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Saturday, May 26, 2018

Leg exercise is critical to brain and nervous system health


Groundbreaking research shows that neurological health depends as much on signals sent by the body’s large, leg muscles to the brain as it does on directives from the brain to the muscles. Published today in Frontiers in Neuroscience, the study fundamentally alters brain and nervous system medicine—giving doctors new clues as to why patients with motor neuron disease, multiple sclerosis, spinal muscular atrophy and other neurological diseases often rapidly decline when their movement becomes limited.
“Our study supports the notion that people who are unable to do load-bearing exercises—such as patients who are bed-ridden, or even astronauts on extended travel—not only lose muscle mass, but their body chemistry is altered at the cellular level and even their nervous system is adversely impacted,” says Dr. Raffaella Adami from the Università degli Studi di Milano, Italy.
The study involved restricting mice from using their hind legs, but not their front legs, over a period of 28 days. The mice continued to eat and groom normally and did not exhibit stress. At the end of the trial, the researchers examined an area of the brain called the sub-ventricular zone, which in many mammals has the role of maintaining nerve cell . It is also the area where  produce new neurons.
Limiting physical activity decreased the number of neural stem cells by 70 percent compared to a control group of mice, which were allowed to roam. Furthermore, both neurons and oligodendrocytes—specialized cells that support and insulate nerve cells—didn’t fully mature when exercise was severely reduced.
The research shows that using the legs, particularly in weight-bearing exercise, sends signals to the brain that are vital for the production of healthy neural cells, essential for the brain and nervous system. Cutting back on exercise makes it difficult for the body to produce new nerve cells—some of the very building blocks that allow us to handle stress and adapt to challenge in our lives.
“It is no accident that we are meant to be active: to walk, run, crouch to sit, and use our  to lift things,” says Adami. “Neurological health is not a one-way street with the brain telling the muscles ‘lift,’ ‘walk,’ and so on.”
The researchers gained more insight by analyzing individual . They found that restricting exercise lowers the amount of oxygen in the body, which creates an anaerobic environment and alters metabolism. Reducing exercise also seems to impact two genes, one of which, CDK5Rap1, is very important for the health of mitochondria—the cellular powerhouse that releases energy the body can then use. This represents another feedback loop.
These results shed light on several important health issues, ranging from concerns about cardio-vascular impacts as a result of sedentary lifestyles to insight into devastating diseases, such as  (SMA), , and , among others.
“I have been interested in  since 2004,” says co-author Dr. Daniele Bottai, also from the Università degli Studi di Milano. “The question I asked myself was: is the outcome of these diseases due exclusively to the lesions that form on the spinal cord in the case of spinal cord injury and genetic mutation in the case of SMA, or is the lower capacity for movement the critical factor that exacerbates the disease?”
This research demonstrates the critical role of movement and has a range of potential implications. For example, missions to send astronauts into space for months or even years should keep in mind that gravity and load-bearing  play an important role in maintaining human health, say the researchers.
“One could say our health is grounded on Earth in ways we are just beginning to understand,” concludes Bottai.
More information: Frontiers in Neuroscience (2018). DOI: 10.3389/fnins.2018.00336

Weight loss after obesity surgery restores testosterone production in obese men


New research presented at this year’s European Congress on Obesity (ECO) in Vienna, Austria (23-26) May shows that weight reduction following a sleeve gastrectomy (obesity surgery), which reduces the size of the stomach, can rapidly reverse obesity-related hypogonadism in morbidly obese men, restoring normal levels of testosterone and sex drive. The study was conducted by Prof Marco Rossato and colleagues at the University of Padova, Italy.
Obesity in men is associated with hypogonadism; a condition in which production of  is reduced, while estrogen  are elevated. These effects seem to be the result of excess body fat interfering with sex steroid metabolism which leads to increased aromatisation of androgens (such as testosterone) into estrogens within the adipose tissue itself. It follows that  loss should improve this hormonal imbalance, and contribute to a reversal of hypogonadism.
Research conducted so far has been limited to evaluating the effects of weight loss on male hypogonadism a long time after the reduction in body fat has occurred, so it was not known how rapidly hormones began to return to normal in human subjects. The goal of this study was to investigate levels of sex steroids immediately after rapid weight loss in a group of obese men who had undergone bariatric surgery, to determine how quickly those changes occurred.
The authors selected a group of 29 obese men with an average age of 40.5 years and an average body mass index (BMI) of 43.4kg/m2 (morbidly obese is defined as >40kg/m2). Blood tests were performed to measure total plasma testosterone, the sex hormones dihydrotestosterone (DHT), estradiol, luteinising hormone (LH), follicle-stimulating hormone (FSH), as well as sex hormone binding globulin (SHBG), prostatic-specific antigen (PSA), and leptin in subjects before and one month after they underwent a sleeve gastrectomy to reduce the size of the stomach. As a control, the team studied a group of 19 healthy age-matched, non-obese male subjects.
The study found that among the obese subjects, 51.6% had hypogonadism and of those who had subnormal total testosterone, those with metabolic syndrome (45.2%) showed lower plasma testosterone than men without metabolic syndrome. BMI and waist circumference were found to be negatively correlated with total testosterone and plasma LH levels. Obese males had lower plasma testosterone than healthy subjects (10.8 vs. 15.7 nmol/L), higher estradiol levels (124.4 vs. 78.8 pmol/L), lower LH and FSH levels (3.6 and 2.5 vs 5.2 and 5.9 IU/L respectively). No differences were observed between the two groups in their DHT and PSA levels.
One month after the , obese subjects showed a significant , averaging 17.2 kg and the proportion with hypogonadism had fallen to 11.6%. Average testosterone levels increased by 85%, to a level greater than that observed in the healthy control group (18.9 vs 15.7 nmol/L). Estradiol levels fell by 35% while PSA levels rose by 70%.
The study demonstrates that while obese males show an elevated prevalence of hypogonadism, this is rapidly reversed (within one month) after significant weight loss following bariatric surgery. Testosterone levels are increased significantly while estradiol levels fall due to the rapid and significant loss of fat mass and the consequent decrease in aromatization of androgens to estrogens that typically occur in adipose tissue.
The authors note that: “The clinical significance of the rapid increase in PSA plasma levels observed one month after bariatric surgery is still obscure and has to be confirmed on a larger number of subjects and after a longer period of observation after surgery and weight reduction maintenance”.
They suggest that “it could be due to the rapid testosterone increase stimulating the prostate and/or to the rapid reduction in plasma volume after “.
The authors also add a note of caution regarding low PSA levels that can be observed in obese men, since these can underestimate the true levels of PSA that would be seen if these men were normal weight. They say: “If you consider that obese males, as with all people with obesity, have higher prevalence of some type of cancer, including prostate cancer for men, this information could be of importance, since it could lead to doctors potentially missing cases of severe prostate disease in .”

Details about formaldehyde in e-cigarettes


Do e-cigarettes produce dangerous formaldehyde levels? This question has split scientific opinion for years. A new study reopens the discussion.
Man vaping
The toxicity of vaping is once again being debated.
Three years ago, researchers at Portland State University in Oregon conducted a study that found previously unknown forms of formaldehyde in the vapor of electronic cigarettes (e-cigarettes).
Following criticism of their work, the researchers revisited their investigation. Their findings are published in the journal Scientific Reports.
This time, they concluded that the risk posed by the formaldehyde content of e-cigarettes is, in fact, greater than they had originally believed.
Formaldehyde is a naturally occurring chemical that is used in the manufacture of building materials and many household products. Industrially, formaldehyde is used as a disinfectant, and as a preservative in medical laboratories and mortuaries.
As well as building materials and cleaning products, formaldehyde can also be found in the smoke from cigarettes, unvented gas stoves, wood-burning stoves, and kerosene heaters.
Since the early 1980s, doctors have suspected that formaldehyde is a carcinogen — a substance capable of causing cancer in living tissue.
And finally, in 2011, after many studies, the Department of Health and Human Services’ National Toxicology Program officially confirmed that formaldehyde is a human carcinogen.

What did the original study report?

The original 2015 study that investigated formaldehyde and e-cigarettes was led by David Peyton, Robert Strongin, and James Pankow. It identified new forms of formaldehyde in e-cigarette vapor that were at levels five to 15 times higher than those in normal cigarettes.
The study also found that these new formaldehyde compounds could be drawn much more deeply into the lungs than the “gaseous” formaldehyde in cigarette smoke, because the new compounds bound to particles in the e-cigarette aerosols.
The researchers discovered the formaldehyde compounds when the vaping device in their study was set at a high heat setting. This proved controversial, as some advocates for e-cigarettes argued that most e-cigarette users would not use such a high setting.
This claim was supported by other scientists in 2017 when they attempted to replicate the Portland team’s results with the device at a lower heat setting.

What did the new study find?

The Portland team argued that the 2017 reinvestigation of their work was flawed because it ignored the new formaldehyde compounds discovered in the 2015 paper.
Instead, the authors of the replication study simply stated that the more common “gaseous” form of formaldehyde would not affect e-cigarette users at intermediate heats.
In their latest study, Peyton, Strongin, and Pankow used an intermediate power setting that was chosen to represent “normal” vaping conditions. They also claim that they used an improved method to collect samples compared with the original 2015 investigation.
Their new study reports that not only are the new formaldehyde types identified in the 2015 study present when e-cigarettes are used at lower, more “normal” heat settings, but also that gaseous formaldehyde is also present in the vapor at dangerous levels.
As the researchers explain, one limitation of the study is that they did not use human subjects, so we do not know how humans would be affected by the formaldehyde in e-cigarettes.
However, Strongin remains concerned about the public health implications of their findings, saying, “In 2016, more than 9 million Americans were current e-cigarette users, including more than 2 million United States middle and high school students.”

Biotech week ahead, May 27


Biotech shares put up a lackadaisical show this week, as reflected by the iShares NASDAQ Biotechnology Index (ETF) IBB 0.2%. With earnings season winding down, FDA decisions and data presentations at conferences served as catalysts for stocks in the week.
Here’re are the key catalytic events in the upcoming week biotech investors need to be mindful about.

Medical/Healthcare/Biotech Conferences

  • European Society of Cardiology, or ESC, World Congress on Acute Heart Failure – May 26-May 29, in Vienna, Austria
  • 2018 American Society of Clinical Oncology Annual Meeting – June 1-5, McCormick Place, Chicago, Illinois

PDUFA Dates

Sunday, May 27
TherapeuticsMD Inc TXMD 5.09%, which was mired in a controversyover a website error following an erroneous post about FDA approval for its vaginal pain treatment candidate TX-004HR, awaits the FDA ruling on May 27.
The candidate was handed a complete response letter, or CRL, on May 8, 2017, citing a lack of long-term endometrial safety. Following a resubmission and FDA’s acceptance of theresubmission on Dec. 19, 2017, the new PDUFA action date was set.
Thursday, May 31
The FDA is set to announce its verdict on KITOV PHARMA LT/S ADR KTOV 0.99%‘s osteoarthritis and hypertension treatment candidate KIT-302 on May 31.

Clinical Trial Outcomes

ABIOMED, Inc. ABMD 0.05% is due to make an oral presentation of the Phase 2b data for its chronic heart failure treatment candidate gencaro at the ESC World Congress on Acute Heart Failure on Sunday, May 27. The data released in February didn’t show any benefit in overall population.

ASCO Presentations

Friday, June 1
Incyte Corporation INCY 2.64% – The company will make an oral presentation of the Phase 1 data for its relapsed/refractory multiple myeloma treatment candidate ruxolitinib at 3:45 p.m. ET.
bluebird bio Inc BLUE 0.61% – Celgene and bluebird bio will present additional Phase 1 data for their relapsed/multiple myeloma treatment candidate bb2121 at 3:45 p.m. ET. Preliminary Phase 1 data released at the American Society of Hematology 2017 meeting showed overall response rate of 94 percent and complete response of 56 percent.
Celgene Corporation CELG 1.14% – The company will present Phase 3 data for its refractory multiple myeloma treatment candidate MM-007. Data released in Febraury showed that the study, dubbed OPTIMISMM, met the primary endpoint of progression free survival.

Saturday, June 2
Syndax Pharmaceuticals Inc SNDX 0.55% – The company will make a poster presentation of its solid tumor pipeline candidate entinostat.
Loxo Oncology Inc LOXO 1.08% – The company is set to present Phase 1 data for its LOXO-292, for treating RET-fusion non-small cell lung cancer, or NSCLC, medullary thyroid cancer and other tumors.
Exelixis, Inc. EXEL 1.66% – Exelixis will present Phase 1 data on its urothelial carcinoma treatment combo cabometyx and nivolumab-ipilimumab combined.
Karyopharm Therapeutics Inc KPTI 1.96% is due to release Phase 2/3 data for selinexsor for treating dedifferentiated liposarcoma.
Endocyte, Inc. ECYT 5.19% – The company will present Phase 3 data for its metastatic castration-resistant prostate cancer treatment candidate Lu-PSMA-617.
Celldex Therapeutics, Inc. (NASDAQ: CLDX – 2) – The company will present a poster of the Phase 2 data for its recurrent/metastatic head and neck squamous cell cancer candidate CDX-3379 at 1:15 pm CT. The company is also scheduled to make a oral presentation of Phase 2 data for its combo solid tumor treatment candidate varlilumab and nivolumab.
Jounce Therapeutics Inc NASDAQJNCEO – The company will present preliminary Phase 1/2 data for its solid tumor candidate JTX-2011. When the abstract data was publish on May 17, thestock slumped about 35 percent, with analyst attributing the stock decline to underwhelming objective response rate shown by the study.
Nektar Therapeutics NKTR 0.77% & Bristol-Myers Squibb Co BMY 0.15% – The companies will present preliminary Phase 1/2 data on NKTR-214-Opdivo combo from a study dubbed PIVOT-02. The combo is being evaluated for treating a variety of cancers, including melanoma, renal cell carcinoma and NSCLC.

Earnings

Wednesday, May 30
Thursday, May 31

IPOs

Quiet Period Expirations
Inspire Medical Systems Inc INSP 6.39% – Priced at $15 on May 3
Unity Biotechnology Inc UBX 1.88% – Priced at $17 on May 3
Aslan Pharmaceuticals ASLN 0.66% – Priced at $7.03 on May 4

Past ASCOs point to top drugs


To prepare for the future, it helps to look back on what has happened in the past. ASCO is a great benchmark for doing that. Drug development does not happen overnight. A pattern of real progress emerges if you view things in the context of two “ASCOs” ago, or five, or ten. I always try to approach it from this macro perspective as I prepare for the conference because it helps set the stage for how today’s new developments might fit in.
Consider the following:
One ASCO ago we were wowed by the ability of precision oncology to treat patients based on a specific genetic mutation (NTRK) rather than where cancer originated in the body. That drug (larotrectinib) is currently in front of FDA and another (Keytruda) has since been the first approved for a non-tumor specific indication. This trend will continue. Roche was smart to buy Ignyta, as these are small but potent indications. They were also smart to invest in Foundation Medicine a few ASCOs ago and their foresight on that is finally paying off. Expect to be hearing about precision strategies for many more ASCOs to come.
Four ASCOs ago, there were no PD-1s approved. Can you believe that? I know it feels more like a decade, but it is important to know that this is still only early days for the class. In those four years, we have learned what types of cancers the drugs work for as monotherapy, in what cases combinations are needed, how many patients of various cancer types are responding, and hints of biomarker strategies are starting to emerge. No doubt there have been disappointments on the combo side of things, but as our understanding of these drugs and the tumor microenvironment improves, so will the chances of something breaking through.
Cell therapy? One ASCO ago this was still just a concept and many doubted it could cross the regulatory finish line. Since then we have seen landmark approvals of CD19 CARs and a rush of investment from all around the world. I don’t think it is an exaggeration to say this is the fastest moving science in oncology. What is on the market today could be obsolete as soon as just a couple ASCOs from now. The next versions of these therapies are likely to be very dynamic and powerful.
Four ASCOs ago there were also no PARP inhibitors approved. While the first (Lynparza) was ahead of its time, it is only now that PARPs are getting interesting with newcomers on the market and some compelling combo trials underway. Combo data has largely been disappointing so far, but I think this is only a matter of time. Merck, a leader in oncology, made a significant investment in a PARP last year and you can bet it is because they see substantial utility in more cancers to come. 2018 could finally be a breakout year for this class.
With that past history in mind, here are things I am watching for at ASCO 2018 to build on the success. Note: these are things I’m personally interested in and this is definitely not an exhaustive list for the entire conference.
Targeted Therapies
Loxo is looking like it might be the star of ASCO two years in a row. Has such a small biotech company ever done that before? Has any company period? Welcome to 2018, where most of the innovation in drug development is coming from the mid and small cap range of our sector. As far as RET goes, this is clearly an excellent target. The only question at this point is whether $LOXO or $BPMC is going to come out on top.
Checkpoints
Merck’s Keynote-042 presentation has a chance to be the biggest news coming out of ASCO. This is Keytruda monotherapy in patients with >1% PD-L1 expression. We already know the trial succeeded on OS but what we don’t know yet is if the success is largely due to strong responses from the high PD-1 patients or if those closer to 1% also saw compelling results. We’ll need to see different cuts at the data at ASCO for the answer. “Chemo free” is a term that is sneaking into the advertising campaigns of these companies lately. With stellar results in low expressers, it would be a big win for immunotherapy and the “chemo free” movement. Good data here might make treatment choices (whether to go mono or combo) quite difficult for some physicians and patients in the future.
Bristol (does anybody remember them?) is presenting IO/chemo combo data from Checkmate-227 in 1L NSCLC patients with <1% tumor PD-L1 expression. The hazard ratio for PFS from the abstract looks comparable to what Merck has presented in the past and will lend some credence to Bristol’s suggestion that these two drugs are in fact Coke and Pepsi. However, we ultimately have to wait for OS results to make a final call on that. This is still an important presentation because Bristol could use some good news in 1L lung. AACR illustrated what a tough hill they have to climb to convince physicians on the validity of TMB so any presentation like this that doesn’t necessarily rely on it is a welcome event for them.
Roche’s IMpower131 late breaker studying Tecentriq in combination with chemo in advanced squamous NSCLC was setting up to be an interesting event (though only PFS data is available). And then the king of lung cancer Merck announced on Wednesday that its Keynote-407 study in the squamous histology hit on both PFS and OS. When it comes to lung cancer, all hail the king.
Cell Therapies
CAR-T was rightfully named ASCO’s 2018 clinical Advance of the Year. Will the data continue to live up to the excitement? Unfortunately there is only one truly enormous CAR-T presentation (BCMA) I see on the schedule this year.
It was a big deal one ASCO ago when bluebird and Legend showed early promise with BCMA CAR-T. To illustrate that cell therapies likely have utility beyond CD19 was a morale booster and I’m sure it was major factor in convincing Gilead and Celgene to do their big acquisitions.
However, BCMA isn’t out of the woods yet. Investors are nervous about relapses/durability. What will BCMA data look like with more time and more patients treated in trials? This could be Friday’s biggest story when bluebird presents an update on their BCMA CAR-T candidate bb2121. They also have a call scheduled Friday afternoon to discuss the data. We might have to broadcast it on loudspeakers at the unofficial tweetup.
Speaking of durability, CD19 CARs have been developed so quickly that we don’t actually know how durable the responses will be over the long-term. It has always been a hypothesis that durability will last for patients who are out a considerable amount of time, but companies still need to prove it. Gilead had long-term data from ZUMA-1 in NHL that looked spectacular at ASH, and ASCO data will likely be similarly good. The more proof these companies can show at major medical meetings that patients have lasting responses, the easier it will be to overcome the payer and logistic challenges that have emerged in the early days of commercial launch. Gilead will also have some Mantle cell lymphoma and ALL data.
To put it mildly, Celgene is having a bad year. After various problems have emerged from past BD deals, they desperately need the Juno acquisition to go smoothly. Or to say it in a glass-half-empty kind of way, they cannot have this one blow up in their face too. Fortunately, so far Juno data has looked good. There will be a JCAR017 update at ASCO in DLBCL and again at EHA. The key here is for it to continue to look competitive with Gilead and Novartis and that no surprising safety issues arise.
There has also been talk this last week about an abstract from a Chinese group comparing 4-1BB CAR-T (Kymriah) directly to CD28 CAR-T (Yescarta) to see if one is better than the other. Their conclusion was that 4-1BB had enhanced safety, efficacy, and expansion. Personally, I think this study is flawed and I wouldn’t draw many conclusions about U.S. products from it.
We know a lot about CAR-T but still know little about TCRs. When will this approach step up to the plate and have a breakout year? It is still too early for that, but look for data from Adaptimmune targeting NY-ESO and MAGE-A10 and data from NCI targeting HPV oncoproteins to provide some clues. The fact that Glaxo opted to continue their Adaptimmune collaboration is a positive sign.
Cytokines
Mike Gladstone
Atlas Venture’s Mike Gladstone had the call of the year last December when he predicted 2018 would be the Year of the Cytokine. We have since seen Bristol pay Nektar $1.85 billion upfront to own essentially 1/3 of its CD122 agonist and then last month Lilly came from out of nowhere to acquire Armo for $1.6 billion. The biology behind cytokines brings a familiarity and comfort factor given the decades it has been researched. Will today’s new approaches to harnessing them be the first major breakthrough in the IO combo race? Already this year $3B+ has been bet on it.
There is a ton riding on the Nektar data at ASCO. Bristol is both in need of positive news after being routed by Merck in 1L NSCLC at AACR and also must justify the cash they threw at Nektar to partner on this. Early data at SITC looked stellar, but it was just that….early data. How will the response rates hold up with more patients on drug and in more types of cancers? The abstract release caused some nervous butterflies and so we will have to look to the full ASCO presentation for more comfort. Nektar is hosting a hugely important analyst meeting on Saturday afternoon that is not to be missed.
Armo’s peg IL10 looked very compelling in pancreatic cancer, NSCLC and RCC. This appears to be a very smart purchase by Lilly even considering the early stage ARMO is at and the high price of the deal. Will another suitor step up and make things interesting before the June 22 tender deadline?
Other IO
Privately held Checkmate Pharma presented compelling data from its TLR9 agonist during a plenary at AACR, but none of the publicly traded TLR9 companies (Dynavax, Idera) have been able to match the excitement. Why? Dynavax traded sharply down when investors reexamined the 60% ORR published in its abstract (PD1 naïve melanoma) after realizing that 5 non-evaluable patients had been left out of the analysis. Will the higher 60%+ number turn out to be true as more data is reported at the conference?
It is always important when you get a first glimpse at clinical data from a company with a unique new platform. CytomX and its probody platform is that company at ASCO 2018. Can they maintain comparable efficacy to checkpoints while lowering the toxicities?
One of the biggest disappointments from the abstract release day was Jounce and its ICOS agonist. While most on Wall Street threw in the towel, there are still a few believers in this concept who are hanging on. The immunotherapy superstar founders of the company will be giving a talk at an analyst event on Monday night. Jounce (and their partner Celgene) needs to walk out of Chicago with some kind of positive because they have no other assets (besides a PD-1) anywhere near the clinic.
Merck KGaA’s PD-L1/TGF-β trap fusion protein looks promising in HPV associated cancers and will be a much-discussed trial. The TGF-β pathway and how it contributes to immunosuppression is a hot topic in general and there are a couple of abstracts addressing this. Expect to see a few new companies IPO soon with TGF-β programs in their pipeline. One just happened on Thursday.
Regeneron might be the only company (out of dozens) developing a new PD-1 that really matters from a competitive standpoint. This is because 1) they are Regeneron and therefore conduct terrific science and 2) they have done a good job of racing theirs through the clinic. How does Cemiplimab stack up against Keytruda and Opdivo? Can they actually compete commercially in existing indications or will they have to settle for using this as a combo development tool like everyone else?
I predict that one future ASCO will be the Year of Bi-specifics. We are not there yet, but watch for a handful of early studies this year to begin to set the stage.
Other Therapies
There has been much anticipation for PARPs to shine in combination with PD-1s, but the data has been lacking so far. Why? Tesaro’s TNBC data from TOPACIO doesn’t look much better than what we’d expect to see with monotherapy unfortunately. Speaking of monotherapy, QUADRA doesn’t seem to shake the ground in late stage ovarian either. The company’s stock has practically gone down every day for a year and many are waiting for it to get cheap enough to finally be acquired. That might not happen at any price until they can demonstrate broader utility.
With Rova-T continuing its cold streak this year, we are looking towards others for positive data in SCLC. PD-1s, PARPs, and lurbinectedin are possible candidates for this terribly aggressive cancer and huge unmet need.
Antibody-drug conjugates are still a thing, though much less today than back in the glory days when Roche was the darling of ASCO with T-DM1. Immunomedics recently filed its BLA for sacituzumab govitecan in triple-negative breast cancer. This uses SN-38, the active metabolite of irinotecan, conjugated to Trop-2. Data from their study presented at ASCO will help us better understand the approvability and commercial viability of the drug.
Thanks a lot for your interest. These have been some of the things I am watching and I hope it helps. Best of luck to all the companies, researchers, physicians, and patients who will no doubt make 2018 another great ASCO.
Brad Loncar is an independent investor focused on biotechnology.

Cancer Research Institute tracks global cell therapy growth as China advances


The Cancer Research Institute is shining a light on the explosive growth of cell therapies in the clinic, spotlighting China’s virtual overnight success in grabbing a lead role in the field. And they’re asking the world’s cancer drug development companies to adopt a new approach that will help the industry manage a finite number of potential trial patients while pointing researchers to the most likely avenue for doing something important — rather than just frittering away badly needed resources.
The nonprofit CRI recently quantified the proliferation of I/O agents in the clinic, capturing our attention with the news that 164 PD-1/L1 therapies were in the pipeline, looking to whittle away at the blockbuster leaders from Merck and Bristol-Myers Squibb. Now we learn from an update in Nature Reviews Drug Discovery — penned by a team that includes Jill O’Donnell‐Tormey and Aiman Shalabi — that they tracked down 753 cell therapies, with 375 in the clinic.
That figure is up 87% in just 6 months, with 350 added to the pipeline around the world.
The tally reveals that “378 are in preclinical phase, 160 in phase I, 205 in phase II, 6 in phase II and 4 approved (2 in the US, 1 in South Korea and 1 in Italy),” reports the CRI. “Interestingly, 404 of the 753 agents are chimeric antigen receptor (CAR) T cell therapies.”
Not surprisingly, the US is in the clear lead here, with 344 programs. But China is number two, and catching up fast, with 203. In a field where academic centers frequently play a lead role in demonstrating their potential, 125 of China’s programs — 62% — are in the hands of academics.
Here’s a look at the global playing field:
cri-report-chart-1-1024x619
In the meantime, it’s getting rapidly easier to get these therapies produced for clinical trials virtually anywhere. “(W)ith the rapid advancement of local cell production technologies, such as CliniMACS Prodigy (Miltenyi Biotec), Cocoon (Lonza) and Beacon (Berkeley Lights), we anticipate a low entry hurdle for local manufacture of cells for investigational clinical use.”
There are 113 targets on the radar in this field, with 73 in the clinic. CD19 rules the roost, for now, with BCMA a growing but still relatively small segment. Here’s a look at the top 30:
cri-report-chart-2-1024x853
The booming oncology research field has delivered some important gains in the last two years. But at this rate, the gold rush for advancing new drugs is spurring the CRI to outline some badly needed reforms. Here are three:
They’re asking the R&D execs here to shift more of their focus to introducing genetic constructs into cells, rather than concentrate on viral vectors, where a production bottleneck has developed.
Rather than squander the limited access to patient volunteers on a massive number of new studies, they want developers to move to adaptive trial designs that accommodate multiple drugs and targets at once.
And with the big push on to expand into solid tumors, CRI wants developers to focus on the most important targets not currently being treated well with existing drugs.
There’s no R&D czar in the world, though, that can demand discipline in this field. Large players have been resistant to being told what to do as much as the smaller players. And everyone wants to control their own economics. The market is driving the growth of the field, but it can’t triage how it grows — unless investors start holding back funds in search of more common sense.

Chicken safety fear as chlorine washing fails bacteria tests


The chlorine washing of food, the controversial “cleaning” technique used by many US poultry producers who want access to the British market post-Brexit, does not remove contaminants, a new study has found.
The investigation, by a team of microbiologists from Southampton University and published in the US journal mBio, found that bacilli such as listeria and salmonella remain completely active after chlorine washing. The process merely makes it impossible to culture them in the lab, giving the false impression that the chlorine washing has been effective.
Apart from a few voluntary codes, the American poultry industry is unregulated compared with that in the EU, allowing for flocks to be kept in far greater densities and leading to a much higher incidence of infection. While chicken farmers in the EU manage contamination through higher welfare standards, smaller flock densities and inoculation, chlorine washing is routinely used in the US right at the end of the process, after slaughter, to clean carcasses. This latest study indicates it simply doesn’t work.
Currently, chlorine-washed chicken is barred from entry to the EU on animal welfare grounds and has become a contentious issue for opponents of liberal trade deals with the US post-Brexit.
Previous studies with similar findings have been dismissed by the US poultry industry as producing “laboratory-only” results with no relevance to the real world. “We therefore tested the strains of listeria and salmonella that we had chlorine-washed on nematodes [roundworms], which have a relatively complex digestive system,” said Professor William Keevil, who led the university team. “All of them died. Many companies and scientists have built their reputations promoting anti-microbial products. This research questions everything they’ve done.”
The study tested contaminated spinach, but Keevil insists the findings apply equally to chicken. “This is very concerning,” he said. The issue, he argues, is less to do with the chicken itself, the contamination of which can be managed by thorough cooking. “It’s that chlorine-washed chicken, giving the impression of being safe, can then cross-contaminate the kitchen.”
The British government has given a series of mixed messages over its willingness to accept chlorine-washed chicken into the UK as part of any post-Brexit trade deal with the US. While Michael Gove, the environment secretary, has insisted animal welfare standards will be maintained, the trade secretary, Liam Fox, told MPs last November: “There are no health reasonswhy you couldn’t eat chickens that have been washed in chlorinated water.”
In a speech delivered last month, Fox referred to “myths” being used to stymie free trade agreements. Last year, Wilbur Ross, the US commerce secretary, insisted the UK would have to accept American foodstandards if it was to secure a trade deal. According to a poll by the consumer association Which, 72% of the British population is opposed to the introduction of chlorine-washed chicken on to the British market.
Recently published analysis by the British food and farming pressure group Sustain, found that the incidence of food poisoning in the US could be 10 times higher than in the UK. The US Centers for Disease Control and Prevention reports that about 380 people die each year in America from foodborne salmonella poisoning. Public Health England reports that, between 2005 and 2015, there was not a single death from salmonella poisoning in England and Wales.
Kath Dalmeny, the chief executive of Sustain, described the Southampton research as a wake-up call. “Those dead nematodes are telling us something,” she said. “This research suggests US chlorine washing may give a false impression of food safety. Proper food safety relies on clean production methods with high animal welfare, resilience to disease, and full traceability and labelling – not just end-of-pipe chemical washes.”
Infection is a recognised hazard of all intensive poultry farming and the UK is not immune, with campylobacter regarded as a major problem within the British chicken flock. Incidences of human illness as a result of campylobacter peaked at nearly 115 per 100,000 of the UK population in 2012, but have since declined as new contamination control measures have been put in place.
A protest against US chlorinated chicken outside the Conservative party conference in Manchester last October.
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 A protest against US chlorinated chicken outside the Conservative party conference in Manchester last October. Photograph: Alamy Stock Photo
“The US vigorously champions chemical washes,” said Richard Griffith, the chief executive of the British Poultry Council. “But this hides the shortcomings in their production methods and belies their attitude both to food safety and being open with consumers. It seems that the US, even with growing scientific evidence, is still trying to offload food on us of higher risk and lower quality than our own.”
Liam Fox declined to comment further on the efficacy of chlorine washing for chicken. However, a government spokesperson said: “We have been clear that we will not lower our high food safety and animal welfare standards as a result of any future free trade agreement.”
The Food Standards Agency went further, essentially tying the hands of British negotiators, by pointing out that only water safe for human consumption can be used to remove surface contamination from poultry carcasses in EU countries. “The current rules will remain in place after the UK leaves the EU,” the FSA said.
Tom Super of the National Chicken Council, the trade association for American chicken farmers, described the concerns over chlorine washing raised by the new study as “silly”, and stressed that America is the second-largest exporter of chicken in the world. “We export product safely to more than 100 countries around the globe,” he said. “We’ve been feeding the same chicken to our families for decades. This has never been an issue of science, rather one of politics and protectionism.”