Phage Therapy Firm APT Lands DoD Contract for Antibiotic Alternative

The Department of Defense has awarded Adaptive Phage Therapeutics a $10.2 million contract to help advance its experimental therapy for the treatment of multidrug-resistant infections.

Gaithersburg, MD-based Adaptive Phage Therapeutics (APT) says it will pursue a two-year multi-site clinical trial as it looks to get the OK from the FDA, which considers phage to be “Generally Regarded as Safe” and has identified phage therapy as a potential alternative to antibiotics.

Phages are bacterial viruses that destroy targeted bacteria—including those which have become resistant to antibiotics—and APT is developing its phage collection, “PhageBank,” to do just that.

According to the company, PhageBank is a library of polymicrobial broad-spectrum phages that can be matched to a specific pathogen. It is used with a companion diagnostic to select the best option for each patient.

“PhageBank incorporates a built-in feedback loop in which any uncovered bacteria are captured as source material for additional phage discovery. The additional phages enrich PhageBank and increase the spectrum of coverage, offering an effective response to evolving bacterial resistance,” explains APT CEO and co-founder Greg Merrill.

Since acquiring rights to PhageBank in 2017 from the US Navy, APT has provided patients access to the therapy under compassionate use.

Now, the company is working toward submitting the necessary data to the FDA in order to begin clinical trials in humans. If given the OK, APT plans to recruit patients with bacterial infections across three study sites in the US over the next 90 days. It will then quickly expand to a fourth site, Merrill tells Xconomy.

“Over the term of the program, APT’s effort is expected to expand terms of the variety of clinical indications and variety of pathogens,” he says. Though further details are undisclosed, the company says the market for the antibiotic alternative could be in excess of $4 billion for its first four planned indications.

“Phages have existed and co-evolved with bacteria over the past 3.8 billion years. There is a practically unlimited number of phages on earth,” he explains. And phages continue to evolve, which Merrill says enables “a broad and continually updated universe of potential options for patients with multi-drug resistant infections.”

The use of phage therapy to treat bacterial infections was first explored in the 1920s, Merrill says, though the emergence of antibiotics put development on the backburner. Today, as the threat of antibiotic resistance grows, however, so has the interest in phage therapy.

“Recent breakthroughs by APT and its collaborators at the biodefense directorate of the US military in bioinformatics, rapid phage-bacteria isolation and matching, and phage purification methods, enable both the rapid administration of phage therapy and a personalized solution tailored to a patient’s individual infection,” says Merrill.

APT in October last year raised approximately $7 million. Investors included Alexandria Venture Investments and an unnamed health care delivery network and New York Stock Exchange-listed life sciences company.

https://xconomy.com/national/2020/01/15/phage-therapy-firm-apt-lands-dod-contact-for-antibiotic-alternative/

FDA Action Alert: Epizyme and Merck

January isn’t a particularly busy month for PDUFA dates for the U.S. Food and Drug Administration (FDA), with only two scheduled for the month. Here’s a look.

Epizyme’s Tazemetostat for Sarcoma

Cambridge, Massachusetts-based Epizyme has a target action date of January 23 for its tazemetostat. The New Drug Application (NDA) is for metastatic or locally advanced epithelioid sarcoma patients not eligible for curative surgery. The drug is under the FDA’s Priority Review.

The NDA is largely based on data from an ongoing Phase II trial of the drug in a 62-patient cohort with epithelioid sarcoma. Tazemetostat is an oral potent, first-in-class EZH2 inhibitor. It is being evaluated as a monotherapy in specific molecularly defined solid tumors, including epithelioid sarcoma and other INI1-negative tumors, as well as in patients with follicular lymphoma, both with and without EZH2 activating mutations.

The drug is also being evaluated as a combination treatment for patients with diffuse large B-cell lymphoma.

In order to garner full approval, Epizyme indicated in July it would initiate a global confirmatory trial, which would compare tezemetostat in combination with doxorubicin compared to placebo plus doxorubicin in about 150 patients. The primary efficacy endpoint would be progression-free survival, with secondary endpoints of overall survival, disease control rate, overall response rate and duration of response.

On December 18, 2019, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 in favor of recommending tazemetostat for this indication. Epithelioid sarcoma is a rare and aggressive soft tissue sarcoma marked by a loss of the INI1 protein. They are usually diagnosed in people between the ages of 20 and 40 years of age, and typically patients do not live past five years from diagnosis.

“We are incredibly pleased by ODAC’s unanimous support of the benefit-risk of tezemetostat in ES, and we appreciate the tremendous support received from sarcoma physicians and their medical teams, advocates, caregivers and most notably, patients with ES,” said Shefali Agarwal, Epizyme’s chief medical officer.”

Also, on December 18, 2019, the company submitted its NDA for tezemetostat for relapsed or refractory follicular lymphoma (FL), with or without EZH2 activating mutations, in patients who have received at least two prior lines of systemic therapy.

Merck’s Dificid for C. Diff Infections

Merck has a target action date of Jan. 24 for its Dificid (fidaxomicin) for oral suspension, and a supplemental NDA (sNDA) for a new indication for use of Dificid tablets and oral suspension for the treatment of Clostridium difficile (C. diff) infections in children aged six months are older. Both applications are under Priority Review.

Dificid is a macrolide antibacterial drug indicated in adults for treatment of C. diff-associated diarrhea (CDAD). C. diff is one of the most common causes of healthcare-related infections in U.S. hospitals, causing about 500,000 infections each year. It is associated with about 29,000 deaths within 30 days of individual diagnosis.

In October 2019, when the FDA accepted the submissions, Nicholas Kartsonis, senior vice president, Clinical Research, infectious diseases and vaccines, Merck Research Laboratories, said, “Evidence indicates the increasing incidence of C. difficile-associated diarrhea among hospitalized children. The filings for the pediatric indication for the new investigational oral suspension formulation of Dificid, as well as for Dificid tablets, underscore Merck’s focus and dedication to developing infectious disease treatments for those with unmet needs.”

The sNDA is built mostly on data from the Phase III SUNSHINE trial, which the company presented at IDWeek 2018 in San Francisco.

https://www.biospace.com/article/fda-action-alert-epizyme-and-merck/

China virus sends shiver through markets as risks mount

Global shares took a beating on Tuesday, wiping out all gains made at the start of the week as mounting concerns about a new strain of coronavirus in China sent a ripple of risk aversion through markets.

Authorities in China confirmed that a new virus could be spread through human contact, reporting 15 medical staff had been infected and a fourth person had died.

Safe-haven bonds and the yen gained as investors were reminded of the economic damage done by the SARS virus in 2002-2003, particularly given the threat of contagion as hundreds of millions travel for the Lunar New Year holidays.

“I’m not an expert in the pandemics, but you can look at previous examples like the SARS outbreak which also originated from Asia,” said Cristian Maggio, Head of Emerging Markets Strategy at TD Securities in London.

Noting that China had initially downplayed the full extent of the SARS outbreak, he said “I think the market might be fearing something similar.”

The mood swing saw MSCI’s All-Country World Index <.MIWD00000PUS> slip 0.4%, wiping out gains made at the start of the week on Monday. Asian markets were hit particularly hard.

Hong Kong, which suffered badly during the SARS outbreak, saw its index fall 2.8%.

Japan’s Nikkei <.N225> lost 0.9% and Shanghai blue chips <.CSI300> 1.7%, with airlines under pressure. The caution spread to E-Mini futures for the S&P 500 which eased 0.5%.

The chill in Asia carried over to European markets, where shares of luxury goods makers – which have large exposure to China – were among the biggest fallers. [.EU]

Germany’s 10-year government bond yield touched one-week lows.

Investors had already been guarded after the International Monetary Fund trimmed its global growth forecasts, mostly due to a surprisingly sharp slowdown in India and other emerging markets.

There had been some relief as U.S. President Donald Trump and French President Emmanuel Macron seemed to have struck a truce over a proposed digital tax.

The two agreed to hold off on a potential tariffs war until the end of the year, a French diplomatic source said.

Trump is due to deliver a speech at the World Economic Forum in Davos later on Tuesday, and trade and tariffs could be on the agenda.

In a tweet late on Monday, Trump said he would be bringing “additional Hundreds of Billions of Dollars back to the United States of America! We are now NUMBER ONE in the Universe, by FAR!!”

ALL STEADY AT BOJ

The Bank of Japan cited lessened trade risks when nudging up forecasts for economic growth after holding a policy meeting on Tuesday.

As widely expected, the BOJ maintained its short-term interest rate target at -0.1% and a pledge to guide 10-year government bond yields around 0%, by a 7-2 vote.

Japan’s yen picked up a bid on the safe-haven move and the dollar dipped to 109.93 from an early 110.17. It also gained on the euro, leaving the single currency lower to the dollar at $1.1090.

Against a basket of currencies, the dollar was steady at 97.638, just off a four-week high of 97.729.

The Australian dollar <AUD=D3> took a knock from the flu worries since it attracts large numbers of Chinese tourists, who tend to be big spenders over the Lunar New Year holidays.

Australia said it would step up screening of some flights from Wuhan.

The outbreak was particularly badly timed as the tourism industry has been mauled already by bushfires sweeping the country.

Spot gold hit a 2-week high of $1,568.35 per ounce, but traded 0.2% lower in early deals in London.

Oil prices slid nearly 1%, having earlier gained on the risk of supply disruption in Libya. [O/R]

Brent crude futures fell 1% to $64.60 a barrel, while U.S. crude fell 0.92% to $58.09 a barrel.

https://www.marketscreener.com/news/China-virus-sends-shiver-through-markets-as-risks-mount–29865190/?countview=0

Dozens of non-oncology drugs can kill cancer cells

Drugs for diabetes, inflammation, alcoholism — and even for treating arthritis in dogs — can also kill cancer cells in the lab, according to a study by scientists at the Broad Institute of MIT and Harvard and Dana-Farber Cancer Institute. The researchers systematically analyzed thousands of already developed drug compounds and found nearly 50 that have previously unrecognized anti-cancer activity. The surprising findings, which also revealed novel drug mechanisms and targets, suggest a possible way to accelerate the development of new cancer drugs or repurpose existing drugs to treat cancer.

“We thought we’d be lucky if we found even a single compound with anti-cancer properties, but we were surprised to find so many,” said Todd Golub, chief scientific officer and director of the Cancer Program at the Broad, Charles A. Dana Investigator in Human Cancer Genetics at Dana-Farber, and professor of pediatrics at Harvard Medical School.

The new work appears in the journal Nature Cancer. It is the largest study yet to employ the Broad’s Drug Repurposing Hub, a collection that currently comprises more than 6,000 existing drugs and compounds that are either FDA-approved or have been proven safe in clinical trials (at the time of the study, the Hub contained 4,518 drugs). The study also marks the first time researchers screened the entire collection of mostly non-cancer drugs for their anti-cancer capabilities.

Historically, scientists have stumbled upon new uses for a few existing medicines, such as the discovery of aspirin’s cardiovascular benefits. “We created the repurposing hub to enable researchers to make these kinds of serendipitous discoveries in a more deliberate way,” said study first author Steven Corsello, an oncologist at Dana-Farber, a member of the Golub lab, and founder of the Drug Repurposing Hub.

The researchers tested all the compounds in the Drug Repurposing Hub on 578 human cancer cell lines from the Broad’s Cancer Cell Line Encyclopedia (CCLE). Using a molecular barcoding method known as PRISM, which was developed in the Golub lab, the researchers tagged each cell line with a DNA barcode, allowing them to pool several cell lines together in each dish and more quickly conduct a larger experiment. The team then exposed each pool of barcoded cells to a single compound from the repurposing library, and measured the survival rate of the cancer cells.

They found nearly 50 non-cancer drugs — including those initially developed to lower cholesterol or reduce inflammation — that killed some cancer cells while leaving others alone.

Some of the compounds killed cancer cells in unexpected ways. “Most existing cancer drugs work by blocking proteins, but we’re finding that compounds can act through other mechanisms,” said Corsello. Some of the four-dozen drugs he and his colleagues identified appear to act not by inhibiting a protein but by activating a protein or stabilizing a protein-protein interaction. For example, the team found that nearly a dozen non-oncology drugs killed cancer cells that express a protein called PDE3A by stabilizing the interaction between PDE3A and another protein called SLFN12 — a previously unknown mechanism for some of these drugs.

These unexpected drug mechanisms were easier to find using the study’s cell-based approach, which measures cell survival, than through traditional non-cell-based high-throughput screening methods, Corsello said.

Most of the non-oncology drugs that killed cancer cells in the study did so by interacting with a previously unrecognized molecular target. For example, the anti-inflammatory drug tepoxalin, originally developed for use in people but approved for treating osteoarthritis in dogs, killed cancer cells by hitting an unknown target in cells that overexpress the protein MDR1, which commonly drives resistance to chemotherapy drugs.

The researchers were also able to predict whether certain drugs could kill each cell line by looking at the cell line’s genomic features, such as mutations and methylation levels, which were included in the CCLE database. This suggests that these features could one day be used as biomarkers to identify patients who will most likely benefit from certain drugs. For example, the alcohol dependence drug disulfiram (Antabuse) killed cell lines carrying mutations that cause depletion of metallothionein proteins. Compounds containing vanadium, originally developed to treat diabetes, killed cancer cells that expressed the sulfate transporter SLC26A2.

“The genomic features gave us some initial hypotheses about how the drugs could be acting, which we can then take back to study in the lab,” said Corsello. “Our understanding of how these drugs kill cancer cells gives us a starting point for developing new therapies.”

The researchers hope to study the repurposing library compounds in more cancer cell lines and to grow the hub to include even more compounds that have been tested in humans. The team will also continue to analyze the trove of data from this study, which have been shared openly (https://depmap.org) with the scientific community, to better understand what’s driving the compounds’ selective activity.

“This is a great initial dataset, but certainly there will be a great benefit to expanding this approach in the future,” said Corsello.

###

This collaboration involved the Broad’s Center for the Development of Therapeutics, the PRISM team, the Cancer Data Sciences team, and the labs of Todd Golub and Matthew Meyerson. The work was funded in part by SIGMA (Carlos Slim Foundation, Slim Initiative in Genomic Medicine for the Americas), the National Institutes of Health, and an anonymous donor.

Paper cited: Corsello S, et al. Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling. Nature Cancer.

https://www.eurekalert.org/pub_releases/2020-01/biom-don011520.php

Australia to screen some flights from China, warns coronavirus difficult to stop

Australia will begin screening passengers arriving from a Chinese city in a bid to stop the spread of a new coronavirus, the country’s chief medical officer said on Tuesday, although authorities warned that an outbreak would be hard to prevent.

Chinese authorities have confirmed more than 200 people have caught the new virus, which causes a type of pneumonia that has killed four people in the central city of Wuhan.

The virus – which can pass from person-to-person – broke out in Wuhan but four cases have been reported in Thailand, Japan and South Korea, raising concerns about its spread through international air travel.

Brendan Murphy, the chief medical officer for the Australian government, said biosecurity officials would begin screening passengers arriving on the three weekly flights to Sydney from Wuhan starting on Thursday.

Passengers would be given an information pamphlet and asked to present themselves if they had a fever or suspected they might have the disease.

Murphy said the measures only offered limited protection.

“You cannot absolutely prevent the spread of disease into the country. The incubation period is probably a week,” Murphy told reporters in Canberra.

“It’s about identifying those with a high risk and making sure those who have a high risk know about it and know how to get medical attention.”

China is the largest source of tourists to Australia, with more than 1 million people arriving last year.

Around 160 flights arrive in Australia from China each week, and Murphy acknowledged Chinese tourists could arrive via other locations. There are only three flights from Wuhan each week, arriving in Sydney.

Australia’s additional screenings come as hundreds of millions of Chinese prepare to travel domestically and abroad during the Lunar New Year holiday that starts this week.

Despite the elevated risk, Murphy said Australia would not begin scanning passengers for higher body temperatures, a precaution previously used during the Severe Acute Respiratory Syndrome (SARS) outbreak.

SARS killed nearly 800 people globally during the 2002/03 outbreak that also started in China, but Murphy said recent evidence indicated body-temperature screening was ineffective and created a false sense of security.

https://www.reuters.com/article/us-china-health-pneumonia-australia/australia-to-screen-some-flights-from-china-warns-coronavirus-difficult-to-stop-idUSKBN1ZK007

Biotech week ahead, Jan. 21

Biotech news flow remained light last week, although there were some notable developments such as FDA panel reviews of opioid pain drugs, a few clinical data readouts, presentations and updates at the JPMorgan Healthcare conference.

Here are the key catalysts that could prove market moving in the unfolding week.

Conferences

American Society of Clinical Oncology, or ASCO, Gastrointestinal Cancers Symposium: Jan. 23-25 in San Francisco, California

PDUFA Dates

The FDA is scheduled to rule on Epizyme Inc’s EPZM 4.62% tazemetostat, an experimental drug to treat metastatic or locally advanced, unresectable epithelioid sarcoma. FDA’s Oncologic Drugs Advisory Committee, which met Dec. 18 to discuss the NDA for tazemetostat, unanimously recommended approval of the drug. The PDUFA date is set for Thursday.

The regulatory agency will announce Thursday its verdict on Merck & Co., Inc.’s MRK 0.22% NDA and sNDA for DIFICID (fidaxomicin) to treat Clostridium difficile infections. The NDA pertains to an oral suspension formulation and the sNDA is for the label expansion of the indication to treat children, ages six and older. Dificid, in tablet formulation, has already been approved to treat Clostridium difficile infections in adults 18 years and older.

Clinical Readouts

ASCO Gastrointestinal Cancers Symposium Presentations

Bellicum Pharmaceuticals Inc BLCM 9.05%: Phase 1 Cohort 5B new translational data for its pancreatic cancer experimental drug BPX-601 (Friday)

Forty Seven Inc FTSV 11.15%: Phase 1b data for magrolimab in combination with cetuximab in colorectal cancer

Earnings

Wednesday

Abbott Laboratories ABT 0.86% (before the market open)
Johnson & Johnson JNJ 0.53% (before the market open)

Thursday

Intuitive Surgical, Inc. ISRG 0.29% (after the market close)

https://www.benzinga.com/general/biotech/20/01/15136889/the-week-ahead-in-biotech-focus-on-epizyme-merck-ahead-of-pdufa-dates-j-j-to-kickstart-big-pharma

Long Island’s Northwell Health Deploying ‘Black Boxes’ In Operating Rooms

Surgery is now being recorded in some Long Island operating rooms.

It’s a high-tech effort to improve safety, similar to black box technology used in airplanes, and it’s not only being reviewed in the event of an accident.

They have them for trains, planes and automobiles, and now black box technology is coming to a hospital near you: Overhead while you are under the knife.

Long Island Jewish Medical Center is the first in the United States to install the OR black box in two operating rooms.

“There is no question that this is going to improve the quality for patients,” said Dr. Louis Kavoussi, a urologist with Northwell Health.

Dr. Kavoussi welcomes the technology in his OR. Cameras and microphones record, and the data is transmitted to a Canadian company that analyzes everything from sterile technique to distractions.

“Who should or should not be coming in or out of the operating room, should telephone calls come in, should there be music played,” Dr. Kavoussi said.

Through algorithms, it can predict a mistake and alert a surgeon.

“We all think as surgeons we are perfect, but we aren’t. And this is an opportunity to use artificial intelligence to analyze what’s going on in the operating room,” Dr. Kavoussi said.

The founder – a surgeon himself – says it’s like professional coaching.

“The reality is as long as there are humans, there will be errors,” said Dr. Teodor Grantcharov, the founder of Surgical Safety Solutions. “We want to create a system that makes it very difficult to make an error.”

Unlike the black boxes in transportation, it will not be used to assign blame. Northwell Health’s chief quality officer says it is used to improve systems, not punish individuals. It’s protected from subpoena in New York state as a quality control project. Patients are not identified.

“It’s not going to be used punitively, and most importantly, the data is de-identified. They blur out the picture of the physicians and nurses and even garble the voices a little if we ever look so no one ever knows whose case was whose,” Dr. Mark Jarrett said.

The plan is to install more of these black boxes in hospitals throughout the Northwell Health system. The more cases, the more data, the more quality control and improvement, officials said.

The technology is already in use in ten hospitals in Canada and western Europe.

Northwell Health Deploying ‘Black Boxes’ In Operating Rooms