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Intrexon, ZIOPHARM and Merck KGaA, Darmstadt, Germany Advancing Next-Generation Non-Viral CAR-T Platform Empowered by Membrane-Bound IL-15 Under RheoSwitch Therapeutic System Control

On April 3, 2017 Intrexon Corporation (NYSE: XON), a leader in the engineering and industrialization of biology to improve the quality of life and health of the planet, ZIOPHARM Oncology (NASDAQ: ZIOP), a biopharmaceutical company focused on new immunotherapies, and Merck KGaA, Darmstadt, Germany, a leading science and technology company, reported an update on the development of next-generation chimeric antigen receptor T cell (CAR-T) therapy for cancer as part of their strategic collaboration and license agreement (Press release, Intrexon, APR 3, 2017, View Source [SID1234518419]).

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Intrexon and ZIOPHARM Oncology, in an exclusive partnership with Merck KGaA, Darmstadt, Germany, are advancing a unique approach to develop therapeutic candidates for two CAR-T targets expressed on a wide range of tumor types, including hematologic malignancies and solid tumors.

The distinctive methodology centers on two technologies: the proprietary RheoSwitch Therapeutic System (RTS) platform to regulate expression of membrane-bound interleukin-15 (mbIL15) co-expressed with CARs and Sleeping Beauty non-viral gene integration.

"Sleeping Beauty and the RTS approach are a powerful combination to improve the manufacturing process and instill control over CAR-modified T cells co-expressing cytokines such as membrane-bound IL-15. The collaboration with Intrexon and Merck KGaA, Darmstadt, Germany, has been a catalyst to progress these next-generation gene therapy technologies. We are excited by the progress and look forward to advancing this innovative approach toward the clinic in mid-2018," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM.

The interleukin-15 (IL-15) cytokine is increasingly recognized as a key driver of therapeutic effect in CAR-T therapy, including in a recent Journal of Clinical Oncology publication which correlated lymphoma remissions with elevated IL-15 levels. Through the RTS gene switch, the expression of mbIL15 can be regulated to help CARs target cancers in a controlled manner, thus providing a new paradigm in T-cell therapy.

Additionally, the non-viral Sleeping Beauty transposon-transposase is an exceptional system for introducing genes encoding CARs and TCRs into T cells that holds multiple advantages over viral-based delivery systems. It simplifies genetic modification, and when coupled with reduced ex vivo processing, offers a pathway to shortened manufacturing and personalized T-cell therapies.

Halozyme’s PEGPH20 Increases Immune Response and Effectiveness of Immunotherapies in Preclinical Cancer Models

On April 3, 2017 Halozyme Therapeutics, Inc. (NASDAQ: HALO), a biotechnology company developing novel oncology and drug-delivery therapies, reported in preclinical models that its investigational drug PEGPH20 increases the number of cancer-fighting white blood cells accumulating in the tumor and the effectiveness of immunotherapies (Press release, Halozyme, APR 3, 2017, View Source [SID1234518418]). The research was presented at the 108th annual meeting of the American Association of Cancer Research (AACR) (Free AACR Whitepaper) and builds upon prior preclinical findings.

"We are encouraged that these findings from our animal models continue to support the potential benefits of remodeling the tumor microenvironment in stimulating an immune response and improving the efficacy of checkpoint inhibitors and cell-based immunotherapies," said Dr. Helen Torley, president and CEO. "We are pleased that PEGPH20 continues to demonstrate significantly improved tumor growth inhibition in certain hard-to-treat hyaluronan-rich cancer models when administered in combination with additional cancer fighting agents."

PEGPH20 is a proprietary enzyme that targets and degrades hyaluronan (HA), a glycosaminoglycan or naturally occurring sugar in the body. HA accumulates in higher concentrations around many solid tumors, potentially constricting blood vessels, impeding the immune response and the access of other therapies.

Research to be presented includes data from a breast cancer mouse model treated with PEGPH20 which showed a significant increase in the accumulation of cancer-fighting CD8+ T cells, also called tumor infiltrating lymphocytes (TILs), compared to mice untreated with PEGPH20. Additional research shows that PEGPH20 administered in combination with an anti-PD-L1 immune checkpoint inhibitor and with Aduro’s Listeria-based vaccine immunotherapy facilitated CD8+ T-cell accumulation and improved effectiveness over what was achieved with either the anti-PD-L1 or Listeria immunotherapy alone.

PEGPH20 increased the anti-PD-L1 effectiveness by 411 percent compared to anti-PD-L1 alone as measured by tumor growth inhibition (93% vs 18.2%, p<0.0001) and increased the accumulation of CD8+ T cells by 176 percent (p=0.0025) in an HA-rich mouse model. Taken together, these data suggest that tumor HA accumulation may act as a barrier to immune cell access and that PEGPH20-mediated HA reduction facilitates increased access of CD8+ T cells.

Halozyme and other researchers are conducting further investigations to determine the potential of combining PEGPH20 with adoptive T cell and other immunotherapies. Halozyme has ongoing clinical studies of PEGPH20 in combination with chemotherapy and immunotherapies, with plans to initiate new studies in a previously announced clinical collaboration with Genentech combining PEGPH20 with atezolizumab, an anti-PD-L1 therapy, in up to eight tumor types.

Halozyme’s AACR (Free AACR Whitepaper) abstracts include:

PEGylated recombinant hyaluronidase PH20 (PEGPH20) enhances tumor infiltrating CD8+ T-cell accumulation and improves checkpoint inhibitor efficacy in murine syngeneic breast cancer models. Abstract 641. Sunday, April 2, 1 to 5 p.m. ET

HTI-1511, a novel anti-EGFR-ADC, overcomes mutation resistance and demonstrates significant activity against multiple tumor types in preclinical studies. Abstract 50. Sunday, April 2, 1 to 5 p.m. ET

Evaluating clinically relevant pharmacological agents in a rat ambulation model to ameliorate PEGylated recombinant hyaluronidase PH20 (PEGPH20)-mediated musculoskeletal adverse events. Abstract 1240. Monday, April 3, 8 a.m. to noon ET

A Phase 1b study of PEGPH20 plus pembrolizumab in patients with selected hyaluronan-high solid tumors. Abstract CT032. Monday, April 3, 8 a.m. to noon ET.

Global phase 3, randomized, double-blind, placebo-controlled study evaluating PEGylated recombinant human hyaluronidase PH20 (PEGPH20) plus nab-paclitaxel and gemcitabine in patients with previously untreated, hyaluronan (HA)-high, stage IV pancreatic ductal adenocarcinoma. Abstract CT066. Monday, April 3, 1 to 5 p.m. ET

Combination of PEGylated recombinant hyaluronidase PH20 (PEGPH20) with Live-attenuated, Double-Deleted (LADD) Listeria enhances tumor infiltrating
CD8+ T cell response and antitumor efficacy in mice. Abstract LB-198. Tuesday, April 4, 8 a.m. to noon ET

PEGylated adenosine deaminase 2 (PEG-ADA2) abrogates the cytoprotective effects of adenosine against chronic lymphocytic leukemia cells. Abstract 5583. Wednesday, April 5, 8 a.m. to noon ET

About PEGPH20

PEGPH20 is an investigational PEGylated form of Halozyme’s proprietary recombinant human hyaluronidase under clinical development for the potential systemic treatment of tumors that accumulate hyaluronan. PEGPH20 is an enzyme that temporarily degrades HA, a dense component of the tumor microenvironment that can accumulate in higher concentrations around certain cancer cells, potentially constricting blood vessels and impeding the access of other therapies. In January, Halozyme announced the positive topline results as of December 2016 of its randomized phase 2 HALO-202 study of PEGPH20 in combination with ABRAXANE (nab-paclitaxel) and gemcitabine chemotherapy in metastatic pancreatic cancer. In the study, PEGPH20 met key endpoints, including in the targeted HA-High patient population.

FDA granted orphan drug designation to PEGPH20 for treatment of pancreas cancer and fast track for PEGPH20 in combination with gemcitabine and nab-paclitaxel for the treatment of metastatic pancreas cancer. Additionally, the European Commission, acting on the recommendation from the Committee for Orphan Medicinal Products of the European Medicines Agency, designated investigational drug PEGPH20 an orphan medicinal product for the treatment of pancreas cancer.

BioCryst Announces Mundipharma Receives Approval for Mundesine® in Japan

On April 3, 2017 BioCryst Pharmaceuticals, Inc. (NASDAQ:BCRX) reported that Mundipharma has obtained regulatory approval of Mundesine (Forodesine hydrochloride) for the treatment of relapsed/refractory PTCL (Peripheral T-Cell Lymphoma) by the Ministry of Health, Labor and Welfare in Japan (Press release, BioCryst Pharmaceuticalsa, APR 3, 2017, View Source [SID1234518417]). Mundesine is a Purine-nucleoside phosphorylase (PNP) inhibitor developed by BioCryst, under an exclusive license with Albert Einstein College of Medicine and Victoria Link Limited. The Ministry’s decision follows successful clinical trials and makes Japan the first country in the world to make Mundesine available for treatment of PTCL.

In 2006, BioCryst entered into an exclusive sub-licensing agreement with Mundipharma for the development and commercialization of forodesine in the field of oncology. This agreement was amended and restated in 2011. As stated in their press release, Mundipharma is working to ensure that patients in Japan receive access to Mundesine as early as possible, which represents another positive step forward, as they strive to deliver more treatment options for cancer patients in Japan. Under the terms of the agreement with Mundipharma, BioCryst will receive tiered royalties ranging from the mid- to high-single digit percentages of net sales of Mundesine.

About Forodesine

Forodesine hydrocloride is an orally-available transition-state analog inhibitor of purine nucleoside phosphorylase (PNP), a purine salvage pathway enzyme that is essential for the proliferation of T-cells and B-cells. Typically, T-cells and B-cells are an essential part of the body’s immune system, but when they multiply uncontrollably they can cause various forms of cancer. Inhibiting PNP produces selective suppression of T-cells and B-cells, inducing apoptosis in both types of cells.

AVEO Announces Milestone Payment from CANbridge for AV-203

On April 3, 2017 AVEO Oncology (NASDAQ:AVEO) reported receipt of a $500,000 milestone payment from CANbridge Life Sciences Ltd., a biopharmaceutical company focused on developing western drug candidates in China and North Asia, related to a technology transfer milestone for AV-203, AVEO’s clinical-stage ErbB3 (HER3) inhibitory antibody candidate (Press release, AVEO, APR 3, 2017, View Source [SID1234518416]). AV-203 has demonstrated preclinical activity in a number of different tumor models including breast, head and neck, lung, ovarian and pancreatic cancers. CANbridge is planning clinical development of AV-203 in squamous cell esophageal cancer as its initial indication.

"Receipt of this milestone payment from CANbridge reflects continued progress by our partner to engineer the manufacturing process for AV-203 in an effort to develop an antibody manufacturing process suitable for commercialization," said Michael Bailey, president and chief executive officer of AVEO. "We look forward to continued progress in this program, and with the balance of our partnered pipeline, including AV-380, a potentially disease modifying treatment for cachexia which is partnered with Novartis, and ficlatuzumab in development for squamous cell carcinoma of the head and neck and acute myeloid leukemia, which is partnered with Biodesix. With these programs advancing, we continue to focus on tivozanib, including continuing our execution of the TIVO-3 and TiNivo studies for our U.S. pivotal clinical strategy, and support of our licensee, EUSA Pharma, in its response to European regulators."

In March 2016, AVEO announced an exclusive collaboration and license agreement, granting CANbridge worldwide rights to AV-203, excluding the United States, Canada, and Mexico. Under the terms of the collaboration and license agreement, CANbridge paid AVEO an upfront payment of $1 million, and AVEO is also eligible to receive up to $133 million in reimbursement and milestone payments, assuming the successful achievement of specified development, regulatory and commercialization objectives. The transaction was awarded the 2016 Deal of the Year by RNDer, a leading Chinese publication providing value-added analysis for pharmaceutical and biotechnology companies conducting business in China. AVEO has retained North American rights to AV-203 and is also eligible for a tiered royalty, with a percentage range in the low double digits, on net sales of AV-203 in the partnered territories.

AVEO also announced today an update to its financial guidance. The Company believes its recently completed underwritten public offering, which yielded net proceeds of $15.5 million (on gross proceeds of $17.3 million), together with its existing cash resources, would be sufficient to fund its operations into the second quarter of 2018. This guidance excludes any potential partnership milestone payments to or from the Company, potential debt or equity financings, acceleration of existing debt principal payments under the term loan with Hercules which could result from non-compliance with the cash covenant of that agreement, or proceeds from any potential future partnership agreements.

As previously guided, top line data from the TIVO-3 trial, AVEO’s ongoing Phase 3 clinical trial of tivozanib in the third-line treatment of patients with refractory renal cell carcinoma (RCC), is anticipated in the first quarter of 2018.

Novartis drug combination Tafinlar® + Mekinist® receives EU approval for BRAF V600-positive advanced non-small cell lung cancer (NSCLC)

On April 3, 2017 Novartis reported the European Commission has approved Tafinlar (dabrafenib) in combination with Mekinist (trametinib) for the treatment of patients with BRAF V600-positive advanced or metastatic non-small cell lung cancer (NSCLC) (Press release, Novartis, APR 3, 2017, View Source [SID1234518400]). The approval marks the first targeted treatment approved for the patient population, who previously had few treatment options, in all 28 member states of the European Union (EU), plus Iceland and Norway. Every year, it is estimated, up to about 36,000 people, or about 1-3% of patients with lung cancer, are diagnosed with BRAF V600-positive NSCLC worldwide[2],[3].

"Today’s approval represents an important milestone for the lung cancer community, especially those patients living with the BRAF V600 mutation who previously had few options," said Bruno Strigini, CEO, Novartis Oncology. "At Novartis we are committed to bringing meaningful scientific advances that fill critical unmet needs to patients."

Today’s EU approval follows a positive opinion granted in February by the Committee for Medicinal Products for Human Use (CHMP), which was based on safety and efficacy of dabrafenib in combination with trametinib in a Phase II, three-cohort, multicenter, non-randomised and open-label study in which patients with stage IV BRAF V600E mutant NSCLC were enrolled (36 treatment-naïve [previously untreated] and 57 previously treated with chemotherapy).

For the primary endpoint of investigator-assessed overall response rate (ORR), 36 treatment-naïve patients receiving 150 mg of Tafinlar twice daily and 2 mg of Mekinist once daily demonstrated an ORR of 61.1% (95% confidence interval [CI]: 43.5%, 76.9%)[1]. In this population, 68% of patients had not progressed after 9 months[1]. The median duration of response (DoR) and progression free survival (PFS) in the previously untreated population were not yet reached at the time of approval[1]. In the previously treated population receiving the same dosage, patients demonstrated an ORR of 66.7% (95% CI: 52.9%, 78.6%)[1]. The response was durable with a median DoR reaching 9.8 months (95% CI: 6.9, 16.0)[1]. An in-depth analysis of data from the treatment-naïve cohort will be presented at an upcoming medical meeting.

The most common adverse events (incidence >20%) were pyrexia, nausea, vomiting, peripheral edema, diarrhea, dry skin, decreased appetite, asthenia, chills, cough, fatigue, rash, and dyspnoea[1].

The US Food and Drug Administration (FDA) granted Tafinlar + Mekinist Breakthrough Therapy designation for advanced or metastatic BRAF V600E-positive NSCLC patients in 2015 and Priority Review in November 2016. Combination use of Tafinlar + Mekinist is also approved in the US, Europe, Australia, Canada, and additional countries for patients with unresectable or metastatic melanoma whose tumors tested positive for the BRAF V600 mutation.

Novartis Commitment to Lung Cancer
Worldwide, lung cancer causes more deaths than colon, breast, and prostate cancer combined, and an estimated 1.8 million new cases of lung cancer are diagnosed each year[2], [4]. Among patients with NSCLC, roughly 30% have an actionable mutation that may be targeted with available therapies[5], [6], [7], [8]. To determine that treatment, medical organizations recommend biomarker testing for patients with lung cancer[9].

Novartis Oncology’s research into targeted therapies has helped transform treatment approaches for patients living with mutation-driven types of lung cancer. Patients with mutation-driven NSCLC may be candidates for treatment with targeted therapies[5].

Novartis continues its commitment to the global lung cancer community through ongoing studies, as well as the exploration of investigational compounds that target genetic biomarkers in NSCLC.

IMPORTANT SAFETY INFORMATION (ISI)
About Tafinlar + Mekinist Combination
Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the US, EU, Australia, Canada, and additional countries. The combination of Tafinlar and Mekinist is also approved for the treatment of advanced non-small cell lung cancer with a BRAF V600 mutation in Europe.

Tafinlar and Mekinist target different kinases within the serine/threonine kinase family – BRAF and MEK1/2, respectively – in the RAS/RAF/MEK/ERK pathway, which is implicated in non-small cell lung cancer (NSCLC) and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.

The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside of the approved indications.

Tafinlar and Mekinist are also indicated in more than 40 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Tafinlar + Mekinist Combination Important Safety Information
Tafinlar + Mekinist combination may cause serious side effects.

Tafinlar in combination with Mekinist should only be used to treat patients with a change (mutation) in the BRAF gene; therefore, doctors should test their patients before treatment, as patients without a BRAF mutation and with a RAS mutation can be at risk of increased cell proliferation in the presence of a BRAF inhibitor.

Doctors should also consider other treatment options for their patients if they had been previously treated with a BRAF inhibitor as single agent, as the limited data available have shown that the efficacy of Tafinlar + Mekinist is lower in these patients.

When Tafinlar is used in combination with Mekinist, or when Tafinlar is administered as monotherapy, it can cause new cancers (both skin cancer and non-skin cancer). Patients should be advised to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or signs and symptoms of other malignancies.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause severe bleeding, and in some cases can lead to death. Patients should be advised to call their healthcare provider and get medical help right away if they have headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like "coffee grounds," have red or black stools that look like tar, or any unusual signs of bleeding.

Tafinlar in combination with Mekinist, or either drug alone, can cause severe eye problems that can lead to blindness. Patients should be advised to call their healthcare provider right away if they get these symptoms of eye problems: blurred vision, loss of vision, or other vision changes, seeing color dots, halo (seeing blurred outline around objects), eye pain, swelling, or redness.

Tafinlar in combination with Mekinist, or Tafinlar alone, can cause fever, which may be serious. When taking Tafinlar in combination with Mekinist, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Patients should be advised to call their healthcare provider right away if they get a fever above 38.5oC (101.3oF) while taking Tafinlar.

Tafinlar in combination with Mekinist, or Mekinist alone, can affect how well the heart pumps blood. A patient’s heart function should be checked before and during treatment. Patients should be advised to call their healthcare provider right away if they have any of the following signs and symptoms of a heart problem: feeling like their heart is pounding or racing, shortness of breath, swelling of their ankles and feet, or feeling lightheaded.

Tafinlar in combination with Mekinist, or Tafinlar alone, can cause abnormal kidney function or inflammation of the kidney. Abnormal kidney function may happen more often for patients with fever or too much fluid loss. Patients should be advised to call their healthcare provider right away if they have a fever above 38.5oC (101.3oF), decreased urine, fatigue, loss of appetite, or discomfort in lower abdomen or back. Tafinlar has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN), therefore caution should be used in this setting.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause abnormal liver function. A patient may feel tired, lose appetite, yellow skin, dark urine colour, or discomfort in abdomen. The liver function abnormality needs to be assessed by laboratory test of the blood. Patients should consult their healthcare provider if they have such experience. Administration of Tafinlar or Mekinist should be done with caution in patients with moderate to severe hepatic impairment.

Elevations in blood pressure have been reported in association with Mekinist in combination with Tafinlar, or with Mekinist alone, in patients with or without pre-existing hypertension. Patients should be advised to monitor blood pressure during treatment with Mekinist and control potential hypertension by standard therapy, as appropriate.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause inflammation of the lung tissue. Patients should notify their doctor if they experience any new or worsening symptoms of lung or breathing problems, including shortness of breath or cough.

Rash is a common side effect of Tafinlar in combination with Mekinist, or with Mekinist alone. Tafinlar in combination with Mekinist, or Mekinist alone, can also cause other skin reactions, which can be severe, and may need to be treated in a hospital. Patients should be advised to call their healthcare provider if they get any of the following symptoms: skin rash that bothers them or does not go away, acne, redness, swelling, peeling, or tenderness of hands or feet, skin redness.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause muscle breakdown, a condition called Rhabdomyolysis. Patients experiencing muscle pain, tenderness, weakness, or a swelling of their muscles should contact their healthcare provide immediately.

Tafinlar in combination with Mekinist, or Tafinlar alone, can uncommonly cause an inflammation of the pancreas (pancreatitis). Patients should be promptly investigated if they experience unexplained abdominal pain and closely monitored if they re-start Tafinlar after a prior episode of pancreatitis.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause blood clots in the arms or legs, which can travel to the lungs and can lead to death. Patients should be advised to get medical help right away if they have the following symptoms: chest pain, sudden shortness of breath or trouble breathing, pain in their legs with or without swelling, swelling in their arms or legs, or a cool or pale arm or leg.

Mekinist in combination with Tafinlar, or Mekinist alone, may increase the risk of developing holes in the stomach or intestine (gastrointestinal perforation). Treatment with Mekinist alone or in combination with Tafinlar should be used with caution in patients with risk factors for gastrointestinal perforation, including concomitant use of medications with a recognized risk of gastrointestinal perforation.

Tafinlar and Mekinist both can cause harm to an unborn baby when taken by a pregnant woman. Tafinlar can also render hormonal contraceptives ineffective.

The most common side effects of Tafinlar + Mekinist combination include fever, nausea, diarrhea, fatigue, chills, headache, vomiting, joint pain, high blood pressure, rash, and cough. The incidence and severity of fever is increased when Mekinist is used in combination with Tafinlar.

Patients should tell their doctor of any side effect that bothers them or does not go away. These are not all of the possible side effects of Tafinlar + Mekinist combination. For more information, patients should ask their doctor or pharmacist.

Patients should take Tafinlar + Mekinist combination exactly as their health care provider tells them. Patients should not change their dose or stop taking Tafinlar + Mekinist combination unless their health care provider advises them to. Mekinist should be taken only once daily (either in the morning or evening, at the same time as Tafinlar). The first and second doses of Tafinlar should be taken approximately 12 hours apart. Patients should take Tafinlar + Mekinist at least 1 hour before or 2 hours after a meal. Do not take a missed dose of Tafinlar within 6 hours of the next dose of Tafinlar. Do not open, crush, or break Tafinlar capsules. Do not take a missed dose of Mekinist within 12 hours of the next dose of Mekinist.