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Tuesday, October 1, 2019

How microbes hack into cells and why cancer drugs might block them


The lowdown on how microbes hack into cells -- and why cancer drugs might stop them
Credit: A. KITTERMAN, Science Signaling {2019) DOI: 10.1126/scisignal

No matter the pathogen—virus, bacterium or fungus—many “pick a specific type of lock” on the surface of cells, which allows the microbe to break and enter into the inner sanctum of the host’s genome.
In a sweeping analysis on how microbes hack into cells and commandeer them, Australian microbiologists say they are also uncovering mechanisms in common between microbes and . Their research suggests that in the not-too-distant future it may be possible to cure infectious diseases with repurposed , medications that can function across a broad range of pathogens, eliminating the need for antibiotics, antivirals and antifungals.
An ultimate hope, these scientists say, is ushering in the era of anti-infectives, drugs that block a vulnerable port of entry for infectious agents.
Writing in the journal Science Signaling, Dr. Gholamreza Haqshenas of Monash Biomedicine Discovery Institute in Australia, and Dr. Christian Doerig, also of Monash, as well as RMIT University in Australia, say a radically diverse group of pathogens have surprisingly evolved to subvert cells in a sly way.
While there are numerous pathways to infection, many microbes enter their hosts by hijacking signaling proteins, a finding that has become increasingly clear in recent years, Haqshenas and Doerig say.
Signaling proteins are molecules that are responsible for sending messages within and between cells. These proteins have segments above and below the cell surface, which are critical to cellular function. So it should come as no surprise, the Australian team says, that microbes responsible for some of the most serious infections have targeted a superfamily of signaling molecules—receptor tyrosine kinases—as their route into the host’s cellular domain.
Haqshenas said a vast range of pathogens have evolved mechanisms to hack into cells by targeting receptor tyrosine kinases, or RTKs. These microbes can bind to the receptor and like a safe cracker, “unlock” the cell.
“To name some important ones: Hepatitis C and ,” Haqshenas told Medical Xpress. “Among bacteria, Salmonella and Listeria monocytogenes; and among fungi, Candida albicans.”
When a bacterium, such as Chlamydia pneumoniae binds to a receptor tyrosine kinase protein on a cell’s surface, the pathogen not only commandeers the cell, it stimulates signaling, the messages that control the cell. The pathogen assumes command of everything including the cell’s structure, its cytoskeleton, thereby easing its entry into the cell.
The RTK superfamily, which has about 58 members, function as the cell receptors for numerous biological growth factors, such as , platelet-derived and , to name a few. These factors are like keys that once bound to the receptor can unlock it and enter the cell. An overabundance of RTKs occurs in some cancers, which can lead to cancer progression. RTK blockers, medications referred to as small-molecule drugs, have been developed to treat a form of leukemia and a rare intestinal cancer, which are marked by excessive RTKs. Gleevec was the first developed in this class and was approved by the U.S. Food and Drug Administration nearly two decades ago.
Although Haqshenas and Doerig report that a veritable rogue’s gallery of viruses can commandeer as an entryway into cells, Doerig underscored “there are other mechanisms of entry for some bacteria.”
Pathogens that use the RTK route to infection have evolved specialized mechanisms that have allowed them to hack their way into host cells via this passageway.
For example, Chikungunya, Ebola, Eastern equine encephalitis and Japanese encephalitis viruses enter cells via RTKs. In addition, cytomegalovirus, dengue, 1, , Lassa, Marburg, respiratory syncytial, yellow fever, West Nile and Zika viruses break and enter through the receptor tyrosine kinase pathway.
The list is longer still, according to Haqshenas and Doerig, who say it also includes Kaposi’s sarcoma-associated herpesvirus, lymphocytic choriomeningitis, Rose River and vaccinia viruses, pathogens that also preferentially hack their way into host cells by unlocking RTKs.
“The commonality of relying on the same RTKs suggests that selective inhibitors against specific RTKs may have broad spectrum anti-infective properties. Definitely worth further investigation,” Doerig said.
Haqshenas likewise sees their new analysis as a springboard to further research that explores the possibility of using existing drugs in new ways against infectious agents.
“Our review highlights the importance of RTKs in the biology of many pathogens of importance to public health,” Haqshenas said. “Currently, RTKs are common targets of anti-cancer drugs. The review highlights that FDA-approved anti-cancer drugs can be repurposed for the treatment of infections caused by a wide range of that must enter host to complete their life cycle.
“This approach will significantly reduce the cost of anti-infective drug development, and, because a cellular protein is targeted, it reduces the chance of drug resistance,” Haqshenas said.

Explore further
Study points to new approach to battling infections

More information: Gholamreza Haqshenas et al. Targeting of host cell receptor tyrosine kinases by intracellular pathogens, Science Signaling {2019) DOI: 10.1126/scisignal.aau9894

Stifel Bullish On Iovance And Fate Therapeutics, Neutral On Bluebird Bio

Stifel initiated coverage on a trio of oncology-focused biotechs Tuesday, recommending buying two and staying sidelined on a third.

The Analyst

Benjamin Burnett initiated coverage of:
bluebird bio Inc NASDAQ: BLUE) with a Hold rating and $109 price target.
Iovance Biotherapeutics Inc NASDAQ: IOVA) with a Buy rating and $27 price target
Fate Therapeutics Inc FATE 4.76% with a Buy rating and $27 price target

Gene Therapy Launch, Multiple Myeloma Uncertainty Temper Optimism On Bluebird

The slow launch anticipated for Zynteglo, bluebird bio’s gene therapy to treat transfusion-dependent β-thalassemia, and competitive programs imparting uncertainty to its multiple myeloma market have left Stifel wary of bluebird bio.
These concerns are likely to be mitigated by a neutral stance on Lenti-D in cerebral adrenoleukodystrophy, an inherited neurological disorder, and Burnett’s confidence in the company’s ability to churn out new assets, providing further diversification for the longer term.

Blockbuster Potential For Iovance’s TIL Product In Melanoma, Cervical Cancer

The market opportunity for an autologous tumor infiltrating lymphocyte therapy in advanced melanoma/cervical cancer settings could reach a peak of more than $2 billion, Burnett said.
The analyst said he expects the upcoming pivotal readouts to be positive. Additionally, the competitive landscape appears to be favorable for Iovance, he said.

Stifel Likes Setup Into FT500, FT516 Data Readouts

The data readout on Fate’s iPSC-derived NK cell cancer immunotherapy FT500 due later this year is likely to validate the safety of the iPSC-derived NK cell platform, Burnett said.
The analyst is also positive about the potential for FT516 to generate competitive efficacy data in acute myeloid leukemia.
“Additionally, we also believe the cadence of INDs, two within the next 6-9 months, will further drive enthusiasm for the platform while diversifying the company’s opportunity set within oncology.”
https://www.benzinga.com/analyst-ratings/analyst-color/19/10/14523033/stifel-bullish-on-iovance-and-fate-therapeutics-neutral-on-bluebird-bio

Esmo 2019 – Clovis is running out of waves to catch

In prostate cancer Clovis could be adopting a more realistic regulatory stance with its Parp than Astrazeneca and Merck & Co. In the long run will it matter much?

Amid much fanfare around successful pivotal trials of Lynparza and Zejula at this year’s Esmo Congress, Clovis Oncology struggled to get much attention for its own Parp inhibitor, Rubraca, despite also presenting registrational data. The situation echoes the larger reality here: as a small fish in this particular pond, Clovis is struggling to compete.
The small biotech’s main reveal at Esmo was the full Triton2 dataset, on which Rubraca will be filed for accelerated approval in a third-line prostate cancer setting. A look at the developing results from Parp inhibitors in this tumour type suggests that Rubraca is just as effective as its rivals – caveats notwithstanding – while Clovis’s focus on patients with BRCA mutations seems an arguably more realistic regulatory strategy than Astrazenca’s (Esmo 2019 – A place for Parps in prostate cancer, September 30, 2019).
The potential presence of Lynparza on the market in an earlier setting than Rubraca is ultimately the more important point here – Astra’s Profound trial was conducted in a second-line setting – and there is little evidence to support retreating patients with a Parp inhibitor. But, should Astra and Merck’s determination to seek approval in a broader patient group slow Lynparza’s progress with regulators, Clovis might achieve a few more months alone on the market.
Cross-trial analysis of Parp inhibitors in prostate cancer, by genetic mutation type

Lynparza: Profound (P3, 2nd-line )  Rubraca: Triton2 (P2; 3rd-line) Zejula: Galahad (P2; 3rd-line)* Lynparza: Toparp-b (P2; 3rd-line)
Mutation type ORR (n) ORR (n) ORR (n) ORR (n)
BRCA1/2
44% (25/57) 41% (12/29) 52% (11/21)
ATM
10% (2/21) 9% (2/22) [Result in all other gene types combined] 8% (1/12)
BRCA1/2 +ATM 33% (84/256) 35% (27/78)** 36% (12/33)**
CDK12
0 (0/9) 0% (0/18)
CHEK2
0 (0/5)
PALB2
n/a 33% (2/6)
Other
39% (5/13) 0% (0/17)
*Galahad selected for patients with biallelic mutations only, though this is no longer considered relevant in predicting response to a Parp inhibitor. **Calculated by Vantage. ORR=objective response rate. Source: Esmo 2019 presentations, Asco 2019 for Toparp-B.
A look at the data on Parp inhibitors in prostate cancer shows that these agents have generated roughly similar response rates, in patients with BRCA1 and 2 mutations. This gene is associated with the strongest responses to Parp inhibition, although other mutations related to homologous recombination repair (HRR) mechanisms are thought to confer sensitivity – a hypothesis that was most definitively confirmed in ovarian cancer over the weekend.
In prostate cancer, however, the role of other genes is far less clear. This is why Astrazeneca’s assertion that it will seek approval in all patients with HRR associated genes is controversial; on an investor call yesterday executives left little doubt that this was in fact their intention.
“We designed Profound specifically with the intention that, if both cohorts were positive, we would be seeking a label in the HRRm population,” said Dave Fredrickson, head of oncology for Astrazeneca.
Exploratory gene-by-gene analysis from Profound.
M Hussain, Esmo 2019 Profound presentation.
Very little breakdown of response by gene mutation type was given at Esmo – Astra said this analysis is still being undertaken – although it is clear that regulators will think hard about a broad label. The ATM cohort is important because these patients were combined with BRCA1/2 patients for the primary analysis of Profound; while these patients seem to respond to Lynparza, very similar responses were seen in the control group, which was either Zytiga or Xtandi.
Clovis also enrolled these patients in Triton2, but Pat Mahaffy, its chief executive, made it clear that the company had no expectation of approval in this subset.
“It’s a little early to speculate on the label, but it will be limited to BRCA mutants,” he told investors on a call over the weekend.
Given that Clovis desperately needs to get Rubraca to market before Lynparza, not stretching the data too far here is probably wise. Particularly as the company’s chances to catch up are fairly distant: pivotal, second-line prostate cancer data are unlikely to emerge before 2022.
In ovarian cancer the company is also lagging: a phase III study testing Rubraca in combination with Opdivo, in a front-line maintenance setting, are slated for 2024.
Sellside forecasts from EvaluatePharma show the Parp market growing strongly, and it is estimated to be worth $5.7bn by 2024. But Rubraca numbers have been falling, along with Clovis’s valuation; its market cap now sits at a mere $215m, after plunging 87% in the last 12 months. A long-rumoured takeout of the company is looking ever more unlikely, particularly since any buyer could presumably pay considerably less in another 12 months.
A changing outlook for the Parp market
Product Company 2020e ($m) 2024e ($m) 12-mth change in 2024 forecast
Lynparza Astrazeneca 1,518 2,871 22%
Zejula Glaxosmithkline 497 1,232 13%
Rubraca Clovis Oncology 217 788 -52%
Talzenna Pfizer 103 354 -72%
Total market incl. others 2,353 5,746
Source: EvaluatePharma.
https://www.evaluate.com/vantage/articles/events/conferences/esmo-2019-clovis-running-out-waves-catch

TCT 2019 – Abbott’s aortic valve disappoints

Portico hits noninferiority, but safety looks doubtful. Abbott might want to prioritise a different approach.
The approval trial of Abbott Laboratories’ Portico catheter-based aortic prosthesis disappointed on safety at the weekend, but promising early results with a different technology, the TriClip tricuspid repair product, might be of more use to the company.
Portico will probably still get approved for aortic replacement, but compared against the wildly successful established products – Edwards Lifesciences’ Sapien and Medtronic’s CoreValve – it will likely be an afterthought in terms of sales.
On the threshold
On the surface the pivotal Portico data, presented on Saturday at the TCT meeting in San Francisco, look positive. Portico was noninferior to Sapien and Medtronic’s CoreValve on the primary efficacy endpoint, a composite of mortality and disabling stroke at one year, in 750 extreme and high-risk symptomatic severe aortic stenosis patients (p=0.006).
But this event rate was numerically higher in the Portico arm, at 14.9% versus 13.4% for the commercial valves. This was driven by all-cause mortality, at 14.3% with Portico compared with 12.0% in the control arm. Rates of paravalvular leak, vascular complications and new pacemaker implantation were all also higher in the Portico arm.
The primary safety endpoint, a composite of mortality, stroke, bleeding requiring blood transfusion, acute kidney injury, or major vascular complications at 30 days, was also numerically higher with Portico, at 13.8% versus 9.6% with Sapien and CoreValve.
The rate of leaflet thrombosis was not presented at TCT despite a relatively high rate of this event having caused the trial to be paused for nearly a year from September 2014. These data should emerge next year.
Abbott intends to launch Portico in the US in about a year’s time, but it seems unlikely that the product will pick up much traction against the various valves in the Sapien and CoreValve ranges, which have about 60% and 35% of the global transcatheter aortic replacement market respectively. Current sellside consensus for Portico, as compiled by EvaluateMedTech, has the device selling $97m this year, rising to just $281m in 2024.
Tri hard
If Edwards and Medtronic have the aortic replacement market sewn up, Abbott is holding its own in a different area: the repair of the mitral valve. Its MitraClip device is forecast to have sales of $707m this year, according to EvaluateMedTech’s sellside consensus, and ought to break the $1bn barrier in 2021.
The company’s TriClip tricuspid repair device is, it seems, on the way to joining its cousin on the market following the presentation of six-month safety data from the Triluminate trial. This study hit its efficacy endpoint in the spring, but it was the safety data cardiologists were waiting for (Abbott shifts to tricuspid repair, May 22, 2019).
At six months 3.7% of the 85 patients in the single-arm trial had had a major adverse event, significantly less than the prespecified goal of 39%. These events were two cardiovascular deaths and one new-onset renal failure.
The US approval trial of TriClip is already under way. Triluminate Pivotal will enrol 700 patients with severe regurgitation in spite of previous treatments, and will compare the use of TriClip with drug therapy.
The primary outcome is a composite of all-cause mortality, tricuspid valve surgery, rate of heart failure hospitalisations, and quality of life improvement, and data could emerge in August 2022. As this date approaches it will be interesting to see whether the sellside sees TriClip going the way of MitraClip – or Portico.
Company Device Technology Trial
Abbott Portico Aortic valve replacement Portico pivotal trial 
Boston Scientific Acurate Neo Aortic valve replacement Scope I
Abbott TriClip Tricuspid valve repair Triluminate Pivotal
Abbott TriClip Tricuspid valve repair Triluminate 
https://www.evaluate.com/vantage/articles/events/conferences/tct-2019-abbotts-aortic-valve-disappoints

Watchdog: DEA allowed rise in opioid production as overdose deaths rose

The Drug Enforcement Agency (DEA) allowed drug makers to increase production of opioids even as overdose deaths were skyrocketing, according to a government watchdog’s scathing report released Tuesday.
While opioid overdose deaths grew by 8 percent per year from 1999 through 2013, and by 71 percent per year between 2013 and 2017, the DEA authorized manufacturers to produce “substantially larger amounts of opioids,” reads the report from the Justice Department’s Office of the Inspector General.
The DEA was “slow” to address the opioid epidemic and did not substantially reduce the number of pills drug makers were permitted to make until 2017, the same year overdose deaths hit a record high, the report says.
“We found that DEA was slow to respond to this growing public health crisis and that its regulatory and enforcement efforts could have been more effective,” said Inspector General Michael Horowitz in a video statement.
The report comes as health officials and state and federal governments look to hold accountable entities that spurned the epidemic, which killed about 400,000 people between 1999 and 2017.
State and local governments have filed hundreds of lawsuits against drug manufacturers and distributors that they argue knowingly caused the epidemic by understating the addictive properties of opioids.
But the report issued Tuesday indicates the federal government also played a role. The DEA, which is charged with keeping controlled substances from being diverted for abuse, had already been criticized by advocates for not using its powers to curb the opioid epidemic.
“Every aspect of the pharmaceutical supply chain bears responsibility for the havoc and senseless death unleashed upon West Virginia – and the DEA is no exception,” said West Virginia Attorney General Patrick Morrisey, who sued the DEA over its quota system.
“For years, the DEA was grossly negligent in its mismanagement of the national drug quota system. Unfortunately, this mismanagement contributed to the senseless death of many Americans.”
Every year, the DEA sets a quota for how many opioid pills drugmakers are allowed to produce in the U.S.
The DEA permitted drugmakers to increase their production of oxycodone, a highly addictive painkiller, by 400 percent between 2002 and 2013, according to the report.
The DEA didn’t substantially cut the quota until 2017, when opioid overdose deaths reached a peak in the U.S., according to the report.
That year, the DEA cut the quota by 25 percent, and a record-high 48,000 people died from opioid overdoses.

Janssen Invokana 1st Drug Approved in 20 Years to Slow Diabetic Kidney Disease

A little more than one year after posting landmark data, Janssen’s Invokana snagged another regulatory approval to reduce the risk of end-stage kidney disease, cardiovascular death and worsening of kidney function in adults with type 2 diabetes and diabetic kidney disease.
On Monday, the U.S. Food and Drug Administration (FDA) awarded Invokana with the new indication. Specifically, the FDA approved Invokana (canagliflozin) as a treatment to reduce the risk of end-stage kidney disease (ESKD), worsening of kidney function, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes and diabetic kidney disease (nephropathy) with a certain amount of protein in the urine. The approvals marks Invokana as the only type 2 diabetes medicine indicated to both treat diabetic kidney disease and reduce the risk of hospitalization for heart failure in patients with T2D and diabetic kidney disease (DKD). T2D is the leading cause of kidney disease in the United States and the fifth fastest-growing cause of death around the world, Janssen noted in its announcement.
James List, global therapeutic head for cardiovascular & metabolism at Janssen Research & Development, touted the approval as a significant new treatment option for diabetic patients. He said the approval “addresses serious unmet needs and could change the trajectory of care for the many millions of patients living with type 2 diabetes and diabetic kidney disease.”
The approval was based on the landmark CREDENCE trial after Invokana demonstrated a 30% reduction in the risk of the primary composite endpoint, which was comprised of progression to doubling of serum creatinine, ESKD and renal or CV death. Invokana reduced the risk of CV death and hospitalization for heart failure by 31%. The medication also reduced major adverse CV events, including nonfatal stroke and CV death, by 20%. The risk of hospitalization for heart failure was reduced by 39%. Also, the CREDENCE study showed no imbalance in amputation or bone fracture, Janssen said.
In the United States, one in three people with T2D has DKD, which multiplies the risk of cardiovascular complications including heart failure and CV death, and puts patients on a trajectory to dialysis and kidney transplant. With this approval, Invokana is the only type 2 diabetes medicine indicated to reduce the risk of hospitalization for heart failure in patients with T2D and DKD, and is the first new treatment option in nearly 20 years indicated to slow the progression of DKD in these patients, Janssen said.
CREDENCE study investigator George Bakris, director of the Comprehensive Hypertension Center at the University of Chicago, said millions of type 2 diabetes patients have DKD and most are not aware of the situation. By the time it is diagnosed, Bakris said the patients have progressed to the point where dialysis is inevitable.
“For nearly two decades, we’ve been searching for a treatment that can help us intervene earlier to slow kidney disease progression. With the approval for this new indication for Invokana, physicians will not only be able to help reduce the risks associated with diabetic kidney disease, but also reduce the risk of hospitalization for heart failure in patients with T2D and DKD,” Bakris said in a statement.
Invokana, a sodium glucose co-transporter 2 (SGLT2) inhibitors, has previously been approved by the U.S. Food and Drug Administration as a treatment to improve glycemic control in adults with type 2 diabetes. SGLT2s are proteins found in the kidneys that are important in the reabsorption of glucose by the kidneys. The drug does come with a black box warning for an increased risk of lower-limb amputations. In the CREDENCE trial, Janssen said there was no imbalance in lower limb amputation or bone fracture in this trial and no new safety signals were identified.
https://www.biospace.com/article/janssen-s-invokana-snags-approval-to-treat-diabetes-related-kidney-disease/

Novartis, Microsoft team for AI drug development

Novartis (NVS -1.3%) and Microsoft (MSFT -0.3%) form a five-year partnership to use AI to design, personalize, and optimize the development of CAR-T cancer therapy.
Novartis is setting up the Novartis AI innovation lab with Microsoft as the partner to bring together NVS data sets with Microsoft’s AI solutions to create new models and applications. The lab will also tackle computational challenges such as the optimization of cell and gene therapies at scale.
Financial terms weren’t disclosed.
https://seekingalpha.com/news/3502937-novartis-microsoft-team-ai-drug-development