We are a clinical-stage biotechnology company developing treatments for
inflammatory diseases, with an initial focus on severe respiratory disorders. We
are developing verekitug, the only known antagonist currently in clinical
development that targets the receptor for Thymic Stromal Lymphopoietin (“TSLP”),
a cytokine which is a clinically validated driver of inflammatory response
positioned upstream of multiple signaling cascades that affect a variety of
immune mediated diseases. Preclinical and clinical data to date demonstrate
verekitug’s highly potent inhibition of the TSLP receptor, which we believe will
translate to a differentiated product profile, including improved clinical
outcomes, substantially extended dosing intervals and the potential to treat a
broad spectrum of patients. We have advanced this highly potent monoclonal
antibody into separate Phase 2 trials for the treatment of severe asthma and
chronic rhinosinusitis with nasal polyps (“CRSwNP”) and plan to initiate
development in chronic obstructive pulmonary disease (“COPD”). Our experienced
team is committed to maximizing verekitug’s unique attributes to address the
substantial unmet needs for patients underserved by today’s standard of care.
There are six biologics approved for the treatment of severe asthma; three of
these are also approved for CRSwNP. One biologic was recently approved for the
treatment of COPD. Total estimated biologics sales in 2023 for asthma in the
United States, Europe and Japan markets were approximately $7.5 billion. In
December 2021, tezepelumab (marketed as Tezspire by Amgen Inc. (“Amgen”) and
AstraZeneca PLC (“AstraZeneca”)), a monoclonal antibody targeting the TSLP
ligand, not the receptor, was approved by the U.S. Food and Drug Administration
(“FDA”) as an add-on maintenance treatment for patients with severe asthma.
Tezepelumab is the first and only treatment for severe asthma without any
phenotype or biomarker limitation, highlighting the benefit of blocking TSLP
signaling early in the inflammatory cascade as compared to other biologics’
mechanisms of action which are further downstream. In May 2024, Amgen and
AstraZeneca reported Phase 2a proof-of-concept data for tezepelumab for the
treatment of moderate to very severe COPD at the American Thoracic Society
(“ATS”) International Conference. This trial reported a reduction in the
frequency of COPD exacerbations that has supported advancement of tezepelumab
into Phase 3 development for COPD. These clinical data further demonstrate the
potential for a TSLP targeted therapy to treat a variety of inflammatory
diseases. Despite the availability of existing biologics for severe respiratory
disease, there remains a high unmet need that limits the utilization of these
therapies, including suboptimal symptom control and frequent dosing intervals.
Verekitug is, to our knowledge, the only monoclonal antibody currently in
clinical development that targets and inhibits the TSLP receptor. In May 2024,
we presented full proof-of-concept data from our multicenter, randomized,
double-blind, placebo-controlled Phase 1b multiple ascending dose (“MAD”)
clinical trial in asthma patients demonstrating that dosing with verekitug led
to rapid and complete TSLP receptor occupancy, and reductions in fractional
exhaled nitric oxide (“FeNO,” a disease-related biomarker) and blood eosinophil
levels (“eos,” a disease-related biomarker) that were rapid, substantial and
sustained for up to 24 weeks after the last dose. This study also demonstrated
that verekitug is approximately 300-fold more potent than tezepelumab (based on
published tezepelumab data), which, combined with verekitug’s pharmacokinetic
(“PK”) profile, enables an extended dosing interval of up to 24 weeks, compared
to tezepelumab (four week dosing interval). Furthermore, clinical data from
our Phase 1b MAD trial indicate an approximately 50% greater effect on FeNO than
has previously been reported for tezepelumab. We have not conducted head-to-head
clinical studies of verekitug against tezepelumab, and note that ongoing and
future clinical trials for verekitug may produce differing clinical activity and
tolerability results. Three Phase 1 clinical trials have been completed for
verekitug across a total of 120 participants, including 32 patients with asthma.
In these trials, which were not designed to support formal statistical
comparisons, verekitug was well tolerated, demonstrated no evidence of
clinically meaningful anti-drug antibodies (“ADAs”), and showed a predictable
and consistent PK profile with high subcutaneous bioavailability. Although
competitive product candidates may be sponsored by organizations with greater
financial resources and expertise to support regulatory approval and market
acceptance, we believe verekitug, if approved, will be the preferred biologic
for the treatment of severe asthma, CRSwNP and COPD based on its extended dosing
interval and effect on broadly accepted disease-associated biomarkers.
Having established clinical proof-of-concept in asthma, we are currently
conducting two separate multi-national, placebo-controlled, randomized Phase 2
clinical trials to investigate the efficacy of two extended dosing intervals of
12 and 24 weeks for patients with severe asthma and 12 weeks for patients with
CRSwNP. These trials have been designed using endpoints that, pending
interactions with regulatory authorities, could allow data from these trials to
support submissions for product approval. Data from these trials are expected in
the second half of 2026 for severe asthma and the second half of 2025 for
CRSwNP. Based on available data from Phase 1 trials with verekitug, we plan to
initiate our first clinical trial in COPD and have commenced planning activities
for a Phase 2 clinical trial, including development of a clinical trial protocol
and regulatory approval strategy, and expect to dose the first COPD patient in
the second half of 2025. Beyond these indications, we believe verekitug has
broad potential, and we intend to leverage its unique attributes to develop it
as a potential therapy for numerous TSLP-driven diseases.
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Leveraging TSLP biology to address unmet needs in severe asthma, CRSwNP and COPD
TSLP overview
Verekitug is a monoclonal antibody that targets and inhibits the TSLP receptor.
TSLP is a member of a class of epithelial cytokines, also including IL-25 and
IL-33, commonly referred to as alarmins. TSLP is primarily produced by
epithelial cells, especially in the lung, gastrointestinal tract and skin.
Dendritic cells, basophils, mast cells, keratinocytes and fibroblasts also
produce TSLP with appropriate stimulation. In response to various environmental
triggers, including viruses, bacteria, allergens, chemical irritants and
physical injury, TSLP can initiate and amplify a wide range of innate and
adaptive immune responses, including supporting epithelial barrier function,
dendritic cell activation, type 2 innate lymphoid cell activation and survival,
immune cell recruitment, induction of type 2 responses and regulation of B cell
function. Beyond type 2 inflammation, data also support a role for TSLP in
propagating non-type 2 inflammatory processes, including IL-17 production,
modulation of airway structural cells and the promotion of fibrosis. As such,
TSLP signaling is a central instigator of multiple downstream biologic pathways
relevant to human diseases that are characterized by epithelial inflammation,
including asthma, CRSwNP and COPD.
The TSLP signaling pathway is well-understood as a contributor to
disease-driving proinflammatory pathways and is a clinically and commercially
validated target for therapeutic development. Historically, development of
biologics for severe asthma and related conditions has focused on type 2
inflammatory cytokines that are activated downstream in the TSLP signaling
pathway, for instance IL-4, IL-5 and IL-13. However, in addition to its effect
on type 2 inflammation, emerging evidence indicates that TSLP also impacts
non-type 2 inflammation, which may result in broader downregulation of pathways
relevant to the pathogenesis of multiple inflammatory diseases. We believe
verekitug has the potential, if approved, to address unmet needs in multiple
diseases characterized by TSLP-driven pathobiology due to the high potency and
potential for extended dosing intervals that we have observed in our preclinical
and clinical development to date.
Only one drug targeting the TSLP pathway has been approved for the treatment of
severe asthma. In December 2021, tezepelumab (marketed as Tezspire by Amgen and
AztraZeneca), a monoclonal antibody targeting the TSLP ligand, was approved by
the FDA as an add-on maintenance treatment for patients with severe asthma.
Tezepelumab is the first and only treatment for severe asthma without any
phenotype or biomarker limitation, highlighting the benefit of blocking TSLP
signaling early in the inflammatory cascade as compared to other biologics’
mechanisms of action which are further downstream. In the Phase 3 clinical trial
of tezepelumab in adults and adolescents with severe, uncontrolled asthma,
patients who received tezepelumab had fewer exacerbations and better lung
function, asthma control and health-related quality of life than those who
received placebo. Based on pooled safety data from the clinical trials of
tezepelumab, Tezspire’s FDA approved label identifies hypersensitivity reactions
following administration as a clinically significant adverse reaction, as well
as pharyngitis, arthralgia and back pain as additional adverse reactions that
occurred at an incidence of greater than or equal to 3% and more common than the
placebo group. Furthermore, a Phase 2a clinical trial for tezepelumab in COPD
patients, which demonstrated a clinically-significant reduction of COPD
exacerbations, the most frequently reported adverse events for tezepelumab were
worsening of COPD (12.1%) and incidents of COVID-19 infections (14.5%, trial
commenced in July 2019), demonstrating a safety and tolerability profile
consistent with that observed for tezepelumab in severe asthma. These clinical
data further demonstrate the potential for a TSLP targeted therapy to treat a
variety of inflammatory diseases.
Severe asthma
Asthma is a common respiratory disease characterized by chronic airway
inflammation that is often underdiagnosed and under-treated. For some people,
asthma can simply be a nuisance, for others it can interfere with daily life and
potentially even be life-threatening. Of the more than 25 million Americans
living with asthma, it is estimated that 5% to 10% suffer from severe asthma.
Severe asthma is defined as asthma that remains uncontrolled despite optimized
treatment with high-dose inhaled corticosteroids or that requires high-dosed
inhaled corticosteroids to prevent symptoms from becoming uncontrolled. It is
estimated that approximately 90% of people with severe asthma are eligible for
biologics, but only 440,000 patients are currently treated with biologics,
suggesting more than 80% of eligible patients are not being optimally treated.
U.S. sales in 2023 of biologics for the treatment of severe asthma is estimated
to be approximately $6.0 billion.
These statistics show there is a large population of people living with
uncontrolled symptoms of severe asthma. Key areas of unmet need for people
living with severe asthma include improved control of exacerbations and symptoms
and reduced treatment burden (e.g. need for frequent injections).
Chronic rhinosinusitis with nasal polyps (CRSwNP)
CRSwNP is an inflammatory disease of the upper airway, marked by chronic
sinonasal inflammation and the presence of inflammatory polyps in the nasal
passages and paranasal sinuses. It is estimated by Sanofi that approximately
900,000 patients in the United States and Europe suffer from CRSwNP. Nasal
polyps are associated with significant morbidity and debilitating symptoms; it
is estimated that 40% to 45% of people with severe asthma also have CRSwNP and
that up to 65% of people with CRSwNP also have asthma, demonstrating a strong
association between the two conditions.
The current treatment options for patients with CRSwNP are corticosteroids,
surgery and, more recently, biologics. Although a treatment option, surgery does
not guarantee symptom relief. Even with surgery, many people with CRSwNP remain
symptomatic, with the recurrence rate of CRSwNP ranging from 20% to 60% within
18 months to four years and increasing to 79% after 12 years. Recurrence is
particularly common for people with severe disease, including those also living
with asthma or who have undergone prior surgeries. The recent FDA approvals of
biologic treatments for CRSwNP have established a well-understood regulatory
pathway and route to commercialization. It is estimated that approximately
200,000 adult patients in the United States, major European markets and Japan
with CRSwNP are eligible for biologics.
Despite these available treatments, the quality of life studies and
post-surgical recurrence rates clearly show that many people with CRSwNP have
uncontrolled symptoms that are impacting their daily life and current treatments
are not meeting their needs.
Chronic obstructive pulmonary disease (COPD)
Similar to asthma, COPD is a chronic inflammatory disease that obstructs airflow
from the lungs. Chronic inflammation causes structural changes within the lungs,
narrowing already small airways and damaging lung parenchyma which causes air
sacs to lose functionality and decreases lung elasticity. It is typically caused
by long-term exposure to irritants, most often cigarette smoke. People with a
history of asthma are also more likely to have COPD. Historically, COPD has been
considered to have elements of both type 2 and non-type 2 immune responses.
COPD is the third leading cause of death worldwide, causing approximately 3.2
million deaths in 2019. Almost 14.2 million Americans, or 6.5% of the adult
population, reported they have been diagnosed with COPD, yet the actual number
is likely higher given that more than half of adults with low pulmonary function
were not aware that they had COPD.
Treatments for COPD are similar to those for asthma and CRSwNP, including
inhaled steroids to reduce inflammation in the airways as well as bronchodilator
inhalers to relax airways and improve airflow. Oxygen and surgery may also be
used for people with severe COPD. Dupilumab (marketed as Dupixent by Sanofi and
Regeneron Pharmaceuticals, Inc.), an interleukin-4 receptor alpha antagonist, is
the only biologic approved for the treatment of COPD.
Despite available treatments, 60% of all COPD patients report some limitations
in their daily activity, with 45% being unable to work and 75% complaining of
difficulty climbing stairs. Given the high levels of morbidity and mortality
associated with COPD, the currently available medicines are not sufficient to
control symptoms or disease progression.
Verekitug: Inhibiting TSLP signaling in severe asthma, CRSwNP and COPD
Verekitug is a novel recombinant fully human immunoglobulin G1 monoclonal
antibody that binds to the TSLP receptor and inhibits its signaling. In 2021, we
acquired verekitug from Astellas Pharma Inc. (“Astellas”). Astellas discovered
the compound and completed preclinical studies and a Phase 1 single ascending
dose (“SAD”) trial, providing the early foundational work for our Phase 1b MAD
trial. In those preclinical studies, which were not designed to support formal
statistical comparisons, verekitug potently inhibited TSLP signaling.
Additionally, verekitug inhibited cytokine production from CD4+ T cells,
suggesting that it may be effective against type 2 and non-type 2 inflammation.
In the Phase 1 SAD trial in 56 healthy volunteers, verekitug demonstrated a
favorable safety profile with no drug-related serious treatment-emergent adverse
events, dose proportional PK and a pharmacodynamic (“PD”) effect consistent with
TSLP antagonism.
We have conducted two additional clinical trials of verekitug: a Phase 1b MAD
trial in patients with asthma and a Japanese ethnobridging study in healthy
volunteers. Across the three clinical trials, we have data from 120 total
participants, including 32 patients with asthma. In these trials, verekitug was
well tolerated, had no clinically meaningful immunogenicity, and showed a
predictable and consistent PK profile with high subcutaneous bioavailability.
Our Phase 1b MAD clinical trial, which enrolled 32 adult participants aged 18 to
60 with mild to moderate asthma, established clinical proof-of-concept for
verekitug in asthma. In the trial, which was not designed to support formal
statistical comparisons, verekitug demonstrated rapid, substantial and sustained
target engagement and maintained maximal inhibition of disease-related
biomarkers in patients with asthma for up to 24 weeks after the last study dose.
Results of the Phase 1b study also demonstrated that verekitug is a potent
inhibitor of the TSLP receptor and has the potential for an extending dosing
interval compared to currently available treatments. Importantly, the PK/PD
modeling that was done based on the preclinical data aligned very closely with
these early clinical results, strengthening our understanding of verekitug’s
attributes and behavior in humans.
We are currently conducting two separate multi-national, placebo-controlled,
randomized Phase 2 clinical trials to investigate the efficacy of two extended
dosing intervals of 12 and 24 weeks for patients with severe asthma and 12 weeks
for patients with CRSwNP. These trials have been designed using endpoints that,
pending interactions with regulatory authorities, could allow data from these
trials to support submissions for product approval. Data from these trials are
expected in the second half of 2026 for severe asthma and the second half of
2025 for CRSwNP. Based on available data from Phase 1 trials with verekitug, we
plan to initiate our first clinical trial in COPD and have commenced planning
activities for a Phase 2 clinical trial, including development of a clinical
trial protocol and regulatory approval strategy, and expect to dose the first
COPD patient in the second half of 2025. Beyond these indications, we believe
verekitug has broad potential, and we intend to leverage its unique attributes
to develop it as a potential therapy for other TSLP-driven diseases.
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We were incorporated under the laws of the State of Delaware in April 2021 under
the name Upstream Bio, Inc. Our principal corporate office is located at 890
Winter Street, Suite 200, Waltham, MA 02451, and our telephone number is
(781) 208-2466. We have one subsidiary, Upstream Bio Securities Corporation,
formed in November 2021 under the laws of the Commonwealth of Massachusetts. Our
website address is www.upstreambio.com.
