Americans Increasingly View People With Mental Illness as a Threat

Despite an absence of supporting evidence, Americans increasingly view people with mental illness as a threat, and many support involuntary hospitalization for such individuals, new research shows.
The increasing stigma toward people with mental illness is “concerning, as it can lead to increasing discrimination,” lead author Bernice Pescosolido, PhD, distinguished professor of sociology at Indiana University in Bloomington, told Medscape Medical News.
“People with mental health problems have to face the challenges of having a major illness. The increasing stigma that we document translates into these people and their families also having to fight the rejection, isolation, and denial of civil rights that may come with an increasing negative climate of fear,” said Pescosolido.
The study was published online October 7 in Health Affairs.

“Mentally Ill Monsters”

Political rhetoric regarding mass shootings that wrongly links violence to mental illness likely plays a role in the evolving public view, the researchers say.
Following the August mass shootings in El Paso, Texas, and Dayton, Ohio, President Trump said publicly that mental illness is linked to gun violence and characterized psychiatric patients as “mentally ill monsters.”
In response, the American Psychiatric Association quickly issued a statement saying that the “overwhelming majority” of people with mental illness are more likely to be victims of violent crime rather than the perpetrators, as reported by Medscape Medical News.

Pescosolido and colleagues examined trends in public perceptions of violence regarding people with mental illness and in support for coerced treatment of these individuals over a 22-year period using data from three National Stigma Studies conducted in 1996, 2006, and 2018.
As part of the studies, respondents were given one of three vignettes describing people who meet clinical criteria for mental disorders or one describing a person with nonclinical “daily troubles.”
Results showed a general increase over time in people’s perceptions that individuals with mental disorders are dangerous. Results also indicated a general increase in support for stripping these individuals of civil rights, significantly so for individuals with schizophrenia.
By 2018, more than 60% of respondents regarded people who met criteria for schizophrenia as being dangerous to others, and 44% to 59% supported coercive treatment (either medication, forced physician visit, or hospitalization), the researchers found.
In addition, 68% of respondents in 2018 viewed people who had alcohol dependence as being dangerous to others, and 26% to 38% supported coercion.
“Lower but substantial percentages” were reported for people with depression; 30% thought that people with major depression were likely to be dangerous to others.
And “remarkably,” 20% of respondents felt that individuals with nonclinical “daily troubles” were likely to pose a threat to others, they report.

Troubling Trends

Pescosolido said these results are troubling because little evidence supports the hypothesis that individuals with mental illness are more likely to commit violence.
Even more troubling, she said, is the increasing risk of using legal means to force individuals who only have problems of daily living, not mental illness, into treatment.
“Given the current state of affairs, it is critical to continue to monitor cultural attitudes, beliefs, and predispositions that link mental illness to violent behavior. The continued existence of such beliefs and their connection in the public mind to forced treatment may drive the adoption of formal public health laws that restrict the lives of people diagnosed with mental illness,” the authors write.
Undertaking efforts to counteract sources of stigma is “daunting but indispensable to public health. We caution against policies based on erroneously linking mental illness and violence. Public policies stoked by political rhetoric will not improve the lives of any Americans,” they conclude.
The research was supported by grants from the National Science Foundation, the Brain and Behavior Research Foundation, the Indiana Consortium for Mental Health Services Research, and the Indiana University Network Science Institute. The authors have disclosed no relevant financial relationships.
Health Aff. Published online October 7, 2019. Abstract
https://www.medscape.com/viewarticle/919700

Menarini Silicon Biosystems banks on cells for its liquid biopsy

The group has the only approved cell-based cancer blood test in the world, but competing in an increasingly cutthroat market will be tough.

Most companies exploring liquid biopsies use technologies that search for and sequence DNA strands shed by tumours into a patient’s blood. Not so Menarini Silicon Biosystems: the company offers Cellsearch, the only FDA-cleared product for the enumeration of entire circulating tumour cells (CTCs) in blood samples.
“With CTCs we can offer a wide range of information compared to circulating tumour DNA [ctDNA],” Fabio Piazzalunga, president of MSB, tells Vantage. “We believe that the future will be linked to single-cell technologies.”
Single cell analysis is a technique that can aid the understanding of metastasis and therapy resistance with more precision than bulk tumour measurements, as well as tease out the role of rare cells in tumour progression. MSB’s Cellsearch technology can perform this testing; the company, a subsidiary of the private Italian pharma company Menarini, bought Cellsearch from Janssen in 2017.
Cellsearch can obtain clinically useful information in a number of ways. Most obvious is simply counting the cells, which can be used as a prognostic marker in metastatic disease, and it is this use for which Cellsearch has FDA clearance, as a way to monitor patients with metastatic breast, colorectal or prostate cancer.
It also has other potential applications for which it is not yet approved. These include measuring tumour antigens such as Her2 and PD-L1, useful for selecting targeted drugs or immunotherapy and monitoring the effectiveness of the treatment, and, based on the analysis of a single cell, acquire “information on tumour heterogeneity and chronicle how its evolution responds to therapy”, Mr Piazzalunga says. The CTCs can be isolated as live cells, providing information on gene expression.
Complementary
The group is not entirely eschewing the other liquid biopsy approach, however. It has a distribution agreement with the Taiwanese company Plexbio under which it distributes the latter’s IntelliPlex circulating tumour DNA analysis technology.
“We believe that the two technologies, CTCs and ctDNA, provide complementary rather than mutually exclusive information,” Mr Piazzalunga says.
MSB is not pursuing new regulatory clearances at the moment. Instead it is developing new uses for its systems; Mr Piazzalunga says it is working towards a new application of the Cellsearch technology related to multiple myeloma.
The system can run a full battery of tests, including the in-depth analyses that are not yet approved by the regulators, on around five patient samples per day, Mr Piazzalunga says. He adds that the company is working towards upgrading the system to allow a shorter turnaround time.
MSB is also moving into another fast-growing area: prenatal testing. Remarkably, cells can pass from a foetus into the mother’s bloodstream, and MSB is working towards developing tests for foetal genetic disorders using a blood draw taken from the mother. The technology will be able to detect several prenatal abnormalities, though Mr Piazzalunga declined to specify exactly what these might be.
The prenatal diagnostic will be a laboratory-developed test sold under a Clia waiver “at the beginning”, Mr Piazzalunga says. “Once we get the necessary clinical evaluation data, we will submit it.”
Too many companies
But liquid biopsy is the big prize. As targeted therapies and immuno-oncology continue their meteoric rise, competition to develop a successful blood-based test to aid patient selection is fierce, and companies are increasingly vying to have their tests put on an equal footing with tissue biopsy (Esmo 2019 – Foundation eyes liquid biopsy rule change, September 30, 2019).
“There are many, many companies in the liquid biopsy space – we believe there are too many,” says Mr Piazzalunga, not unreasonably. He believes that the market will come to a crunch point after which the less successful cancer blood test developers fall by the wayside. After that, he says, a couple of dozen test makers will remain, “and we count on being one of those”.
Having FDA clearance for a cell-counting test in three metastatic, solid tumour indications is a commercial advantage, Mr Piazzalunga says. Tests such as Foundation Medicine’s FoundationOne Liquid and Guardant Health’s Guardant360, both of which use circulating DNA rather than CTCs, are on sale in the US as lab-developed tests but are not approved or cleared by regulators.
At least one other company is also looking at CTCs: the UK-based group Angle (Interview – Aiming for a new Angle on liquid biopsy, July 25, 2017).
MSB will not disclose its sales, though Mr Piazzalunga says it is “by far the market leader” in CTC, with more 45,000 CTC tests run per year. By contrast Guardant360 is forecast to have sales of $185m in 2019 – and should Guardant’s test gain the FDA’s imprimatur too, it will likely see a bit of a sales boost.
Competition is only getting more intense, and doctors will only be convinced of the utility of cell-based tests by positive clinical data. It is data that will determine whether MSB ends up as one of the last groups standing.
https://www.evaluate.com/vantage/articles/interviews/menarini-silicon-biosystems-banks-cells-its-liquid-biopsy

Novo goes early to leapfrog haemophilia gene therapies

Novo Nordisk took an early step towards genome editing with yesterday’s Bluebird tie-up, and isn’t ruling out a move into conventional gene therapies.
Novo Nordisk claims to be a leader in haemophilia, but looks to have missed the boat with the first wave of gene therapies for the disorder.
The group acknowledged this yesterday when it struck a deal with Bluebird Bio covering in vivo genome editing, which it hopes will become the next big thing. But, like many Novo collaborations, the project is extremely early, and the haemophilia space could look very different in several years’ time.
In haemophilia A, the initial focus of the Novo-Bluebird project, several gene therapies are approaching the market. The most advanced, Biomarin’s valoctocogene roxaparvovec (valrox), is set to be filed by the end of this year, and is expected to become the third-biggest seller in the disease by 2024, according to EvaluatePharma sellside consensus.
Meanwhile, Novo’s next haemophilia hope, the tissue factor pathway inhibitor concizumab, is forecast to bring in just $47m that year. That asset is due to begin phase III development this year.

Top five haemophilia A therapies in 2024
				Annual sales ($m)
Product	Company	Description	Status	2018	2024e
Hemlibra	Roche/Chugai	Anti-factor IXa/X bispecific MAb	Marketed	230	3,979
Eloctate	Sanofi/Swedish Orphan Biovitrum	Factor VIII	Marketed	1,239	1,234
Valoctocogene roxaparvovec (valrox)	Biomarin	AAV-factor VIII gene therapy	Filing imminent	–	1,212
Advate/Adynovate	Takeda	Factor VIII	Marketed	2,860	1,173
NovoSeven	Novo Nordisk	Factor VII	Marketed	1,033	595
Source: EvaluatePharma.

Valrox and other conventional gene therapies are based around a viral vector that delivers the gene for a missing clotting factor to patients’ livers – factor VIII in the case of haemophilia A.
Meanwhile, Novo and Bluebird hope to elicit a genetic change directly in patients using the latter’s megaTAL editing technology.
Daniel Timmerman, vice-president of Novo’s biopharm transformational research unit, admitted that were the company to start developing a traditional haemophilia gene therapy now, its chances of being competitive would be “relatively slim”.
However, he stopped short of ruling out such a move. “Classic gene therapies are still attractive for Novo. We’re interested in new opportunities close to where we’re already working,” he told Vantage, citing rare genetic diseases as an area of interest for Novo and also a sector that “lends itself well to gene therapies”.
Given Novo’s reputation as a builder rather than a buyer, this seems unlikely to translate into a big acquisition. But perhaps this possibility should not be completely dismissed given the Danish group’s strategy shift last year, not long after it tried and failed to buy Ablynx (Novo casts its net wider but shrinks in the process, September 19, 2018).
MegaTALented?
Various methods are currently being explored for in vivo genome editing. Bluebird’s megaTAL platform essentially combines aspects of two better-known technologies: Talens and meganucleases.
The TAL motif is responsible for DNA binding, while the meganuclease part provides the DNA strandbreak, Mr Timmerman explained. He highlighted megaTALs’ specificity and the possibility of limiting off-target effects.
When asked why Novo had chosen not to work with traditional Talens – a space dominated by the French Car-T player Cellectis – Mr Timmerman said intellectual property had been a consideration, but that the main attraction was Bluebird’s technology.
He added that, while other genome editing modalities, including Talens, required two proteins to carry out DNA cleavage, megaTALs only needed a single molecule. This simplicity could turn out to be an advantage in a sector where caution around safety is high, he said, but conceded that this needed to be proven.
It will be a while before it becomes clear whether Novo has made a good move. The groups hope to have a candidate to take into preclinical testing by the end of the three-year collaboration.
No financial details of the deal were given, and Bluebird will continue to develop megaTALs for other applications.
Rivals include Casebia Therapeutics, a joint venture between Bayer and Crispr Therapeutics that is investigating Crispr/Cas9 in haemophilia, among other diseases. Sangamo Therapeutics has an in vivo editing candidate for haemophilia B based on its zinc finger technology, as well as its conventional AAV-vector based haemophilia A gene therapy.
Mr Timmerman noted that genome editing held the promise of a truly lifelong correction of a faulty gene, which might not be the case with gene therapies. He conceded, however, that the approach could also raise the risk of a lifelong genetic error being inadvertently introduced. No wonder Novo is taking it slowly.
https://www.evaluate.com/vantage/articles/news/deals/novo-goes-early-leapfrog-haemophilia-gene-therapies

UCB goes to Ra for a complementary approach

The $2bn takeout of Ra Pharmaceuticals provides solace for investors bemoaning the biotech market’s poor performance.

With biotech indices in the doldrums some assets are affordable again. Step forward Ra Pharmaceuticals, a group whose stock had come off 30% in the past 10 weeks, making it a perfect target for the acquisition-hungry UCB of Belgium.
The rationale for the deal is zilucoplan, Ra’s sole asset of note, which UCB hopes will boost its presence in complement-mediated diseases, most importantly myasthenia gravis. And more broadly, fuelled by optimism over the takeout’s 110% premium, many investors will look to the move as a sign that the biotech market’s pitiful performance is bottoming out.
Surprisingly, however, UCB already has a project that targets complement-mediated diseases, and does so in a way that differs from many competitors: rozanolixizumab is an inhibitor of the neonatal FcRn receptor, which is thought to control the recycling of IgG and thus reduce the activation of complement that is thought to cause autoimmune diseases like myasthenia gravis.
Ra’s zilucoplan, meanwhile, works by binding complement C5, and inhibiting its cleavage into C5a and C5b. This strategy is being pursued by several companies, including Apellis, Roche and Regeneron, which are trying to challenge the leading C5 inhibitor, Alexion’s Soliris (Ra joins the challenge to Alexion’s Soliris stranglehold, December 12, 2018).
Thus UCB’s acquisition can be read in one of two ways. Either the group is concerned that the FcRn approach is not all it was cracked up to be, and needs something better to maintain its challenge, or it wants to give itself multiple shots on goal. On a call today the Belgian group insisted that the deal was complementary, and cited the possibility of a combinatorial approach.
Alexion monopoly
Certainly, the monopoly of the mighty Alexion will prove hard to overcome. Soliris is notorious for being one of the world’s most expensive drugs, and Ra had indicated that competing on price was one possibility; UCB says it aims to price zilucoplan “in a very competitive way”.
But Alexion has no fewer than four fingers in the complement-mediated disease pie: Soliris, the Soliris follow-on Ultomiris, and two FcRn projects: ALXN1830, acquired through the takeover of Syntimmune, and ABY-039, a subcutaneous asset licensed earlier this year from Affibody.
While myasthenia gravis is UCB’s initial focus the group played up zilucoplan’s potential in other diseases, including amyotrophic lateral sclerosis. Last month the project became one of 30 selected for an academia-sponsored study called Healy ALS, based on the theory that complement-related proteins are implicated in this CNS disease.

Selected players in complement-mediated diseases
Project	Company	Mechanism	Delivery	Status
Soliris	Alexion	Anti-complement factor C5 MAb	IV	Sold for PNH, HUS & MG
Ultomiris	Alexion	Anti-complement factor C5 MAb	IV, working on SC	Sold for PNH, filed for HUS, ph3 MG
Rozanolixizumab	UCB	Anti-FcRn MAb	IV & SC	Ph3 MG
Zilucoplan	UCB (ex Ra)	Complement factor C5 inhibitor	SC	Ph 3 MG; ph2 PNH
Efgartigimod	Argenx	Anti-FcRn Ab fragment	IV, working on SC	Ph3 MG
APL-2	Apellis	Complement factor C3 inhibitor	SC	Ph3 PHN
RG6107/SKY059	Roche	Anti-complement factor C5 MAb	SC	Ph2 PNH
Pozelimab	Regeneron	Anti-complement factor C5 MAb	IV & SC	Ph2 PNH
ACH-4471	Achillion	Anti-complement factor D	Oral	Ph2 PNH
M281	Momenta	Anti-FcRn MAb	IV, SC planned	Ph2 MG
IMVT-1401	Roivant	Anti-FcRn MAb	SC	Ph2 MG
Synt001/ALXN1830	Alexion (ex Syntimmune)	Anti-FcRn MAb	IV, SC planned	Ph2 MG
ABY-039	Alexion/Affibody	Anti-FcRn bivalent Ab mimetic	SC	Ph1
Source: EvaluatePharma. PNH=paroxysmal nocturnal hemoglobinuria; HUS=haemolytic uremic syndrome; MG=myasthenia gravis.

Apart from the competition in the market, another concern is anticompetitive authorities – particularly at a time when Bristol-Myers Squibb’s takeover of Celgene and Roche’s purchase of Spark have been delayed by an unusually strict stance by the US FTC.
Indeed, it is worth considering whether UCB/Ra’s putative position in complement-mediated diseases might also be construed as anticompetitive. Perhaps Alexion’s position dispels such fears, however, and UCB today said it was confident that the Ra deal did not raise anticompetitive concerns, without elaborating further.
The all-cash transaction will see UCB pay $48 for each Ra share – the stock had previously maxed out at $36 in July – amounting to $2.5bn in total, or $2.1bn net of Ra’s cash balance.
The proof of UCB’s wisdom will be seen in early 2021, when zilucoplan’s pivotal myasthenia gravis study, Raise, reads out; a phase III trial of rozanolixizumab should yield data at roughly the same time, and the two projects are expected to generate 2024 sales of $406m and $136m respectively, according to EvaluatePharma’s sellside consensus.
Stifel analysts today opined that the UCB/Ra deal was exactly what small/mid-cap cap biotech needed right now. It is probably too soon to gauge the move’s effect on the overall space, but this morning Apellis and Momenta crept up 4% and 1%.
https://www.evaluate.com/vantage/articles/news/deals/ucb-goes-ra-complementary-approach

Frequency Therapeutics launches mid-stage study of hearing loss candidate

Dosing is underway in a Phase 2a clinical trial evaluating Frequency Therapeutics’ (FREQ +1.5%) lead candidate FX-322 in patients with stable sensorineural hearing loss (SNHL) (the most common type).

The primary efficacy endpoints are three measures of hearing ability at day 210 compared to placebo. The estimated completion date is September 2020.

The company says FX-322 is a small molecule designed to treat the underlying cause of SNHL by regenerating hair cells via the activation of progenitor cells in the cochlea (spiral cavity in the inner ear).

https://seekingalpha.com/news/3505021-frequency-therapeutics-launches-mid-stage-study-hearing-loss-candidate-fxminus-322

J&J offloads midphase pain program to Neumentum

Neumentum has licensed a midphase oral analgesic from Johnson & Johnson. The agreement covers an asset that came through a phase 2 pain trial in 2015 only to stall following the completion of the study.
J&J tested two doses of the drug, JNJ-10450232, in a trial of 269 subjects with dental pain after the surgical removal of teeth. The study compared the analgesic efficacy of capsules of JNJ-10450232 to that of placebo and acetaminophen over the six hours after treatment. Secondary endpoints looked at the change in pain intensity at multiple time points from 15 minutes to 24 hours after treatment.
The higher dose of JNJ-10450232—1000 mg—performed comparably to acetaminophen against the primary endpoint, although patients on the comparator reported numerically bigger improvements in pain in the first two hours of the trial.

Public references to JNJ-10450232, which were scant prior to the start of the phase 2 trial, dried up completely after J&J reported the data on ClinicalTrials.gov. Now, Neumentum wants to give the drug a second life and, in doing so, further its bid to become a leading non-opioid analgesic company.
“By strategically expanding our pipeline, Neumentum will be well positioned to address patients’ and providers’ needs for acute pain relief in both hospital and community settings, with both IV and oral non-opioid products,” Neumentum CEO Scott Shively said in a statement. “There is a real lack of innovation in the pain management space, despite a growing need for new options that are safe and effective.”
Neumentum wants to take JNJ-10450232, which it describes as neither an opioid nor a nonsteroidal anti-inflammatory drug, forward in the treatment of moderate to moderately severe acute pain. The deal, financial details of which were not disclosed, also gives Neumentum control of a portfolio of backup compounds.
JNJ-10450232 will slot into a pipeline spearheaded by NTM-001, a ketorolac formulation designed for the short-term management of moderately severe acute pain that requires opioid-level painkilling.
https://www.fiercebiotech.com/biotech/j-j-offloads-midphase-pain-program-to-neumentum

Seattle Genetics Starts Phase 3 for Breast Cancer Combo

Seattle Genetics, Inc. (Nasdaq:SGEN) today announced dosing of the first patient in HER2CLIMB-02, a randomized phase 3 clinical trial evaluating investigational agent tucatinib versus placebo, in combination with standard-of-care ado-trastuzumab emtansine (T-DM1, Kadcyla^®), for patients with locally advanced or metastatic HER2-positive (HER2+) breast cancer. This trial is intended to support registration in the U.S. Tucatinib is an oral, small molecule tyrosine kinase inhibitor that is highly selective for HER2.

“We are building a comprehensive strategy for tucatinib in combination with other medicines across a range of HER2-positive cancers,” said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. “We are pleased to advance this tucatinib clinical trial with the vision of improving combination outcomes for patients with HER2-positive metastatic breast cancer who receive T-DM1. This trial has the potential to support tucatinib use in earlier lines of therapy.”
HER2CLIMB-02 is a multi-center, randomized, double-blind, placebo-controlled phase 3 trial designed to evaluate tucatinib versus placebo, in combination with T-DM1, in patients with unresectable locally-advanced or metastatic HER2+ breast cancer, including those with brain metastases, who have had prior treatment with a taxane and trastuzumab in any setting. The primary endpoint is progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints include overall survival, objective response rate and duration of response. The trial is expected to enroll approximately 460 patients. More information about this phase 3 trial, including enrolling centers, is available at www.clinicaltrials.gov.
https://www.biospace.com/article/releases/seattle-genetics-announces-initiation-of-phase-3-clinical-trial-of-tucatinib-in-combination-with-ado-trastuzumab-emtansine-t-dm1-kadcyla-for-patients-with-advanced-or-metastatic-her2-positive-breast-cancer/