Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation,   jcm@btobioinnovation.com

Zika virus

US Health officials said 279 pregnant women in the US and its territories have tested positive for Zika infection.

Acquisitions /mergers/joint-ventures

Sanofi, still very aggressive in acquiring Medivation, has now put forward a list of 8 candidates to replace the entire current Medivation board in a move it had “no choice” but to make, given its rejection of Sanofi’s $9.3 billion offer and refusal to come to the bargaining table. “There have been published reports that you have signed confidentiality agreements with other parties. If that is accurate, we cannot see how you have not done so with us,” Sanofi CEO Brandicourt wrote in a letter to Medivation’s board. According to Bloomberg Celgene and Gilead have joined a list of rumored suitors including AstraZeneca, Novartis and Pfizer.

Arbor Pharmaceuticals (Atlanta, GA, USA) acquires XenoPort (Santa Clara, CA, USA) for $467 million, a 60% premium over last Friday’s closing price. Xenoport’s marketed portfolio consists mainly of  Horizant^® (gabapentin enacarbil), indicated for moderate-to-severe primary restless legs syndrome and postherpetic neuralgia, and Regnite^®(gabapentin enacarbil) extended-release tablets, which have been approved in Japan and also indicated for moderate-to-severe primary restless legs syndrome.

Bayer has confirmed its offer to acquire Monsanto in an all cash bid that values the company at $62 billion. Monsanto rejected the offer as too low but said it remained open to further deal discussions.

Business

PDI Therapeutics (La Jolla, CA, USA), a cancer immunotherapy company, has been launched by Avalon Ventures as part of an extended partnership with GlaxoSmithKline. PDI Therapeutics is developing antibodies that inhibit protein disulfide isomerases (PDIs) to treat cancer. Overexpression of PDI can allow tumor cells to evade a patient's immune system, PDI inhibition can permit natural killer or T cells to identify and destroy the tumor cells. PDI Therapeutics is the eight company launched through the Avalon alliance with GSK and is eligible for a combined $10 million in series A funding from Avalon and R&D support from GSK.

PDL Biopharma (Incline Village, Nev, USA) acquires rights to two Novartis’ anti-hypertensive drugs, Tekturna or aliskiren and Tekturna HCT, or aliskiren and hydrochlorothiazide, in the US for up to 214 million.

Wuxi NextCODE (Shanghai, China) has joined Huawei (Shenzhen, China), a Chinese telecom provider, to launch an offering named the China Precision Medicine. Nature said Chinese officials plan to spend more than $9 billion on precision medicine efforts over the course of 15 years, compared to about $215 million for the US multiyear effort.

Japanese leading pharmaceuticals, Astellas Pharma, Kyowa Hakko Kirin, Daiichi Sankyo, Eisai, Ono Pharmaceutical and Chugai Pharmaceutical enter a collaboration with the National Cancer Center, the National Center for Global Health and Medicine, and the Agency for Medical Research and Development to provide cell and tissue samples in a program focused on new therapies on cancer, diabetic nephropathy and mental illnesses, by forming 5 working groups. Japan's Prime Minister Shinzo Abe has pushed for greater cooperation between the country's research network and drug and device companies, with the setup of the Agency for Medical Research and Development in 2015. Earlier this month, Astellas Pharma, Daiichi Sankyo and Takeda Pharmaceutical also said they would work together on a biomarker database of healthy patients that could be used in clinical studies and shared with in-house and outside researchers.

Approval of drugs and vaccines

The European Commission approves:

GlaxoSmithKline’s Strimvelis, an ex-vivo stem cell gene therapy for the treatment of an ultra-rare disorder called Severe Combined Immunodeficiency due to Adenosine Deaminase (ADA) deficiency which affects about 15 children in Europe each year. Strimvelis is administered once and does not rely on a third party donor. The patient's own bone marrow cells are removed and a vector is used to insert a normal copy of the ADA gene into the cells, which are then reintroduced into the patient via intravenous infusion.  Strimvelis, developed by GlaxoSmithKline and Italian firms Fondazioine Telethon and Ospedale San Raffaele, is the first corrective gene therapy for children to gain regulatory clearance anywhere in the world. It is the second gene therapy approved in Europe, following uniQure's Glybera (alipogene tiparvovec), approved in November 2012 for the treatment of lipoprotein lipase deficiency.

…and gives conditional approval to Janssen’s Darzalex, or daratumumab, a CD38 directed monoclonal antibody, as a treatment for relapsed or refractory multiple myeoloma patients who experience disease progression. Janssen must now provide results from two Phase 3 studies of Darzalex used in combination with standard treatments for the disease (lenalidomide/dexamethasone and bortezomib/dexamethasone) for regulators to consider a full approval.

US FDA approves Sequirus’ (Holly Spring, NC, USA) Flucel Vax Quadrivalent, as the first four-strain, cell-culture derived, inactivated seasonal influenza vaccine for patients at least four years old. The traditional flu vaccines are trivalent, consisting of two influenza A viruses and one influenza B strain, although Sanofi's quadrivalent flu vaccine was approved by the FDA in December 2014 for use in adults

…and CSL Behring’s (King of Prussia, PA, USA) AFSTYLA, a long-acting recombinant factor VIII single-chain therapy, for the treatment of adults and children with hemophilia A.

US FDA rejects AstraZeneca’s ZS-9, or sodium zirconium cyslosilicate for the treatment of hyperkalemia. In the Complete Response Letter (CRL) the FDA refers to observations from a pre-approval on site manufacturing inspection as well as the receipt of recently submitted data which it has yet to review. The CRL does not require the generation of new clinical data. AstraZeneca had acquired the rights to ZS-9 through its $2.7 billion acquisition of ZS Pharma in December 2015.

European regulators have removed the black warning from the label of Pfizer's smoking cessation drug Champix, or varenicline, and buprion, on the back of data from a post-marketing surveillance study backing its neuropsychiatric safety

Drugs at clinical stage

The US FDA’s Endocrinologic and Metabolic Drugs Advisory Committee has recommended Novo’s IDegLira (voting 16 to 0), a fixed combination of Degludec and Liraglutide, as well as Sanofi’s iGlarLixi (voting 12 to 2) a fixed combination of Lantus and Lixisenatide for approval for glycemic control in type 2 diabetes. Both combination are pairing basal insulins with GLP-1 drugs which could provide diabetics with better way to control blood sugar while reducing some of the complication associated with insulin use.  Both drugs could be approved sometime in August but may face marketing challenges with payers being rather reluctant to give fixed combination a favorable spot on recent formularies. Launches are now predicted to be rather slow.

US FDA grants breakthrough status to Celator Pharmaceuticals’ (Ewing, NJ, USA) Vyxeos nano-powered blood cancer therapy for the treatment of adults with acute myeloid leukemia. Vyexos also known as CPX-351, is a 5:1 formulation of the standard cancer treatments cytarabine and daunorubicin, packaged in a nano-scale delivery platform that boost efficacy while limiting the risks of administering each drug on its own.

US FDA grants fast-track status:

to Edge Therapeutics (Berkeley Heights, NJ,USA), EG-1962, a nimodipine microparticle formulation for the treatment of subarachnoid hemorrhage.

…and to Novavax’s (Gaithersburg, MD, USA) RSV F-Protein nanoparticle vaccine candidate to protect older population against a respiratory infection known as Respiratory Syncytial Virus (RSV).

US FDA grants orphan status to Anavex Life Science’s (New York City, NY, USA) ANAVEX 2-73 as a treatment for Rett syndrome, a rare non-inherited genetic postnatal progressive neurodevelopmental disorder that occurs almost exclusively in girls and leads to severe impairments. The Rett syndrome is caused by mutations in the MECP2 gene which strikes all racial and ethnic groups and occurs worldwide in approximately 1 in every 10,000-15,000 live female births. The hallmark of Rett syndrome is near constant repetitive hand movements while awake. It is characterized by normal early growth and development up to 18 months, followed by a slowing of development, loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, problems with walking, seizures and intellectual disability.

AstraZeneca reports a phase 3 clinical trial showing Faslodex or fulvetrant to be superior to Aridex or anastrozole in extending progression-free survival in postmenopausal women with hormone receptor positive breast cancer who had not had prior hormonal treatment.

Medical Devices and Diagnosis News

US FDA approves Titan Pharmaceuticals (South San Francisco, CA, USA) and Braeburn Pharmaceuticals’ (Princeton,NJ, USA) Probuphine, the first buprenorphine implant to help treat people addicted to opioids, painkillers and heroin. Probuphine is a subdermal implant, which continuously delivers a low-level dose of buprenorphine for up to six months. Until now, buprenorphine for the treatment of opioid dependence was only approved as a pill or a film placed under the tongue or on the inside of a person's cheek until it dissolved.

US FDA advisory panel recommended St Jude’s (Saint Paul, Minn, USA) Amplatzer PFO Occluder for the prevention of stroke. St. Jude's device helps prevent recurring ischemic strokes in individuals who have had at least one other unexplained stroke and who have a hole between the upper chambers of their heart, or a patent foramen ovale (PFO). PFO-closure devices also represent "one of the most controversial areas of cardiovascular devices/medicine, with strong proponents and equally strong critics," St Jude picked up its stroke prevention device through the $1.3 billion acquisition of AGA Medical back in 2010. St. Jude finished out a study of Amplatzer that lasted 13 years and it took 8 years to enroll 980 patients, who were followed for about 5 years each.

Senseonics (Germantown, MD, USA) has signed an exclusive distribution agreement with Roche Diagnostics to commercialize its Eversense Continous Glucose Monitoring System, a tiny glucose monitor implant, which feeds data to a smartphone app via a small transmitter patch, in Germany, Italy and the Netherlands, a few days after it received its CE mark. Under the terms of the deal, Roche receives exclusive right to sell Eversense in the specified European countries with an option to expand upon in the future with additional products and territories.

Patients suffering from acute coronary syndromes who are high risks for bleeding during angioplasty exhibit fewer complications when a drug-coated stent is used versus a bare metal stent. Previous studies indicated that at least one in six patients undergoing angioplasty to treat narrowed coronary arteries of the heart were at a high risk of bleeding. Those patients are typically treated with bare-metal stents in conjunction with one month of dual antiplatelet therapy to reduce the risk of bleeding. “The most important take-home message is that using a drug-coated stent plus one month of dual antiplatelet therapy not only improves the efficacy of PCI (angioplasty) in patients with acute coronary syndromes and high risk of bleeding compared to use of bare metal stent, but also increases safety with less cardiac death, myocardial infarction and stent thrombosis,” Dr. Christoph Naber, lead author, told News Medical. “Current guidelines may need to be revised and bare metal stents can no longer be recommended for these patients.”

Science and Technology

A study performed at the Harvard University (Cambridge, MA, USA) and at the Massachusetts General Hospital (Boston, MA, USA) suggest that blood-brain barrier weakens with age and that amyloid-β (Aβ) peptide may not be the “bad boy” in Alzheimer’s disease (AD). In the work published in Science Translational Medicine, the scientists led by Professors Kumar and Tanzi show that Aβ is a natural antibiotic that protects the brain from infection and thatAβ aggregates trap and imprison bacterial pathogens.

Abstract

“We previously reported in vitro evidence suggesting that Aβ is an antimicrobial peptide. We present in vivo data showing that Aβ expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD. We show that Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide. Collectively, our data are consistent with a model in which soluble Aβ oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating β-amyloid fibrils mediate agglutination and eventual entrapment of unatttached microbes. Consistent with our model, bacterial infection of the brains of transgenic 5XFAD mice resulted in rapid seeding and accelerated β-amyloid deposition, which closely colocalized with the invading bacteria. Our findings raise the intriguing possibility that β-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for Aβ, as has been described for other antimicrobial peptides and these findings identify inflammatory pathways as potential new drug targets for treating AD.

A recent study led by José Stoute at Pennsylvania State College of Medicine and published in EBioMedicine shows that Plasmodium falciparum, the most deadly malaria parasite, uses several mechanisms to evade the human immune system and invade red blood cells in using the complement arm to do so. The complement system is made up of proteins that complement antibodies that fight infections. In a successful immune response, the production of antibodies against a pathogen trigger complement proteins. But in the case of malaria infection, the parasite hijacks the immune system as it has been demonstrated in other infectious diseases, such as dengue virus.

Automotive Toyota Motor teams up with DEKA (Dean Kamen, the inventor of the Segway), to create a next-generation wheelchair for disabled and elderly people. Toyota will help DEKA launch its iBOT motorized wheelchair. The chair includes two sets of powered wheels that rotate to allow the user to "walk" up and down stairs, and also a "standing" configuration that helps people rise from sitting level to 6 feet in height.

Cost, Pricing and Market Access

UK National Institute for Health and care Excellence recommends:

the use of three drugs for the treatment of patients with type 2 diabetes who are ineligible for metformin, namely AstraZeneca’s Forxiga, or dapagliflozin, Boehringer Ingelheim’s Jardiance, or empagliflozin and Janssen and Eli Lilly’s Invokana or canagliflozin. The three drugs were considering cost effective compared with DPP-4 inhibitors with incremental cost effectiveness ratio (ICERs) of less than £29,300 per quality-adjusted life year (QALY) gained.

the use of Novartis’ Zykadia, or ceritinib, for the treatment of advanced anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) in adults who have previously been treated with Pfizer’s Xalkori or crizotinib. The NHS list price of Zykadia is £4,923 for a 30-day supply, and NICE's Committee concluded that the most plausible incremental cost effectiveness ratio (ICER) was likely to be lower than £50,000 per QALY gained when including the discount.

….and turns down Eli Lilly’s Portrazza or necitumumab, for the treatment of locally advanced or metastatic epidermal growth factor receptor (EGRF) expressing squamous non-small-cell lung cancer that had not been treated with chemotherapy. NICE concluded that the most plausible ICERfor the Portrazza, compared with gemcitabine plus cisplatin was £110,000-£170,000 per QALY gained was likely to be towards the upper end of this range, and thus far outside the realm of what is normally considered value for money.

Guidelines by the European Society of Cardiology, the American College of Cardiology, the American Heart Association and the Heart Failure Society of America recommend that “in patients with chronic symptomatic heart failure with reduced ejection fraction NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by Entresto is recommended to further reduce morbidity and mortality.”

Miscellaneous

Eli Lilly says it has the potential to launch 20 new products in the period 2014-2023 and expects an average of two new indications for already approved drugs.

China CFDA may see a massive brain drain of skilfull people to move to companies of the private sector according to a former CFDA official. The source was quoted as saying the pay gap between public service levels of around RMB120,000 ($18,320) annually and the private sector at RMB600,000 ($91,520), provided incentive to leave.

Management changes at:

Gilead Sciences where John Milligan, the incoming CEO, has recalled the former head of commercial operations, Kevin Young, from retirement, to serve as chief operating officer, sees Paul Carter, who has been in the job for only two years, leave and names Martin Silverstein, a former executive at Anthem and former consultant at Boston Consulting Group, as executive vice president of strategy to oversee Gilead’s corporate development, commercial planning and alliance management functions.

… and Sanofi. A few months after the unveiling of its “strategic roadmap 2020”, Olivier Brandicourt is shaking up its executive management team. Pascal Witz, who has been running the diabetes and cardiovascular business since 2015, is leaving and is being replaced by Peter Guenter. Olivier Charmeil, who was in charge of Sanofi Pasteur takes Guenter’s position to run the General Medicines and Emerging Market and is replaced by David Loew, who is promoted to the Executive Committee. Carsten Hellman, General Manager of Merial, has accepted the position of President and CEO of ALK, but will stay with Sanofi until the end of the year to support the transfer of Merial to Boehringer Ingelheim. Suresh Kumar, EVP of External Affairs, has decided to return to the United States for personal reasons. A new Executive Vice President to run the Consumer Healthcare Business will be appointed soon.

Bioevents

4^th Annual IBA World Life Sciences Conference on June 3-4 in San Francisco (USA)

ASCO Annual Meeting on June 3-6 in Chicago (USA)

BIO International Convention on June 6-9 in San Francisco (USA)

APinnov on June 14 in Paris (France)

BIO Pharm America on September 13-15 in Boston (USA)

7^th Innovation Days on October 3-4 in Paris (France)

BIO Europe on November 7-9 in Cologne (Germany)

BIO Latam on November 29-30 in San Juan (Puerto Rico)

Biofit 2016 on November 30-December 1 in Lille (France)

IMPORTANT NOTICE

This document has been prepared by btobioinnovation and is provided to you for information purposes only.  The information contained in this document has been obtained from sources that btobioinnovation believes are reliable but btobioinnovation does not warrant that it is accurate or complete. The views presented in this document are those of btobioinnovation’s editor at the time of writing and are subject to change.  btobioinnovation has no obligation to update its opinions or the information in this document.

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