On April 23, 2018 Castle Biosciences, Inc., a provider of molecular diagnostics to improve cancer treatment decisions, reported presentation of results demonstrating that the use of the DecisionDx-Melanoma gene expression profile (GEP) test with American Joint Committee on Cancer (AJCC) staging can improve accuracy of recurrence and metastasis risk for patients with localized cutaneous melanoma (Press release, Castle Biosciences, APR 23, 2018, View Source [SID1234525585]).

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The study titled, "Improved identification of high-risk, Stage I-II cutaneous melanomas with the combination of American Joint Committee on Cancer staging and a 31-gene expression profile test result," was presented as a poster at the 3rd Annual Real World Dermatology for Physician Assistants and Nurse Practitioners conference, held April 20-22, 2018 in Orlando, Florida.

"In this large Stage I-II melanoma study population, the DecisionDx-Melanoma test improved risk prediction when used in combination with AJCC risk assessment and showed independent prognostic value," commented study co-author Robert W. Cook, PhD, Vice President, Medical Affairs and R&D at Castle Biosciences. "Providing this information for risk assessment is important to help guide patient management decisions for improved patient outcomes."

Study Background

For patients with cutaneous melanoma, accurate assessment of recurrence risk is important to guide management plans including imaging based surveillance, follow-up frequency and sentinel lymph node biopsy recommendations that can lead to early detection of metastatic disease. National guidelines suggest surveillance plans based on AJCC stage, with Stage I-IIA considered low risk and Stage IIB-IV considered high risk. The DecisionDx-Melanoma GEP test accurately and independently predicts risk of recurrence and metastasis, classifying patients as Class 1A (lowest risk) Class 1B/2A (lower or intermediate risk) or Class 2B (highest risk).

This study of 485 Stage I and II patients from a multicenter cohort with long-term outcomes assessed the use of AJCC staging combined with results from the DecisionDx-Melanoma GEP test to improve recurrence risk prediction.

Key Study Findings:

Patients who were classified as high risk by both AJCC staging (Stage IIB-C) and the GEP test (Class 2B) had significantly lower 5-year recurrence-free survival (RFS 33.4%), distant metastasis-free survival (DMFS 49.5%) and melanoma specific survival (MSS 86.7%) compared to those identified as low risk by both methods (RFS 96.1%, DMFS 97.3%, MSS 99.6%, p<0.0001 for all comparisons).
Importantly, patients who were assessed as low risk using AJCC staging (Stage I-IIA) but high risk using the GEP test also demonstrated significantly worse outcomes (RFS 60.9%, DMFS 75.8%, MSS 85.9%) compared to patients who were assessed as low risk using both methods (p<0.0001 for all comparisons).
Multivariate Cox regression analysis indicated that both GEP high risk and AJCC high risk were significant and independent predictors of RFS (GEP HR 6.8; AJCC HR 2.98, p<0.0001, both groups) and DMFS (GEP HR 8.5; AJCC HR 2.5, p<0.001, both groups). For MSS, GEP Class 2B was the only significant predictor (GEP HR 43.8, p<0.001; AJCC HR 1.04, p<0.94).
Clinical Impact of DecisionDx-Melanoma Test

A second poster titled, "Clinical impact of a 31-gene expression profile test for cutaneous melanoma patients: a review of clinical utility studies," was also presented at the conference.

The poster highlights key findings across 5 published clinical utility studies, including:

In prospective and retrospective multicenter clinical utility studies, the inclusion of the DecisionDx-Melanoma test in risk assessment resulted in significant differences in follow-up and surveillance when comparing low- and high-risk patients.
Findings across multiple clinical impact studies show that incorporation of the GEP test consistently impacts clinical management decisions for approximately 1 in 2 patients tested.
Use of the DecisionDx-Melanoma GEP test in combination with conventional staging methods can help develop a more efficient and individualized follow-up plan based on clinical factors and tumor biology.
About DecisionDx-Melanoma
The DecisionDx-Melanoma test uses tumor biology to predict individual risk of melanoma recurrence and sentinel lymph node positivity independent of traditional factors. Using tissue from the primary melanoma, the test measures the expression of 31 genes. The test has been validated in three multicenter studies that have included 690 patients and have demonstrated consistent results. Performance has also been confirmed in four prospective studies including 702 patients. The consistent high performance and accuracy demonstrated in these studies, which combined have included over 1,300 patients, provides confidence in disease management plans that incorporate DecisionDx-Melanoma test results. Prediction of the likelihood of sentinel lymph node positivity has also been validated in two prospective multicenter studies which included over 1,400 patients. Clinical impact has been demonstrated in multicenter and single-center studies showing that test results impact clinical management decisions for one of every two patients tested. More information about the test and disease can be found at www.SkinMelanoma.com.

On April 21, 2018 Molecular Partners AG (SIX: MOLN), a clinical-stage biopharmaceutical company developing a new class of drugs known as DARPin therapies*, reported that preliminary results from the ongoing Phase 2 study of MP0250 with bortezomib and dexamethasone in patients with relapsed refractory multiple myeloma (RRMM) were presented at the 1st European Myeloma Network Meeting in Turin (Press release, Molecular Partners, APR 21, 2018, View Source [SID1234525567]).

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The presentation in Turin focused on results from the first dose cohort of MP0250 with respect to safety and efficacy. Eight patients were treated with 8 mg/kg of MP0250 and five out of these eight patients showed a documented response: Four patients reached a partial response (PR) and one patient reached a very good partial response (VGPR) at the cut-off date. Four out of the five patients are still on treatment with individual treatment durations of 13, 21, 24 and 33 weeks, respectively. The safety profile was consistent with the known safety profiles of bortezomib and MP0250, respectively. The independent dose escalation committee recommended to continue the clinical study at the higher dose of 12mg/kg and the first patient in the second dose cohort has been dosed recently.

Prof. Dr. Hartmut Goldschmidt (Medical Clinic V, University clinic Heidelberg), the Primary Investigator of the phase 2 study, commented: "We are encouraged by the initial efficacy and good tolerability data of MP0250 in combination with bortezomib and dexamethasone. Despite upcoming new treatment options, multiple myeloma remains an incurable disease and new molecules with innovative mechanism of actions are needed."

"We are pleased by the remarkable activity and the good safety profile that we have seen in the first cohort of this study. We are looking forward to patients being treated with the higher dose of MP0250 (12 mg/kg) and the additional phase 1b/2 study of MP0250 in combination with osimertinib in EGFR-mutated NSCLC," said Dr. Andreas Harstrick, Chief Medical Officer at Molecular Partners.

MP0250 is a proprietary DARPin drug candidate neutralizing VEGF and HGF and thus blocking key escape pathways and resistance. Increases in VEGF and HGF are associated with disease progression in multiple myeloma and have been linked to poor prognosis. They are known to be able to stimulate neovascularization, bone destruction, and myeloma proliferation, migration, and adhesion in the bone marrow. MP0250 shows activity in many preclinical tumor models, including in multiple myeloma models in which it enhances the effects of bortezomib on inhibition of M protein production and bone lysis and reduces invasion of tumor cells. MP0250 has shown a favorable safety profile in a phase 1 clinical study in 45 patients with advanced solid tumors.

In the ongoing phase 2 clinical study[1], the safety and efficacy of MP0250 is examined in combination with bortezomib (Velcade) and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM) who have failed standard therapies. The study is performed in Germany, Poland and Italy. A total of 40 patients are planned to be treated, 12 patients in the dose-escalation phase (Part 1) to establish a safe dose, and an additional 28 patients in the dose-expansion phase (Part 2) resulting in a total of 34 patients at the target dose.

Additional safety and efficacy data are expected by the end of 2018.

An additional phase 1b/2 study will evaluate MP0250 in combination with osimertinib in patients with EGFR-mutated NSCLC pretreated with osimertinib. The study is conducted in the US and is open for patient enrollment2.

[1] ClinicalTrials.gov identifier NCT03136653
2 ClinicalTrials.gov identifier NCT03418532

Financial Calendar
April 26, 2018 – Q1 2018 Management Statement
August 30, 2018 – Publication of 2018 Half-year Results
November 01, 2018 – Q3 2018 Management Statement
View Source

About the DARPin Difference
DARPin therapeutics are a new class of protein therapeutics opening an extra dimension of multi-specificity and multi-functionality. DARPin candidates are potent, specific, safe and very versatile. They can engage in more than 5 targets at once, offering potential benefits over those offered by conventional monoclonal antibodies or other currently available protein therapeutics. The DARPin technology is a fast and cost-effective drug discovery engine, producing drug candidates with ideal properties for development and very high production yields.
With their good safety profile, low immunogenicity and long half-life in the bloodstream and the eye, DARPin therapies have the potential to advance modern medicine and significantly improve the treatment of serious diseases, including cancer and sight-threatening disorders. Molecular Partners is partnering with Allergan to advance clinical programs in ophthalmology, and is advancing a proprietary pipeline of DARPin drug candidates in oncology. The most advanced global product candidate is abicipar, a molecule currently in Phase 3, in partnership with Allergan.
Several DARPin molecules for various ophthalmic indications are also in development. The most advanced systemic DARPin molecule, MP0250, is in Phase 1 clinical development for the treatment of solid tumors and in Phase 2 development for hematological tumors. In addition, Molecular Partners intends to further evaluate MP0250 for solid tumors in a phase 1b/2 trial for EGFR-mutated NSCLC. MP0274, the second-most advanced DARPin drug candidate in oncology, has broad anti-HER activity; it inhibits HER1, HER2 and HER3-mediated downstream signaling via Her2, leading to induction of apoptosis. MP0274 has moved into Phase 1. Molecular Partners is also advancing a growing preclinical pipeline that features several immuno-oncological development programs. DARPin is a registered trademark owned by Molecular Partners AG.

Shire notes the announcement made by Takeda and confirms it has received a fourth proposal on 20 April 2018 regarding a possible offer for the Company (the "Fourth Proposal") (Press release, Shire, APR 20, 2018, View Source [SID1234525816]).

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The Fourth Proposal comprises £26 per share in new Takeda shares, to be listed in Japan and in the US through an ADR listing, and £21 per share in cash, representing a potential value of £47 per share and approximately £44 billion for the total issued and to be issued share capital of the Company. Based on Takeda’s current market capitalisation, Shire shareholders would own approximately 49 per cent. of the enlarged Takeda.

The Board of Shire is considering its position with respect to the Fourth Proposal and will issue a further announcement in due course.

This announcement is made without the consent of Takeda.

Person responsible

Stephen Williams, Deputy Company Secretary, is responsible for arranging the release of this announcement on behalf of the Company.

Publication on a website

In accordance with Rule 26.1 of the Code, a copy of this announcement will be made available, subject to certain restrictions relating to persons resident in restricted jurisdictions, on Shire’s website at www.shire.com by no later than noon (London time) on the business day following this announcement. The content of this website is not incorporated into and does not form part of this announcement.

Further information

This announcement is not intended to, and does not, constitute or form part of any offer, invitation or the solicitation of an offer to purchase, otherwise acquire, subscribe for, sell or otherwise dispose of, any securities whether pursuant to this announcement or otherwise.

The distribution of this announcement in jurisdictions outside the United Kingdom may be restricted by law and therefore persons into whose possession this announcement comes should inform themselves about, and observe, such restrictions. Any failure to comply with the restrictions may constitute a violation of the securities law of any such jurisdiction.

Citigroup Global Markets Limited, which is authorised by the Prudential Regulation Authority and regulated in the UK by the Financial Conduct Authority and the Prudential Regulation Authority in the United Kingdom, is acting for Shire and no one else in connection with the matters described in this announcement and shall not be responsible to anyone other than Shire for providing the protections afforded to clients of Citigroup Global Markets Limited, or for giving advice in connection with the matters described in this announcement or any matter referred to therein.

Goldman Sachs International, which is authorised by the Prudential Regulation Authority and regulated by the Financial Conduct Authority and the Prudential Regulation Authority in the United Kingdom, is acting for Shire and no one else in connection with the matters described in this announcement and will not be responsible to anyone other than Shire for providing the protections afforded to clients of Goldman Sachs International, or for giving advice in connection with the matters described in this announcement or any matter referred to herein.

Morgan Stanley & Co. International plc, which is authorised by the Prudential Regulation Authority and regulated by the Financial Conduct Authority and the Prudential Regulation Authority in the United Kingdom, is acting for Shire and no one else in connection with the matters described in this announcement and will not be responsible to anyone other than Shire for providing the protections afforded to clients of Morgan Stanley & Co. International plc, or for giving advice in connection with the matters described in this announcement or any matter referred to herein.

Disclosure requirements of the Code

Under Rule 8.3(a) of the Code, any person who is interested in 1% or more of any class of relevant securities of an offeree company or of any securities exchange offeror (being any offeror other than an offeror in respect of which it has been announced that its offer is, or is likely to be, solely in cash) must make an Opening Position Disclosure following the commencement of the offer period and, if later, following the announcement in which any securities exchange offeror is first identified. An Opening Position Disclosure must contain details of the person’s interests and short positions in, and rights to subscribe for, any relevant securities of each of (i) the offeree company and (ii) any securities exchange offeror(s). An Opening Position Disclosure by a person to whom Rule 8.3(a) applies must be made by no later than 3.30 pm (London time) on the 10th business day following the commencement of the offer period and, if appropriate, by no later than 3.30 pm (London time) on the 10th business day following the announcement in which any securities exchange offeror is first identified. Relevant persons who deal in the relevant securities of the offeree company or of a securities exchange offeror prior to the deadline for making an Opening Position Disclosure must instead make a Dealing Disclosure.

Under Rule 8.3(b) of the Code, any person who is, or becomes, interested in 1% or more of any class of relevant securities of the offeree company or of any securities exchange offeror must make a Dealing Disclosure if the person deals in any relevant securities of the offeree company or of any securities exchange offeror. A Dealing Disclosure must contain details of the dealing concerned and of the person’s interests and short positions in, and rights to subscribe for, any relevant securities of each of (i) the offeree company and (ii) any securities exchange offeror(s), save to the extent that these details have previously been disclosed under Rule 8. A Dealing Disclosure by a person to whom Rule 8.3(b) applies must be made by no later than 3.30 pm (London time) on the business day following the date of the relevant dealing.

If two or more persons act together pursuant to an agreement or understanding, whether formal or informal, to acquire or control an interest in relevant securities of an offeree company or a securities exchange offeror, they will be deemed to be a single person for the purpose of Rule 8.3.

Opening Position Disclosures must also be made by the offeree company and by any offeror and Dealing Disclosures must also be made by the offeree company, by any offeror and by any persons acting in concert with any of them (see Rules 8.1, 8.2 and 8.4).

Details of the offeree and offeror companies in respect of whose relevant securities Opening Position Disclosures and Dealing Disclosures must be made can be found in the Disclosure Table on the Takeover Panel’s website at www.thetakeoverpanel.org.uk, including details of the number of relevant securities in issue, when the offer period commenced and when any offeror was first identified. You should contact the Panel’s Market Surveillance Unit on +44 (0)20 7638 0129 if you are in any doubt as to whether you are required to make an Opening Position Disclosure or a Dealing Disclosure.

On April 20, 2018 Nordic Nanovector ASA (OSE: NANO) reported that it has appointed Tone Kvåle to the position of Interim Chief Executive Officer (CEO) in addition to her current role as Chief Financial Officer (Press release, Nordic Nanovector, APR 20, 2018, View Source [SID1234553506]). The appointment is made to conform to Norwegian Companies Law. A search for a full-time CEO is progressing.

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On April 20, 2018 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported promising early data from an investigator-initiated pilot study evaluating the combination of CDX-301 and stereotactic body radiotherapy (SBRT) in patients with advanced non-small cell lung cancer (NSCLC). CDX‑301 (recombinant human Flt3 ligand) is a potent hematopoietic cytokine that uniquely expands dendritic cells and hematopoietic stem cells (Press release, Celldex Therapeutics, APR 20, 2018, View Source [SID1234525560]). This translational study is the culmination of significant preclinical research into strategically combining radiation and immunotherapy to effectively treat aggressive tumors and is supported by a Small Business Innovation Research (SBIR) grant from the National Cancer Institute to Celldex in collaboration with Albert Einstein College of Medicine, part of Montefiore. The data were presented during a plenary session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 earlier this week by Nitin Ohri, M.D., Attending Physician, Montefiore and Assistant Professor, Department of Radiation Oncology, Einstein, and principal investigator on the study.

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The concept that increasing the number of dendritic cells with Flt3 ligand combined with an ablative course of radiation to the primary tumor induces a systemic anti-tumor response, suppresses metastases and promotes survival and immune memory was demonstrated through preclinical studies led by Dr. Chandan Guha and colleagues at the Einstein College of Medicine.1 Based on this seminal work, a Phase 2 pilot study of CDX-301 in combination with SBRT was initiated at the Montefiore Einstein Center for Cancer Care. The study is currently enrolling up to 29 patients, and the primary objective is progression-free survival at four months after treatment (PFS4). Key secondary objectives include evaluation of dose-limiting toxicities and response rate in non-irradiated tumors, where tumor shrinkage from radiation therapy or CDX-301 independently would not be expected. Responses were particularly impressive when classified by PERCIST (PET Response in Solid Tumors) criteria, in which a partial response is at least a 45% reduction of total glycolytic activity, a volumetric measure of disease burden. The presentation included data from nine patients, seven of whom were previously treated with anti-PD(L)1 checkpoint inhibitors. The one-week course of treatment included subcutaneous injections of CDX-301 and SBRT directed to a single lung tumor lesion.

Key Highlights

PFS4 was achieved in 56% (5/9) of patients overall (n=9; enrollment ongoing) and in 100% (5/5) of patients who experienced partial responses (PRs) by PERCIST
Notably, PRs were observed in non-irradiated tumors in 56% (5/9) of patients at two months; 3 PRs (3/9) were confirmed by immune-related response criteria (irRC)
In the patients previously treated with immune checkpoint inhibitors, 71% (5/7) experienced PRs and PFS4 versus 0% (0/2) in patients not treated with an anti-PD(L)1 therapy
SBRT in combination with CDX-301 induced and reactivated anti-tumor immune responses in patients who had progressive disease on checkpoint inhibitors
No dose-limiting toxicities were observed
"The combination of CDX-301 and radiation produced a significant decrease in tumor burden after just one course of treatment, even in non-irradiated tumors. We saw a longer period of survival for several of our patients with advanced lung cancer," said Dr. Ohri. "We are looking forward to completing enrollment in the study, determining an optimal dosing regimen and identifying additional immune modulating agents."

"Of particular interest is the potential correlation of clinical benefit with those patients who previously were treated with PD-1 blockade therapy, suggesting SBRT and CDX-301 may be able to reboot the immune system for an effective anti-tumor response," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "We believe that the activity of this combination may potentially be augmented by the addition of CDX-1140, our unique CD40 agonist antibody, which is designed to activate dendritic cells and is currently in a Phase 1 dose-escalation study."

Additionally, Celldex and its collaborating investigators presented four posters at the AACR (Free AACR Whitepaper) Annual Meeting 2018:

Poster CT058: Molecular and clinical activity of CDX-3379, an anti-ErbB3 monoclonal antibody, in head and neck squamous cell carcinoma: A preoperative "window of opportunity" study (Duvvuri, et al)

A "window-of-opportunity" study enrolled 12 patients to evaluate the effect of CDX-3379 on phosphorylated ErbB3 (pErbB3) and other potential biomarkers in patients with head and neck squamous cell carcinoma (HNSCC). Patients with newly diagnosed HNSCC received two doses of CDX-3379, at a two-week interval prior to tumor resection. CDX-3379 reduced pErbB3 levels in 83% (10/12) of patient samples, with greater than or equal to 50% decreases in 58% of patients (7/12), which met the primary study objective. Stable disease was observed in 92% (11/12) of patients prior to surgery, and a patient with HPV-negative disease experienced significant tumor shrinkage (92% in primary tumor; 26% in metastatic lesion). CDX-3379 was well-tolerated, and no treatment-related adverse events were observed.
Poster 876: Effective reduction of PD-L1 expression by simultaneous blockade of EGFR and HER3 (ErbB3) in head and neck cancer (Chen, et al)

Investigators examined the effects of combining CDX-3379, a monoclonal antibody targeting ErbB3, and cetuximab, a monoclonal antibody targeting EGFR, in xenograft models of head and neck squamous cell carcinoma. Combining CDX-3379 and cetuximab inhibited tumor growth more potently than cetuximab alone. Mechanistic studies demonstrated a reduction of PD-L1 expression from the combination.
Poster 3816: Efficacy of CDX-1140, an agonist CD40 antibody, in preclinical tumor models (Thomas, et al)

Building off previously presented preclinical work, CDX-1140 was further characterized showing tumor shrinkage and prolonged survival in several xenograft models. These preclinical studies support the potential of CDX-1140 having direct anti-tumor effects on CD40-positive tumors that may supplement its activity as an immune activating agent.
Poster 5624: Development of novel bispecific immune modulating antibodies (Vitale, et al)

Celldex’s initial bispecific antibody (BsAb) couples CD27 co-stimulation with blockade of the PD-L1/PD-1 pathway, using novel highly active anti-PD-L1 antibodies. The BsAb was more potent in human T cell activation and anti-tumor activity, compared to the combined CD27 and PD-L1 antibodies. Enhanced efficacy has been attributed to more efficient cross-linking of the BsAb/CD27 receptor, resulting in stronger T cell activation.
The CDX-301 presentation and all posters are available on the "Publications" page of the "Science" section of the Celldex website.

About CDX‑301
CDX-301 (Flt3L) is a potent hematopoietic cytokine that has demonstrated a unique capacity to increase the number of circulating dendritic cells in both laboratory and clinical studies, including CD141+ dendritic cells critical for cross-presenting tumor antigens to cytotoxic T cells. In addition, CDX‑301 has shown impressive results in models of cancer, infectious diseases and inflammatory/autoimmune diseases. Celldex believes this ligand may hold significant opportunity for synergistic development in combination with other proprietary molecules in the Company’s portfolio.

About CDX-3379
CDX-3379 is a human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody that selectively binds and inhibits ErbB3 activity. ErbB3 may be an important receptor regulating cancer cell growth and survival as well as resistance to targeted therapies, and it is expressed in many cancers, including head and neck, thyroid, breast, lung and gastric cancers, as well as melanoma. The proposed mechanism of action for CDX-3379 sets it apart from other drugs in development in this class due to its ability to block both ligand-independent and ligand-dependent ErbB3 signaling by binding to a unique epitope. It has a favorable pharmacologic profile, including a longer half-life and slower clearance relative to other drug candidates in this class. CDX-3379 also has potential to enhance anti-tumor activity and/or overcome resistance in combination with other targeted and cytotoxic therapies to directly kill tumor cells.

About CDX-1140
CDX-1140 is a fully human monoclonal antibody targeted to CD40, a key activator of immune response that is found on dendritic cells, macrophages and B cells and is also expressed on many cancer cells. Potent CD40 agonist antibodies have shown encouraging results in early clinical studies; however, systemic toxicity associated with broad CD40 activation has limited their dosing. CDX-1140 has unique properties relative to other CD40 agonist antibodies: potent agonist activity is independent of Fc receptor interaction, contributing to more consistent, controlled immune activation; CD40L binding is not blocked, leading to potential synergistic effects of agonist activity with activated T cells in lymph nodes and tumors; and the antibody does not promote cytokine production in whole blood assays. CDX-1140 activates dendritic cells and other CD40 expressing cells and has also shown direct anti-tumor activity in preclinical models of lymphoma. The Company believes that the potential for CDX-1140 will be best defined in combination studies with other immunotherapies or conventional cancer treatments.

References
1. Chakravarty, et al. Cancer Res. 1999. 59(24):6028-32.