DUBLIN, Nov. 9, 2020 /PRNewswire/ -- Alkermes
plc (Nasdaq: ALKS) today announced the presentation of new
data from the ARTISTRY clinical development program for ALKS 4230,
Alkermes' investigational engineered interleukin-2 (IL-2) variant
immunotherapy, at the Society for Immunotherapy of Cancer's (SITC)
35th Anniversary Annual Meeting, being held virtually
Nov. 11-14, 2020. The company
will present preliminary safety, tolerability and
pharmacokinetic/pharmacodynamic data from the dose-escalation stage
of ARTISTRY-2, the ongoing phase 1/2 study evaluating ALKS 4230
administered subcutaneously (SC) either once-weekly or
once-every-three-weeks. A detailed analysis of clinical responses
observed in ovarian cancer patients and other new updates from
ARTISTRY-1, the ongoing phase 1/2 study investigating ALKS 4230
administered intravenously (IV), will also be presented. Both
studies are evaluating ALKS 4230 as a monotherapy and in
combination with the PD-1 inhibitor pembrolizumab
(KEYTRUDA®) in patients with heavily pretreated advanced
solid tumors.
"Accumulating evidence across the ARTISTRY clinical program
provides insight into ALKS 4230's potential as a novel treatment
option, both as monotherapy in melanoma and in combination with
pembrolizumab, for a number of tumor types that do not typically
respond to current standards of care. The responses observed with
the combination regimen in platinum-resistant ovarian cancer,
triple negative breast cancer, and recently in cervical cancer, are
encouraging signs of ALKS 4230's potential utility in these
cancers," said Ira Winer, M.D.,
Ph.D., Associate Professor, Division of Gynecologic Oncology,
Wayne State University and Karmanos
Cancer Institute. "In addition, the data presented at SITC
from ARTISTRY-2 in patients with advanced solid tumors showed a
safety profile and immune response comparable to ALKS 4230
administered intravenously, indicating that ALKS 4230 may offer an
alternate subcutaneous dosing option for patients."
"The ALKS 4230 subcutaneous dose-escalation data in heavily
pretreated patients with certain solid tumors demonstrated
expansion of tumor-killing CD8+ T cells and NK cells consistent
with the expansion observed with intravenous dosing of ALKS 4230.
These data support the potential for once-weekly or
once-every-three-week subcutaneous dosing of ALKS 4230, for which
we expect to identify our recommended phase 2 dose by year-end,"
said Craig Hopkinson, M.D., Chief
Medical Officer and Executive Vice President of Research &
Development at Alkermes. "Further, based on the durable complete
and partial responses observed in the ARTISTRY-1 intravenous dosing
study in tumor types with high unmet need and limited treatment
options for patients, we are considering potential regulatory
strategies that may support expeditious development paths in both
monotherapy and combination settings."
The two posters are available on the SITC website at
https://sitc.sitcancer.org/2020/abstracts/titles/. Highlights from
the poster presentations, which reflect data as of Sept. 29, 2020 unless otherwise noted,
include:
Poster #671: Phase 1/2 Study of Subcutaneously Administered
ALKS 4230, a Novel Engineered Cytokine, as Monotherapy and in
Combination With Pembrolizumab, in Patients With Advanced Solid
Tumors: ARTISTRY-2
The ongoing dose-escalation stage of
ARTISTRY-2 is evaluating the safety and tolerability of ascending
doses of SC ALKS 4230 administered either once-weekly (Q7) or
once-every-three-weeks (Q21) as lead-in monotherapy for six weeks,
followed by combination with pembrolizumab. The
pharmacokinetic/pharmacodynamic (PK/PD) data presented include
seven dose-escalation cohorts of SC ALKS 4230 (Q7: 0.3, 0.6, 1, 3
mg; Q21: 1, 3, 10 mg):
- ALKS 4230 was assessed in 43 heavily pretreated patients with
refractory solid tumors. Of these, 30 patients completed the
monotherapy lead-in portion of the study and initiated combination
treatment with pembrolizumab.
- Treatment with SC ALKS 4230 resulted in a dose-dependent
increase in circulating natural killer (NK) cells and CD8+ T cells,
with an approximately 16-fold and 3-fold expansion, respectively,
at the 3 mg Q7 dose. At the 10 mg Q21 dose there was an
approximately 6-fold and 3-fold expansion in NK cells and CD8+ T
cells, respectively. There was a minimal, non-dose-dependent change
in regulatory T (Treg) cells.
-
- The NK and CD8+ T cell expansions observed for the 3 mg Q7 and
10 mg Q21 SC doses were equivalent or greater compared to the
expansions observed in ARTISTRY-1 at the 3 µg/kg/day and 6
µg/kg/day IV doses of ALKS 4230, respectively.
- Compared to the 6 µg/kg/day IV dose, the recommended phase 2
dose (RP2D) identified for ARTISTRY-1, the 3 mg and 10 mg doses of
SC ALKS 4230 induced higher levels of interferon gamma, a cytokine
that has been associated with antitumor efficacy in clinical
studies.1 Relative to IV ALKS 4230, SC ALKS 4230 induced
a lower, transient upregulation of IL-6 concentrations.
- ALKS 4230 at the SC doses studied showed a safety and
tolerability profile consistent with the anticipated pharmacologic
effects and what has been observed with IV ALKS 4230. The most
commonly reported adverse events (AEs) across the ARTISTRY-2 study
were injection site reactions, fever, chills, fatigue, nausea and
lymphopenia. One patient experienced dose-limiting AEs at the 10 mg
Q21 dose (grade 3 nausea, vomiting, and fatigue). Following a dose
reduction, the patient continued on study.
- Preliminary clinical benefit was observed, even in
immunotherapy-pretreated patients. As of the data cutoff date, 11
patients had continued on therapy for more than 6 months.
- The maximum tolerated dose and the RP2D for SC ALKS 4230 have
not yet been determined.
Poster #689: Clinical Outcomes of Ovarian Cancer Patients
Treated With ALKS 4230, a Novel Engineered Cytokine, in Combination
With Pembrolizumab: ARTISTRY-1 Trial
Data presented from the
ongoing ARTISTRY-1 study focused on the subset of PD-1/L1
unapproved patients with progressive, resistant ovarian cancer who
received ALKS 4230 administered intravenously in combination with
pembrolizumab. These data provide an updated and more in-depth view
of responses previously reported at the 2020 European Society for
Medical Oncology (ESMO) Virtual Congress. In addition, new data on
the effects of IV ALKS 4230 monotherapy on the tumor
microenvironment (TME) and additional updates from other tumor
types were presented.
- Of the 13 evaluable ovarian cancer patients in the PD-1/L1
unapproved cohort, five patients with platinum-resistant ovarian
cancer experienced clinical benefit, both in terms of durability
and deepening of response. As of the data cutoff date, these five
patients remained on therapy for a range of approximately 5 to 21
months.
- Antitumor activity has also been observed in patients with
certain other women's cancers who received IV ALKS 4230 in
combination with pembrolizumab, including a durable immune partial
response in triple negative breast cancer and a new partial
response in cervical cancer.
- An analysis of paired biopsies taken from a melanoma patient
who received the 6 µg/kg/day monotherapy dose of IV ALKS 4230 in
the dose-escalation phase of ARTISTRY-1 showed an increase in
tumor-infiltrating CD8+ T cells and an increase in PD-L1 expression
in the TME. In addition, the ratio of CD8+ T cells to
Treg cells increased in this patient. High CD8+ T
cell/Treg cell ratios, independent of treatment type,
have been reported to be associated with better prognosis among
multiple tumor types, including ovarian tumors.2 These
data provide supporting evidence of ALKS 4230's immunostimulatory
impact on the TME and provide rationale for combining ALKS 4230
with pembrolizumab in ovarian cancer patients.
- Among patients in the PD-1/L1 unapproved cohort,
treatment-related AEs have been generally transient and manageable,
with the majority being grade 1 or 2 in severity. The most commonly
reported AEs in this cohort were chills, fever and nausea.
- Based on the durable and deepening responses observed with ALKS
4230 in combination with pembrolizumab in ovarian cancer, the
company is planning a new prospective study to evaluate this
combination regimen in platinum-resistant and
bevacizumab-experienced ovarian cancer patients.
About ALKS 4230
ALKS 4230 is an investigational,
novel, engineered fusion protein comprised of modified
interleukin-2 (IL-2) and the high affinity IL-2 alpha receptor
chain, designed to selectively expand tumor-killing immune cells
while avoiding the activation of immunosuppressive cells by
preferentially binding to the intermediate-affinity IL-2 receptor
complex. The selectivity of ALKS 4230 is designed to leverage the
proven antitumor effects of existing IL-2 therapy while mitigating
certain limitations.
About the ARTISTRY Clinical Development
Program
ARTISTRY is an Alkermes-sponsored clinical
development program evaluating ALKS 4230 in patients with advanced
solid tumors.
ARTISTRY-1 and ARTISTRY-2 are phase 1/2 studies
evaluating the safety, tolerability, efficacy and pharmacokinetic
and pharmacodynamic effects of ALKS 4230 in patients with
refractory advanced solid tumors, in both monotherapy and
combination settings with the PD-1 inhibitor pembrolizumab
(KEYTRUDA®). In ARTISTRY-1, ALKS 4230 is administered as
an intravenous infusion daily for five consecutive days. In
ARTISTRY-2, ALKS 4230 is administered subcutaneously and is being
evaluated with once-weekly and once-every-three-week dosing
schedules.
ARTISTRY-3 is a phase 2 study evaluating the clinical and
immunologic effects of ALKS 4230 monotherapy administered
intravenously on the tumor microenvironment of a variety of
advanced, malignant solid tumors.
About Alkermes
Alkermes plc is a fully integrated,
global biopharmaceutical company developing innovative medicines in
the fields of neuroscience and oncology. The company has a
portfolio of proprietary commercial products focused on addiction
and schizophrenia, and a pipeline of product candidates in
development for schizophrenia, bipolar I disorder,
neurodegenerative disorders, and cancer. Headquartered in
Dublin, Ireland, Alkermes plc has
an R&D center in Waltham,
Massachusetts; a research and manufacturing facility in
Athlone, Ireland; and a
manufacturing facility in Wilmington,
Ohio. For more information, please visit Alkermes' website
at www.alkermes.com.
Note Regarding Forward-Looking Statements
Certain
statements set forth in this press release constitute
"forward-looking statements" within the meaning of the Private
Securities Litigation Reform Act of 1995, as amended, including,
but not limited to, statements concerning: the potential
therapeutic value of ALKS 4230 as a cancer immunotherapy when used
as monotherapy or in combination across multiple tumor types; and
the details and status of, and plans for, the clinical development
of ALKS 4230, including the timing for identification of the
recommended phase 2 dose of SC ALKS 4230 for ARTISTRY
2, potential regulatory strategies to support expeditious
development paths of ALKS 4230 in monotherapy and combination
settings, and the company's plans for a new study to evaluate ALKS
4230 in combination with pembrolizumab in platinum-resistant and
bevacizumab-experienced ovarian cancer patients. You are cautioned
that forward-looking statements are inherently uncertain. Although
the company believes that such statements are based on reasonable
assumptions within the bounds of its knowledge of its business and
operations, the forward-looking statements are neither promises nor
guarantees and they are necessarily subject to a high degree of
uncertainty and risk. Actual results may differ materially from
those expressed or implied in the forward-looking statements due to
various risks and uncertainties. These risks and uncertainties
include, among others, whether ALKS 4230, as a monotherapy or in
combination, could be shown to be unsafe or ineffective; whether
preclinical results and data from ongoing clinical studies for ALKS
4230—whether as a monotherapy or in combination—will be predictive
of future or final results from such studies, results of future
clinical studies or real-world results; whether future clinical
trials or future stages of ongoing clinical trials for ALKS 4230,
as a monotherapy or in combination, will be initiated or completed
on time or at all; changes in the cost, scope and duration of, and
clinical trial operations for, development activities for ALKS
4230, including changes relating to the impact of the novel
coronavirus (COVID-19) pandemic; and those risks and uncertainties
described under the heading "Risk Factors" in the company's Annual
Report on Form 10-K for the year ended Dec.
31, 2019, the company's Quarterly Report on Form 10-Q for
the quarter ended June 30, 2020 and
in subsequent filings made by the company with the U.S. Securities
and Exchange Commission (SEC), which are available on the SEC's
website at www.sec.gov. Existing and prospective investors are
cautioned not to place undue reliance on these forward-looking
statements, which speak only as of the date hereof. Except as
required by law, the company disclaims any intention or
responsibility for updating or revising any forward-looking
statements contained in this press release.
KEYTRUDA® is a registered trademark
of Merck Sharp & Dohme Corp.
1. Ni L, Lu J. Cancer Med. 2018;7:4509–4516.
10.1002
2. Sato E, et al. Proc Natl Acad Sci U S A.
2005;102(51):18538-18543
Alkermes Contacts:
For Investors: Sandy Coombs, +1 781 609 6377
For Media: Sourojit Bhowmick, Ph.D.,+1 781 609 6397
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SOURCE Alkermes plc