Allogene raises another $120m to develop ‘off-the-shelf’ CAR-Ts

Investors have backed US biotech Allogene and its off-the-shelf CAR-T technology to the tune of $120 million in a second funding round.

Participants were mainly first-time investors – led by Perceptive Advisors, other backers included Deerfield Management Company, Fidelity Management and Research Company, Franklin Templeton Investments on behalf of certain clients, and Surveyor Capital.

Also on board were funds and accounts advised by T. Rowe Price Associates, Inc., the University of California Office of the Chief Investment Officer, venBio Select Advisor, as well as additional large mutual funds.

Earlier this year San Francisco-based Allogene, a start-up biotech led by former Kite executives Arie Belldegrun and David Chang, took over from Pfizer in a partnership to develop allogeneic, “off-the-shelf” chimeric antigen receptor T-cell (CAR-T) therapies with Cellectis.

The latest fundraiser builds on the $300 million the company raised when the project began in April, when Pfizer also took a 25% stake in the biotech.

Gilead’s and Novartis’s approved CAR-T therapies are autologous – meaning they require the time-consuming and expensive procedure of harvesting a patient’s T-cells, before they are genetically modified to attack cancer cells and then injected back into the patient.

Cellectis’ off-the-shelf therapies are in contrast allogeneic, developed from engineered T-cells from a healthy donor for use in multiple patients.

The companies hope that the therapies will be just as effective as the approved CAR-T therapies, but cheaper and more convenient to manufacture and administer to patients.

Allogene’s CEO and co-founder, David Chang, said: “We are very pleased to significantly expand our investor base with support from a distinguished syndicate who understands the cell therapy landscape.”

“Our goal is to maintain our leadership in allogeneic CAR-T therapy and be the first company to develop and commercialise an allogeneic CAR-T product. This financing will help us accelerate the development of our broad portfolio and invest in world class technical operations to make potentially lifesaving cell therapies more readily accessible to patients.”

Cellectis’ most advanced drug is UCART19, which is in early stage development, and has been tested in adult and paediatric patients with relapsed or refractory CD19-positive B-cell acute lymphoblastic leukaemia.

Servier has sponsored two early-stage studies and acquired exclusive rights to UCART19 from Cellectis in 2015.

https://pharmaphorum.com/news/allogene-raises-another-120m-to-develop-off-the-shelf-car-ts/

Myokardia: Major study shows thickened heart poses higher risk of disease, death

A new study of almost 4,600 patients with a disease that causes a thickened heart muscle shows that the genetically caused disorder is more dangerous than previously thought.

Dr. Daniel Jacoby, a co-author of the study, which is online and which will be published in the Oct. 2 issue of the journal Circulation, said the understanding of hypertrophic cardiomyopathy until now has underestimated how lethal a disease it can be if not monitored and treated. Jacoby is director of the Comprehensive Heart Failure Program at Yale New Haven Hospital and a co-author of the paper.

“It’s a totally different understanding of the condition and the implication is pretty significant,” Jacoby said of the study, which involved eight international medical centers over several years and was based on the Sarcomeric Human Cardiomyopathy Registry (known as SHaRe). “People need to be monitored and we need disease-altering therapy. This is not a benign condition that can be managed adequately with current therapies.”

Jacoby said HCM is the most common inherited cardiomyopathy, which refers to a group of diseases that makes it harder for the heart to pump blood. According to the Hypertrophic Cardiomyopathy Association, it affects one in 500 people or more than 700,000 Americans, but Jacoby said the rate may be as high as one in 350.

SHaRe was launched in 2014 by the biopharmaceutical company MyoKardia, which is developing a medication to treat the disease. Jacoby said all that can be done now is to limit the squeezing of the heart muscle, relaxing it with beta blockers or calcium channel blockers, and treating illnesses caused or exacerbated by cardiomyopathy: heart failure (a major symptom is shortness of breath), atrial fibrillation and ventricular tachycardia, which are forms of irregular heartbeat. According to the paper, “sudden cardiac death” is also a threat to those with the disease.

This is the first analysis of the SHaRe data to be published. “The previous information had suggested that the mortality might be similar to the general population or even slightly lower than the general population,” Jacoby said.

A normal heart muscle is 1 centimeter thick, but in a person with HCM it may be 50 percent thicker. “It can be so thick that it can block blood flow out of the heart,” Jacoby said. “It can lead to increased stiffness of the heart.”

He said the new findings were important because “up until very recently, existing treatments were thought to be probably adequate to normalize quality of life and life expectancy with patients with HCM.

“This publication confirms our clinical observations that more needs to be done to help patients with this condition in order to avoid complications from it later in life,” he said.

According to the study, which examined more than 24,000 patient-years, the risk of death was three times greater among those with HCM than in those without the disease, at similar ages. And the younger a patient is diagnosed, the greater the chance of other illnesses occurring as the patient ages, so early diagnosis is vital, Jacoby said. Most complications appear between the ages of 50 and 70.

Atrial fibrillation is an irregular heartbeat coming from the top of the heart, which can result in palpitations and stroke, Jacoby said, while ventricular tachycardia is “a very, very fast heart rhythm arising from the bottom chambers of the heart that makes it impossible for the heart to pump sufficient blood to the brain.”

Most threatening is that, as a result of ventricular tachycardia, “HCM is the No. 1 cause of sudden cardiac death in otherwise healthy young people,” he said.

Jacoby said that for about half the patients, the genes causing the disease can be identified, but that “there are multiple genes that can cause this condition.” Someone with a family member who has HCM should see a heart specialist, he said.

“One impact of knowing this is we can determine which patients need to be followed more closely and which don’t need as close follow-up,” he said.

There are other causes of a thickened heart muscle, such as uncontrolled high blood pressure, Jacoby said. Over time, the organ continues “to remodel … to change and adapt to the condition,” he said. That “may involve progressive stiffening of the heart muscle or additional scarring of the heart.”

Because of its seriousness, “we need to monitor for development of new problems, treat them symptomatically, and we need to develop new medications to prevent this process from happening,” Jacoby said. While there is no treatment for HCM itself, the related heart ailments can be treated.

“If you have hypertrophic cardiomyopathy, there is no doubt that you [should] have a minimum yearly checkup at an expert center,” such as Yale New Haven, he said. The hospital has been designated one of 29 Centers of Excellence by the Hypertrophic Cardiomyopathy Association, the only one in Connecticut to have earned the designation. “We have reduced mortality in our program,” Jacoby said.

At Yale New Haven’s Heart and Vascular Center, doctors will “screen you and your family, help you understand the genetic impact of this condition on your family … and monitor for these complications and provide therapy when necessary,” he said.

Signs that a person has hypertrophic cardiomyopathy are “a heart murmur, an abnormal EKG, symptoms or a family member is affected by the condition,” Jacoby said.

The drug that MyoKardia is testing in clinical trials is called mavacamten. Yale New Haven Hospital is one of the sites where the trial is being conducted. The aim is to “normalize that squeezing power” in the heart, Jacoby said. Mavacamten “may slow or reverse this disease process and it certainly improves symptoms in some patients already.”

The eight heart centers that participate in SHaRe are from the United States, Italy, the Netherlands and Brazil. The lead author is Dr. Carolyn Ho, medical director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital in Boston.

“Clinicians around the world have always known that this is a serious condition, but it hasn’t been until the international collaboration that came about through the SHaRe registry that we were able to understand the exact level of risk associated with this condition,” Jacoby said.

https://www.marketscreener.com/MYOKARDIA-INC-24749772/news/Myokardia-Major-study-shows-thickened-heart-poses-higher-risk-of-disease-death-27233855/

Monitoring at home yields better blood pressure control

Home blood pressure monitoring improved hypertension control and saved medical costs, according to results of a pilot initiative presented at the American Heart Association’s Joint Hypertension 2018 Scientific Sessions.

American Heart Association/American College of Cardiology guidelines stress the importance of home blood pressure monitoring for optimal high blood pressure management.

However, according to Roy R. Champion, M.Sc., B.S.N., clinical quality R.N. at Scott and White Health Plan, Temple, Texas, home blood pressure monitoring isn’t a common part of most treatment plans. Based on trends noted during medical record reviews, Champion said less than one in five providers were including home blood pressure monitoring in documentations for hypertension patients.

“Meanwhile, in the charts that did use home blood pressure monitoring, approximately 86 percent of those patients had their hypertension under control,” Champion said.

Home monitoring combined with doctor visits to measure a patient’s blood pressure helps to avoid numbers skewed by “white-coat hypertension,” when blood pressure is high in a medical setting but not in everyday life, and “masked hypertension,” when blood pressure is normal in a medical setting but high at home.

Champion studied the impact of an intervention that provided free home blood pressure monitors, online and print resources for tracking their readings, and monitoring reminders to 2,550 adult patients with persistent uncontrolled high blood pressure. In each case, the patient’s provider would know the patient received a free at-home blood pressure monitor and resources for how to use it.

They found:

• By their 3rd office visit, nearly 67 percent of patients had their blood pressure controlled.
• Nearly 60 percent of patients had blood pressure control by their sixth visit.

Champion attributed the decline from the third to sixth visit to providers’ adjusting blood pressure medications based on information from home blood pressure monitoring. Patients only had to see their doctors a few times to settle on the ideal medication amount, he said.

• At the end of the intervention, systolic blood pressures had decreased an average 16.9 mmHg and diastolic blood pressures fell an average 6.5 mmHg.
• In the six months after the intervention, nearly 80 percent of the participants achieved blood pressure under control using the Healthcare Effectiveness Data and Information Set (HEDIS) 2018 standards.
• Using the 2017 AHA/ACC guidelines, 72 percent achieved hypertension control.

“Even with the more stringent guidelines, we showed home blood pressure monitoring is vital to achieving control among hypertensive patients,” Champion said.

• Each kit, including the monitor, cost an average $38.50; yet, the cost savings from the intervention were substantial. The intervention reduced needed office visits by 1.2 office visits per participant per year and significantly reduced emergency department and medication costs.

Home monitoring helps providers better understand patients’ everyday blood pressure numbers in a cost-saving way that doesn’t increase the burden on patients or providers, Champion said.

 Explore further: How low is too low? Study highlights serious risks for intensive blood pressure control

https://medicalxpress.com/news/2018-09-home-yields-blood-pressure.html

Lifestyle changes reduce the need for blood pressure medications

Men and women with high blood pressure reduced the need for antihypertensive medications within 16 weeks after making lifestyle changes, according to a study presented at the American Heart Association’s Joint Hypertension 2018 Scientific Sessions, an annual conference focused on recent advances in hypertension research.

Lifestyle changes are the first step in reducing blood pressure according to the 2017 American College of Cardiology/American Heart Association Hypertension Guideline.

“Lifestyle modifications, including healthier eating and regular exercise, can greatly decrease the number of patients who need blood pressure-lowering medicine. That’s particularly the case in folks who have blood pressures in the range of 130 to 160 mmHg systolic and between 80 and 99 mmHg diastolic,” said study author Alan Hinderliter, M.D., associate professor of medicine at University of North Carolina in Chapel Hill.

The researchers studied 129 overweight or obese men and women between ages 40 and 80 years who had high blood pressure. Patients’ blood pressures were between 130-160/80-99 mmHg but they were not taking medications to lower blood pressure at the time of the study. More than half were candidates for antihypertensive medication at the study’s start, according to recent guidelines.

Researchers randomly assigned each patient to one of three 16-week interventions. Participants in one group changed the content of their diets and took part in a weight management program that included behavioral counseling and three-times weekly supervised exercise. They changed their eating habits to that of the DASH plan, a nutritional approach proven to lower blood pressure. DASH emphasizes fruits, vegetables and low-fat dairy and minimizes consumption of red meat, salt and sweets. Participants in the second group changed diet only, focusing on the DASH diet with the help of a nutritionist. The third group didn’t change their exercise or eating habits.

The researchers found:

• Those eating the DASH diet and participating in the weight management group lost an average 19 pounds and had reduced blood pressure by an average 16 mmHg systolic and 10 mmHg diastolic at the close of the 16 weeks.
• Those following only the DASH eating plan had blood pressures decrease an average 11 systolic/8 diastolic mmHg.
• Adults who didn’t change their eating or exercise habits experienced a minimal blood pressure decline of an average 3 systolic/4 diastolic mmHg.
• By the study’s end, only 15 percent of those who had changed both their diet and their exercise habits needed antihypertensive medications, as recommended by the 2017 AHA/ACC guideline, compared to 23 percent in the group that only changed their diet. However, there was no change in the need for medications among those who didn’t change their diet or exercise habits—nearly 50 percent continued to meet criteria for drug treatment.

Hinderliter suspects lifestyle modifications would be just as helpful to people with a higher risk of cardiovascular disease and in patients on medications for high blood pressure but that needs confirmation in future studies, he said.

 Explore further: Low sodium-DASH diet combination dramatically lowers blood pressure in hypertensive adults

https://medicalxpress.com/news/2018-09-lifestyle-blood-pressure-medications.html

New T cell behavior find has major implications for cancer immunotherapy

Scientists at the University of Colorado Anschutz Medical Campus have discovered that disease-fighting T cells, elicited from vaccines, do not require glucose for their rapid reproduction, a finding with major implications for the development of immunotherapies for cancer patients.

In the study, published today in the journal Science Immunology, researchers from CU Anschutz, along with colleagues from the Mayo Clinic and the University of Pennsylvania, examined T cells that arose in the body’s immune system after they received a subunit vaccination—a vaccine that uses just part of a disease-causing virus.

They found that these critical white blood cells, which attack and kill infection, did not rely on glucose to fuel their rapid division which occurs every two to four hours. Instead, they used another cellular engine, the mitochondria, to support their expansion.

“The knowledge that this magnitude of cell division can be supported by mitochondrial function has a number of potential practical implications for the development of future vaccines,” said the study’s senior author Ross Kedl, Ph.D., professor of immunology and microbiology at the University of Colorado School of Medicine.

Kedl said T cells responding to infection usually depend on glucose for fuel. So do cancerous tumors. When T cells come up against tumors, they end up competing for glucose and the T cells often lose.

But when a T cell doesn’t need glucose, he noted, it has a better chance of defeating tumor cells.

“T cells generated by subunit vaccination are ideally suited for use against cancer in conjunction with drugs that block aerobic glycolysis, a metabolic pathway to which the cancer is addicted,” Kedl said. “Tumor growth can be inhibited while the T cells are free to attack the tumor instead of competing against it for access to glucose.”

Lead author Jared Klarquist, Ph.D., explained that scientists have historically studied T cell responses to infection with the idea that if they could understand how the cells respond, they could create better vaccines. Kedl and colleagues had already discovered a non-infectious vaccine method that could induce the same level of T cell immunity as those using infection.

Since then, researchers in Kedl’s lab have found that the rules governing T cell responses to an infectious agent are very different from the cell’s response to a subunit vaccine. And the fact that T cells derived from subunit vaccines don’t require glucose to reproduce is a major finding.

“Prior to these findings, it was generally thought that whereas the mitochondria are good at making energy, T cells need glucose to produce the raw materials like proteins, fats and nucleic acids (like DNA) required to turn one cell into two,” said Klarquist. “Knowing how the immune response is fueled after vaccination provides potential opportunities for metabolic or nutritional interventions for boosting a vaccine-elicited immune response.”

Kedl agreed. “Perhaps most intriguing, however, is the application of this knowledge to cancer immunotherapy,” he said.

The lab is currently exploring how these strategies might positively influence the outcomes of immune-based cancer treatments that are already in the clinic.

 Explore further: Cancer cells hijack glucose, alter immune cells

More information: “Clonal expansion of vaccine-elicited T cells is independent of aerobic glycolysis,” Science Immunology(2018). immunology.sciencemag.org/look … 6/sciimmunol.aas9822

https://medicalxpress.com/news/2018-09-discovery-cell-behavior-major-implications.html

‘Mindful’ feel less pain; MRI imaging pinpoints supporting brain activity

Greater deactivation of the posterior cingulate cortex, a brain region associated with processing self-related thoughts, was associated with lower pain and higher trait mindfulness. Credit: Wake Forest Baptist Medical Center

Ever wonder why some people seem to feel less pain than others? A study conducted at Wake Forest School of Medicine may have found one of the answers—mindfulness. “Mindfulness is related to being aware of the present moment without too much emotional reaction or judgment,” said the study’s lead author, Fadel Zeidan, Ph.D., assistant professor of neurobiology and anatomy at the medical school, part of Wake Forest Baptist Medical Center. “We now know that some people are more mindful than others, and those people seemingly feel less pain.”

The study is an article in press, published ahead-of-print in the journal Pain.

The researchers analyzed data obtained from a study published in 2015 that compared mindfulness meditation to placebo analgesia. In this follow-up study, Zeidan sought to determine if dispositional mindfulness, an individual’s innate or natural level of mindfulness, was associated with lower pain sensitivity, and to identify what brain mechanisms were involved.

In the study, 76 healthy volunteers who had never meditated first completed the Freiburg Mindfulness Inventory, a reliable clinical measurement of mindfulness, to determine their baseline levels. Then, while undergoing functional magnetic resonance imaging, they were administered painful heat stimulation (120°F).

Whole brain analyses revealed that higher dispositional mindfulness during painful heat was associated with greater deactivation of a brain region called the posterior cingulate cortex, a central neural node of the default mode network. Further, in those that reported higher pain, there was greater activation of this critically important brain region.

The default mode network extends from the posterior cingulate cortex to the medial prefrontal cortex of the brain. These two brain regions continuously feed information back and forth. This network is associated with processing feelings of self and mind wandering, Zeidan said.

“As soon as you start performing a task, the connection between these two brain regions in the default mode networkdisengages and the brain allocates information and processes to other neural areas,” he said.

“Default mode deactivates whenever you are performing any kind of task, such as reading or writing. Default mode network is reactivated whenever the individual stops performing a task and reverts to self-related thoughts, feelings and emotions. The results from our study showed that mindful individuals are seemingly less caught up in the experience of pain, which was associated with lower pain reports.”

The study provided novel neurobiological information that showed people with higher mindfulness ratings had less activation in the central nodes (posterior cingulate cortex) of the default network and experienced less pain. Those with lower mindfulness ratings had greater activation of this part of the brain and also felt more pain, Zeidan said.

“Now we have some new ammunition to target this brain region in the development of effective pain therapies. Importantly this work shows that we should consider one’s level of mindfulness when calculating why and how one feels less or more pain,” Zeidan said. “Based on our earlier research, we know we can increase mindfulness through relatively short periods of mindfulness meditation training, so this may prove to be an effective way to provide pain relief for the millions of people suffering from chronic pain.”

 Explore further: Mindfulness meditation trumps placebo in pain reduction

https://medicalxpress.com/news/2018-09-mindful-people-pain-mri-imaging.html

Biotech week ahead, Sept. 10

After recording stellar gains of 4.3 percent in the week ended Aug. 31 to close the month in the green, the iShares NASDAQ Biotechnology Index (ETF) IBB 0.57% saw a moderation in momentum in the holiday-shortened week ending Sept. 7. Some mixed clinical trial results and profit-taking are apparently weighing on the sector.

The following are catalytic events in the coming week for biotech investors to watch.

Conferences

• 4th International Conference on Hypertension & Healthcare: Sept. 10-11 in Zurich, Switzerland
• 33rd International Conference on Dental Medicine and Surgery: Sept. 10-11 in Singapore City, Singapore
• 5th World Summit on Trauma and Reconstructive Surgery: Sept. 10-11 in Singapore City
• 47th World Congress on Microbiology: Sept. 10-11 in London
• 24th European Pediatrics Conference: Sept. 10-11 in Copenhagen, Denmark
• World Cardiology and Cardiologist Meeting: Sept. 11-12 in Stockholm, Sweden
• European Conference on Optometry and Vision Science: Sept. 11-12 in Stockholm
• Morgan Stanley 16th Annual Global Healthcare Conference: Sept. 12-14 at the Grand Hyatt New York
• 27th European Academy of Dermatology and Venerology, or EADV, Congress: Sept. 12-16 in Paris, France
• 11th Annual Congress on Immunology & Immuno-technology: Sept. 13-14 in Zurich Hilton Airport Hotel, Zurich
• 14th Euro Obesity and Endocrinology Congress:  Sept. 13-14 in London
• 6th International Conference on Brain Disorders and Therapeutics: Sept. 13-15 in Copenhagen
• 3rd International Conference on Neuro-Oncology and Brain Tumor: Sept. 14-15 in Singapore City
• 29th International Conference on Psychiatry & Mental Health: Sept. 14-15 in Singapore City

Clinical Trial Results

Incyte Corporation INCY 4.21% is due to present Phase 2 data for its ruxolitinib for treating atopic dermatitis between Sept. 12 and 16 at the 27th EADV Congress in Paris. The stock has been trending upward recently.

Kiniksa Pharmaceuticals Ltd KNSA 2.74%, which went public in June, will present Phase 1a data on its atopic dermatitis treatment KPL-716 Sept. 15 at the 27th EADV Congress in Paris.

Q3 Release Schedule • Omeros Corporation OMER 2.14% is scheduled to release Phase 2 data for its OMS721 for treating IgA nephropathy. • ZEALAND PHARMA/S ADR ZEAL 11.76%will release Phase 3 data for its dasiglucagon to treat severe hypoglycemia in diabetes. •Galectin Therapeutics Inc. GALT 9.56% is due to release Phase 1 data for its melanoma treatment combination GR-MD-02 and Merck & Co., Inc.’s MRK 0.42% Keytruda. •GALAPAGOS NV/S ADR GLPG 2.42% and Gilead Sciences, Inc. GILD 0.91% are set to release Phase 3 data for their rheumatoid arthritis candidate filgotinib, which is being evaluated in the FINCH 2 study. Galapagos is also due to release Phase 2 data for its combo treatment GLPG 2451+2222+2737 for treating cystic fibrosis. • Novo Nordisk A/S (ADR) NVO 0.04% will release Phase 2 data for its concizumab, which is being evaluated as a treatment option for hemophilia A. The company is also set to release the Phase 3 extension data for its adult growth hormone deficiency treatment candidate somapacitan. • Celsion Corporation CLSN is likely to release Phase 1b data for its ovarian cancer treatment candidate GEN-1. • Johnson & Johnson JNJ 0.36% will release primary analysis of Phase 2 data for its Imetelstat for treating myelofibrosis. • Palatin Technologies, Inc. PTN 3.45% is scheduled to release Phase 1 data for its inflammatory bowel disease candidate PL-8177. • Geron Corporation GERN 2.18% andJohnson & Johnson are scheduled to release data from the Phase 2 IMbark study for Imetelstat to treat myelofibrosis. • Amarin Corporation plc (ADR) AMRN 1.25% is due to release Phase 3 data for its Vascepa to treat high triglycerides with mixed dyslipidemia. •Progenics Pharmaceuticals, Inc. PGNX 4.29% will release top-line Phase 3 data for its 1404, which helps visualize prostate cancer by treating prostate-specific membrane antigen. •AnaptysBio Inc ANAB 1.89% is due to release Phase 2a data for its ANB020 that is being evaluated for severe adult eosinophilic asthma. • Amicus Therapeutics, Inc. FOLD 3.14% is scheduled to release updated Phase 1/2 data for its Pompe disease treatment candidate ATB200. • argenx SE – ADR ARGX 0.07% will release Phase 2 data for its immune thrombocytopenia treatment ARGX-113. • CTI BioPharma Corp CTIC 0.54% is due to release interim Phase 2 data for Pacritinib, its pipeline candidate for myelofibrosis.

Earnings

Monday

• Applied Genetic Technologies Corp AGTC 2.3% (after the market close)
• Avid Bioservices Inc CDMO 2.47% (after the market close)

Wednesday

• Eyepoint Pharmaceuticals Inc EYPT 4.31% (before the market open)

IPO

Principia Biopharma, an immuno-oncology company, is set to offer 4.69 million shares in an IPO at a per-share price estimated between $15 and $17. The company plans to list its shares on the Nasdaq under the ticker symbol PRNB.

https://www.benzinga.com/general/biotech/18/09/12314714/the-week-ahead-in-biotech-conferences-clinical-trial-results-earnings