beginning on
page 168 of this prospectus for additional information regarding
underwriting compensation.
Certain of our existing stockholders, including affiliates of our
directors, have indicated an interest in purchasing an aggregate of
up to $37.5 million of shares of our common stock in this offering
at the initial public offering price. However, because indications
of interest are not binding agreements or commitments to purchase,
the underwriters may determine to sell more, less or no shares in
this offering to any of these stockholders, or any of these
stockholders may determine to purchase more, less or no shares in
this offering. The underwriters will receive the same underwriting
discount on any shares purchased by these stockholders as they will
on any other shares sold to the public in this offering.
We have granted the underwriters an option to purchase up to
865,500 additional shares of our common stock to cover over
allotments. The underwriters can exercise this option at any time
within 30 days after the date of this prospectus.
Seattle Genetics, Inc. has agreed to purchase from us, concurrently
with this offering in a private placement, $5.0 million of shares
of our common stock at a price per share equal to the initial
public offering price. The shares of common stock purchased in the
concurrent private placement will not be subject to any
underwriting discounts or commissions. See “Concurrent Private
Placement.”
The underwriters expect to deliver the shares of our common stock
to purchasers on or about , 2018.
Neither the Securities and Exchange Commission nor any state
securities commission has approved or disapproved of these
securities or determined if this prospectus is truthful or
complete. Any representation to the contrary is a criminal
offense.
MORGAN STANLEY COWEN SUNTRUST ROBINSON HUMPHREY WEDBUSH
PACGROW
, 2018
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Through and including , 2018 (25 days after the date of this
prospectus), all dealers effecting transactions in these
securities, whether or not participating in this offering, may be
required to deliver a prospectus. This delivery requirement is in
addition to the obligation of dealers to deliver a prospectus when
acting as underwriters and with respect to their unsold allotments
or subscriptions.
You should rely only on the information contained in this
prospectus or in any free writing prospectus we file with the
Securities and Exchange Commission. Neither we nor the underwriters
have authorized anyone to provide you with information other than
that contained in this prospectus or any free writing prospectus
prepared by or on behalf of us or to which we have referred you. We
take no responsibility for, and can provide no assurance as to the
reliability of, any other information that others may give you. We
and the underwriters are offering to sell, and seeking offers to
buy, common stock only in jurisdictions where offers and sales are
permitted. The information contained in this prospectus is accurate
only as of the date on the front cover page of this prospectus, or
other earlier date stated in this prospectus, regardless of the
time of delivery of this prospectus or of any sale of our common
stock.
The market data and certain other statistical information used
throughout this prospectus are based on independent industry
publications, governmental publications, reports by market research
firms, or other independent sources that we believe to be reliable
sources. Although we believe that these sources are reliable, we
have not independently verified the information contained in such
publications. While we are not aware of any misstatements regarding
any third- party information presented in this prospectus, their
estimates, in particular, as they relate to projections, involve
numerous assumptions, are subject to risks and uncertainties, and
are subject to change based on various factors, including those
discussed under the section titled “Risk Factors” and elsewhere in
this prospectus. Some data are also based on our good faith
estimates.
Page Prospectus Summary 1 Risk Factors 12 Special Note Regarding
Forward-Looking Statements 57 Use of Proceeds 59 Dividend Policy 61
Capitalization 62 Dilution 64 Selected Consolidated Financial Data
67 Management’s Discussion and Analysis of Financial
Condition
and Results of Operations 69 Business 89 Management 134 Executive
Compensation 141
Page Director Compensation 149 Certain Relationships and Related
Party Transactions 151 Principal Stockholders 154 Description of
Capital Stock 157 Shares Eligible for Future Sale 162 Material U.S.
Federal Income Tax Considerations for Non-U.S.
Holders of Common Stock 164 Underwriters 168 Concurrent Private
Placement 175 Legal Matters 176 Experts 176 Where You Can Find More
Information 176 Index to Consolidated Financial Statements
F-1
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PROSPECTUS SUMMARY
This summary highlights information contained elsewhere in this
prospectus and does not contain all of the information that you
should consider in making your investment decision. Before
investing in our common stock, you should carefully read this
entire prospectus, including our consolidated financial statements
and the related notes included elsewhere in this prospectus. You
should also consider, among other things, the matters described
under “Risk Factors,” “Business,” and “Management’s Discussion and
Analysis of Financial Condition and Results of Operations,” in each
case appearing elsewhere in this prospectus. Unless the context
otherwise requires, we use the terms “Unum,” “company,” “we,” “us,”
and “our” in this prospectus to refer to Unum Therapeutics Inc.
and, where appropriate, our subsidiary.
Overview
We are a clinical-stage biopharmaceutical company focused on the
development and commercialization of novel immunotherapy products
designed to harness the power of a patient’s immune system to cure
cancer. Our proprietary technology, called antibody-coupled T cell
receptor (ACTR), is a universal, engineered cell therapy that is
intended to be used in combination with a wide range of
tumor-specific antibodies to target different tumor types. Our
product candidates are composed of ACTR T cells co-administered
with approved and commercially available antibodies or antibodies
in preclinical or clinical development. Our vision is to use our
ACTR platform to transform cancer treatment and deliver patient
cures in many different hematologic and solid tumor cancers,
improving upon current cell therapies.
In our ongoing Phase I clinical trial using our lead ACTR
construct, ACTR087, to treat adult patients with relapsed or
refractory non-Hodgkin lymphoma (r/r NHL), we have demonstrated
clinical proof of concept, as evidenced by ACTR T cell expansion
and persistence, a favorable tolerability profile at the first dose
level, and anti-tumor activity. We recently completed patient
enrollment into the dose escalation phase of this trial and are
advancing towards testing in an expanded patient cohort using an
optimized dose of ACTR087 to support potential registration
trials.
Our pipeline also includes two additional product candidates in
clinical testing. We have commenced a Phase I clinical trial of
ACTR707, a modified ACTR construct, used in combination with
rituximab in adult patients with r/r NHL and a Phase I clinical
trial of ACTR087 used in combination with the novel antibody
SEA-BCMA in adult patients with r/r multiple myeloma. Further, we
expect to file an investigational new drug application (IND) in
2018 for ACTR707 used in combination with trastuzumab, an
FDA-approved antibody, to treat patients with solid tumor cancers
that overexpress the human epidermal growth factor receptor 2
(HER2+ cancers). In the longer term, we aim to leverage our ACTR
platform to develop a broad range of product candidates to address
many different hematologic and solid tumor cancers.
Immuno-oncology, the use of a patient’s immune system to treat
cancer, is one of the most actively pursued areas of research in
drug discovery and development. Adoptive cell therapies are one
immuno-oncology approach for cancer treatment. Adoptive cell
therapy starts with the isolation of immune cells from a patient,
followed by genetic modification of these cells outside the
patient’s body. Modified cells are then re-introduced into the
patient to treat disease. Chimeric antigen receptor (CAR)-T cells
are one type of adoptive cell therapy. While CAR-T’s efficacy in
hematologic cancers has been impressive, limited clinical data have
been reported on the use of CAR-Ts in solid tumor cancers and the
results have been much less encouraging than in the hematologic
cancer setting. Severe side effects, such as cytokine release
syndrome (CRS) and neurotoxicity, have been observed in some
patients. For certain CARs, on-target, off-tumor effects have led
to patient deaths. These toxicities and specific solid tumor
challenges create a need to better control the activity of these
therapies.
Our product candidates use patient-derived T cells, which are
genetically modified to express the ACTR protein and
co-administered with a tumor-specific antibody. ACTR is a chimeric
protein which combines
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components from proteins normally found on both T cells and natural
killer cells, two types of human immune cells. The natural killer
cell component enables binding to tumor cell-bound antibodies and
the T cell component enables potent cytotoxicity, proliferation,
and persistence. Tumor-targeting antibodies administered with ACTR
T cells bind to the surface of the tumor cell and, in effect, label
it for ACTR T cell attack. When an ACTR T cell encounters a tumor
cell bound with antibodies, it binds to those antibodies and kills
the tumor cell through a process known as antibody-dependent
cellular cytotoxicity (ADCC), a function not normally observed with
T cells. No special modification of the tumor-specific antibody is
required in order for ADCC to take place.
ACTR T cells can be directed to a wide range of different cancer
cell antigens through the co-administration of antigen-specific
antibodies. Thus, we believe an ACTR T cell can be used in many
different cancer types. Preclinical data from in vivo testing show
that ACTR T cell-mediated tumor killing activity may be adjusted by
modulating the dose of the targeting antibodies. This ability to
adjust ACTR T cell activity could make it possible to define an
optimal dose through clinical testing to maximize tumor-killing
activity and minimize toxicity.
We have a broad product pipeline that includes three clinical stage
product candidates:
• Our most advanced product candidate, ACTR087 used in combination
with rituximab, is being tested in adult patients with r/r NHL in
an ongoing Phase I clinical trial called ATTCK-20-2. Two dose
levels were explored in the dose escalation phase of this trial.
Expansion and persistence of ACTR T cells was observed in all
patients evaluable for response in both tested dose levels for as
long as monitoring continued, consistent with what has been
observed in CAR-T trials. At the first dose level of this trial,
seven patients were treated with ACTR087 used in combination with
rituximab and six patients were evaluable for response. Of the six
evaluable patients, two complete responses and one partial response
were observed. As of March 7, 2018, one of the complete responses
was ongoing. No adverse events commonly associated with T cell
activation (CRS or neurotoxicity) of any grade were observed. At
the second dose level of this trial, nine patients were treated
with ACTR087 used in combination with rituximab (a tenth patient
was treated at the first dose level due to patient cell production
limitations). Six of these patients were evaluable for response at
the 42-day follow-up as of March 7, 2018. Three partial responses
have thus far been observed, one of which was ongoing as of March
7, 2018. We also observed dose-limiting toxicities in three
patients within this cohort and concluded that under this treatment
regimen, the second dose level exceeds the maximum tolerated dose.
We recently completed patient enrollment into the dose escalation
phase of this trial and are advancing towards testing in an
expanded patient cohort using an optimized dose of ACTR087 to
support potential registration trials. We plan to report
preliminary data from this expansion cohort at the end of 2018. In
parallel with this ongoing Phase I clinical trial, we plan to
initiate a Phase II clinical trial exploring ACTR087 used in
combination with rituximab in adult patients with r/r NHL who
received prior CD19 CAR-T therapy.
• Our second clinical stage product candidate, ACTR707 used in
combination with rituximab, is being tested in adult patients with
r/r NHL in a Phase I, multi-center, open-label clinical trial
called ATTCK-20-03. ACTR707 is a modified ACTR construct designed
to generate a more potent and sustained immune response to overcome
immunosuppressive tumor microenvironments commonly found in solid
tumor cancers. ACTR707 demonstrated activity against both
hematologic and solid tumor cancers in preclinical studies. We are
currently enrolling and dosing patients, and we expect to report
initial data from the clinical trial in the fourth quarter of 2018.
We plan to continue enrolling patients in this trial into 2019. We
expect to leverage data from the Phase I clinical trial in future
studies by combining ACTR707 with a variety of antibodies targeting
different cancers.
• Our third clinical stage product candidate, ACTR087 used in
combination with SEA-BCMA, is the first product candidate resulting
from our
strategic collaboration with Seattle Genetics, Inc. (Seattle
Genetics). We are currently enrolling and dosing adult patients
with r/r multiple myeloma in a Phase I multi-center trial and we
expect to report initial data from this trial in the fourth quarter
of 2018.
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• ACTR707 used in combination with trastuzumab is currently in late
preclinical development as a potential treatment for HER2+ solid
tumor cancers. We plan to file an IND and initiate clinical testing
of ACTR707 used in combination with trastuzumab in 2018.
Our Pipeline
The following table summarizes our product candidate
pipeline:
We have obtained and retained worldwide commercial rights to the
majority of our product candidates, including our lead product
candidate, ACTR087 used in combination with rituximab. We intend to
establish our own commercial organization in the United States
where we believe we can address physicians with a direct specialty
sales force. Our commercial strategy for markets outside the United
States may include the use of strategic partners or the
establishment of our own commercial infrastructure. We plan to
further evaluate these alternatives as we approach potential
approval of our product candidates.
In June 2015, we announced a global strategic collaboration with
Seattle Genetics to identify, research, develop, and commercialize
two novel antibody-coupled ACTR therapies incorporating Seattle
Genetics’ proprietary antibodies. Under the terms of the
collaboration, we will conduct preclinical research and clinical
development activities through Phase I clinical trials and Seattle
Genetics will provide all of the funding for those activities. We
plan to work together to co-develop and fund product candidates
after Phase I clinical trials. We will co-commercialize any
successfully developed product candidates and share equally any
profits and losses on any co-developed product candidates in the
United States. Seattle Genetics retains exclusive commercial rights
outside of the United States. The first product candidate under our
collaboration is ACTR087 used in combination with Seattle Genetics’
SEA-BCMA antibody for r/r multiple myeloma.
Clinical development and commercialization of ACTR products are
supported by our efforts to optimize manufacturing from the initial
collection of a patient’s white blood cells through the re-infusion
of a formulated ACTR T cell product (i.e., from “vein-to-vein”). To
this end, we have developed a largely automated ACTR manufacturing
process with quality, scalability, cost, and consistency in mind.
We are currently addressing clinical manufacturing needs for both
viral vector and ACTR T cells with contract manufacturing
organizations (CMOs) to increase flexibility and mitigate risks. As
our product candidates advance through clinical trials, we expect
to secure commercial manufacturing capacity using one or more CMOs
or by establishing our own commercial manufacturing good
manufacturing practices (GMP) facility.
We believe that the quality of our people has a strong and positive
impact on our ability to develop and capitalize on our ACTR
platform. We have assembled a team of highly skilled and
experienced employees, directors, scientific advisors, and
consultants with broad capabilities in oncology drug discovery
and
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development. In addition, our scientific founder and an inventor of
our key patents relating to ACTR087, Dario Campana, M.D., Ph.D., is
considered a world leader in cancer cell therapy. Dr. Campana
continues to support our efforts as Chair of our Scientific
Advisory Board.
Our Strategy
Our goal is to transform cancer treatment through the application
of our universal ACTR platform in a wide range of hematologic and
solid tumor cancers. Key elements of our strategy include the
following objectives:
• Expedite clinical development, regulatory approval, and
commercialization of our product candidate ACTR087 used in
combination with rituximab. We plan to continue to advance our lead
product candidate, ACTR087 used in combination with rituximab, for
the treatment of adult patients with r/r NHL. If we believe the
Phase I data are compelling, we plan to discuss with the FDA the
potential to move to a registration trial in adult patients with
r/r NHL upon completion of the current Phase I clinical trial.
Additionally, we plan to submit regulatory filings to enable a
Phase II clinical trial in 2018 to evaluate ACTR087 used in
combination with rituximab in adult patients with r/r NHL who
received prior CD19 CAR-T therapy.
• Leverage our universal ACTR platform to broaden our product
portfolio rapidly and cost effectively. ACTR is an investigational
engineered cell therapy that we believe can be used in combination
with a wide range of tumor-targeting antibodies to pursue different
antigens and cancer indications. ACTR does not need to be modified
for use with different antibodies, and antibodies do not need to be
modified for use with ACTR. This allows us to leverage our
investment in ACTR and the investment by third parties in existing
antibodies across different ACTR–antibody combinations, tumor
types, and indications. We expect the universality of our ACTR
platform will allow us to prosecute four product candidates by the
end of 2018.
• Expand our pipeline with increased focus on solid tumor product
candidates. With a particular aim at creating an ACTR that
addresses the specific challenges associated with attacking solid
tumor cancers, we have developed a modified ACTR construct called
ACTR707. We plan to use ACTR707 to rapidly progress ACTR product
candidates targeting solid tumor cancers into clinical development,
starting with ACTR707 used in combination with trastuzumab for
HER2+ cancers. We aim to continue to improve the functionality of
the ACTR T cell in solid tumor cancers through (i) additional
genetic modifications to exploit new supporting biology in the
tumor microenvironment and (ii) introducing new manufacturing
process modifications.
• Establish manufacturing capacity and leverage our process
development capabilities to create a competitive advantage in T
cell manufacturing. We designed a process using a closed automated
system to support our clinical development plans and have devoted
significant resources to optimizing process development. We
currently engage CMOs to use our process for production of GMP
material. In the future, we intend to establish our own GMP
manufacturing facility.
• Establish commercialization and marketing capabilities to support
current and future product candidates. We plan to establish a U.S.-
focused specialty sales and marketing organization in advance of
receipt of regulatory approval of the first ACTR product candidate.
We intend to leverage the infrastructure developed for our first
approved ACTR product to facilitate commercialization of any
additional product candidates for which we gain approval. In
addition, we will build upon physician familiarity and experience
with the first approved ACTR product to accelerate adoption of
subsequent products.
4
Risks Associated with Our Business
Our ability to implement our business strategy is subject to
numerous risks, as more fully described in the section entitled
“Risk Factors” immediately following this prospectus summary. These
risks include, among others:
• We have incurred net losses in every year since our inception and
anticipate that we will continue to incur net losses in the future.
If we fail to obtain additional financing, we may be unable to
complete the development and commercialization of our product
candidates.
• Since the number of patients that we have dosed, or plan to dose,
in our ongoing or planned Phase I clinical trials is small, the
results from
such clinical trials, once completed, may be less reliable than
results achieved in larger clinical trials, which may hinder our
efforts to obtain regulatory approval for our product
candidates.
• Our product candidates may cause undesirable side effects or have
other properties that could halt their clinical development,
prevent their regulatory approval, require expansion of the trial
size, limit their commercial potential, or result in significant
negative consequences. For example, in the second dose level of our
ongoing Phase I clinical trial called ATTCK-20-2, we have observed
ACTR087-related serious adverse events (SAEs), including two
patient deaths. We also experienced one non-ACTR087-related death
that followed an ACTR087- related severe CRS. These events resulted
in the FDA placing the trial on clinical hold pending submission of
certain information relating to the ATTCK-20-2 clinical trial. The
clinical hold was removed in February 2018, following review of
this information by the FDA. However, if we continue to observe
severe side effects in our clinical trials, such trials may be
halted or put on an additional clinical hold prior to completion if
there is determined to be an unacceptable safety risk for
patients.
• Our clinical trials may fail to demonstrate adequately the safety
and efficacy of any of our product candidates, which would prevent
or delay
regulatory approval and commercialization. The FDA regulatory
approval process is lengthy and time-consuming, and we may
experience significant delays in the clinical development and
regulatory approval of our product candidates.
• Our business is highly dependent on the success of ACTR087 used
in combination with rituximab or ACTR707 used in combination with
rituximab, our lead product candidates, and other ACTR-antibody
combinations that we may develop.
• Our ACTR T cell product candidates represent a novel approach to
cancer treatment, which creates significant challenges for
us.
• We have entered into a strategic collaboration with Seattle
Genetics and may form or seek collaborations or strategic alliances
or enter into additional licensing arrangements in the future, and
we may not realize the benefits of such alliances or licensing
arrangements.
• We face significant competition from other biotechnology and
pharmaceutical companies, and our operating results will suffer if
we fail to compete effectively.
• We rely and will rely on third parties to conduct our clinical
trials. If these third parties do not properly and successfully
carry out their contractual duties or meet expected deadlines, we
may not be able to obtain regulatory approval of or commercialize
our product candidates. We expect to rely on third parties to
manufacture our clinical product supplies, and we may rely on third
parties for at least a portion of the manufacturing process of our
product candidates, if approved. Our business could be harmed if
those third parties fail to provide us with sufficient quantities
of clinical product supplies or product candidates or fail to do so
at acceptable quality levels or prices.
• We depend on intellectual property licensed from third parties
and termination of any of these licenses could result in the loss
of significant rights, which would harm our business.
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Concurrent Private Placement
Seattle Genetics has agreed to purchase from us, concurrently with
this offering in a private placement, $5.0 million of shares of our
common stock at a price per share equal to the initial public
offering price. See “Concurrent Private Placement.”
Corporate History
We were incorporated under the laws of the State of Delaware in
March 2014. Our principal executive office is located at 200
Cambridge Park Drive, Suite 3100, Cambridge, Massachusetts 02140,
and our telephone number is (617) 945-5576. Our website address is
www.unumrx.com. We do not incorporate the information on or
accessible through our website into this prospectus, and you should
not consider any information on, or that can be accessed through,
our website as part of this prospectus.
Implications of Being an Emerging Growth Company
We qualify as an “emerging growth company” as defined in the
Jumpstart Our Business Startups Act of 2012, as amended (JOBS Act).
As an emerging growth company, we may take advantage of specified
reduced disclosure and other requirements that are otherwise
applicable generally to public companies. These provisions
include:
• only two years of audited financial statements in addition to any
required unaudited interim financial statements with
correspondingly reduced “Management’s Discussion and Analysis of
Financial Condition and Results of Operations” disclosure;
• reduced disclosure about our executive compensation
arrangements;
• no non-binding advisory votes on executive compensation or golden
parachute arrangements; and
• exemption from the auditor attestation requirement in the
assessment of our internal control over financial reporting.
We may take advantage of these exemptions for up to five years or
such earlier time that we are no longer an emerging growth company.
We would cease to be an emerging growth company on the date that is
the earliest of (i) the last day of the fiscal year in which we
have total annual gross revenues of $1.07 billion or more; (ii) the
last day of our fiscal year following the fifth anniversary of the
date of the closing of this offering; (iii) the date on which we
have issued more than $1 billion in nonconvertible debt during the
previous three years; or (iv) the date on which we are deemed to be
a large accelerated filer under the rules of the Securities and
Exchange Commission (SEC). We may choose to take advantage of some
but not all of these exemptions. We have taken advantage of reduced
reporting requirements in this prospectus. Accordingly, the
information contained herein may be different from the information
you receive from other public companies in which you hold
stock.
We have irrevocably elected to “opt out” of the exemption for the
delayed adoption of certain accounting standards and, therefore,
will be subject to the same new or revised accounting standards as
other public companies that are not emerging growth
companies.
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THE OFFERING Common stock offered by us 5,770,000 shares.
Concurrent private placement Seattle Genetics, Inc. (Seattle
Genetics) has agreed to purchase from us, concurrently with
this
offering in a private placement, $5.0 million of shares of our
common stock at a price per share equal to the initial public
offering price, or 384,615 shares, based on an assumed initial
public offering price of $13.00 per share, which is the midpoint of
the price range set forth on the cover page of this prospectus. We
will receive the full proceeds from the sale and will not pay any
underwriting discounts or commissions with respect to the shares of
common stock that are sold in the private placement. The sale of
these shares of common stock to Seattle Genetics will not be
registered under the Securities Act of 1933, as amended, and these
shares will be subject to a 180-day lock-up agreement with the
underwriters for this offering. We refer to the private placement
of these shares as the concurrent private placement. The closing of
this offering is not conditioned upon the closing of the concurrent
private placement.
Common stock to be outstanding immediately after this offering and
the concurrent private placement
29,585,667 shares (30,451,167 shares if the underwriters exercise
their option to purchase additional shares in full).
Underwriters’ option to purchase additional shares We have granted
a 30-day option to the underwriters to purchase up to an aggregate
of
865,500 additional shares of common stock from us at the public
offering price, less underwriting discounts and commissions, on the
same terms as set forth in this prospectus. The underwriters may
exercise this option solely for the purpose of covering
over-allotments, if any, made in connection with the offering of
the shares of common stock offered by this prospectus.
Use of proceeds We estimate that we will receive net proceeds from
the sale of shares of our common stock in
this offering of approximately $67.0 million, or $77.4 million if
the underwriters exercise their option to purchase additional
shares in full, assuming an initial public offering price of $13.00
per share, which is the midpoint of the price range set forth on
the cover page of this prospectus, and after deducting estimated
underwriting discounts and commissions and estimated offering
expenses payable by us. Our proceeds from the concurrent private
placement will be $5.0 million. We intend to use the net proceeds
from this offering and the concurrent private placement, together
with our existing cash, cash equivalents, and marketable
securities, to advance ACTR087 used in combination with rituximab
for adult patients with r/r B cell non-Hodgkin lymphoma through the
completion of our ongoing Phase I clinical trial; to fund a Phase
II clinical trial of ACTR087 used in combination with rituximab for
adult patients with r/r non-Hodgkin lymphoma who received prior
CD19 CAR-T therapy; to advance ACTR707 used in combination
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with rituximab for adult patients with r/r B cell non-Hodgkin
lymphoma through the completion of our Phase I clinical trial; to
advance ACTR707 used in combination with trastuzumab through
submission of an IND and to fund our Phase I clinical trial for
this product candidate; and the remainder to develop product
candidates in earlier stages of development and any additional
product candidates that we select, to expand headcount and internal
capabilities, and for working capital and other general corporate
purposes. For a more complete description of our intended use of
the proceeds from this offering and the concurrent private
placement, see “Use of Proceeds.”
Risk factors You should carefully read the “Risk Factors” section
of this prospectus for a discussion of
factors that you should consider before deciding to invest in our
common stock. Proposed Nasdaq Global Market symbol “UNUM”
Certain of our existing stockholders, including affiliates of our
directors, have indicated an interest in purchasing an aggregate of
up to $37.5 million of shares of our common stock in this offering
at the initial public offering price. However, because indications
of interest are not binding agreements or commitments to purchase,
the underwriters may determine to sell more, less or no shares in
this offering to any of these stockholders, or any of these
stockholders may determine to purchase more, less or no shares in
this offering.
The number of shares of our common stock to be outstanding after
this offering and the concurrent private placement is based on
23,431,052 shares of our common stock outstanding as of January 31,
2018, after giving effect to the automatic conversion of all
outstanding shares of our preferred stock as of January 31, 2018
into an aggregate of 13,229,362 shares of common stock upon the
closing of this offering, and excludes:
• 3,150,889 shares of our common stock issuable upon the exercise
of stock options outstanding as of January 31, 2018, at a weighted
average exercise price of $4.01 per share;
• 982,525 shares of our common stock available for future issuance
as of January 31, 2018 under our 2015 Stock Incentive Plan, as
amended
(2015 Plan), which will become available for issuance under our
2018 Stock Option and Incentive Plan (2018 Plan) upon effectiveness
of the 2018 Plan;
• 2,547,558 shares of our common stock reserved for future issuance
under our 2018 Plan, which will become effective upon the date
immediately preceding the date of the effectiveness of the
registration statement of which this prospectus is a part (of which
we expect to grant options to purchase an aggregate of 777,071
shares of our common stock, with an exercise price per share equal
to the initial public offering price in this offering, to certain
of our employees and non-employee directors in connection with this
offering); and
• 314,000 shares of our common stock reserved for future issuance
under our 2018 Employee Stock Purchase Plan, which will become
effective upon the effectiveness of the registration statement of
which this prospectus is a part.
Unless otherwise indicated, all information in this prospectus
reflects or assumes the following:
• the filing of our amended and restated certificate of
incorporation and the effectiveness of our amended and restated
bylaws upon the closing of this offering;
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• the automatic conversion of all outstanding shares of our
preferred stock into an aggregate of 13,229,362 shares of common
stock upon the closing of this offering;
• no exercise of outstanding options after January 31, 2018;
• the issuance and sale by us in the concurrent private placement
of 384,615 shares of common stock to Seattle Genetics, based on an
assumed initial public offering price of $13.00 per share, which is
the midpoint of the price range set forth on the cover page of this
prospectus;
• a 1-for-1.5701314513884 reverse split of our common stock
effected on March 16, 2018; and
• no exercise by the underwriters of their option to purchase up to
865,500 additional shares of common stock in this offering.
9
Summary Consolidated Financial Data
You should read the following summary consolidated financial data
together with our consolidated financial statements and the related
notes appearing elsewhere in this prospectus and the “Selected
Consolidated Financial Data” and “Management’s Discussion and
Analysis of Financial Condition and Results of Operations” sections
of this prospectus. We have derived the consolidated statement of
operations data for the years ended December 31, 2015, 2016, and
2017 and the consolidated balance sheet data as of December 31,
2017 from our audited consolidated financial statements appearing
elsewhere in this prospectus. Our historical results are not
necessarily indicative of the results that may be expected in the
future, and our results for any interim period are not necessarily
indicative of results that may be expected for any full year. Year
Ended December 31, 2015 2016 2017
(in thousands, except per share
data) Consolidated Statement of Operations Data: Collaboration
revenue $ 2,986 $ 6,355 $ 8,360
Operating expenses: Research and development 6,852 21,992 29,832
General and administrative 2,726 3,433 4,680
Total operating expenses 9,578 25,425 34,512
Loss from operations (6,592) (19,070) (26,152)
Other income (expense): Interest income — 265 386 Other income, net
— 681 274
Total other income, net — 946 660
Net loss (6,592) (18,124) (25,492) Accretion of redeemable
convertible preferred stock to redemption value (43) (64)
(65)
Net loss attributable to common stockholders $ (6,635) $(18,188)
$(25,557)
Net loss per share attributable to common stockholders, basic and
diluted(1) $ (0.65) $ (1.78) $ (2.51)
Weighted average common shares outstanding, basic and diluted(1)
10,190 10,190 10,192
Pro forma net loss per share attributable to common stockholders,
basic and diluted (unaudited)(2) $ (1.09)
Pro forma weighted average common shares outstanding, basic and
diluted (unaudited)(2) 23,421
(1) See Note 13 to our consolidated financial statements appearing
elsewhere in this prospectus for details on the calculation of
basic and diluted net
loss per share attributable to common stockholders. (2) See Note 13
to our consolidated financial statements appearing elsewhere in
this prospectus for details on the calculation of basic and diluted
pro
forma net loss per share attributable to common stockholders.
10
As of December 31, 2017
Actual Pro Forma(2) Pro Forma
As Adjusted(3) (in thousands) Consolidated Balance Sheet Data:
Cash, cash equivalents, and marketable securities $ 40,961 $ 40,961
$ 113,709 Working capital(1) 31,189 31,189 104,521 Total assets
49,115 49,115 120,490 Redeemable convertible preferred stock 77,151
— — Total stockholders’ equity (deficit) (48,846) 28,305 100,264
(1) We define working capital as current assets less current
liabilities. (2) The pro forma balance sheet data give effect to
the automatic conversion of all outstanding shares of our preferred
stock into an aggregate of
13,229,362 shares of common stock upon the closing of this
offering. (3) The pro forma as adjusted balance sheet data give
further effect to (i) our issuance and sale of 5,770,000 shares of
common stock in this offering at
an assumed initial public offering price of $13.00 per share, which
is the midpoint of the price range set forth on the cover page of
this prospectus, after deducting estimated underwriting discounts
and commissions and estimated offering expenses payable by us and
(ii) the issuance and sale by us in the concurrent private
placement of 384,615 shares of common stock to Seattle Genetics,
Inc., based on the assumed initial public offering price.
The pro forma as adjusted information discussed above is
illustrative only and will change based on the actual initial
public offering price and other terms of this offering determined
at pricing. A $1.00 increase (decrease) in the assumed initial
public offering price of $13.00 per share, which is the midpoint of
the price range set forth on the cover page of this prospectus,
would increase (decrease) the pro forma as adjusted amount of each
of cash, cash equivalents, and marketable securities, working
capital, total assets, and total stockholders’ equity by $5.4
million, assuming that the number of shares offered by us, as set
forth on the cover page of this prospectus, remains the same and
after deducting estimated underwriting discounts and commissions
and estimated offering expenses payable by us. An increase
(decrease) of 1,000,000 shares in the number of shares offered by
us, as set forth on the cover page of this prospectus, would
increase (decrease) the pro forma as adjusted amount of each of
cash, cash equivalents, and marketable securities, working capital,
total assets, and total stockholders’ equity by $12.1 million,
assuming no change in the assumed initial public offering price per
share and after deducting estimated underwriting discounts and
commissions and estimated offering expenses payable by us.
11
RISK FACTORS
Investing in our common stock involves a high degree of risk. You
should carefully consider the risks described below, as well as the
other information in this prospectus, including our financial
statements and the related notes and “Management’s Discussion and
Analysis of Financial Condition and Results of Operations,” before
deciding whether to invest in our common stock. The occurrence of
any of the events or developments described below could harm our
business, financial condition, results of operations and growth
prospects. In such an event, the market price of our common stock
could decline and you may lose all or part of your investment.
Additional risks and uncertainties not presently known to us or
that we currently deem immaterial also may impair our business
operations.
Risks Related to Our Business and Industry
We have incurred net losses in every year since our inception and
anticipate that we will continue to incur net losses in the
future.
We are a clinical-stage biopharmaceutical company with a limited
operating history. Investment in biopharmaceutical product
development is highly speculative because it entails substantial
upfront capital expenditures and significant risk that any
potential product candidate will fail to demonstrate adequate
effect or an acceptable safety profile, gain regulatory approval
and become commercially viable. We have no products approved for
commercial sale and have not generated any revenue from product
sales to date, and we continue to incur significant research and
development and other expenses related to our ongoing operations.
As a result, we are not profitable and have incurred losses in each
period since our inception in March 2014. For the years ended
December 31, 2015, 2016, and 2017, we reported net losses of $6.6
million, $18.1 million, and $25.5 million, respectively. As of
December 31, 2017, we had an accumulated deficit of $51.3 million.
We expect to continue to incur significant losses for the
foreseeable future, and we expect these losses to increase as we
continue our research and development of, and seek regulatory
approvals for, product candidates.
Even if we succeed in commercializing one or more of our product
candidates, we will continue to incur substantial research and
development and other expenditures to develop and market additional
product candidates. We may encounter unforeseen expenses,
difficulties, complications, delays and other unknown factors that
may adversely affect our business. The size of our future net
losses will depend, in part, on the rate of future growth of our
expenses and our ability to generate revenue. Our prior losses and
expected future losses have had and will continue to have an
adverse effect on our stockholders’ equity and working
capital.
Our ACTR T cell product candidates represent a novel approach to
cancer treatment, which creates significant challenges for
us.
Our ACTR T cell product candidates involve (1) harvesting T cells
from the patient’s blood via leukapheresis, (2) genetically
engineering the T cells to incorporate the ACTR transgene, (3)
expanding the number of engineered T cells to the desired dose
level and (4) infusing the engineered ACTR T cells back into the
patient with or following the administration of the antibody.
Advancing this novel and personalized investigational therapy
creates significant challenges for us, including:
• educating medical personnel about the administration of the
ACTR-combination therapy;
• educating medical personnel regarding the potential side effect
profile of our product candidates, such as the potential adverse
side effects related to cytokine release syndrome, neurotoxicity or
autoimmune or rheumatologic disorders;
• administering chemotherapy to patients in advance of
administering our product candidates, which may increase the risk
of adverse side effects;
• sourcing clinical and, if approved, commercial, supplies for the
materials used to manufacture and process our product
candidates;
12
• manufacturing viral vectors to deliver ACTR to T cells;
• developing a robust and reliable ACTR T cell manufacturing
process, including efficiently managing shipment of patient cells
from and to clinical sites, minimizing potential contamination to
the cell product and effectively scaling manufacturing capacity to
meet demand;
• managing costs of inputs and other supplies while scaling
production;
• using medicines to manage adverse side effects of our product
candidates, which may not adequately control the side effects
and/or may have a detrimental impact on the efficacy of the
treatment;
• obtaining and maintaining regulatory approval from the U.S. Food
and Drug Administration (FDA); and
• establishing sales and marketing capabilities upon obtaining any
regulatory approval to gain market acceptance of a novel
therapy.
In developing our product candidates we have not exhaustively
explored different options in the design of the ACTR construct and
in the method for manufacturing ACTR T cells. We may find our
existing ACTR T cells and manufacturing process may be
substantially improved with future design or process changes,
necessitating development of new backup ACTR constructs and further
clinical testing and delaying launch of our first products. For
example:
• We have made a large number of ACTR constructs and used
preclinical tests to select product candidates to advance into
clinical testing. The
preclinical tests are limited in their ability to predict behavior
in patients. As we gain clinical experience with ACTR, new
learnings may prompt us to select other ACTR constructs for
clinical development.
• We have used a retroviral vector to deliver ACTR to T cells. In
the future, we may find that a lentiviral vector offers advantages.
Switching from retroviral to lentiviral delivery would necessitate
additional process development and clinical testing and delay
existing product candidates.
• The process by which patient cells are converted into an ACTR T
cell has many steps that can influence quality and activity. We
have explored a subset of variables and expect to continue to
improve and optimize the manufacturing process. Depending upon the
nature of the process changes, we may be compelled to perform
bridging studies and/or to re-start clinical development, causing
delays in time to market and potentially introducing a risk of
failure if new processes do not perform as expected.
Our business is highly dependent on the success of ACTR087 used in
combination with rituximab or ACTR707 used in combination with
rituximab, our lead product candidates, and other ACTR-antibody
combinations that we may develop.
Our business and future success depend on our ability to obtain
regulatory approval of and then successfully commercialize one of
our product candidates, such as ACTR087 used in combination with
rituximab and other product combinations that we develop using
antibodies in combination with ACTR087 or ACTR707. All of our
product candidates, including ACTR087 used in combination with
rituximab and ACTR 707 used in combination with rituximab, are in
the early stages of development and will require additional
clinical and non-clinical development, regulatory review and
approval, substantial investment, access to sufficient commercial
manufacturing capacity and significant marketing efforts before we
can generate any revenue from product sales. In addition, because
ACTR087 used in combination with rituximab and ACTR707 used in
combination with rituximab are our two most advanced product
candidates, and because all our other product candidates are based
on our ACTR platform, if either of these product candidates
encounters safety, efficacy, or manufacturing problems,
developmental delays, regulatory, or commercialization difficulties
or other problems, our development plans and business would be
significantly harmed. For example, our Phase I clinical trial for
ACTR087 used in combination with rituximab was placed on clinical
hold in December 2017 pending submission of certain information
relating to the trial. The clinical hold was removed in February
2018, following review of this information by the FDA.
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Our clinical trials may fail to demonstrate adequately the safety
and efficacy of any of our product candidates, which would prevent
or delay regulatory approval and commercialization.
Before obtaining regulatory approvals for the commercial sale of
our product candidates, including ACTR087 used in combination with
rituximab and other product candidates that we develop using
antibodies in combination with ACTR087 and ACTR707, we must
demonstrate through lengthy, complex and expensive preclinical
testing and clinical trials that our product candidates are both
safe and effective for use in each target indication. Clinical
testing is expensive and can take many years to complete, and its
outcome is inherently uncertain. Failure can occur at any time
during the clinical trial process, and, because our product
candidates are in an early stage of development, there is a high
risk of failure and we may never succeed in developing marketable
products. The results of preclinical studies and early clinical
trials of our product candidates may not be predictive of the
results of later-stage clinical trials. There is typically an
extremely high rate of attrition from the failure of product
candidates proceeding through clinical trials. Product candidates
in later stages of clinical trials may fail to show the desired
safety and efficacy profile despite having progressed through
preclinical studies and initial clinical trials. A number of
companies in the biopharmaceutical industry have suffered
significant setbacks in advanced clinical trials due to lack of
efficacy, insufficient durability of efficacy, or unacceptable
safety issues, notwithstanding promising results in earlier trials.
Most product candidates that commence clinical trials are never
approved as products.
Any clinical trials that we may conduct may not demonstrate the
efficacy and safety necessary to obtain regulatory approval to
market our product candidates. If the results of our ongoing or
future clinical trials are inconclusive with respect to the
efficacy of our product candidates, if we do not meet the clinical
endpoints with statistical and clinically meaningful significance,
or if there are safety concerns associated with our product
candidates, we may be prevented or delayed in obtaining marketing
approval for such product candidates. In some instances, there can
be significant variability in safety or efficacy results between
different clinical trials of the same product candidate due to
numerous factors, including changes in trial procedures set forth
in protocols, differences in the size and type of the patient
populations, changes in and adherence to the clinical trial
protocols and the rate of dropout among clinical trial
participants.
We designed our Phase I clinical trial of ACTR087 used in
combination with rituximab, called ATTCK-20-2, primarily to assess
safety and efficacy in adult patients with r/r NHL. The preliminary
results from the Phase I clinical trial of ACTR087 used in
combination with rituximab may not be indicative of the final
analysis of this Phase I clinical trial, especially given the small
number of patients that we plan to dose in the trial. In addition,
the Phase I results may not predict results for any further
clinical testing of ACTR087 used in combination with rituximab or
other product candidates that we have developed, or may develop in
the future, using antibodies in combination with ACTR087 and
ACTR707 or in different indications.
Additionally, as of the most recent data cutoff date of March 7,
2018, approximately 12% (two out of 17) of ACTR087 treated patients
in ATTCK-20-2 experienced ACTR087-related severe cytokine release
syndrome (CRS) and 6% (one out of 17) of patients experienced
ACTR087-related neurotoxicity, which was fatal. Of the two events
of CRS, one patient subsequently experienced a fatal case of
enterococcal sepsis considered related to ACTR087 and one patient
subsequently experienced a fatal case of sepsis considered not
related to ACTR087. These events resulted in the FDA placing this
trial on clinical hold in December 2017 pending submission of
certain information relating to the ATTCK-20-2 clinical trial. The
clinical hold was removed in February 2018, following review of
this information by the FDA. Several protocol and dosing changes
were made in early 2018, which we expect to reduce the incidence of
severe adverse events and better manage those events that do occur.
If severe safety events are observed in patients treated in the
future in spite of the modifications outlined above, the FDA may
determine, at any time, that there is an unacceptable safety risk
for patients and we may be required to stop the trial prior to its
completion or our ongoing clinical trials may be halted or put on
further clinical holds prior to completion.
In addition, even if the trials are successfully completed,
clinical data are often susceptible to varying interpretations and
analyses, and we cannot guarantee that the FDA or foreign
regulatory authorities will interpret the
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results as we do, and more trials could be required before we
submit our product candidates for approval. For instance, although
our lead product candidates will be dosed in refractory patients
with antibodies that the patients have already received, we plan to
test future product candidates in patients that have never received
the co-administered antibody in prior treatment and with antibodies
that have never been independently evaluated for safety or
efficacy. As a result, it may be difficult to demonstrate that the
ACTR construct, rather than the antibody alone, is causing an
observed effect. We cannot guarantee that the FDA will view the
ACTR construct as having efficacy even if positive results are
observed in these clinical trials. To the extent that the results
of the trials are not satisfactory to the FDA or foreign regulatory
authorities for support of a marketing application, approval of our
product candidates may be significantly delayed, or we may be
required to expend significant additional resources, which may not
be available to us, to conduct additional trials in support of
potential approval of our product candidates.
We cannot guarantee that our product candidates will show any
functionality in the solid tumor environment.
While we plan to develop product candidates for use in solid tumor
cancers, including ACTR707 used in combination with trastuzumab for
HER2+ cancers, we cannot guarantee that our product candidates will
show any functionality in the solid tumor environment. The cellular
environment in which solid tumor cancers exist is inimical to T
cells due to several factors including: (1) immunosuppressive cells
(e.g., regulatory T cells (Tregs), myeloid derived suppressor cells
(MDSCs)), (2) immunosuppressive enzymes and signaling molecules
(e.g., IDO1, TGF-beta), (3) limited nutrients (e.g., oxygen,
glucose), and (4) toxic metabolites (e.g., reactive oxygen species,
lactic acid). Together, these factors can limit the ability of T
cells, including ACTR T cells, both to penetrate into the solid
tumor and to function properly once there. As a result of these and
other solid tumor challenges, our product candidates may not
demonstrate efficacy in solid tumors. For example, our ACTR-based
product candidates may not be able to access the solid tumor, and
even if they do, they may not be able to exert anti-tumor effects
in an immunosuppressive tumor microenvironment. In addition, the
safety profile of our product candidates may differ in a solid
tumor setting. If we are unable to make our product candidates
function in solid tumor cancers, our development plans and business
may be significantly harmed.
Since the number of patients that we have dosed, or plan to dose,
in our ongoing or planned Phase I clinical trials is small, the
results from such clinical trials, once completed, may be less
reliable than results achieved in larger clinical trials, which may
hinder our efforts to obtain regulatory approval for our product
candidates.
A study design that is considered appropriate for regulatory
approval includes a sufficiently large sample size with appropriate
statistical power, as well as proper control of bias, to allow a
meaningful interpretation of the results. In our ongoing Phase I
clinical trial of ACTR087 used in combination with rituximab, for
example, we have analyzed the dose-limiting toxicities of ACTR087
used in combination with rituximab in only 17 patients with r/r NHL
so far, 12 of whom were evaluable for anti-tumor effects. The
preliminary results of trials with smaller sample sizes, such as
our ongoing Phase I clinical trial for ACTR087 used in combination
with rituximab, can be disproportionately influenced by the impact
the treatment had on a few individuals, which limits the ability to
generalize the results across a broader community, thus making the
study results less reliable than studies with a larger number of
patients. As a result, there may be less certainty that such
product candidates would achieve a statistically significant effect
in any future clinical trials. If we conduct any future clinical
trials, we may not achieve a statistically significant result or
the same level of statistical significance, if any, that we may see
in our Phase I clinical trial, once we complete the trial.
We may not be able to file investigational new drug applications
(INDs) or IND amendments to commence additional clinical trials on
the timelines we expect, and even if we are able to, the FDA may
not permit us to proceed.
We expect to submit an IND for ACTR707 used in combination with
trastuzumab in 2018. However, our timing of filing on the product
candidate is dependent on further research. We cannot be sure that
submission of
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an IND will result in the FDA allowing further clinical trials to
begin, or that, once begun, issues will not arise that suspend or
terminate such clinical trials. Additionally, even if such
regulatory authorities agree with the design and implementation of
the clinical trials set forth in an IND or clinical trial
application, we cannot guarantee that such regulatory authorities
will not change their requirements in the future. These
considerations also apply to new clinical trials we may submit as
amendments to existing INDs.
We have limited experience as a company conducting clinical trials
or managing a manufacturing facility for our product
candidates.
We have limited experience as a company in conducting clinical
trials. In part because of this lack of experience, we cannot be
certain that our ongoing clinical trials will be completed on time
or if the planned clinical trials will begin or be completed on
time, if at all. Large-scale trials would require significant
additional financial and management resources and reliance on
third-party clinical investigators, contract research organizations
(CROs), or consultants. Relying on third-party clinical
investigators or CROs may force us to encounter delays that are
outside of our control.
In the future, we also intend to operate our own manufacturing
facility, which will require significant resources, and we have
limited experience as a company in expanding or managing a
manufacturing facility. In part because of this lack of experience,
we cannot be certain that our manufacturing facility will be
completed on time, if at all, or if the planned clinical trials
will begin or be completed on time, if at all. In part because of
our inexperience, we may have unacceptable or inconsistent product
quality success rates and yields, and we may be unable to maintain
adequate quality control, quality assurance and qualified
personnel. In addition, if we switch from one manufacturing
facility to our own manufacturing facility for one or more of our
product candidates in the future, we may need to conduct additional
preclinical studies to bridge our modified product candidates to
earlier versions. Failure to successfully create and operate our
proposed manufacturing facility could adversely affect the
commercial viability of our product candidates.
Our product candidates may cause undesirable side effects or have
other properties that could halt their clinical development,
prevent their regulatory approval, require expansion of the trial
size, limit their commercial potential, or result in significant
negative consequences.
Undesirable side effects caused by our product candidates could
cause us or regulatory authorities, including institutional review
boards (IRBs), to interrupt, delay, or halt clinical trials and
could result in a more restrictive label or the delay or denial of
regulatory approval by the FDA or other comparable foreign
regulatory authorities. Further, clinical trials by their nature
utilize a sample of the potential patient population. With a
limited number of subjects and limited duration of exposure, rare
and severe side effects of our product candidates may only be
uncovered with a significantly larger number of patients exposed to
the drug. Because of our dose escalation design for our clinical
trials, undesirable side effects could also result in an expansion
in the size of our clinical trials, increasing the expected costs
and timeline of our clinical trials. Additionally, results of our
trials could reveal a high and unacceptable severity and prevalence
of side effects or unexpected characteristics.
In certain trials of CAR-based products, which also use an
engineered T cell, side effects, such as CRS and neurotoxicity,
arose that resulted in risk, injury, or death to the patients. We
observed some of these side effects in the second dose level of our
Phase I clinical trial of ACTR087 used in combination with
rituximab, called ATTCK-20-2. These events resulted in the FDA
placing the trial on clinical hold pending submission of certain
information relating to the ATTCK-20-2 clinical trial. The clinical
hold was removed in February 2018, following review of this
information by the FDA. We will likely continue to observe some or
all of these side effects in our clinical trials at additional
dosage levels. We have established safety management and monitoring
guidelines for clinical investigators to detect and treat potential
side effects. However, there is no guarantee that these medical
interventions will be effective in preventing negative effects to
the patient. Additionally, if we do continue to observe severe side
effects in our clinical trials, our ongoing clinical trials may be
halted or put on an additional clinical hold prior to completion if
there is an unacceptable safety risk for patients.
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Autoimmune reaction triggered by an interaction between a patient’s
naturally occurring antibodies and ACTR T cells is a theoretical
safety risk unique to the ACTR approach. If a patient’s
self-generated antibodies were directed to a target expressed on
the surface of cells in normal tissue (i.e., autoantibodies), ACTR
would be directed to attack these tissues, potentially resulting in
off-tumor effects. These autoantibodies may be present whether or
not the patient has an active autoimmune disease. In our clinical
testing, we have taken steps to minimize the likelihood of this
happening (e.g., excluding patients with a history of autoimmune
disease from our trials and screening for the presence of certain
autoantibodies). To date, we have not observed any autoimmune
adverse effects in clinical testing of ACTR. There is no guarantee,
however, that we will not observe autoimmune reactions in the
future and no guarantee that if we do, that we will be able to
implement interventions to address the risk.
If unacceptable toxicities arise in the development of our product
candidates, we could suspend or terminate our trials or the FDA or
comparable foreign regulatory authorities, or local regulatory
authorities such as IRBs, could order us to cease clinical trials.
Competent national health authorities, such as the FDA, could also
deny approval of our product candidates for any or all targeted
indications. Treatment-related side effects could also affect
patient recruitment or the ability of enrolled patients to complete
the trial or result in potential product liability claims. In
addition, these side effects may not be appropriately recognized or
managed by the treating medical staff, as toxicities resulting from
T cell therapy are not normally encountered in the general patient
population and by medical personnel. We expect to have to train
medical personnel using ACTR to understand the side effect profile
of ACTR for both our planned clinical trials and upon any
commercialization of any product candidates, if approved.
Inadequate training in recognizing or managing the potential side
effects of ACTR could result in patient deaths. Any of these
occurrences may harm our business, financial condition and
prospects significantly.
If we encounter difficulties enrolling patients in our clinical
trials, our clinical development activities could be delayed or
otherwise adversely affected.
We may experience difficulties in patient enrollment in our
clinical trials for a variety of reasons. The timely completion of
clinical trials in accordance with their protocols depends, among
other things, on our ability to enroll a sufficient number of
patients who remain in the study until its conclusion. The
enrollment of patients depends on many factors, including:
• the patient eligibility criteria defined in the protocol;
• the size of the patient population required for analysis of the
trial’s primary endpoints;
• the proximity of patients to trial sites;
• the design of the trial;
• our ability to recruit clinical trial investigators with the
appropriate competencies and experience;
• our ability to obtain and maintain patient consents;
• reporting of the preliminary results of any of our clinical
trials; and
• the risk that patients enrolled in clinical trials will drop out
of the trials before the manufacturing and infusion of our product
candidates or trial completion.
In addition, our clinical trials will compete with other clinical
trials for product candidates that are in the same therapeutic
areas as our product candidates, and this competition will reduce
the number and types of patients available to us because some
patients who might have opted to enroll in our trials may instead
opt to enroll in a trial being conducted by one of our competitors.
Since the number of qualified clinical investigators is limited, we
expect to conduct some of our clinical trials at the same clinical
trial sites that some of our competitors use, which will reduce the
number of patients who are available for our clinical trials at
such clinical trial sites. Moreover, because our product candidates
represent a departure from more commonly used methods for cancer
treatment, potential patients and their doctors may be inclined to
use conventional therapies, such as
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chemotherapy and hematopoietic stem cell transplantation, rather
than enroll patients in any future clinical trial. Additionally,
because some of our clinical trials are in patients with
relapsed/refractory cancer, the patients are typically in the late
stages of the disease and may experience disease progression
independent from our product candidates, making them unevaluable
for purposes of the trial and requiring additional
enrollment.
Delays in patient enrollment may result in increased costs or may
affect the timing or outcome of our ongoing and planned clinical
trials, which could prevent completion or commencement of these
trials and adversely affect our ability to advance the development
of our product candidates.
Clinical trials are expensive, time-consuming, and difficult to
design and implement.
Human clinical trials are expensive and difficult to design and
implement, in part because they are subject to rigorous regulatory
requirements. Because our product candidates are based on new
technology and engineered on a patient-by-patient basis, we expect
that they will require extensive research and development and have
substantial manufacturing and processing costs. In addition, costs
to treat patients with relapsed or refractory cancer and to treat
potential side effects that may result from our product candidates
can be significant. Accordingly, our clinical trial costs are
likely to be significantly higher than those for more conventional
therapeutic technologies or drug product candidates. In addition,
our proposed personalized product candidates involve several
complex and costly manufacturing and processing steps, the costs of
which will be borne by us.
The market opportunities for our product candidates may be limited
to those patients who are ineligible for or have failed prior
treatments, and may be small, and our estimates of the prevalence
of our target patient populations may be inaccurate.
Cancer therapies are sometimes characterized as first line, second
line, or third line, and the FDA often approves new therapies
initially only for a particular line of use. When cancer is
detected early enough, first line therapy is sometimes adequate to
cure the cancer or prolong life without a cure. Whenever first line
therapy, usually chemotherapy, antibody drugs, tumor-targeted small
molecules, hormone therapy, radiation therapy, surgery, or a
combination of these, proves unsuccessful, second line therapy may
be administered. Second line therapies often consist of more
chemotherapy, radiation, antibody drugs, tumor-targeted small
molecules, or a combination of these. Third line therapies can
include hematopoietic stem cell transplantation in certain cancers,
chemotherapy, antibody drugs, and small molecule tumor-targeted
therapies, more invasive forms of surgery, and new revolutionary
technologies. We expect to initially seek approval of our product
candidates in most instances at least as a third line therapy, for
use in patients with relapsed or refractory metastatic cancer.
Subsequently, for those products that prove to be sufficiently safe
and beneficial, if any, we would expect to seek approval as a
second line therapy and potentially as a first line therapy, but
there is no guarantee that our product candidates, even if approved
as a third or subsequent line of therapy, would be approved for an
earlier line of therapy, and, prior to any such approvals, we may
have to conduct additional clinical trials.
Our projections of both the number of people who have the cancers
we are targeting, as well as the subset of people with these
cancers in a position to receive a particular line of therapy and
who have the potential to benefit from treatment with our product
candidates, are based on our beliefs and estimates. These estimates
have been derived from a variety of sources, including scientific
literature, surveys of clinics, patient foundations or market
research, and may prove to be incorrect. Further, new therapies may
change the estimated incidence or prevalence of these cancers. The
number of patients may turn out to be lower than expected.
Additionally, the potentially addressable patient population for
our product candidates may be limited or may not be amenable to
treatment with our product candidates. For instance, we expect
ACTR087 used in combination with rituximab to initially target a
small patient population that suffers from r/r NHL. Even if we
obtain significant market share for our product candidates within
our addressable patient population, because the potential target
populations are small, we may never achieve profitability without
obtaining regulatory approval for additional indications, including
use as first or second line therapy.
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If we fail to develop additional product candidates, our commercial
opportunity will be limited.
We have developed a pipeline of product candidates and intend to
pursue clinical development of additional product candidates that
combine ACTR T cells with different antibodies and target different
tumor types. Developing, obtaining regulatory approval for and
commercializing additional product candidates will require
substantial additional funding beyond the net proceeds of this
offering and is prone to the risks of failure inherent in medical
product development. We cannot provide you any assurance that we
will be able to successfully advance any of these additional
product candidates through the development process.
Even if we receive FDA approval to market additional product
candidates for the treatment of cancer, we cannot assure you that
any such product candidates will be successfully commercialized,
widely accepted in the marketplace or more effective than other
commercially available alternatives. If we are unable to
successfully develop and commercialize additional product
candidates, our commercial opportunity will be limited. Moreover, a
failure in obtaining regulatory approval of additional product
candidates may have a negative effect on the approval process of
any other, or result in losing approval of any approved product
candidate.
ACTR therapies rely on the use of antibodies to target specific
cancers, which are developed by third parties. We are limited in
our ability to apply ACTR to a wider range of potential target
cancers by our ability to partner for or acquire these antibodies
on commercially reasonable terms.
ACTR therapies require the use of tumor-specific antibodies, which
guide the ACTR and bind to the antigens on the surface of a tumor,
to target specific types of cancers. Many of our current and
proposed clinical trials rely on the use of commercially available
and well-understood antibodies, such as rituximab and trastuzumab.
Our ability to develop and commercialize our ACTR T cells used in
combination with rituximab, trastuzumab, or any other FDA-approved
antibody will depend on our ability to purchase such antibodies on
commercially reasonable terms for the clinical trials and their
availability for the commercialized product, if approved.
We also plan to expand the use of our ACTR platform in combination
with one or more other antibodies that have not yet been approved
for marketing by the FDA or similar regulatory authorities outside
of the United States, as planned with our product candidate ACTR087
used in combination with SEA-BCMA in adult patients with r/r
multiple myeloma. Our ability to develop product candidates using
unapproved antibodies will rely on our ability to acquire such
antibodies through partnerships or collaborations on commercially
reasonable terms. However, we cannot be certain that potential
future collaborations will provide us with a steady supply of
antibodies that we can utilize in combination with ACTR to develop
future product candidates. If we are unable to enter into such
strategic collaborations on commercially reasonable terms or fail
to realize the benefits of any such collaboration, we may be
limited to using approved antibodies in combination with ACTR087,
ACTR707, or any other future ACTR construct we may develop.
We have entered into a collaboration agreement with Seattle
Genetics, Inc. (Seattle Genetics), pursuant to which Seattle
Genetics will generate antibodies against two target antigens to
use in combination with ACTR T cells to develop future product
candidates. Under the agreement, Seattle Genetics had the option to
elect a third target antigen, but its option expired unexercised in
June 2017. We cannot be certain that the collaboration agreement
with Seattle Genetics will provide us with antibodies that we can
successfully combine with ACTR T cells.
The failure to enter into a successful collaboration or the expense
of purchasing an approved antibody may delay our development
timelines, increase our costs and jeopardize our ability to develop
ACTR087, ACTR707, or any other future ACTR construct we may develop
as a commercially viable drug, which could result in delays in
product development and harm our business.
ACTR therapies rely on the use of antibodies to target specific
cancers, which the FDA may revoke approval for or may not approve,
independent of the safety or efficacy of our ACTR T cells.
We have developed, are developing, and intend to develop product
candidates using ACTR087 or ACTR707 used in combination with one or
more currently approved antibodies, such as rituximab for r/r NHL
and
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trastuzumab for HER2+ cancers. If the FDA or similar regulatory
authorities outside of the United States revoke approval of any
antibodies we use in combination with ACTR087, ACTR707 or any other
future cell product candidates based on our ACTR platform, we will
not be able to market any products made in combination with such
revoked antibodies.
If safety or efficacy issues arise with any of these antibodies, we
could experience significant regulatory delays, and the FDA or
similar regulatory authorities outside of the United States may
require us to redesign or terminate the applicable clinical trials.
In addition, the approval of ACTR in combination with an antibody
may require clinical trials to demonstrate the safety and efficacy
of the therapeutic antibody on its own. If the antibodies we use in
combination with ACTR087, ACTR707, or any other future ACTR
construct we may develop are replaced as the standard of care for
the indications we choose to target, the FDA or similar regulatory
authorities outside of the United States may require us to conduct
additional clinical trials. In addition, if manufacturing or other
issues result in a shortage of supply of the antibodies with which
we determine to combine with ACTR087, ACTR707, or any other future
ACTR construct we may develop, we may not be able to complete
clinical development of ACTR087, ACTR707, or any other future ACTR
construct we may develop on our current timeline or at all.
Even if ACTR087, ACTR707, or any other future ACTR construct we may
develop were to receive marketing approval or be commercialized for
use in combination with other existing antibodies, we would
continue to be subject to the risks that the FDA or similar
regulatory authorities outside of the United States could revoke
approval of an antibody used in combination with ACTR087, ACTR707,
or any other future ACTR construct we may develop, or that safety,
efficacy, manufacturing or supply issues could arise with these
existing antibodies. Combination therapies are commonly used for
the treatment of cancer, and we would be subject to similar risks,
such as revocation of regulatory approval for one part of the
combination therapy, if we develop any of our other product
candidates for use in combination with other antibodies. This could
result in our own products being removed from the market or being
less successful commercially.
We also plan to consider ACTR087, ACTR707 or any other future
product candidates based on our ACTR platform in combination with
one or more other antibodies that have not yet been approved for
marketing by the FDA or similar regulatory authorities outside of
the United States, as planned with our product candidate ACTR087
used in combination with SEA-BCMA in adult patients with r/r
multiple myeloma. We will not be able to market and sell ACTR087,
ACTR707 or any other future product candidates based on our ACTR
platform in combination with any such unapproved antibodies that do
not ultimately obtain marketing approval, either as a standalone or
used in combination with our ACTR T cells. If the FDA or similar
regulatory authorities outside of the United States determines that
we need to demonstrate the separate safety or efficacy of the
applicable antibodies, or if safety, efficacy, manufacturing, or
supply issues arise with the antibodies we choose to evaluate in
combination with ACTR087, ACTR707 or any other future ACTR
construct we may develop, we may be unable to obtain approval of or
market ACTR087, ACTR707 or any other future ACTR construct we may
develop.
If the FDA or similar regulatory authorities outside of the United
States revoke their approval or do not approve these other
antibodies, or if safety, efficacy, manufacturing, or supply issues
arise with the antibodies we choose to evaluate in combination with
ACTR087, ACTR707 or any other future ACTR construct we may develop,
we may be unable to obtain approval of or market ACTR087, ACTR707
or any other future ACTR construct we may develop.
We currently have no marketing and sales organization and have no
experience in marketing products. If we are unable to establish
marketing and sales capabilities or enter into agreements with
third parties to market and sell our product candidates, if
approved, we may not be able to generate product revenue.
We currently have no sales, marketing or distribution capabilities
and have no experience in marketing products. We intend to develop
an in-house marketing organization and sales force, which will
require significant
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capital expenditures, management resources and time. We will have
to compete with other pharmaceutical and biotechnology companies to
recruit, hire, train and retain marketing and sales
personnel.
If we are unable or decide not to establish internal sales,
marketing and distribution capabilities, we will pursue
collaborative arrangements regarding the sales and marketing of our
products, if approved. For instance, if any co-developed products
under our collaboration with Seattle Genetics are approved, we plan
to co-commercialize them wi