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

Highlights from the AACR (Washington DC, April 1-5)

New Immunotherapy Combination Shows Promise for Patients With Advanced Melanoma Treatment with a combination of ipilimumab (Yervoy) and Coxsackievirus A21 (CVA21; Cavatak), a bioselected, nongenetically altered common cold RNA virus, led to durable responses in a number of patients with advanced melanoma, including some whose melanoma had progressed despite prior treatment with an immune checkpoint inhibitor, and fewer than anticipated adverse events,  “In recent years, the number of treatment options for patients with advanced melanoma has increased with the development of immune checkpoint inhibitors such as ipilimumab,” said Brendan D. Curti, MD,  director of the Clinical Biotherapy Program and codirector of the Melanoma Program at the Earle A. Chiles Research Institute of Providence Cancer Center  in Portland, Oregon (USA).

Adding the investigational immunotherapy indoximod, a selective indoleamine 2,3-dioxygenase (IDO1) inhibitor to pembrolizumab (Keytruda) increased the proportion of patients with advanced melanoma who responded to treatment compared with previously reported response rates for pembrolizumab monotherapy, according to interim results from an early clinical trial.  “We set out to investigate whether we could improve upon this response rate by adding an inhibitor of the IDO pathway to pembrolizumab “We are excited to share interim results from the phase II portion of this clinical trial, because the data show that 52 percent of patients treated with a combination of pembrolizumab and the IDO-pathway inhibitor indoximod had a partial or complete response without significant added toxicities,” said Yousef N. Zakharia, MD, assistant professor in the Department of Internal Medicine at the University of Iowa, Iowa City (USA). When given alone pembrozilumab gave a 33% overall response in a similar setting.

Whole-genome sequencing conducted on a large cohort of 3,007 childhood cancer patients who had survived for five years or longer, indicated that many survivors harbor mutations in cancer predisposition genes, significantly increasing their risk of developing a subsequent neoplasm (SN) later in life. Overall, 25.5 percent of the survivors developed a SN by age 45, most commonly non-melanoma skin cancer, meningioma, thyroid, and breast cancer.The results showed that 12 percent of the survivors had a pathogenic or likely pathogenic mutation in one of 156 genes associated with an increased risk of cancer. The most common mutations were in the genes of RB1, NF1, BRCA2, BRCA1, and TP53.

An associated lower risk of cancer, particular colorectal cancer, under regular aspirin use had been suspected for many years. A study performed by Yin Cao, an instructor in Medicine ant the Clinical and Translational Epidemiology Unit at Massachusetts General Hospital and Harvard Medical School further examined the role of aspirin in overall and cancer-specific mortality. The researchers studied 86,206 women between 1980 and 2012, and 43,977 men y from 1986 to 2012.The study findings showed that over the 32 years of follow-up time, 22,094 women and 14,749 men died. Of them, 8,271 women and 4,591 men died of cancer. Compared with non-regular aspirin use, overall mortality risk was 7 % lower for women and 11% lower for men who regularly used aspirin. Cancer mortality risk was 7% lower for women and 15% lower for men who regularly used aspirin. The researchers observed benefits at dosages ranging from 0.5 standard aspirin tablets per week to seven aspirin tablets per week. The strongest reduction in relative risk was for colorectal cancer—31% for women and 30% for men who regularly took aspirin. Women who took aspirin had an 11% lower risk of dying of breast cancer, and men who took aspirin had a 23% risk of dying of prostate cancer. 

Shorter sleep duration was associated with increased risk of death from prostate cancer in men under the age of 65 according to a retrospective study including two large, long-term cohort studies of the American Cancer Society. In all, the analysis included 407,649 men from the Cancer Prevention Study-I (CPS-I)  followed from 1950 through 1972, and 416,040 men from the Cancer Prevention Study-II (CPS-II), followed from 1982 through 2012.

Mergers, Acquisitions and Joint Ventures

Astellas Pharmaca (Tokyo, Japan) acquires Ogeda (Gosselies, Belgium), for about $860 million, and gets access to fezolinetant, or ESN36, as a treatment for menopause-related symptoms, also known as hot flashes. The drug which directly tar­gets the tachykinin NK3 re­cep­tor is act­ing on “spe­cific neu­rons that con­trol body tem­per­a­ture to mimic the ef­fects of es­tro­gen, but in a non-hor­monal man­ner, to di­rectly and safely ad­dress the basis for HF in menopausal women.” In a phase 2b study, ESN36 has shown a 93% reduction in hot flashes versus 54% in the placebo group. Under the terms of the deal, Astellas will make a upfront payment of € 500 million and milestone fees of up to €300 million more.

Sucampo (Gaithesburg, MD, USA) acquires Vtesse (Rockville, MD, USA), a rare disease company in a $200 million buyout and gets access to VTS-270, as a treatment for malfunction of lipid transport.

Business

Calypso Biotech (Geneva, Switzerland) a spinoff of Merck KGaA, licenses CALY-001, an anti-MMP-9 monoclonal antibody as a treatment of inflammatory bowel disease to EA Pharma, a 60-40 joint venture between Eisai and Ajinomoto. Under the terms of the deal EA will make an undisclosed upfront payment as well as development and regulatory milestones and pay royalties on sales.

Eisai (Tokyo, Japan) has been granted an exclusive license to safinamide, a treatment for Parkinson’s disease, from Meiji Seika Pharma (Tokyo, Japan) in Japan, the Philippines, South Korea, Taiwan and several other Asian Countries. Financial terms of the deal were not disclosed. The drug was approved by the European Commission in February 2015 as add-on therapy to levodopa alone or in combination with other Parkinson’s disease drugs. Swiss approval followed in November 2015.

Novartis exercises its opt in to license Lubris Biopharma’s (Boston, MA, USA) EFC843, a recombinant human lubricin, for ophthalmic indications including dry eye. Financial terms were not disclosed.

Approval of drugs and vaccines

The European Commission approves Novartis’ the combination of Tafinlar, or dabranefib and Mekinist, or trametinib, as a treatment for the treatment of patients with BRAF V600-positive advanced/metastatic non-small lung cancer (NSCLC). The combination was first approved in the EU in September 2015 for BRAF V600-positive melanoma.

The US FDA approves Teva’s Austedo, or deutetetabenzanine as a treatment for Huntington chorea, the first approved deuterated drug in the world. Teva got access to the drug through the acquisition of Auspex in 2015 for $3.5 billion. “Chorea is a major symp­tom for many liv­ing with Hunt­ing­ton dis­ease. It im­pacts pa­tients’ func­tion­al­ity and ac­tiv­i­ties of daily liv­ing, and there have been lim­ited treat­ment op­tions for these pa­tients,” said Michael Hay­den, the CSO at Teva. “

The US FDA rejects Merck’s application to add cardiovascular outcomes to Januvia, a DDP-4 inhibitor, approved as a treatment for type 2 diabetes in a complete response letter

According to an analysis published in the New England Journal of Medicine, the US FDA has outpaced the European Medicines Agency (EMA) both on the number of new medicine approved as well as the length of review times in the period between 2011 and 2015. According to the data, the US FDA approved  170 new therapeutic agents over the timeframe, compared with 144 approved by the EMA Also, regulatory reviews by the FDA were 60 days shorter on average than those undertaken by its European peer. The analysis also revealed that the FDA approved 43.5 percent of applications for orphan drugs, compared with 25 percent for the EMA. Among the 142 therapeutic agents that were approved by both agencies, the median total review time was 303 days for the FDA and 369 days for the EMA.

Drugs at clinical stage

The US FDA grants breakthrough status to Regeneron Pharmaceutical’s Evinacumab, as a treatment for patients with homozygous familial hypercholesterolemia.

The US FDA grants orphan status to Redhill Biopharma’s (Tel Aviv, Israël) yeliva® for the treatment of cholangiocarcinoma.

The US FDA grants Akari Therapeutic’s (New York, USA and London, UK) Coversin fast track status for the treatment of paroxysmal nocturnal hemoglobinuria, an ultra-rare, life-threatening and debilitating hematological disorder. It is an autoimmune disease due to an acquired genetic deficiency which causes dysregulation or uncontrolled activation of the complement component of the immune system. 

The US FDA will undertake a priority review of Bristol-Myers Squiib’s Opdivo, a checkpoint inhibitor, as a treatment for patients with mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (CRC). dMMR occurs when the proteins that repair mismatch errors in DNA replication are missing or non-functional, which leads to MSI-H tumours in certain types of cancer, including CRC.

The National Institutes for Health of Allergy and Infectious Diseases has started testing its Zika vaccine candidate in a multisite phase 2/2b trial, which aims to enroll at least 2,490 healthy volunteers in Central and South America as well as the US. The targeted countries include Puerto Rico, Brazil, Peru, Costa Rica, Panama, Mexico and the U.S., all of which have reported confirmed or potential active transmission of Zika.

Medical Devices and Diagnosis News.

The US FDA allows 23andME (Mountain View, CA, USA), to sell the company genetic’s health risks test to detect a person’s genetic predisposition for 10 diseases. The agency said the genetic health tests should be regulated as a medical device.

Reva Medical (San Diego, CA, USA) gets a CE Mark for Fantom, its drug –eluting bioresorbable coronary scaffold. Abbot’s Absorb was the first completely resorbable coronary stent ever approved. Several physicians are still skeptical about the merits and value of bioresorbable scaffolds and are awaiting more data prior to switching to non-metal stents.

Nordic Pharma (Paris, France) has launched Nordimet, the first button-free, once-weekly PEN device containing the active substance methotrexate – across the UK, for patients with auto-immune conditions a new means of administering treatment with a Disease Modifying Anti-Rheumatic Drug (DMARD). According to the firm, the new button-free design removes the need for patients, who may have painful joints, to press a button to administer their injection, and Nordimet also has an innovative double-click mechanism that audibly clicks and gently vibrates at the start and at the end of the injection to give patients confidence that a full dose has been administered.

B. Braun (Melsungen, Germany) and Royal Philips (Amsterdam, The Netherlands) are collaborating to work on ultrasound-guided regional anesthesia and vascular access products and make it easier to perform regional anesthesia, starting with a mobile ultrasound platform expected to act as a launchpad for future products. “By partnering with B. Braun, we have created a solution for ultrasound-guided regional anesthesia comprising the Xperius ultrasound system, decision support software, echogenic needles, and a suite of services,” Philips’ Rob Cascella said in a statement.

Novocure (Saint Helier, Jersey) presented positive survival data for the phase 2 pilot trial of its noninvasive therapy in patients with pancreatic cancer. The trial investigated the safety and efficacy of the company’s Tumor Treating Fields technology in combination with nab-paclitaxel and gemcitabine, according to a statement. The new study posted a median progression-free survival of 12.7 months, compared to the 5.5 months for historical controls. The one-year survival rate was 72%, compared to 35% in the historical controls.

Science & Technology

University of Pennsylvania scientists have devised a new imaging test to measure the amount of PARP-1 enzyme in ovarian cancer patients, which could help identify which patients would benefit most from treatments that target PARP-1. These treatments have the potential to vastly improve the outlook for patients with ovarian cancer. The American Cancer Society reports that only 20% of ovarian cancer cases are detected early. And the five-year survival rate for ovarian cancers that have spread is 73% for regional cases and just 29% for distant cases, versus 92% for localized ovarian cancer that's caught in the early stages.

Cost, Pricing and Market Access

Pharma companies are warning that changes to the way the National Institute for Health & Care Excellence (NICE) and NHS England (NHSE) assess new medicines, which came into affect on April 1, will hinder patient access to the latest treatments. In a survey of member companies of the Association of the British Pharmaceutical Industry (ABPI), 71 percent said they believe that the new system will see their companies prioritise the launch of new medicines in European countries over the UK, while 89 percent said patient access to cost-effective medicines in the UK will decrease as a result .Under the new framework, any new medicines found to be cost effective by NICE but likely to overshoot a budget impact limit of £20 million in any year within the first three years of use will be subject to a second process for price negotiation before they can be made available on the NHS. NICE also announced that rare disease treatments deemed to provide significant QALY benefits will be assessed by its Highly Specialised Technologies (HST) committee against a maximum threshold of £300,000 per QALY.

Miscellaneous

A recent investigation into alleged bribes by Novartis to sell more drugs in Greece entered a new act, as Greek Justice Minister Stavros Kontonis told a state news agency Novartis likely bribed “thousands” of government officials and doctors . At the ANA radio he said a “great number” of the country’s officials and doctors were involved in the scheme “to promote drugs in an illegal and anti-scientific manner,” according to Medical Xpress. From what he has seen, Kontonis said, “it must be thousands who were directly bribed from Switzerland.” A Novartis spokeswoman said the company "heard that he made this comment on the radio, so it is not necessarily an official development that we could comment or speculate on".

Sanofi Pasteur agreed to pay around  $20 million to settle allegations that it overcharged the Department of Veterans Affairs for its products. The company voluntarily reported the “calculation and reporting error” with the VA in 2012, and has since “cooperated fully and negotiated in good faith with the government,” according to a statement from the company.

GlaxoSmithKline is voluntarily recalling more around 600,000 Ventolin asthma inhalers from U.S. hospitals, pharmacies, retailers and wholesalers due to a defect that may cause them to deliver fewer doses than indicated. GSK said it had received an elevated number of product complaints about a bulging of the outside wrapper, suggesting a leak of the propellant that delivers the medicine

People on the move:

Bill Sibold is promoted Executive Vice President Sanofi Genzyme and Member of the Executive Committee and will replaces long time Genzyme head David Meeker as of July 1, 2017.

Bioevents

Strategic Alliance Management Congress on May 1-3, in Philadelphia (USA)

BIOTrinity on May 8-10, in London (UK)

China BIO Partnering Forum on May 10-11 in Suzhou (China)

9^thAnnual China BIO International Partnering Forum on May 31-June 1 in Zhuhai (China)

The Health Industry Sumitt (tHIS) 2017 on May 15-18 in Shanghai (China)

2017 BIO-IT World Conference & Expo on May 23-25 in Boston (USA)

BIO International Convention on June 19-22 in San Diego (USA)

MedFIT on June 28-29 in Grenoble (France)

Nordic Life Science Days (NLS) 2017 on September 12-14 in Malmö-Copenhagen (Sweden and Denmark)

BIOPharm America on September 26-27 in Boston (USA)

BIO Latin America on October 26-28 in Sao Paulo (Brazil)

BIO Europe on November 6-8 in Berlin (Germany)

World Congress on Biomedical Engineering 2017 on November 9-11 in Xian (China)

BIOFIT on November 28-29 in Strasbourg (France)

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