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Checkmate Pharmaceuticals Presents Clinical Data at the 2018 American Association for Cancer Research (AACR) Annual Meeting

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CMP-001 - pembrolizumab combination reverses resistance to PD-1
inhibition in patients with advanced melanoma who had progressed on
prior anti-PD-1 therapy

CMP-001 shows deep and durable clinical responses in both injected
and noninjected lesions

Checkmate
Pharmaceuticals
(Checkmate) announced the first presentation of data
from an ongoing Phase 1b study evaluating CMP-001, Checkmate's Toll like
receptor 9 (TLR9) agonist, in combination with pembrolizumab
(KEYTRUDA®), an anti-PD-1 therapy, in patients with advanced melanoma
resistant to prior anti-PD-1 checkpoint inhibition. CMP-001 is designed
to activate innate immunity to convert "uninflamed" tumors, which
generally do not respond to anti-PD-1 therapy, into "inflamed" tumors,
which are PD-1 responsive. Data were presented in the clinical trials
plenary session on Tuesday, April 17 at the American Association for
Cancer Research (AACR) annual meeting in Chicago by principal
investigator Mohammed Milhem, MBBS, clinical professor of internal
medicine, University of Iowa, Iowa City.

The combination of CMP-001 and pembrolizumab was generally well
tolerated and induced deep and durable clinical responses with systemic
regression of noninjected cutaneous, nodal, hepatic, and splenic
metastases in patients who had progressed on a median of 2 prior
therapies. "The abscopal effect observed in these patients is a hallmark
of successful intratumoral immunotherapy treatment," said Dr. Milhem.
"In this patient population, pembrolizumab alone would be unlikely to
provide more than a 7% response rate. If the current results are
confirmed, it appears that this combination could offer an effective
treatment option for patients with advanced melanoma who are not
responsive to pembrolizumab," he noted.

As of March 27, 2018, 85 patients had been treated in the
trial; 44 patients were enrolled in the dose escalation phase, while 41
patients have been enrolled in the ongoing expansion phase. CMP-001 was
administered intratumorally (IT) into one or more accessible lesion(s),
and response assessed in all target lesions, both injected and
noninjected, as well as non-target lesions by RECIST v1.1.
Study therapy was continued until progression, toxicity, investigator
decision or withdrawal of consent. Baseline and on-therapy serum was
collected for cytokine analysis at various timepoints.
Immunohistochemical and RNA-Seq analysis was performed on available pre-
and post-treatment tumor biopsies.

Data were presented on 69 patients in the Intent To Treat (ITT)
population, defined as those who received at least one dose of CMP-001
in the Dose Escalation (44 patients) and Dose Expansion (25 patients)
phases of the study, and who had at least one follow-up scan or who
discontinued treatment for any reason prior to having a follow-up scan
as of March 27, 2018.

  • The Objective Response Rate (ORR) by RECIST v1.1 in the ITT population
    was 22.0% (15/69; 95% confidence interval 13-33%), including 2
    complete responses and 13 partial responses.
  • Among the 15 RECIST responders, 11 remain on study; 1 has withdrawn
    due to progressive disease, and 3 have withdrawn consent (1 with
    progressive disease, and 1 each with a complete response and a partial
    response).
  • Six of the responders continuing on study have maintained their
    response over 6 months and, of these 2 have maintained their responses
    over 84 weeks: median response duration has not been reached.
  • Three additional patients who continued study therapy beyond their
    initial progression responded according to iRECIST criteria.
  • Of the 18 patients who responded by either RECIST or iRECIST, 17 had
    previously progressed on anti-PD-1, either as monotherapy, and/or in
    combination with other agents, including IDO inhibitors (N=4), TLR9
    agonist (N=1), or CCR4 agonist (N=1). In addition to their prior
    treatment with one or more anti-PD-1 regimens, 5 of the 18 responders
    to CMP-001 + pembrolizumab had received prior therapy with ipilimumab
    monotherapy.

The combination of CMP-001 and pembrolizumab was generally well
tolerated in this study population. No maximum tolerated dose was
identified during the dose escalation phase of the study. Two subjects
discontinued study therapy due to toxicity.

Translational studies supported the expected CMP-001 mechanism of action
of activating TLR9 in tumor-associated plasmacytoid dendritic cells
(pDC), showing:

  • Median 5.9 fold increase in serum CXCL10 (IP-10), a chemokine induced
    by interferons.
  • Increased CD8+ T cells and PD-L1 expression in injected and
    noninjected post-treatment biopsies by immunohistochemistry.
  • Induction of a "T cell-inflamed", PD-1 response associated,
    transcriptional signature in post-treatment biopsies by RNA-Seq.
  • A low frequency of tumor-associated pDC in baseline tumor biopsies
    from patients who subsequently progressed (N=9; mean %pDC = 0.1,
    SD=0.1, range 0.02-0.4), and an approximately ten times higher
    baseline frequency of tumor-associated pDC in patients who
    subsequently responded to therapy or had stable disease (N=7; mean
    %pDC = 1.2, SD=1.3, range 0.02-3.6).

"CMP-001 stimulation of the TLR9 pathway in pDC activates the immune
system, providing a synergistic anti-tumor effect when combined with
checkpoint inhibitors that block tumor-mediated immune suppression,"
observed Dr. Art Krieg, Checkmate's founder and CEO. "We are pleased
with the data from this ongoing study showing that CMP-001 in
combination with pembrolizumab can reverse resistance to PD-1
inhibition. The duration of response, which is ongoing in most of the
responders, is particularly encouraging and supports further clinical
development of CMP-001. The mechanism of action of CMP-001 is not
specific to melanoma, and should apply across most or perhaps all tumor
types, including those that have not been PD-1 responsive in the past,"
he said.

CMP-001 is being evaluated in multiple tumor types to assess its safety,
activity, alternative routes of administration and combination with
other immunotherapies and modalities. For information on CMP-001 trials
that are currently recruiting patients, please visit www.clinicaltrials.gov.

About Checkmate's Phase 1b Study (CMP-001-001)

CMP-001-001(NCT02680184) is an ongoing, multicenter two-part, open label
Phase 1b clinical study phase with advanced melanoma. The study is being
conducted at 13 sites in the USA.

The primary objective of the study is to determine the recommended phase
2 dose (RP2D) of CMP-001 when given in combination with pembrolizumab in
PD-1 resistant patients. Secondary objectives are to assess the safety
profile of CMP-001 when given in combination with pembrolizumab, and to
assess the pharmacodynamic effects of the addition of CMP-001 to
pembrolizumab on serum concentrations of CXCL10 (IP-10).

Part 1 of the study utilized a dose escalation scheme to identify the
RP2D and schedule. During dose escalation, patients were enrolled to
cohorts of ≥ 3 patients at CMP-001 doses of 1, 3, 5, 7.5, and 10 mg in
two dosing schedules (weekly for 7w, followed by q3w; or weekly for 2w,
followed by q3w). The 5 mg dose and weekly dosing schedule for 7w,
followed by q3w were selected as the RP2D and dosing schedule, and are
being evaluated in the ongoing dose expansion phase of the study.

Part 2 of the study is also enrolling and is evaluating the safety and
efficacy of CMP-001 administered as monotherapy at the same RP2D and
schedule selected in Part 1 of the study.

About CMP-001

CMP-001 is a first in class CpG-A TLR9 agonist that is encapsulated in a
virus-like particle (VLP). It is the only CpG-A TLR9 agonist in clinical
trials and differs from other CpG classes by having a native DNA
backbone that induces the highest levels of type I interferon (IFN).

The highly immunogenic VLP of CMP-001 provides multiple advantages
beyond protecting the native DNA CpG-A from degradation, which include
facilitating lymphatic distribution, and promoting broader immune
activation via anti-VLP IgG immune complexes that also drive productive
uptake into the target plasmacytoid dendritic cells (pDC). The type 1
IFN production resulting from TLR9 mediated activation of pDC upon
CMP-001 uptake, leads to recruitment of conventional dendritic cells and
other antigen presenting cells, and T cell activation toward tumor
associated antigens. Together, these CMP-001 activities can convert the
tumor microenvironment from "uninflamed", to "inflamed", and promote a
systemic anti-tumor cytotoxic T cell response.

Based on analyses of gene expression in human tumors showing that
increased IFN gene expression is associated with better response to PD-1
inhibition, it is believed that this mechanism of action may restore,
enable or improve responses to anti-PD-1/PD-L1 therapeutics.

About Checkmate

Checkmate Pharmaceuticals is a clinical stage company that is leveraging
its expertise in the field of CpG oligonucleotides to discover and
develop immunotherapies designed to increase the efficacy of existing
immunotherapies and to provide new treatment options for patients and
their healthcare providers. Checkmate's lead product candidate, CMP-001,
is an investigational cancer immunotherapeutic that has been shown to
reverse resistance to PD-1 therapy in some patients.

Checkmate is a privately held company headquartered in Cambridge, MA.

Information regarding Checkmate is available at www.checkmatepharma.com.

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