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July 9, 2024
E. Rand Sutherland
Chief Executive Officer
Upstream Bio, Inc.
460 Totten Pond Road, Suite 420
Waltham, MA 02451
Re: Upstream Bio, Inc.
Draft Registration Statement on Form S-1
Submitted June 12, 2024
CIK No. 0002022626
Dear E. Rand Sutherland:
We have reviewed your draft registration statement and have the
following comments.
Please respond to this letter by providing the requested information
and either submitting
an amended draft registration statement or publicly filing your registration
statement on EDGAR.
If you do not believe a comment applies to your facts and circumstances or do
not believe an
amendment is appropriate, please tell us why in your response.
After reviewing the information you provide in response to this letter
and your amended
draft registration statement or filed registration statement, we may have
additional comments.
Draft Registration Statement on Form S-1
Prospectus Summary
Overview, page 1
1. We note your disclosure here, and throughout the prospectus, that
verekitug is a first-in-
class antagonist. This term suggests that your product candidate is
effective and likely to
be approved. Please revise to delete such references throughout your
registration
statement.
2. We note your disclosures relating to the regulatory approvals and
commercial successes
of other companies. Please provide balancing disclosure, as you do on
page 36, that such
companies may have significantly greater financial resources and
expertise such that they
may be more successful than you in obtaining regulatory approvals and
achieving
widespread market acceptance.
3. Please clarify, if true, that the $6 to $10 billion estimation refers to
global annual peak
sales, or otherwise advise and please provide balancing disclosure that
you do not have a
July 9, 2024
Page 2
COPD product in development.
4. We note your disclosures on page 2, and elsewhere, regarding comparing
your product
candidate to tezepelumab and dupilumab. Please disclose here, and in the
Business
section, whether such observations were based on head-to-head trials. In
this regard, we
note your disclosure on page 35 that [i]n most cases, [you] do not
currently plan to
run head-to-head clinical trials evaluating verekitug or any other
potential future product
candidates against the current standards of care, which may make it more
challenging for
verekitug or any other potential future product candidates to compete
against the current
standards of care due to the lack of head-to-head clinical trial data.
5. With respect to the data and observations based on preclinical and
clinical trials disclosed
in the summary, including those sponsored by others, please disclose
whether serious
adverse events were observed.
6. Please explain how you determined on page 2 that verekitug is the only
monoclonal
antibody currently in clinical development that targets and inhibits the
TSLP receptor.
7. We note that you describe the Phase 2 trial as "pivotal." Please clarify
what you mean by
pivotal in this instance.
8. Please define FPI in the pipeline table on page 2 and revise the
footnote to the table to
explain the activities that need to be completed in order to initiate
development in COPD.
TSLP Overview, page 3
9. We note you statement that you believe verekitug has the potential to be
an impactful
treatment due to its high potency, extended dosing interval and ability
to address unmet
needs in multiple diseases characterized by TSLP-driven pathobiology.
Please revise to
remove these and similar statements, as efficacy determinations are
within the sole
jurisdiction of the FDA and other similar foreign regulators. You may
include information
regarding data observed in studies and trials but may not include the
company's
conclusions based on such data.
Verekitug: Inhibiting TSLP signaling in severe asthma, CRSwNP and COPD, page 4
10. Please disclose when you plan to initiate clinical development in COPD.
11. We note your disclosures regarding results from preclinical and clinical
trials
demonstrating that verekitug inhibited TSLP signaling, inhibited
cytokine production
from CD4+ T cells, and demonstrated "rapid, substantial and sustained
target
engagement and maintained maximal inhibition of disease-related
biomarkers in
patients with asthma. Please disclose whether such results are
statistically significant, or
otherwise advise.
12. Please disclose the number of volunteers for the Phase 1 SAD trial and
Phase 1b MAD
trial.
Our Team and Investors, page 5
13. We note your disclosure on page 6 that you have raised approximately
$400 million from
premier biotechnology investors. Please provide balancing
disclosure that prospective
investors should not rely on such investors investment decisions,
that these investors may
have different risk tolerances and that the shares purchased in the
referenced financings
July 9, 2024
Page 3
may have been conducted at a significant discount to the IPO price, if
true.
Management's Discussion and Analysis of Financial Condition and Results of
Operations
Critical Accounting Estimates and Significant Judgments
Stock-based compensation, page 109
14. Once you have an estimated offering price range, please explain to us
the reasons for any
differences between recent valuations of your common stock leading up to
the planned
offering and the midpoint of your estimated offering price range. This
information will
facilitate our review of your accounting for stock compensation.
Business
The role of TSLP in severe asthma, CRSwNP, COPD and related inflammatory
diseases, page
121
15. Please revise Figure 2 on page 122 to clarify the diseases you are
planning to target with
your drug candidate.
Biologic therapies for severe asthma, page 124
16. We note your disclosure that the clinical and regulatory progress of
tezepelumab
represents a significant derisking for your own development
program. Please remove
this statement and any other statements that imply that you will be
successful in
mitigating risk associated with drug development.
Preclinical Data
Target engagement and inhibition, page 132
17. With respect to the preclinical studies, please disclose, if true, that
Astellas conducted
such studies, or otherwise advise. In addition, please disclose if the
results were
statistically significant, and any observed serious adverse events.
Phase 1 SAD clinical trial safety and tolerability data, page 135
18. Please ensure the superscripts are legible in the graphic.
Ongoing and planned clinical trials, page 143
19. Please disclose the number of patients enrolled to date in the VIBRANT
and VALIANT
trial.
COPD, page 144
20. Please clarify whether the additional endpoints will be primary or
secondary, or
otherwise advise.
Intellectual Property, page 146
21. We note your disclosures relating to your owned patent families. We also
note your
disclosure on page 149 regarding licensing certain intellectual property
from Lonza.
Please disclose, if material, whether you license any patents. To the
extent you do, please
disclose the type of patent protection (e.g., composition of matter,
use, or process), the
patent expiration dates, and the applicable jurisdictions. In addition,
please clarify what
indications the Lonza license covers.
July 9, 2024
Page 4
Asset purchase and license agreements, page 148
22. With respect to the Maruho and Lonza license agreements, please disclose
the payments
received or made to date, any expiration dates, and any potential
development, regulatory
and commercial milestone payments.
Executive Compensation
Executive compensation arrangements, page 185
23. We note your disclosure that you have entered into employment agreements
with each of
your named executive officers. Please describe the material terms of
such agreements
with your current CEO and CFO. In addition, please file the employment
or offer letter
agreements with your executive officers as exhibits pursuant to Item
601(b)(10) of
Regulation S-K or tell us why you believe such filing is not required.
Certain relationships and related party transactions, page 195
24. We note your disclosure on page 95 that Maruho, for which you have an
exclusive license
agreement, is a related party. We also note on page 175 that Atsushi
Sugita, who has
served on your Board of Directors since 2021, is also the President and
CEO of
Maruho. Please disclose any related party transactions under Item 404(a)
of Regulation S-
K or otherwise advise. Also, please tell us whether any other officers,
directors or
principal shareholders are affiliated with Maruho. Finally, please
provide, if material,
corresponding risk factor disclosure.
General
25. Please supplementally provide us with copies of all written
communications, as defined in
Rule 405 under the Securities Act, that you, or anyone authorized to do
so on your behalf,
present to potential investors in reliance on Section 5(d) of the
Securities Act, whether or
not they retain copies of the communications.
Please contact Franklin Wyman at 202-551-3660 or Kevin Kuhar at
202-551-3662 if you
have questions regarding comments on the financial statements and related
matters. Please
contact Jimmy McNamara at 202-551-7349 or Chris Edwards at 202-551-6761 with
any other
questions.
Sincerely,
Division of
Corporation Finance
Office of Life
Sciences