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Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling.

One of the challenges for targeting B-Raf(V600E) with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-Raf(WT), as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the ‘DFG-in/αC-helix-out’ conformation (Type IIB) likely will exhibit improved selectivity for B-Raf(V600E). To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-Raf(V600E)/B-Raf(WT) biochemical ((b)S), cellular ((c)S) selectivity, and the phospho-ERK activation ((p)A). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-Raf(V600E) selectivity.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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Roche reports solid sales growth in the first quarter of 2016

On April 19, 2016 Roche reported solid sales growth in the first quarter of 2016 (Press release, Hoffmann-La Roche , APR 18, 2016, View Source [SID:1234511052]).

Group sales up 4%1 at constant exchange rates, 5% in Swiss francs

Pharmaceuticals Division sales increase 4%, driven by oncology and immunology medicines

Diagnostics Division sales grow 5%, led by immunodiagnostic product demand

US FDA grants priority review for investigational cancer immunotherapy medicine atezolizumab in bladder and lung cancer and breakthrough therapy designation for ocrelizumab in multiple sclerosis

Outlook for 2016 confirmed
Key figures January – March

In millions of CHF
As % of sales
% change

2016 2015 2016 2015 At CER In CHF
Group Sales 12,414 11,833 100 100 +4 +5
Pharmaceuticals Division 9,800 9,322 79 79 +4 +5
– United States 4,716 4,392 38 37 +3 +7
– Europe 2,319 2,178 19 18 +5 +6
– Japan 853 763 7 6 +4 +12
– International* 1,912 1,989 15 18 +4 -4
Diagnostics Division 2,614 2,511 21 21 +5 +4
* Asia–Pacific, EEMEA (Eastern Europe, Middle East, Africa), Latin America, Canada, Others

Roche CEO Severin Schwan said: "We have started the year with solid growth in both our Pharmaceuticals and Diagnostics Divisions. The marketing applications of important investigational medicines are well underway. The FDA granted priority review for atezolizumab in two indications and breakthrough therapy designation for ocrelizumab in primary progressive multiple sclerosis. Overall, we are on track to meet our full-year targets for 2016."

Group
In the first quarter of 2016, Group sales rose 4% to CHF 12.4 billion. Sales in the Pharmaceuticals Division were up 4% to CHF 9.8 billion with Europe growing 5%, driven by Perjeta, MabThera and RoActemra. Pharmaceuticals sales in the US increased 3%, led by Esbriet, Xolair and HER2-positive breast cancer medicines. The recently launched medicines Cotellic in skin cancer and Alecensa in lung cancer have had a good start. In the US, sales of Tamiflu and Lucentis declined. The main growth contributors in the International region (+4%) were Avastin, MabThera and Herceptin; this growth was partly offset by lower Pegasys sales due to competition from a new generation of treatments. In Japan, sales rose 4% driven by Avastin, HER2 medicines and Alecensa.

In Diagnostics, sales grew 5% to CHF 2.6 billion, driven primarily by strong growth in Asia-Pacific (+16%) and Latin America (+21%). In Europe, the Middle East, and Africa (EMEA) sales increased 1% while they remained stable in North America and declined by 3% in Japan. Strong growth was recorded for the immunodiagnostic, molecular and tissue diagnostics businesses. Diabetes Care sales were impacted by challenging market conditions, especially in North America.

Portfolio progress
In March and April respectively, Roche’s lead investigational cancer immunotherapy medicine atezolizumab was granted priority review by the FDA for marketing applications in two indications, advanced bladder cancer and non-small cell lung cancer (NSCLC). Both filings were submitted under FDA breakthrough therapy designations and are based on pivotal phase II data. Atezolizumab is being investigated in a broad phase III clinical programme in solid and hematologic cancers.

The FDA granted breakthrough therapy designation (BTD) for ocrelizumab in primary progressive multiple sclerosis in February. Ocrelizumab is the first investigational medicine to receive BTD in multiple sclerosis. Since 2013, the FDA has granted BTDs for 12 indications of Roche medicines. Roche plans to file ocrelizumab for both relapsing and primary progressive multiple sclerosis in the first half of 2016.

In March, Roche provided an update on two identical phase III studies of lebrikizumab in people with severe asthma. While one study met its primary clinical endpoint, the second did not achieve statistical significance. Roche is analysing the data to help determine next steps in the asthma programme.

In April, the FDA granted Venclexta (venetoclax) accelerated approval for people with a hard-to-treat type of chronic lymphocytic leukemia. Venclexta is the first approved medicine designed to help restore a process in which cells self-destruct by selectively blocking a protein called BCL-2. Venclexta is being jointly developed with AbbVie.

In February, Roche received US approval for Gazyva for the treatment of people with relapsed or rituximab-refractory follicular lymphoma, the most common type of indolent non-Hodgkin lymphoma (NHL), based on phase III results. European approvals are expected later this year. Gazyva is being studied in a large clinical programme in NHL, and phase III data in diffuse large B cell lymphoma, an aggressive type of NHL, are expected later this year.

Mustang Bio Announces Presentations of MB-101, a Novel IL13Ra2-specific CAR-T cells Product in Clinical Development, at the American Society of Gene and Cell Therapy 19th Annual Meeting

On April 18, 2016 Mustang Bio, Inc. ("Mustang"), a Fortress Biotech (NASDAQ: FBIO) Company, reported that two abstracts pertaining to its MB‐101 (IL13Rα2‐specific CAR‐T cells) product candidate in development were selected for presentation at the upcoming American Society of Gene and Cell Therapy 19th Annual Meeting (ASGCT) (Free ASGCT Whitepaper), to be held May 4‐7, 2016, at the Marriott Wardman Park Hotel in Washington, DC (Press release, Fortress Biotech, APR 18, 2016, View Source [SID:1234511047]).

Pre‐clinical Oral Presentation:

Title: Optimization of IL13Rα2‐specific CAR T cells for Clinical Development Using Orthotopic Human Glioblastoma Models in NSG Mice
o Abstract Number: 275
o Session: Oral Abstract Session 243 – Cancer‐Immunotherapy, Cancer Vaccines I
o Date and Time: Thursday, May 5, 2016; 4:00 – 5:45 PM ET
o Location: Marriott Wardman Park Hotel, Washington 4
o Presenter: Dr. Christine Brown, Associate Director, T cell Therapeutics Research Laboratory at the City of Hope Medical Center ("COH")
Clinical Oral Presentation:

Title: Phase I Study of Second Generation Chimeric Antigen Receptor–Engineered T cells Targeting IL13Rα2 for the Treatment of Glioblastoma
o Abstract Number: 247
o Session: Scientific Symposium 201 – Clinical Trials Spotlight
o Date and Time: Thursday, May 5, 2016; 8:00 AM – 10:00 AM ET
o Location: Marriott Wardman Park Hotel, Thurgood Marshall NE
o Presenter: Dr. Benham Badie, Vice Chair and Professor, Department of Surgery, Chief, Division of Neurosurgery, Director, Brain Tumor Program and Neurosurgeon at the City of Hope Medical Center ("COH")

Copies of the above referenced abstracts can be viewed online through the ASGCT (Free ASGCT Whitepaper) meeting website at the following links:
View Source!/4077/presentation/566
View Source!/4077/presentation/1013

About Glioblastoma multiforme (GBM)
Glioblastomas (GBM) are tumors that arise from astrocytes—the star‐shaped cells that make up the supportive tissue of the brain. These tumors are usually highly malignant (cancerous) because the cells reproduce quickly and they are supported by a large network of blood vessels. GBM is the most common brain and central nervoussystem (CNS) malignancy, accounting for 15.1% of all primary brain tumors, and 55.1% of all gliomas. There are an estimated 12,120 new glioblastoma cases predicted in 2016 in the U.S. Malignant brain tumors are the most common cause of cancer‐related deaths in adolescents and young adults aged 15‐39 and the most common cancer occurring among 15‐19 year olds in the U.S. (Brain Tumor Statistics. American Brain Tumor Association. December 2015). While GBM is a rare disease (2‐3 cases per 100,000 person life years in the U.S. and E.U.), it is quite lethal with 5‐year survival rates historically less than 10%. Chemotherapy with temozolomide and radiation are shown to extend mean survival from ~12 to ~15 months, while surgery remains the standard of care.GBM remains difficult to treat due to the inherent resistance of the tumor to conventional therapies. Treatment is further complicated by the susceptibility of the brain to damage, difficulty of the brain to repair itself and limitation to drugs crossing the blood brain barrier. Immunotherapy approaches targeting brain tumors offer promise over conventional treatments.

About MB‐101 (IL13Rα2‐specific CAR‐T cells)
IL13Rα2 is an attractive target for CAR‐T therapy as it has limited expression in normal tissue but is over‐ expressed on the surface of the majority of GBM. CAR‐T cells designed to express a membrane‐tethered IL‐13 receptor ligand (IL‐13) incorporating a single point mutation display high affinity for IL13Rα2 and reduced binding to IL13Rα1 in order to reduce healthy tissue targeting.

We are developing an optimized CAR‐T product incorporating enhancements in CAR design and T‐cell engineering to improve antitumor potency and T‐cell persistence. We include a second generation hinge optimized CAR containing mutations in the IgG4 linker to reduce off target Fc interactions, as well as the 41BB (CD137) co‐stimulatory signaling domain for improved survival and maintenance of memory T‐cells, and extracellular domain of CD19 as a selection/safety marker. In order to further improve persistence, memory T‐cells are enriched and genetically engineered using a manufacturing process that limits ex vivo expansion in order to reduce T‐cell exhaustion and maintain a memory T‐cell phenotype.

Syros Pharmaceuticals Presents Data Demonstrating Significant Anti-Cancer Activity of SY-1425 in Preclinical Models of Acute Myeloid Leukemia

On April 18, 2016 Syros Pharmaceuticals reported that SY-1425, a potent and selective retinoic acid receptor alpha (RARα) agonist, was observed to inhibit the growth of cancer cells and prolong survival in in vivo models of acute myeloid leukemia (AML) with a novel RARA biomarker discovered by the Company (Press release, Syros Pharmaceuticals, APR 18, 2016, View Source [SID:1234511012]). The biomarker was found in approximately 25 percent of AML and myelodysplastic syndrome (MDS) patient tissue samples. These data were presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans.

"SY-1425 represents a promising therapeutic option for novel genomically defined subsets of AML and MDS patients," said Nancy Simonian, MD, Chief Executive Officer of Syros. "Based on our preclinical data, which show a strong link between our biomarker and response to treatment with SY-1425, we are committed to rapidly advancing this first-inclass therapy for these currently underserved patients. Positive results from a Phase 2 clinical study would not only be beneficial to patients but also validate our pioneering approach of analyzing the non-coding region of DNA to advance the field of genomics-based medicine."

The data presented at AACR (Free AACR Whitepaper) shows that the RARA biomarker discovered by Syros is predictive of response to treatment with SY-1425 in AML cell lines and patient-derived xenograft (PDX) models of AML. Treatment with SY-1425 was observed to inhibit cancer growth and prolong survival in PDX models of AML with the RARA biomarker but not in models of AML without the biomarker. Highlights of the data include:

Greatly reduced tumor burden in the blood, bone marrow and spleen in PDX mouse models with the RARA biomarker treated with SY-1425 compared to untreated mice; by contrast, no effect was seen in PDX models of AML without the biomarker.

Prolonged survival with 100 percent of mice with the RARA biomarker treated with SY-1425 alive at the end of the 35-day study; by contrast, none of the untreated mice survived beyond 25 days; also, by contrast, no survival benefit was seen in PDX models of AML without the biomarker.

Significant survival benefit in mice treated with SY-1425 compared to mice treated with ATRA, a pan-agonist of RAR, RAR and RARA, in a PDX model with the RARA biomarker.

Using its gene control platform, Syros identified a specialized regulatory region of noncoding DNA known as a super-enhancer that is associated with the RARA gene in subsets of AML and MDS patients. The super-enhancer is believed to lock cells in an immature, proliferative state. Treatment with SY-1425 in cancer cells with the RARA super-enhancer appears to promote differentiation of these cells. Syros in-licensed SY-1425, which is approved in Japan as tamibarotene to treat acute promyelocytic leukemia, to develop and commercialize SY-1425 in North America and Europe for all cancers.

Syros plans to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration and initiate a Phase 2 clinical trial of SY-1425 in mid-2016 in subsets of AML and MDS patients with the RARA biomarker. The Company continues to research the role of the RARA super-enhancer in other cancers and plans to pursue additional indications upon achieving proof-of-concept in AML and MDS.

Multiple myeloma phase II study of BioInvent’s antibody BI-505 ready to start

On April 18, 2016 BioInvent International (BINV) reported that patient recruitment into the trial can now start in the upcoming clinical Phase II study with the antibody BI-505 in patients with multiple myeloma, as necessary regulatory approvals have been obtained. The first patient is expected to be dosed in May (Press release, BioInvent, APR 18, 2016, View Source [SID:1234511007]).

Multiple myeloma is a bone marrow cancer which affects more than 120,000 people globally every year [1]. Initial treatment is often successful, but unfortunately, most patients will relapse and in 2015, nearly 90,000 patients died as a result of the disease [2]. BI-505 is a novel immuno-oncology treatment with the potential to prevent or delay relapse of multiple myeloma.

"The start of this Phase II study is an important milestone in the development of BI-505, an antibody with the potential to offer multiple myeloma patients a longer and healthier life," says Anna Wickenberg, Vice President of Clinical Development at BioInvent.

The clinical study will be conducted by BioInvent in collaboration with investigators at the University of Pennsylvania in the United States. It aims to document the ability of BI-505 to deepen the therapeutic response and thereby prevent or delay relapse of multiple myeloma in patients undergoing autologous stem cell transplantation (ASCT) with high-dose melphalan as part of their standard of care. The study will enroll approximately 90 patients undergoing ASCT whereof half will receive BI-505 as an add-on treatment to their standard of care.

The study is open-label, randomized, and includes a control group receiving only standard treatment. The open-label design will allow for patient outcomes to be monitored on an individual basis throughout the study. The primary efficacy evaluation of BI-505 will be made after 100 days with the primary endpoint being the proportion of patients in stringent complete response (sCR). Patients will thereafter be followed over three years to document progression-free survival (PFS). As a secondary endpoint, patients will also be monitored for any residual, disease known as "Minimal Residual Disease" (MRD), to assess deep responses.

To the editors:

About BI-505
BI-505 is a human antibody against ICAM-1 developed by BioInvent which will be clinically tested in cooperation with researchers at University of Pennsylvania as an immuno-oncological therapy to prevent or delay relapse in patients with multiple myeloma (a form of bone marrow cancer) undergoing stem-cell transplantation. Preclinical data indicates improved activity against myeloma when BI-505 is administered in combination with Velcade or Revlimid. BI-505’s favourable safety profile has been demonstrated in a previous phase I trial. This and the unique mechanism of action, "flagging" remaining myeloma cells for elimination by actively recruited macrophages, as well as the potential to inhibit ICAM-1 dependent survival signals between myeloma cells and tumour stroma, indicate a unique possibility of improving the therapeutic effect of stem-cell transplantation and other cancer therapies.