SUZHOU, China, Oct. 7, 2024
/PRNewswire/ -- MediLink Therapeutics (Suzhou) Co., Ltd.
("MediLink"), a clinical-stage biotech company, today announced a
global clinical trial collaboration and supply agreement with Amgen
Inc. Amgen will lead a global clinical study to evaluate the
therapeutic potential of the combination of MediLink's
B7-H3-targeting antibody-drug conjugate (ADC) YL201 and Amgen's
DLL3- and CD3-targeting bispecific T-cell engager (BiTE®)
IMDELLTRA™ in extensive-stage small cell lung cancer (ES-SCLC)
under the clinical trial collaboration and supply agreement.
MediLink will provide the investigational drug YL201 for the
combination study.
This open-label, global, multi-center Phase Ib clinical study is
designed to evaluate the safety, tolerability, pharmacokinetics,
and efficacy of this combination regimen in ES-SCLC patients.
Both YL201 and IMDELLTRA™ have shown potential in ES-SCLC. In
May of this year, IMDELLTRA™ received accelerated approval from the
FDA and is currently marketed in the US for the treatment of adult
patients with ES-SCLC with disease progression on or after
platinum-based chemotherapy. This indication is approved under
accelerated approval based on overall response rate and duration of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in a
confirmatory trial(s). The efficacy of YL201 monotherapy is
encouraging in ES-SCLC. MediLink has announced the data of a Phase
I/II clinical trial of YL201 in patients with advanced solid tumors
including SCLC as a selected oral presentation at the ESMO Congress
2024. This clinical trial collaboration aims to explore the
potential of the two innovative drugs in the treatment of ES-SCLC
and offer a novel and synergetic mechanism of action for clinical
benefit.
About ES-SCLC
SCLC is an aggressive high-grade neuroendocrine carcinoma with
extremely poor outcomes [1]. SCLC comprises roughly 15%
(~0.36 million new cases) of the 2.4 million new lung cancer cases
worldwide each year [2].
Approximately two-thirds of patients with SCLC present with
extensive-stage (ES) disease at diagnosis, featuring tumors
with distant metastasis or exceeding an area that can be treated
within a single radiation field [3-5]. Patients with
ES-SCLC, compared with patients with limited-stage (LS-SCLC),
manifested with worse prognosis as the median expected overall
survival is ~12 months following initial therapy and a 5-year
overall survival rate of 3% [6-8].
About YL201
YL201 is an innovative ADC that specifically targets B7-H3.
B7-H3 is overexpressed on different malignant cells and
cancer-initiating cells of various tumor types, but has a
restricted expression in normal tissue [9], indicating
its potential as an ADC drug target. YL201 has been developed by
utilizing MediLink's Tumor Microenvironment Activable
LINker-payload (TMALIN®) conjugated with a highly specific B7-H3
antibody. Currently, YL201 is being investigated in four Phase I or
II studies, including one global Phase I clinical study.
About IMDELLTRA™
IMDELLTRA™ is a first-in-class, targeted immunotherapy
engineered by Amgen researchers that binds to both DLL3 on tumor
cells and CD3 on T cells, activating T cells to kill
DLL3-expressing SCLC cells. This results in the formation of a
cytolytic synapse with lysis of the cancer cell
[10-11]. DLL3 is a protein that is expressed on the
surface of SCLC cells in ~85-96% of patients with SCLC, but is
minimally expressed on healthy cells, making it an exciting target
[12-13].
IMPORTANT SAFETY INFORMATION
WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITY
including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY
SYNDROME
- Cytokine release syndrome (CRS), including serious or
life-threatening reactions, can occur in patients receiving
IMDELLTRATM. Initiate treatment with
IMDELLTRATM using the step-up dosing schedule to reduce
the incidence and severity of CRS. Withhold IMDELLTRATM
until CRS resolves or permanently discontinue based on
severity.
- Neurologic toxicity, including immune effector
cell-associated neurotoxicity syndrome (ICANS), including serious
or life-threatening reactions, can occur in patients receiving
IMDELLTRATM. Monitor patients for signs and symptoms of
neurologic toxicity, including ICANS, during treatment and treat
promptly. Withhold IMDELLTRATM until ICANS resolves or
permanently discontinue based on severity.
WARNINGS AND PRECAUTIONS
- Cytokine Release Syndrome (CRS): IMDELLTRATM
can cause CRS including serious or life-threatening reactions. In
the pooled safety population, CRS occurred in 55% of patients who
received IMDELLTRATM, including 34% Grade 1, 19% Grade
2, 1.1% Grade 3 and 0.5% Grade 4. Recurrent CRS occurred in 24% of
patients, including 18% Grade 1 and 6% Grade 2.
Most events (43%) of CRS occurred after the first dose, with 29%
of patients experiencing any grade CRS after the second dose and 9%
of patients experiencing CRS following the third dose or later.
Following the Day 1, Day 8, and Day 15 infusions, 16%, 4.3% and
2.1% of patients experienced ≥ Grade 2 CRS, respectively. The
median time to onset of all grade CRS from most recent dose of
IMDELLTRATM was 13.5 hours (range 1 to 268 hours). The
median time to onset of ≥ Grade 2 CRS from most recent dose of
IMDELLTRATM was 14.6 hours (range: 2 to 566 hours).
Clinical signs and symptoms of CRS included pyrexia,
hypotension, fatigue, tachycardia, headache, hypoxia, nausea, and
vomiting. Potentially life-threatening complications of CRS may
include cardiac dysfunction, acute respiratory distress syndrome,
neurologic toxicity, renal and/or hepatic failure, and disseminated
intravascular coagulation (DIC).
Administer IMDELLTRATM following the recommended
step-up dosing and administer concomitant medications before and
after Cycle 1 IMDELLTRATM infusions as described in
Table 3 of the Prescribing Information (PI) to reduce the risk of
CRS. Administer IMDELLTRATM in an appropriate health
care facility equipped to monitor and manage CRS. Ensure patients
are well hydrated prior to administration of
IMDELLTRATM.
Closely monitor patients for signs and symptoms of CRS during
treatment with IMDELLTRATM. At the first sign of CRS,
immediately discontinue IMDELLTRATM infusion, evaluate
the patient for hospitalization and institute supportive care based
on severity. Withhold or permanently discontinue
IMDELLTRATM based on severity. Counsel patients to seek
medical attention should signs or symptoms of CRS occur.
- Neurologic Toxicity, Including ICANS:
IMDELLTRATM can cause serious or life-threatening
neurologic toxicity, including ICANS. In the pooled safety
population, neurologic toxicity, including ICANS, occurred in 47%
of patients who received IMDELLTRATM, including 10%
Grade 3. The most frequent neurologic toxicities were headache
(14%), peripheral neuropathy (7%), dizziness (7%), insomnia (6%),
muscular weakness (3.7%), delirium (2.1%), syncope (1.6%), and
neurotoxicity (1.1%).
ICANS occurred in 9% of IMDELLTRATM-treated patients. Recurrent
ICANS occurred in 1.6% of patients. Most patients experienced ICANS
following Cycle 2 Day 1 (24%). Following Day 1, Day 8, and Day 15
infusions, 0.5%, 0.5% and 3.7% of patients experienced ≥ Grade 2
ICANS, respectively. The median time to onset of ICANS from the
first dose of IMDELLTRATM was 29.5 days (range: 1 to 154 days).
ICANS can occur several weeks following administration of
IMDELLTRATM. The median time to resolution of ICANS was 33 days
(range 1 to 93 days).
The onset of ICANS can be concurrent with CRS, following
resolution of CRS, or in the absence of CRS. Clinical signs and
symptoms of ICANS may include but are not limited to confusional
state, depressed level of consciousness, disorientation,
somnolence, lethargy, and bradyphrenia.
Patients receiving IMDELLTRATM are at risk of neurologic adverse
reactions and ICANS resulting in depressed level of consciousness.
Advise patients to refrain from driving and engaging in hazardous
occupations or activities, such as operating heavy or potentially
dangerous machinery, in the event of any neurologic symptoms until
they resolve.
Closely monitor patients for signs and symptoms of neurologic
toxicity and ICANS during treatment. At the first sign of ICANS,
immediately evaluate the patient and provide supportive therapy
based on severity. Withhold IMDELLTRATM or permanently
discontinue based on severity.
- Cytopenias: IMDELLTRATM can cause
cytopenias including neutropenia, thrombocytopenia, and anemia. In
the pooled safety population, decreased neutrophils occurred in 12%
including 6% Grade 3 or 4 of IMDELLTRATM-treated
patients. The median time to onset for Grade 3 or 4 neutropenia was
29.5 days (range: 2 to 213). Decreased platelets occurred in 33%
including 3.2% Grade 3 or 4. The median time to onset for Grade 3
or 4 decreased platelets was 50 days (range: 3 to 420). Decreased
hemoglobin occurred in 58% including 5% Grade 3 or 4. Febrile
neutropenia occurred in 0.5% of patients treated with
IMDELLTRATM.
Monitor patients for signs and symptoms of cytopenias. Perform
complete blood counts prior to treatment with
IMDELLTRATM, before each dose, and as clinically
indicated. Based on the severity of cytopenias, temporarily
withhold, or permanently discontinue IMDELLTRATM.
- Infections: IMDELLTRATM can cause
serious infections, including life-threatening and fatal
infections. In the pooled safety population, infections, including
opportunistic infections, occurred in 41% of patients who received
IMDELLTRATM. Grade 3 or 4 infections occurred in 13% of
patients. The most frequent infections were COVID-19 (9%, majority
during the COVID-19 pandemic), urinary tract infection (10%),
pneumonia (9%), respiratory tract infection (3.2%), and candida
infection (3.2%).
Monitor patients for signs and symptoms of infection prior to
and during treatment with IMDELLTRATM and treat as clinically
indicated. Withhold or permanently discontinue IMDELLTRATM based on
severity.
- Hepatotoxicity: IMDELLTRATM can cause
hepatotoxicity. In the pooled safety population, elevated ALT
occurred in 42%, with Grade 3 or 4 ALT elevation occurring in 2.1%.
Elevated AST occurred in 44% of patients, with Grade 3 or 4 AST
elevation occurring in 3.2%. Elevated bilirubin occurred in 15% of
patients; Grade 3 or 4 total bilirubin elevations occurred in 1.6%
of patients. Liver enzyme elevation can occur with or without
concurrent CRS. Monitor liver enzymes and bilirubin prior to
treatment with IMDELLTRATM, before each dose, and as
clinically indicated. Withhold IMDELLTRATM or
permanently discontinue based on severity.
- Hypersensitivity: IMDELLTRATM can cause
severe hypersensitivity reactions. Clinical signs and symptoms of
hypersensitivity may include, but are not limited to, rash and
bronchospasm. Monitor patients for signs and symptoms of
hypersensitivity during treatment with IMDELLTRATM and
manage as clinically indicated. Withhold or consider permanent
discontinuation of IMDELLTRATM based on severity.
- Embryo-Fetal Toxicity: Based on its mechanism of
action, IMDELLTRATM may cause fetal harm when
administered to a pregnant woman. Advise patients of the potential
risk to a fetus. Advise females of reproductive potential to use
effective contraception during treatment with
IMDELLTRATM and for 2 months after the last dose.
ADVERSE REACTIONS
- The most common (> 20%) adverse reactions were CRS
(55%), fatigue (51%), pyrexia (36%), dysgeusia (36%), decreased
appetite (34%), musculoskeletal pain (30%), constipation (30%),
anemia (27%) and nausea (22%). The most common (≥ 2%) Grade 3 or 4
laboratory abnormalities were decreased lymphocytes (57%),
decreased sodium (16%), increased uric acid (10%), decreased total
neutrophils (6%), decreased hemoglobin (5%), increased activated
partial thromboplastin time (5%), decreased potassium (5%),
increased aspartate aminotransferase (3.2%), decreased white blood
cells (3.8%), decreased platelets (3.2%), and increased alanine
aminotransferase (2.1%).
- Serious adverse reactions occurred in 58% of patients. Serious
adverse reactions in > 3% of patients included CRS (24%),
pneumonia (6%), pyrexia (3.7%), and hyponatremia (3.6%). Fatal
adverse reactions occurred in 2.7% of patients including pneumonia
(0.5%), aspiration (0.5%), pulmonary embolism (0.5%), respiratory
acidosis (0.5%), and respiratory failure (0.5%).
DOSAGE AND ADMINISTRATION: Important Dosing
Information
- Administer IMDELLTRATM as an intravenous
infusion over one hour.
- Administer IMDELLTRATM according to the step-up
dosing schedule in the IMDELLTRATM PI (Table 1) to
reduce the incidence and severity of CRS.
- For Cycle 1, administer recommended concomitant medications
before and after Cycle 1 IMDELLTRATM infusions to
reduce the risk of CRS reactions as described in the PI (Table
3).
- IMDELLTRATM should only be administered by a
qualified healthcare professional with appropriate medical support
to manage severe reactions such as CRS and neurologic toxicity
including ICANS.
- Due to the risk of CRS and neurologic toxicity, including
ICANS, monitor patients from the start of the
IMDELLTRATM infusion for 22 to 24 hours on Cycle 1 Day 1
and Cycle 1 Day 8 in an appropriate healthcare setting.
- Recommend that patients remain within 1 hour of an appropriate
healthcare setting for a total of 48 hours from start of the
infusion with IMDELLTRATM following Cycle 1 Day 1
and Cycle 1 Day 8 doses, accompanied by a caregiver.
- Prior to administration of IMDELLTRATM evaluate
complete blood count, liver enzymes, and bilirubin before each
dose, and as clinically indicated.
- Ensure patients are well hydrated prior to administration
of IMDELLTRATM.
Please see IMDELLTRA™ full Prescribing
Information, including BOXED WARNINGS
About MediLink Therapeutics
MediLink Therapeutics, founded in 2020, is a clinical stage
biotech company dedicated to developing conjugated drugs with
global competitiveness. MediLink has developed its proprietary
TMALIN® ADC technology platform, enabling the generation of
homogeneous ADC with high drug-antibody ratio and improved
therapeutic window for the treatment of solid tumors. MediLink aims
to provide improved treatment options for global patients and
address unmet medical needs. The company is headquartered in
Suzhou, China and has established
R&D sites in Shanghai, China
and Boston, US.
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