On January 30, 2018 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported that it has entered into a clinical trial collaboration with MedImmune, the global biologics research and development arm of AstraZeneca (Press release, Innate Pharma, JAN 29, 2018, View Source [SID1234523634]). The Phase I/II study (STELLAR-001) will evaluate the safety and efficacy of durvalumab, an anti-PD-L1 immune checkpoint inhibitor, in combination with Innate’s investigational anti-C5aR monoclonal antibody, IPH5401, as a treatment for patients with selected solid tumors.

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"Our collaboration with MedImmune provides further evidence of Innate’s commitment to exploring the full combination potential of IPH5401 as we progress our immuno-oncology portfolio," said Mondher Mahjoubi, Chief Executive Officer of Innate Pharma. "We believe IPH5401 could become an important partner in PD-1/PD-L1 combination strategies."

The Phase I part of the trial is expected to establish a recommended dose regimen of IPH5401 in combination with durvalumab in selected solid tumors, and the Phase II part will assess the safety and efficacy of the combination in these patients. The study will be conducted by Innate and the costs will be equally shared by both parties. The agreement between Innate Pharma and MedImmune is non-exclusive.

Both durvalumab and IPH5401 are cancer immunotherapies, a potent class of treatments that use the body’s own immune system to help fight cancer. Durvalumab blocks PD-L1 interactions with PD-1 and CD80, countering the tumor’s immune-evading tactics and inducing an immune response. Preclinical findings suggest that C5aR blockade increases immune-mediated tumor killing and efficacy of checkpoint inhibitors. Complement cascade factor 5a (C5a), secreted by tumor cells, attracts and stimulates C5aR-overexpressing myeloid-derived suppressor cells (MDSC) and neutrophils in the tumor microenvironment. Part of the innate immune system, these types of cells promote tumor growth by secreting inflammatory mediators, immunosuppressive cytokines and angiogenic factors. They potently suppress T and NK cells and hamper the activities of PD-1/PD-L1 checkpoint blockers.

Innate Pharma and AstraZeneca have an existing co-development and commercialization agreement for monalizumab, a first-in-class humanized IgG4 targeting NKG2A receptors expressed on tumor infiltrating cytotoxic NK and CD8 T lymphocytes.

On January 29, 2018 Diffusion Pharmaceuticals Inc. (NASDAQ:DFFN) ("Diffusion" or "the Company"), a clinical-stage biotechnology company focused on extending the life expectancy of cancer patients, reported that the first patient has been dosed in the Company’s Phase 3 clinical trial with trans sodium crocetinate ("TSC") in patients with newly-diagnosed inoperable glioblastoma multiforme ("GBM"), a type of brain cancer (Press release, Diffusion Pharmaceuticals, JAN 29, 2018, View Source [SID1234523612]). The INTACT (INvestigating Tsc Against Cancerous Tumors) trial will compare standard of care ("SOC") radiation therapy ("RT") and chemotherapy plus TSC against SOC alone.

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"We are pleased to be dosing patients so soon following the opening of the INTACT trial just a few weeks ago," said David Kalergis, Chief Executive Officer of Diffusion Pharmaceuticals. "We believe that this Phase 3 study will offer new hope for inoperable GBM patients who are administered TSC along with their standard therapies."

The INTACT Phase 3 study follows a previous Phase 2 GBM study in which the inoperable patient subgroup showed a nearly four-fold increase in survival compared with historical controls when TSC was added to their treatment regimen (40.0% alive at two years vs. 10.4%). TSC’s unique mechanism of action affects the tumor micro-environment, making treatment-resistant cancer cells more susceptible to the tumor-killing power of conventional RT and chemotherapy (temozolomide) by re-oxygenating the hypoxic portion of the tumor. The Company believes that a largely intact GBM tumor vasculature with limited surgical resection is conducive to TSC’s tumor re-oxygenation properties, and that this contributed to the survival increase in the Phase 2 GBM inoperable patient subgroup.

The trial will screen 300 patients and enroll 264 with the expectation that results from 236 patients will be available for analysis. Enrolled patients will be randomized in a 1:1 ratio into treatment and control groups. Patients in the treatment group will receive SOC temozolomide and RT plus an intravenous bolus of TSC administered shortly before their SOC treatments. Patients in the control group will receive SOC alone. The study will compare overall survival at two years between patients in the two groups. Up to 100 clinical sites in the U.S. and Europe are expected to participate.

About the GBM Phase 3 INTACT Trial

The INTACT clinical trial is an open-label, randomized, controlled, Phase 3 safety and efficacy registration trial. Subjects will be randomized at baseline to SOC for first-line treatment of GBM plus TSC, or to SOC alone. The SOC for GBM is temozolomide plus RT for 6 weeks followed by 28 days of rest, followed by 6 cycles of post-radiation temozolomide treatment.

For patients randomized to the TSC group, TSC will be administered during both the RT and post-radiation temozolomide treatment periods.

During the RT treatment period subjects will receive:

Focal RT delivered as 60Gy/30 fractions scheduled at 2Gy/day for 5 days each week (Monday through Friday) for 6 weeks.
Temozolomide 75 mg/m2 orally once daily (usually administered the night preceding each RT session) starting the evening before the first RT session over a period of 42 calendar days with a maximum of 49 days.
TSC 0.25 mg/kg IV for 3 days each week (e.g., Monday, Wednesday, Friday, or other schedule that supplies a minimum 3 TSC doses per week) administered between 45 to 60 minutes prior to each RT session.
During the 28-day rest period all subjects will receive no treatment.

During the post-radiation 6-cycle temozolomide treatment period:

All subjects will receive 28-day oral temozolomide (150 mg/m2 first cycle and 200 mg/m2 all subsequent cycles as tolerated) administered on Day 1-5 (Monday through Friday) of each 28-day cycle.
Controls will receive oral temozolomide at night at home per the SOC and are not required to attend clinic visits during this period.
Subjects randomized to TSC will receive TSC 1.5 mg/kg (or another dose if recommended by the Data Safety Monitoring Board ("DSMB") 1.5 to 2 hours before their temozolomide dose during the daytime for 3 days during the first week of each 28-day cycle (Days 1, 3, and 5; e.g., Monday, Wednesday, Friday or other schedule that supplies at minimum 3 TSC doses per week). The Tuesday, Thursday doses will be given at night at home. Long-acting antiemetics may be administered prior to daytime temozolomide dosing on Days 1, 3, 5.
The safety, tolerability and pharmacokinetics ("PK") of TSC at higher doses than 0.25 mg/kg with temozolomide will be assessed during adjuvant therapy. TSC at doses between 0.25 mg/kg and up to 1.5 mg/kg in combination with concomitant temozolomide will be assigned (not randomized) in the first 8 subjects enrolled in the INTACT trial. These patients will undergo RT plus temozolomide plus TSC treatment (0.25 mg/kg) for 6 weekly cycles followed by 4 weeks of rest in standard fashion. At the Week 10 clinic visit the same 8 subjects will be assigned to treatment, with 2 subjects each assigned to TSC at doses of 0.25, 0.50, 1.0, and 1.5 mg/kg. These subjects will be studied in parallel for 2 28-day cycles with inclusion of appropriate blood sampling collection for TSC and temozolomide PK. The DSMB will examine the resultant safety data after 2 cycles (Weeks 11 through 18 of post-radiation temozolomide treatment period; Days 1 to 56). The DSMB may recommend continued use of the 1.5 mg/kg TSC dose for the post-radiation temozolomide treatment period, or may prescribe another dose based on their observations. Subjects then entering into the INTACT trial will be randomized at baseline between TSC plus SOC, or SOC alone.

Further details about the trial protocol are available at www.clinicaltrials.gov.

The baseline assessment for determining progression-free survival overall response rate and to rule out pseudo-progression will be at 10 weeks via MRI using the modified Response Assessment in Neuro-Oncology scale. The hazard ratio for the trial will be 0.67, which corresponds to 22% two-year survival in the TSC arm, the lower limit of the 95% confidence interval for the biopsy-only subjects in Diffusion’s Phase 2 trial, and 10% survival in the SOC arm. The estimated median survival is therefore 10 months for the SOC arm vs. 14.9 months for the TSC plus SOC arm. In order to achieve 80% power, the trial requires 118 subjects in each arm.

The study will achieve the designed 80% statistical power at 198 events, where an event is defined as death. The first analysis will occur at the earlier of two years follow-up for all subjects or 198 events. If the first analysis is at 198 events, the analysis will be a standard 2-sided stratified log-rank test at the 훼=0.05 significance level. If the first analysis is at two years, the Company will perform the analysis using the O’Brien-Fleming Method.

About Treatment-Resistant Cancers and TSC

Oxygen deprivation at the cellular level (hypoxia) is the result of rapid tumor growth, causing the tumor to outgrow its blood supply. Cancerous tumor cells thrive with hypoxia and the resultant changes in the tumor microenvironment cause the tumor to become resistant to RT and chemotherapy. Using a novel, proprietary mechanism of action, Diffusion’s lead drug TSC appears to counteract tumor hypoxia – and therefore treatment resistance – by safely re-oxygenating tumor tissue, thus enhancing tumor kill and potentially prolonging patient life expectancy. Oxygen levels of normal tissue appear to remain unaffected upon administration of TSC.

On January 29, 2018 Cellectar Biosciences (Nasdaq: CLRB), a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of drugs for the treatment of cancer, reported that it has enrolled the first patient in the diffuse large B-cell lymphoma (DLBCL) cohort of its Phase 2 clinical trial of CLR 131, its lead radiotherapeutic Phospholipid Drug ConjugateTM (PDCTM) (Press release, Cellectar Biosciences, JAN 29, 2018, View Source [SID1234523611]). This group represents the fourth and final cohort of the company’s Phase 2 study for patients with relapsed or refractory B-cell hematologic cancers. The Company expects to enroll up to 10 patients with DLBCL into this cohort prior to conducting an interim analysis. If these interim data are positive, the DLBCL cohort could be expanded by an additional 10-20 patients.

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"DLBCL is a rare hematologic cancer with few treatment options and the expansion of the Phase 2 trial provides the opportunity to further explore the broad treatment potential of CLR 131 in an area of significant unmet need. We are now exploring CLR 131 in six hematologic malignancies and we expect to initiate Phase 1 studies in head & neck cancer and pediatric tumors in 2018," stated James Caruso, president and chief executive officer of Cellectar Biosciences. "Importantly, we are able to undertake our development plans with modest shareholder investment as our Phase 2 study is partially funded through a National Cancer Institute (NCI) Small Business Innovation Research grant. In addition, the Phase 1 head & neck study will be predominantly funded through a NCI Specialized Programs of Research Excellence grant and costs for the pediatric study will be shared with our partners at the University of Wisconsin."

About the Phase 2 Study of CLR 131

We are conducting the Phase 2 study for patients with relapsed or refractory B-cell hematologic cancers in approximately 10 leading cancer centers in the United States. These hematologic cancers include multiple myeloma (MM), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and DLBCL.

The study’s primary endpoint is clinical benefit response (CBR), with additional secondary endpoints of progression free survival (PFS), median overall survival (OS) and other markers of efficacy following a single 25.0 mCi/m2 dose of CLR 131, with the option for a second 25.0 mCi/m2 dose approximately 75-180 days later.

In addition to the CLR 131 infusion(s), MM patients will receive 40 mg oral dexamethasone weekly for up to 12 weeks. Efficacy responses will be determined in accordance with the latest International Multiple Myeloma Working Group criteria. Efficacy for all lymphoma patients will be determined according to Lugano criteria. More information about the trial, including eligibility requirements, can be found at www.clinicaltrials.gov, reference NCT02952508.

About Diffuse Large B-Cell Lymphoma

According to the Lymphoma Research Foundation, diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin’s lymphoma (NHL), accounting for about 30 percent of newly diagnosed cases of NHL in the United States.

The American Cancer Society’s most recent estimates for NHL for 2018 project approximately 74,680 people (41,730 males and 32,950 females) will be diagnosed with NHL including both adults and children. They estimate that approximately 19,910 people will die from this cancer (11,510 males and 8,400 females).

DLBCL occurs in both men and women, although it is slightly more common in men. Although DLBCL can occur in childhood, its incidence generally increases with age, and roughly half of patients are over the age of 60.

DLBCL is an aggressive (fast-growing) lymphoma that can arise in lymph nodes or outside of the lymphatic system, in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. Often, the first sign of DLBCL is a painless, rapid swelling in the neck, underarms, or groin that is caused by enlarged lymph nodes. For some patients, the swelling may be painful. Other symptoms may include night sweats, fever, and unexplained weight loss. Patients may notice fatigue, loss of appetite, shortness of breath, or pain.

About CLR 131

CLR 131 is an investigational compound under development for a range of orphan designated cancers. It is currently being evaluated as a single-dose treatment in a Phase I clinical trial in patients with relapse or refractory (R/R) MM as well as in a Phase II clinical trial for R/R MM and select R/R lymphomas with either a one- or two-dose treatment. Based upon preclinical and interim Phase I study data, treatment with CLR 131 provides a novel approach to treating solid and hematological tumors and may provide patients with therapeutic benefits, including overall survival, an improvement in progression-free survival, surrogate efficacy marker response rate, and overall quality of life. CLR 131 utilizes the company’s patented PDC tumor targeting delivery platform to deliver a cytotoxic radioisotope, iodine-131, directly to tumor cells. The FDA has granted orphan drug designation for CLR 131 in the treatment of MM.

About Phospholipid Drug ConjugatesTM (PDCsTM)

Cellectar’s product candidates are built upon its patented cancer cell-targeting delivery and retention platform of optimized phospholipid ether-drug conjugates (PDCs). The PDC platform provides selective delivery of a diverse range of oncologic payloads to cancerous cells, whether a hematologic cancer or solid tumor, the primary tumor, a metastatic tumor or cancer stem cells. The selective delivery of oncologic payloads allows for the modification of the payloads’ therapeutic window which may maintain or enhance drug potency while reducing the number and severity of adverse events. The PDC platform takes advantage of a metabolic pathway utilized by all tumor cell types in all stages of the tumor "cycle." This property allows the PDC molecules to gain access to the intracellular compartment of the tumor cells and for the PDCs to continue to accumulate over time, which enhances drug efficacy. The PDC platform’s mechanism of entry does not rely upon specific cell surface epitopes or antigens as are required by other targeted delivery platforms. In addition to the benefits provided by the mechanism of entry, PDCs offer the potential advantage of having the ability to be conjugated to molecules in numerous ways, thereby increasing the types of molecules selectively delivered via the PDC. The PDC platform possesses the potential for the discovery and development of the next generation of cancer-targeting agents.

On January 29, 2018 Sanofi [Euronext: SAN; NYSE: SNY] and Ablynx [Euronext Brussels and Nasdaq: ABLX], a biopharmaceutical company engaged in the discovery and development of Nanobodies, reported that they entered into a definitive agreement under which Sanofi will offer to acquire all of the outstanding ordinary shares, including shares represented by American Depositary Shares (ADSs), warrants and convertible bonds of Ablynx at a price per Ablynx share of €45 in cash, which represents an aggregate equity value of approximately €3.9 billion (Press release, Ablynx, JAN 29, 2018, View Source [SID1234523602]). The transaction was unanimously approved by both the Sanofi and Ablynx Boards of Directors.

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Sanofi’s Chief Executive Officer Olivier Brandicourt commented, "With Ablynx, we continue to advance the strategic transformation of our Research and Development, expanding our late-stage pipeline and strengthening our platform for growth in rare blood disorders. This acquisition builds on a successful existing partnership. We are also pleased to reaffirm our commitment to Belgium, where we have invested significantly over the years in our state-of-the-art biologics manufacturing facility in Geel. We intend to maintain and support the Ablynx science center in Ghent."

Ablynx’s Chief Executive Officer Edwin Moses noted, "Since our founding in 2001, our team has been focused on unlocking the power of our Nanobody technology for patients. The results of our work are validated by clinical data. As we look ahead, we believe Sanofi’s global infrastructure, commitment to innovation and commercial capabilities will accelerate our ability to deliver our pipeline. Our Board of Directors feels strongly that this transaction represents compelling value for shareholders and maximizes the potential of our pipeline to the benefit of all stakeholders."

Sustaining Innovation in R&D

The acquisition of Ablynx continues Sanofi’s commitment to breakthrough innovation, focused on technologies addressing multiple disease targets with single multi-specific molecules.

Nanobodies are a novel class of proprietary next generation biologicals. Ablynx is at the leading edge of Nanobody technology supporting a deep pipeline of more than 45 proprietary and partnered candidates for a wide range of therapeutic areas such as hematology, inflammation, immuno-oncology and respiratory diseases. Eight Nanobodies have entered clinical development.

Sanofi is committed to accelerating development and maximizing the commercial potential of Ablynx’s ongoing and emerging programs.

Strengthening Sanofi’s Platform in Rare Blood Disorders

Ablynx’s most-advanced product in development is caplacizumab (anti-vWF Nanobody), a wholly-owned development program for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP). The product is already filed in the European Union and expected to be filed in the U.S. during the first half of this year. Caplacizumab, if approved, would be the first-in-class treatment for this acute, life-threatening disease.

The addition of caplacizumab to Sanofi’s platform strengthens its position in rare blood disorders, complementing the recently announced agreements to acquire Bioverativ and obtain global rights for fitusiran from Alnylam.

Combining Complementary Capabilities to Address Respiratory Syncytial Virus (RSV) Infections

Ablynx’s ALX-0171, an inhaled anti-RSV Nanobody, currently in Phase 2b, is a potential breakthrough for the symptomatic treatment of RSV infections—for which there is no widely used therapy available—and is very complementary to Sanofi Pasteur RSV associated programs.

Delivering Long-Term Shareholder Value

The addition of Ablynx is anticipated to drive meaningful long-term value for Sanofi’s shareholders by enhancing its pipeline and research capabilities. Including R&D expenses, the acquisition is expected to be neutral to Business EPS1 in 2018 and 2019.

Transaction Terms

Under the terms of the agreement, Sanofi will launch public offers to acquire all of the outstanding ordinary shares (including shares represented by ADSs), warrants and convertible bonds of Ablynx in cash. Sanofi has complied with the formalities set forth in the Belgian takeover legislation and filed the mandatory documents with the Belgian Financial Services and Markets Authority (FSMA). A notice was published by the FSMA on its website.

The consummation of the public offers is subject to customary conditions, including the tender of securities representing at least 75% of the outstanding shares of Ablynx at the end of the initial acceptance period of the Belgian Tender Offer, and the receipt of required regulatory approvals. The public offers are expected to be launched by the beginning of the second quarter of 2018.

In accordance with the Belgian requirement of certainty of funds, Sanofi has entered into a bank credit facility, BNP Paribas Fortis SA/NA acting as the sole credit facility arranger. Subject to the satisfaction or waiver of customary closing conditions, the transaction is expected to close by the end of the second quarter 2018.

Morgan Stanley and Lazard are acting as financial advisors to Sanofi. J.P. Morgan is acting as financial advisor to Ablynx. Weil, Gotshal & Manges LLP and NautaDutilh are serving as legal counsels to Sanofi. Eubelius CVBA, Goodwin Procter LLP and Linklaters LLP are serving as legal counsels to Ablynx.

Sanofi Conference Call

Sanofi will host a webcast live on Sanofi’s website at 2.30pm CET / 8.30am EST on Monday, 29 January 2018. The webcast details and full presentation will be made available on Sanofi’s Investor Relations webpage.

1 Business EPS is a non-GAAP financial measure (see appendix to Sanofi press release on quarterly results for a definition)

On January 29, 2018 Sumitomo Dainippon Pharma reported its Supplementary Financial Data
for the Third Quarter of the Year Ending March 31, 2018 (Press release, Dainippon Sumitomo Pharma, JAN 29, 2018, View Source [SID1234523624]).

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