Blinatumomab will change the future of relapsed/refractory Acute Lymphoblastic Leukemia patients?

During the ASCO 2014, Amgen had shown the latest data of a novel ALL treatment, Blinatumomab.

Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. Blinatumomab is currently investigated for acute lymphoblastic leukemia (ALL), specially in persistence or relapse/ refractory after chemotherapy indicates resistance to chemotherapy. As the current ALL treatment were knowing for the high toxicity and low medical response, Blinatumomab can offer a real medical alternative.  Blinatumomab, was designed as orphan drug by the FDA for ALL in 2008. Blinatumomab binds to CD19, a protein which is expressed solely by B cells and is overexpressed in ALL tumor cells. Blinatumomab also binds to cytotoxic T cells through an interaction with the protein CD3, redirecting T cells to lyse CD19-expressing B-precursor ALL cells. The Phase II study of blinatumomab, reflect the potential of this molecule as an first-in-class bispecific T cell antibody.

The results showed that 43% of the 189 blinatumomab-treated patients achieved complete remission (CR) or CR with partial hematological recovery (CRh) within the first two cycles of therapy, with 80% of responses occurring within the first cycle. The median relapse-free survival was 5.9 months, and OS was 6.1 months. In total, patients were treated with more than five cycles of blinatumomab.

In cycle 1, patients underwent a run-in phase of 9μg blinatumomab per day for the first week, with 28μg per day for the remaining three weeks.

In cycle 2, patients were treated with 28μg blinatumomab per day.

The primary endpoint assessment of CR/CRh was performed at the end of the second cycle, and patients who responded to blinatumomab therapy were eligible to receive three additional cycles of therapy.

Current acute lymphoblastic leukemia chemotherapies were mainly composed by four-drug combination of vincristine, prednisone, anthracycline, and cyclophosphamide or L-asparaginase, or a five-drug combination including vincristine, prednisone, anthracycline, cyclophosphamide, and L-asparaginase. Although, the treatment related high mortality rate around 20 to 30%. Otherwise, there is an important unmet need for innovative therapies, more safe and efficient for the patient.

If Blinatumomab will demonstrate efficacy and safety in ALL treatment, the new compound will have the chance to reach a high pricing regarding the FDA orphan drug accreditation. Blinatumomab is currently investigated in the Phase III TOWER trial versus the investigator’s choice of standard of care chemotherapy in adult subjects with R/R precursor B-cell ALL.

Regarding the blinatumomab’s result shown in ASCO convincing results in adult patients with R/R ALL, and the important medical need, blinatumomab seems to be a possible multi-indication revolution for ALL, and non-Hodgkin’s lymphoma patients.

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Pfizer And GSK To Initiate Study Of Novel Combination Therapy In Patients With Melanoma

Pfizer Inc. announced that it has entered into an agreement with GSK to explore the anti-cancer efficacy and the safety of GSK’s trametinib (GSK1120212) combined with Pfizer’s palbociclib (PD-0332991) in a Phase I/II study (Study 200344) in patients with advanced/metastatic melanoma.

Study 200344 is a dose-escalation, open-label study designed to determine the recommended combination regimen (RCR) for trametinib plus palbociclib in patients with melanoma.  The study will also evaluate the effect of the combination on tumor biomarkers, safety and anti-cancer activity in patients with BRAFV600 wild type melanoma, including those with NRAS mutations.

“Pfizer Oncology is committed to maximizing the value of our portfolio for patients through the study of novel combinations.  This includes combining our own cancer medicines with each other, as well as with those of other companies where there is strong scientific rationale,” said Garry Nicholson, president and general manager, Pfizer Oncology Business Unit.  “Emerging data suggest the potential for trametinib and palbociclib to work together to treat melanoma.  We look forward to collaborating with GSK to explore this potential and evaluate the clinical activity of this combination in melanoma.”

The two companies will collaborate on the study, which GSK will conduct.  Financial terms of the agreement were not disclosed.

Trametinib, a reversible inhibitor of MEK1 and MEK2, is approved by the U.S. Food and Drug Administration (FDA) under the name Mekinist® for the treatment of adult patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation as detected by an FDA-approved test.  Mekinist is not indicated for the treatment of patients who have received a prior BRAF inhibitor therapy.

Palbociclib is an investigational oral and selective inhibitor of cyclin dependent kinases (CDK) 4 and 6.  In April 2013, palbociclib received Breakthrough Therapy designation by the FDA for the potential treatment of patients with breast cancer. Palbociclib is not approved for any indication in any markets.

Source: Pfizer

FDA clears Bayer, Onyx Pharmaceuticals’ Nexavar for late-stage differentiated thyroid cancer

The FDA on Friday approved Bayer and Onyx Pharmaceuticals’ Nexavar (sorafenib) for the treatment of patients with late-stage differentiated thyroid cancer. Pamela A. Cyrus, head of US medical affairs for Bayer, remarked « Nexavar is the first and only FDA-approved therapy for this type of thyroid cancer and is a positive development for patients who previously had limited treatment options. »

The approval was supported by a study involving 417 patients with radioactive iodine-refractory locally recurrent or metastatic, progressive differentiated thyroid cancer. Study data showed that the therapy extended progression-free survival by 41 percent, as patients treated with Nexavar displayed a progression-free survival of 10.8 months, versus 5.8 months for the placebo arm.

Nexavar gained expanded US approval for the treatment of late-stage differentiated thyroid cancer under the FDA’s priority reviewprogramme. The drug was previously approved for the treatment of advanced kidney cancer and for advanced liver cancer.

Onyx was acquired by Amgen earlier this year for $10.4 billion, granting the latter rights to Nexavar.

Zaltrap,is the new mCRC Sanofi’s blockbuster ?

From a long time Sanofi is a major company in oncology with various blockbuster Taxotere (docetaxel / Sanofi ) or Eloxatin (oxaliplatin/ Sanofi) are manly considered as  standard. In metastatic colorectal cancer they are a multiple chemotherapy regimens were Sanofi are already an important actor, otherwise with the patent cliff is clear that Sanofi have to find new product in order to keep a leading position within the oncology market. The success of Avastin in the mCRC has generated an interest in angiogenesis inhibitors for CRC. As a result, there is a high level of competition between new anti-angiogenesis agents in the CRC pipeline.

Saying this, Zaltrap (aflibercept; Regeneron/Sanofi) is the first targeted therapy launched by Sanofi. The positive result of Phase III VELOUR is an evidence of the potential Zaltrap success. Zaltrap is a human recombinant protein composed by segments of the human vascular endothelial growth factor receptors 1 and 2 (VEGFR1/2) and portion of human immunoglobulin G1 (IgG1)

The design of the VELOUR Phase III trial show that Zaltrap was being developed for use in the second-line metastatic colorectal cancer (mCRC) after Avastin  in the first-line setting. Sanofi is investigating the indication for naïve patient didn’t be treated by Avastin. Obviously Zaltrap have to differentiate from Avastin in order to face future competitors such as brivanib (BMS)

Zaltrap received in august 2012 an FDA approval for use in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) to treat patients with metastatic colorectal cancer (mCRC) that are resistant to or have progressed following an oxaliplatin-containing regimen. In Europe Zaltrap received this marketing authorization from the EMA in February 2013.

Zaltrap is positioned in the second line mCRC treatment when Avastin fails or as an alternative in indications where Avastin is not approved, in order to avoid a direct competition with Avastin.

 

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Rexahn Pharmaceuticals Announces Publication of Preclinical Data for Novel Anti-Cancer Compound RX-3117

Rockville, MD, September 30, 2013 – Rexahn Pharmaceuticals, Inc. today announced the on-line publication of preclinical results for RX-3117 in a peer reviewed medical journal, Investigational New Drugs, in an article titled, “Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360)”. Investigational New Drugs is an interdisciplinary journal presenting the latest investigations and discussions of critical questions appropriate to the entire field of new anticancer drug development.

Peter D. Suzdak, Ph.D., Rexahn’s Chief Executive Officer, commented, “The broad spectrum of anti-tumor activity against human cancer cell lines, oral bioavailability in cancer patients, and improved preclinical and clinical safety profile suggest that RX-3117 may represent a major advance in the treatment of solid cancer tumors. Rexahn anticipates initiating a Phase I clinical study in cancer patients with solid tumors in the fourth quarter of 2013.”

The published study characterized the broad spectrum of potent anti-tumor effects of RX-3117 against 50 different human cancer cell lines (including colon, lung, renal and pancreas) and its unique mechanism of activation in cancer cells. In addition, RX-3117 was shown to be effective in gemcitabine resistant human cancer cell lines. Although RX-3117 shares some properties with other nucleoside compounds such as gemcitabine, its cytotoxicity profile, metabolism and mechanism of action make it distinct and potentially clinically superior to existing nucleoside compounds.

Prof. Dr. Godefridus J. (Frits) Peters, Head Laboratory Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands, and lead author of the published results, commented, “RX-3117 is an exciting new nucleoside analog with unique properties both regarding its mechanism of action and its pharmacology. Its excellent oral bioavailability fits very well with the current tendency to give anticancer drugs orally. Its mechanism of action gives several leads for future combination therapies with different drugs.”

About RX-3117
RX-3117 is a novel small molecule nucleoside compound that is incorporated into DNA or RNA of cancer cells and inhibits both DNA and RNA synthesis which induces apoptotic cell death of tumor cells. RX-3117 also mediates the down-regulation of DNA methyltransferase 1 (DNMT1), an enzyme responsible for the methylation of cytosine residues on newly synthesized DNA and also a target for anticancer therapies. Preclinical studies have shown RX-3117 to be effective in both inhibiting the growth of various human cancer xenograft models, including colon, lung, renal and pancreas, as well as overcoming chemotherapeutic drug resistance.

RX-3117 has demonstrated a broad spectrum anti-tumor activity against 50 different human cancer cell lines and efficacy in 12 different mouse xenograft models. The efficacy in the mouse xenograft models was superior to that of gemcitabine. In addition, in human cancer cell lines made resistant to the anti-tumor effects of gemcitabine, RX-3117 still retains its full anti-tumor activity.

In August 2012, Rexahn reported the completion of an exploratory Phase I clinical trial of RX-3117 in cancer patients conducted in Europe, to investigate the oral bioavailability, safety and tolerability of the compound. In this study, oral administration of RX-3117 demonstrated an oral bioavailability of 34-58% and a plasma half-life (T1/2) of 14 hours. In addition, RX-3117 was safe and well tolerated in all subjects throughout the dose range tested.

The Investigational New Drug (IND) application for RX-3117 filed in July 2013 has now cleared the 30 day review period by the US Food and Drug Administration (FDA). Rexahn expects to initiate a Phase I clinical trial in cancer patients during the fourth quarter of 2013. Additionally, Rexahn will be exploring potential partnering opportunities with oncology focused pharmaceutical companies.

About Prof. Dr. Godefridus J. (Frits) Peters
Dr. Peters is head of the Laboratory Medical Oncology of the VU University Medical Center in Amsterdam (the Netherlands). The research of Prof. Peters is focused on translation of preclinical pharmacology of anticancer agents to the clinic. Dr. Peters has published more than 500 peer reviewed articles, review chapters and abstracts in high profile scientific journals. Drug classes studied include antifolates, other antimetabolites, platinum analogs, topoisomerase inhibitors, taxanes and more recently anti-signalling protein kinase inhibitors. He is/was a member of 20 editorial boards, was founder and first president of the Purine and Pyrimidine Society, and is chair of the EORTC-Pharmacology and Molecular Mechanisms Group.

About Rexahn Pharmaceuticals, Inc.
Rexahn Pharmaceuticals is a clinical stage biopharmaceutical company dedicated to developing best-in-class therapeutics for the treatment of cancer. Rexahn currently has three clinical stage oncology candidates, Archexin®, RX-3117, and SupinoxinTM (RX-5902) and a robust pipeline of preclinical compounds to treat multiple types of cancer. Rexahn has also developed proprietary drug discovery platform technologies in the areas of Nano-Polymer-Drug Conjugate Systems (NPDCS), nano-medicines, 3D-GOLD, and TIMES. For more information, please visit http://www.rexahn.com.

Safe Harbor
To the extent any statements made in this press release deal with information that is not historical, these are forward-looking statements under the Private Securities Litigation Reform Act of 1995. Such statements include, but are not limited to, statements about Rexahn’s plans, objectives, expectations and intentions with respect to future operations and products and other statements identified by words such as “will,” “potential,” “could,” “can,” “believe,” “intends,” “continue,” “plans,” “expects,” “anticipates,” “estimates,” “may,” other words of similar meaning or the use of future dates. Forward-looking statements by their nature address matters that are, to different degrees, uncertain. Uncertainties and risks may cause Rexahn’s actual results to be materially different than those expressed in or implied by Rexahn’s forward-looking statements. For Rexahn, particular uncertainties and risks include, among others, the difficulty of developing pharmaceutical products, obtaining regulatory and other approvals and achieving market acceptance; the marketing success of Rexahn’s licensees or sublicensees; the success of clinical testing; and Rexahn’s need for and ability to obtain additional financing. More detailed information on these and additional factors that could affect Rexahn’s actual results are described in Rexahn’s filings with the Securities and Exchange Commission, including its most recent annual report on Form 10-K and subsequent quarterly reports on Form 10-Q. All forward-looking statements in this news release speak only as of the date of this news release. Rexahn undertakes no obligation to update or revise any forward-looking statement, whether as a result of new information, future events or otherwise.

 

Source: Rexahn Pharmaceuticals

FDA approves Roche’s Kadcyla (trastuzumab emtansine), the first antibody-drug conjugate for treating HER2-positive metastatic breast cancer

New personalised medicine helped people in Phase III study live longer, compared to standard treatment

Roche  announced that the U.S. Food and Drug Administration (FDA) has approved Kadcyla (trastuzumab emtansine or T-DM1) for the treatment of people with HER2-positive metastatic breast cancer (mBC) who have received prior treatment with Herceptin (trastuzumab) and a taxane chemotherapy. Kadcyla is the fourth medicine from Roche to receive FDA approval for people with advanced cancers within the past two years.

An antibody-drug conjugate (ADC) is a new kind of targeted cancer medicine that can attach to certain types of cancer cells and deliver chemotherapy directly to them. Kadcyla is the first FDA-approved ADC for treating HER2-positive mBC, an aggressive form of the disease.

“Kadcyla is an antibody-drug conjugate representing a completely new way to treat HER2-positive metastatic breast cancer, and it helped people in the EMILIA study live nearly six months longer,” said Hal Barron, M.D., Roche’s Chief Medical Officer and Head, Global Product Development. “We currently have more than 25 antibody-drug conjugates in our pipeline and hope this promising approach will help us deliver more medicines to fight other cancers in the future.”

Kadcyla is made up of the antibody, trastuzumab, and the chemotherapy, DM1, joined together using a stable linker. Kadcyla combines the mechanisms of action of both trastuzumab and DM1, and it is the first Roche ADC approved by the FDA. Roche has studied ADC science for more than a decade and has eight ADCs in Phase I or Phase II studies for different types of cancer.

Roche has also submitted a Marketing Authorisation Application to other Regulatory Authorities around the world, including the European Medicines Agency (EMA), for Kadcyla for the treatment of people with HER2-positive mBC. This application is currently under review by the EMA.

Kadcyla efficacy in HER2-positive mBC

The FDA approval of Kadcyla is based on results from EMILIA (TDM4370g/BO21977), an international, Phase III, randomised, open-label study comparing Kadcyla alone to lapatinib in combination with Xeloda (capecitabine) in 991 people with HER2-positive locally advanced breast cancer or mBC who had previously been treated with Herceptin and a taxane chemotherapy. Results include:1

  • The study met both co-primary efficacy endpoints of overall survival and progression-free survival (PFS; as assessed by an independent review committee).
  • People who received Kadcyla lived a median of 5.8 months longer (overall survival) than those who received the combination of lapatinib and Xeloda, the standard of care in this setting (median overall survival: 30.9 months vs. 25.1 months).
  • People receiving Kadcyla experienced a 32 percent reduction in the risk of dying compared to people who received lapatinib and Xeloda (HR=0.68; p=0.0006).
  • People who received Kadcyla lived significantly longer without their disease getting worse (PFS) compared to those who received lapatinib plus Xeloda (HR=0.65, 35 percent reduction in the risk of disease worsening or death, p<0.0001; median PFS 9.6 months vs. 6.4 months).
  • No new safety signals were observed and adverse events (AEs) were consistent with those seen in previous studies, with fewer people who received Kadcyla experiencing Grade 3 or higher (severe) AEs than those who received lapatinib plus Xeloda (43.1 percent vs. 59.2 percent).
  • For people receiving Kadcyla, the most common (occurring in more than 2 percent of participants) Grade 3 or higher AEs were low platelet count (14.5 percent), increased levels of enzymes released by the liver and other organs (8.0 percent), low red blood cell count (4.1 percent), low levels of potassium in the blood (2.7percent), nerve problems (2.2percent) and tiredness (2.5percent).

 

Source: Roche 

Roche’s obinutuzumab (GA101) delayed disease progression longer than MabThera/Rituxan in people with one of the most common forms of blood cancer

  • Phase III CLL11 study showed GA101 plus chlorambucil, a chemotherapy, was superior to MabThera/Rituxan plus chlorambucil in helping people with previously untreated chronic lymphocytic leukemia live longer without their disease worsening
  • Final data from the CLL11 study will be submitted to the American Society of Hematology’s 55th Annual Meeting in December 2013

Roche  announced positive results from the phase III CLL11 study. At a pre-planned interim analysis, an independent data monitoring committee determined that the study met its primary endpoint showing that GA101 plus chlorambucil helped people live significantly longer without their disease worsening (progression-free survival; PFS) compared to MabThera/Rituxan plus chlorambucil. The CLL11 study is being conducted in cooperation with the German CLL Study Group (GCLLSG). These final data were reached well ahead of the target completion date in 2014 as a result of the magnitude of difference seen between the two study arms. No new safety signals for GA101 or MabThera/Rituxan were identified in this analysis, and adverse events were similar to those observed in the first stage of the study which was previously reported earlier this year.

“The positive final results from the CLL11 study show the promise that GA101 could hold for people with CLL,” said Hal Barron, M.D., Roche’s Chief Medical Officer and Head, Global Product Development. « It is important to explore the potential of this medicine in other types of blood cancer, and our broad development program includes studies in aggressive and indolent lymphoma that compare GA101with MabThera/Rituxan. »

GA101 is the first type II anti-CD20 medicine that is glycoengineered, which means specific sugar molecules in GA101 were modified to change its interaction with the body’s immune cells.

This modification creates a unique antibody that is designed to act as an immunotherapy, engaging the patient’s own immune system to help attack the cancerous cells; in addition, GA101 binds to CD20 with the aim of inducing direct cell death.

These data will be submitted for consideration to the 55th Annual Meeting of the American Society of Hematology (ASH) in New Orleans, which is taking place December 7-10, 2013.

Based on an earlier analysis (stage 1) of the CLL11 study, marketing applications for GA101 were submitted to regulatory authorities including the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) in April, 2013. Due to the significance of the positive trial results and the serious and life threatening nature of CLL, the FDA granted the GA101 application both Breakthrough Therapy Designation and Priority Review.

 

Source : Roche