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Friday, October 11, 2019

Blood test raises hopes of tackling ‘silent killer’ abdominal aortic aneurysms

It is the ‘silent killer’ that claimed the life of Albert Einstein and affects 1% of men over the age of 65, but researchers at the University of Dundee believe they may be able to reduce the number of fatalities caused by abdominal aortic aneurysms.
Aneurysms are the swelling and weakening of the arterial wall. Aortic aneurysms occur in the aorta, which delivers blood from the heart to organs. Aneurysms are often called a silent killer, because patients can display no symptoms until the aneurysm bursts. Around 80% of all patients with a ruptured aneurysm die from the condition.
A team from the University’s School of Medicine have devised a test that detects the presence of desmosine, an amino acid that diseased aortas release into the blood and urine. They believe this can improve the diagnosis and monitoring of aortic aneurysms while possibly aiding effort to develop new therapies to slow down their progression.
Men aged 65 and over are most at risk and may be invited for ultrasound screening. If an aortic aneurysm is detected, they will be asked to attend regular follow up checks but, as aneurysms do not expand at a linear rate, this means rapid growth between screenings may be missed.
Furthermore, the size of an aneurysm does not always correlate to how close it is to rupturing. However, the Dundee researchers believe that measuring the level of desmosine is a more effective way of identifying which patients are in most urgent need of treatment.
Dr Anna Maria Choy, Senior Clinical Lecturer and Honorary Consultant Cardiologist at the University, said, “At the moment, patients are offered surgery when the aneurysm reaches a size where it is felt to be in danger of rupturing. The problem is that aortic aneurysms can progress quite unpredictably and rapidly between tests. Sometimes they stay the same for a long time then have sudden expansion and they can also rupture when not of a particularly significant size.
“All this means we need to find a better way to detect and monitor aneurysms as it is a terrible amount of uncertainty for patients and their families to live with. We established that desmosine was released into the blood when this disease was present so we looked at whether testing for this might add to the screening.
“Looking at a retrospective collection of samples from aneurysm patients, we found that not only was this effective in detecting aneurysms, it improved predicting complications and outcomes. This could potentially help to save lives by picking up danger signs missed by the current screening programme and identifying which patients should be offered surgery.”
Ruptured aortic aneurysms cause 5,000 deaths in the UK each year, and are responsible for 1 in 75 deaths of men over 65. The incidence is growing as the population ages while smokers, diabetics and people with hypertension are among other at-risk groups.
Desmosine derives from elastin protein. As suggested by its name, elastin provides blood vessels with their unique elastic character to expand and stretch. When someone develops an aneurysm, this protein gets broken down and is released into blood and urine.
The Dundee team and their co-investigators from Edinburgh, Leicester and Singapore checked the desmosine levels of patients with aneurysms ranging from the very mild to extremely severe. They found it was not just an effective indicator of the size of the aneurysm but also the likelihood of the patient developing complications.
Dr Jeffrey Huang, a principal investigator who developed the desmosine assay, said, “Where available, screening programmes have helped reduce the number of fatalities but it is quite resource-intensive. It is potentially more cost-effective and patient-friendly to go to your GP for a simple blood test rather than going to hospital for an ultrasound.
“More importantly, our test has shown to be more effective in predicting outcomes than size alone so there is the potential to save lives.”
At the moment there is no medical intervention known to slow the progression of aneurysms but Dr Choy and Dr Huang believe the test they have developed can help to guide the development of therapies through clinical trials by giving faster and clearer readings of the levels of desmosine and therefore aortic destruction.
“Next we want to test this research in women who experience a higher mortality rate event though they are less likely to be diagnosed with an aneurysm,” continued Dr Choy. “It may also prove significant for people with genetic diseases that lead to diseased aortic walls. The bottom line is that in any disease of the aorta we think this amino acid may have a role to play in detection, prediction and follow up.”
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The research was funded by the Scottish Government Chief Scientist Office and Tenovus Trust Scotland and was published by the Journal of the American Heart Association.
https://www.eurekalert.org/pub_releases/2019-10/uod-btr101119.php

Tariffs take toll on Philips margin goal in blow to shares

Philips warned it will miss its 2019 profit margin target on Thursday due to trade tariffs and poor results at its Connected Care arm, wiping around 3 billion euros ($3.3 billion)off the Dutch healthcare technology group’s market value.

The trade war between the United States and China has forced Philips to shift production and to seek other suppliers for components in recent months to avoid punitive tariffs.
But this has proved harder to achieve than earlier expected, while tariffs rose faster than previously announced, Chief Executive Frans van Houten told reporters.
“Tariffs have gone up, definitions have become clearer”, Van Houten said, adding: “The impact has gone up, while mitigating actions have been delayed.”
Philips shares were down 8% at 0820 GMT after the warning.
Earlier this year, Philips said the trade war between Washington and Beijing was forcing it to move hundreds of millions of euros worth of production from the U.S. to China, and vice versa, to avoid tariffs.
These mainly hurt Philips’ connected care business, which specialises in remote patient monitoring, for instance through software platforms and devices that allow doctors to share patient information.
Sales of connected care were 3 billion euros ($3.3 billion) last year, on total group revenues of 18.1 billion euros.
The connected care arm is more exposed to trade tariffs than Philips’ two larger businesses, which make hospital equipment such as medical scanners and personal health products such as toothbrushes, as it offers many more and smaller products.
“This means we need a lot of small actions, which all add up”, Van Houten said.
“In diagnosis & treatment we have fewer products, while in personal health the volumes are higher, so a single action there has greater effect on the whole.”
MARGIN GOAL MISS
Margins at the struggling Connected Care division not only dropped in the third quarter as tariffs hit, but also because factories lowered production to get rid of high inventories.
Philips has repeatedly said rising life expectancy and associated chronic diseases would lead to growing demand for devices that allow patients to stay at home, while their data is monitored.
But Van Houten last year also said demand for such products would remain modest in 2019.
Philips now expects its adjusted EBITA margin to only improve by 10 to 20 basis points this year, well off its previous 100 basis point goal.
“Based on this profit warning we expect 2019 adjusted EBITA to come down by low-to-mid-single digit”, ING analyst Marc Hesselink said.
Philips did stick to its target of improving comparable sales by 4% to 6% this year, as Van Houten said he continued to see good growth in all his businesses.
Preliminary third quarter results, also released on Thursday, showed sales are expected to have increased 6% in the quarter to 4.7 billion euros, while adjusted earnings before tax, interest and amortisation (EBITA) increased 3% to 583 million euros.
A 78 million euros impairment on connected care pushed net profit down around 30% to 210 million euros.

https://www.marketscreener.com/ROYAL-PHILIPS-6289/news/Royal-Philips-Tariffs-take-toll-on-Philips-margin-goal-in-blow-to-shares-29359473/

SoftBank-backed Vir Biotechnology’s shares tumble in market debut

Shares of SoftBank-backed Vir Biotechnology Inc fell as much as 28% in one of the worst market debuts in recent months, adding to the gloom in the IPO market after WeWork’s failed attempt to list its stock.

Vir’s disastrous IPO deals another blow to Japan’s SoftBank, which is still smarting from the botched initial public offering of WeWork last month following increased investor skepticism regarding the office-sharing startup’s path to profitability.
SoftBank’s $100-billion (78.9 billion pounds) Vision Fund owns 19.8% of Vir after the offering, a slight decrease from its pre-IPO stake of 21.2%. (https://bit.ly/318hWfg)
Investors and experts tracking recent IPOs believe companies thinking of going public in the next 12-18 months would be extremely wary of the recent backlash against loss-making firms.
Vir posted revenue of $10.7 million for 2018, a nearly four-fold jump from a year earlier, but its losses also ballooned by 66% to roughly $116 million in the same period.
Shares of the San Francisco-based infectious disease researcher opened at $16.15 after its initial public offering was priced at the low end of its $20 to $22 per share price range. It raised $142.9 million from the offering.
At the day’s low of $14.17, the company was valued at slightly over $1.5 billion.
Vir researches new therapies for infectious diseases such as hepatitis, tuberculosis and HIV, and counts some of the most high-profile investors in the industry among its backers.
Co-founded by Arch Venture Partners’ Robert Nelsen, both SoftBank’s Vision Fund and the Bill & Melinda Gates Foundation are among its biggest backers. Biogen Inc’s former Chief Executive Officer George Scangos is its CEO.
JP Morgan, Goldman Sachs, Cowen and Barclays are among the lead underwriters for Vir’s IPO.

https://www.marketscreener.com/BIOGEN-INC-4853/news/Biogen-SoftBank-backed-Vir-Biotechnology-s-shares-tumble-in-market-debut-29368438/

OxyContin maker Purdue gets brief shield from litigation

OxyContin maker Purdue Pharma LP won a court order on Friday briefly pausing the sprawling opioid litigation against the company so it can try to make headway on its proposed legal settlement that it says is worth $10 billion (7.9 billion pounds).

The company and its controlling Sackler family have been accused in more than 2,600 lawsuits, mostly brought by states and local governments, of improper marketing of its opioid products and fuelling a nationwide crisis.
The plaintiffs in the bulk of those cases support the proposed settlement, but at least 24 states oppose it.
U.S. Bankruptcy Judge Robert Drain on Friday approved a stay of all litigation until Nov. 6.
The company hopes over the coming weeks it can to convince the hold-out states to agree to extend the stay on litigation to six months, as the governments backing the settlement have agreed to.
Drain also hoped the brief stay would give the parties time to hammer out a protocol for sharing documents and financial information about Purdue and the Sackler family in a way that would win the trust of the hold-out states.
Just prior to Friday’s six-hour hearing, Purdue attorney Marshall Huebner said the company, the official committee of unsecured creditors and the Sacklers worked out an information sharing agreement.
The agreement would allow the committee to assess the settlement, and the Sacklers also agreed to provide information about their wealth and would agree to refrain from taking any material action with their property.
Privately-held Purdue filed for bankruptcy last month to help it implement the proposed deal, which will transfer Purdue’s ownership to a public trust owned by the plaintiffs. In addition, the family has also pledged to contribute at least $3 billion to the settlement.
Drain said the public deserves an accounting of the company’s role in the crisis, which has led to some 400,000 deaths from 1999 to 2017, according to U.S. statistics.
However, he said he feared a “trial becomes an autopsy” that destroys the value of Purdue, adding that most trials leave many unresolved questions.
“There are trials where people stand up and say ‘I did it.’ But that mostly happens on Perry Mason,” he said, referring to the popular TV show from the 1950s and ’60s featuring a lawyer who won virtually every case.
Drain also urged the parties to determine the best way to divvy up the settlement proceeds, echoing comments he had made on Thursday.

https://www.marketscreener.com/news/OxyContin-maker-Purdue-gets-brief-shield-from-litigation–29366729/

Vaping Illness: A New Name and Expanded Clinical Guidance

If patients have respiratory or gastrointestinal symptoms, ask about use of e-cigarettes or vaping, the CDC urged.
As the number of cases have ballooned to now 1,299 across the nation, experience has grown such that the agency released official interim guidance for clinicians on what it’s now calling EVALI (e-cigarette, or vaping, product use-associated lung injury).
“When we first distributed advice for clinicians back in late August, the guidance was based on limited experience clinicians had caring for a relatively small number of patients,” Anne Schuchat, MD, principal deputy director of the CDC, said on a phone call Friday with reporters, adding, “We are not seeing meaningful dropoff in new cases.”
Over the summer, it was easier to distinguish the vaping injury from respiratory infection, but that’s changing as flu season sets in.
“It will become increasingly difficult to fully exclude the possibility of infection,” Ram Koppaka, MD, PhD, a medical officer in the CDC’s National Center for Immunization and Respiratory Diseases, told reporters on the briefing call.
Consider “that any given individual may have lung injury, they may have an infection, or they may have both,” he said. “It may be necessary upfront to treat for more than one process at a time while testing is done, while a patient’s course is followed to provide a better indication which of those possibilities is at play.”
Among 339 patients with medical chart information submitted to the FDA so far, 95% diagnosed with EVALI initially presented with respiratory symptoms and 77% had GI symptoms, like abdominal pain, nausea, vomiting, and diarrhea in some cases preceding the respiratory symptoms.
In the document published in Morbidity & Mortality Weekly Report, the CDC recommended asking patients with such symptoms about vaping along with what types of substances were used (most EVALI has been found in people who vaped THC) and as many specifics about it as possible.
While “EVALI is considered a diagnosis of exclusion because, at present, no specific test or marker exists for its diagnosis,” the agency suggested measuring oxygen saturation and vital signs, a respiratory viral panel, and complete blood count and urine toxicology testing, including tests for THC.
Along with a chest x-ray looking for infiltrates for all patients with a history of vaping and respiratory or GI symptoms, consider a chest CT for evaluation of severe or worsening disease, complications, or other illnesses, they suggested.
Consultation with a pulmonologist would be good, and “there should be a low threshold for consulting with critical care physicians,” the document noted, as 47% of EVALI patients were admitted to the ICU and 22% required intubation and mechanical ventilation.
Some patients can be managed on an outpatient basis if they have better than 95% oxygen saturation, are clinically stable, and can assure follow-up within 24 to 48 hours, because some patients with initially mild symptoms rapidly worsened within that time frame.
For treatment, consider starting corticosteroids and influenza antivirals, and strongly consider early initiation of antimicrobial drugs for community-acquired pneumonia, the CDC recommendations said.
And strongly advise patients to stop vaping and get the flu shot and pneumococcal vaccine, it added, reaffirming it’s advice that everyone — regardless of lung injury — stop vaping THC entirely and consider stopping vaping tobacco as well (13% of EVALI has been in exclusive tobacco vapers). “There’s no safe tobacco product,” Schuchat reemphasized.
So far, there have been fewer than five documented cases where patients bounced back to the hospital after discharge, with a range of 5 to 55 days.
It’s not clear whether it was due to resumption of vaping, corticosteroid taper, or increased susceptibility to infection, Schuchat said.
After discharge, the CDC recommended following up within 1 to 2 weeks with repeat testing.
The CDC noted that it is developing ICD-10 codes for EVALI.
https://www.medpagetoday.com/pulmonology/smoking/82701

Upcoming events – Roche braves liver cancer and Incyte looks for a new Jak

In liver cancer Roche hopes to succeed where Bristol failed, while Incyte tests its Jakafi follow-on in first-line graft-versus-host disease.
Welcome to your weekly roundup of approaching clinical readouts. Roche’s Imbrave-150, a phase III study in first-line liver cancer testing Tecentriq plus Avastin against the standard of care, Bayer’s Nexavar, is due to read out in weeks, and what makes it especially interesting is that investors can handicap the result.
This is courtesy of GO30140, a randomised multi-cohort phase I study updated at Esmo, that showed liver cancer subjects given Tecentriq plus Avastin having a 45% reduced chance of progression compared with those given Tecentriq alone (p=0.0108).
That said, Imbrave-150 tests a truly front-line setting; in GO30140 patients had to be naive to systemic therapy and to have unresectable hepatocellular carcinoma, effectively indicating a slightly later line of therapy as subjects might have received radiotherapy, for instance.
Notably, no GO30140 subjects got Nexavar, so comparison necessitates looking across studies. Nexavar’s US label cites 5.5 months of median PFS, which is only slightly shorter than the 5.6 months of the combo in GO30140. Considering the earlier-line population, Tecentriq plus Avastin might be expected to confer longer PFS in Imbrave-150 versus GO30140.
Imbrave-150 did not enrol high PD-L1 expressers, which given the result of Bristol-Myers Squibb’s failed Checkmate-459 trial looks dubious. However, the Swiss company will be relying on the Avastin part of the combo to boost efficacy in PD-L1 non-expressers.
Perhaps the most intriguing signal from GO30140, which also enrolled subjects unselected for PD-L1 status, was that Roche was able to demonstrate the additive effect of Avastin over Tecentriq alone. But at Esmo the discussant of GO30140 cautioned that it was not clear whether Avastin could turn “cold” tumours “hot”, or which patients should get the combo.
Nevertheless, Evercore ISI’s Umer Raffat reckons the GO30140 data were strong enough to suggest that liver cancer is the indication in which Roche could at last differentiate its immuno-oncology offering.
Selected Roche trials in hepatocellular carcinoma
Study Design Setting Data Trial ID
GO30140 Includes Tecentriq + Avastin and Tecentriq-only cohorts Inoperable subjects naive to systemic therapy mPFS 5.6mth for combo, vs 3.4mth for monotherapy NCT02715531
Imbrave-150 Tecentriq + Avastin vs Nexavar First line OS & PFS co-primaries; reads out in Q4 2019 NCT03434379
Source: Roche & clinicaltrials.gov.
Incytes Gravitas
The first pivotal data are due before the end of the year for Incyte’s itacitinib in acute graft-versus-host disease (GVHD). Gravitas-301 is testing itacitinib, a Jak 1 inhibitor, plus corticosteroids, versus placebo and steroids in 439 steroid-naive patients.
The primary endpoint is overall response rate at day 28, and the study is powered to show a 16-percentage point improvement in the active arm over control, and a 40% reduction in non-relapse mortality at 6 months, a key secondary endpoint.
Incyte already has a Jak inhibitor approved for GVHD in the shape of Jakafi; the Jak 1 and 2 inhibitor got the go-ahead here in May but only in second-line, steroid-refractory patients, on the back of a single-arm phase II trial that showed a 55% ORR.
Jakafi has got off to a strong start in GVHD and Incyte has guided to sales of $80m for the year.
Analysts reckon that Incyte will want to diversify away from Jakafi, given approaching competition from Celgene’s Inrebic, and generic erosion in 2028. Importantly, itacitinib also offers more attractive economics: Incyte owns all rights to itacitinib, while Jakafi is licensed to Novartis outside the US.
Second-line GVHD affects around 3,000 new patients per year in the US, versus some 15,000 first-line patients, according to Incyte.
The group plans to file a US NDA for itacitinib early next year. A first-line trial in chronic GVHD patients is ongoing.
Incyte’s GVHD trials

Acute GVHD Chronic GVHD
First line: itacitinib Gravitas-301 (NCT03139604): itacitinib vs placebo, results by YE 2019 Gravitas-309 (NCT03584516): itacitinib vs placebo, primary completion 2023
Second line: Jakafi Reach1 (NCT02953678): single-arm study, accelerated approval May 2019 Reach3 (NCT03112603): Jakafi vs best available therapy, results by YE 2019
Reach2 (NCT02913261): Jakafi vs best available therapy, results by YE 2019
Source: Company presentation, clinicaltrials.gov
https://www.evaluate.com/vantage/articles/events/upcoming-events/upcoming-events-roche-braves-liver-cancer-and-incyte-looks

Storm clouds gather for biotech flotations

Only seven drug developers managed to float on Western exchanges in the third quarter, and new issues in October have struggled, with Biontech the latest example.
Is the IPO window shutting for biopharma? Evidence is mounting that this might be the case, from a big drop in the number of flotations in the third quarter, to downsized offerings and a handful of aborted attempts. And, for those that do manage to get away, a warm welcome is far from guaranteed.
The backdrop to this is a very rocky period on the stock market: Nasdaq, the US exchange on which most young drug developers try to list, took a tumble at the end of September, and drug stocks were singled out for particular punishment. The Nasdaq Biotechnology Index slumped 8% in the final weeks of September, and started October down on the year.
As a result many companies are being forced to accept lower – some would argue more realistic – valuations. A case in point is Biontech, which had to strip 20% from its IPO price and reduce the number of shares on sale to win support from public investors. The mRNA player ended up raising only $150m; it had initially been targeting up to $264m.
Biontech shares, which started trading yesterday, fell 5% to $14.24, giving the company a $3.2bn market cap. That is still a huge valuation for a group with only a handful of projects in the clinic and much left to prove. Many investors believe that its valuation will continue to sag, echoing its US rival Moderna’s experience, particularly as the cash-hungry German company, which employs an astonishing 1,000 people, will soon need more money.
All eyes will now be on Vir Biotechnology, the subject of another huge offering, which is set to float today. The company’s IPO has been priced at $20, the low end of its proposed range; this would raise the infectious disease specialist $143m and give it a $2.2bn market cap.
Doing what is necessary
Biontech did what was needed to go public, unlike ADC Therapeutics, which pulled its Nasdaq IPO in early October, citing adverse market conditions. This was certainly a testing time on the markets, but the company was also gunning for some very big numbers: its proposed terms would have given it a market cap of $2bn and $200m of fresh funds.
A commitment from insiders to buy 57% of the new stock was not enough to convince public investors, and presumably ADC declined to trim its valuation to tempt them on board.
Another company that pulled its IPO in early October was Monopar Therapeutics, which was lining up a $40m flotation. It is hard to see market conditions improving to the extent that these companies will be able to return any time soon, unless they are willing to negotiate on valuation.
These upsets in October were largely foreshadowed in the third quarter: only seven companies listed on Western exchanges during this time, representing the slowest three-month period for biopharma flotations in more than two years.
The total amount raised was boosted by two substantial offerings, from Springworks and IGM Biosciences, which managed to get out before the markets turned south at the end of September, and are just about managing to stay in the black.
Many companies will be hoping to float before the US enters its full-blown election period, when political uncertainty and the inevitable heightened scrutiny of drug prices are likely to prompt many investors to seek less volatile propositions. But, as conditions stand currently, it is hard to see the final months of 2019 generating a much prettier picture than the previous quarter.
Support for biopharma flotations has far from dried up, if the amount of money some of these companies have been able to raise is anything to go by. But unsubstantiated valuations are increasingly being questioned. Whether the punishment comes in the form of a downsized IPO or a falling share price post-float, a new reality is forming.
Biggest biotech IPOs on Western exchanges in Q3 2019 (all Nasdaq unless stated otherwise)
Company Primary focus Amount raised ($m) Premium/(discount); float price to initial offer Share price change since float to end Q3
Springworks Therapeutics Rare diseases and oncology 186.3 6% 20%
IGM Biosciences Oncology 175.0 0% 11%
Satsuma Pharmaceuticals Migraine 82.5 0% 0%
Mirum Pharmaceuticals Rare diseases 75.0 0% (33%)
Fulcrum Therapeutics Genetic diseases 72.0 (6%) (59%)
Source: EvaluatePharma.
https://www.evaluate.com/vantage/articles/data-insights/ipo/storm-clouds-gather-biotech-flotations