Interrupting androgen production: New drug target to combat prostate cancer

A study by an international team of researchers from University Children’s Hospital Bern and the Autonomous University of Barcelona has discovered how the production of specific human sex hormones known as androgens is interrupted. These findings can help in development of new therapeutic approaches, as the overproduction of androgens is associated with many diseases including prostate cancer in men and polycystic ovary syndrome in women.

One in seven men in Europe are diagnosed with prostate cancer. While majority of cases are treated with surgical procedures and hormone therapy, in about 70’000 cases tumor growth continues even after surgical castration (castration-resistant prostate cancer), where chemotherapeutic intervention is required.

One promising target has been the enzyme CYP17A1, which produces a precursor of androgens. Current treatment options include a drug called abiraterone. However, abiraterone has strong side effects and the life extension gained from treatment is only a few months.

Now a research team led by Amit Pandey from the Department of Pediatrics, Inselspital Bern and the Department for Biomedical Research of the University of Bern, in collaboration with Vall d”Hebron Research Institute in Barcelona, has reported a gene mutation that damages the specific enzyme CYP17A1 which controls the production of androgens. The results of this study, published in the Open-Access Journal “Pharmaceuticals,” could lead to a more efficient therapeutic approach for the treatment of castration-resistant prostate cancer. “Abiraterone, a CYP17A1 inhibitor, has been one the biggest breakthough drugs to combat advanced cancer. But resistance to this drug is still a major problem. Having a second line therapy as suggested by the current study, could be an effective way to control prostate cancer disease progression. This is a most exciting result,” says Mark A Rubin, Director of the Department for Biomedical Reseach and Prostate Cancer Investigator.

Gene mutation prevents androgen production

Amit Pandey in Bern has been investigating how prostate cancer drugs work and found that the drug abiraterone changes many metabolic pathways. Collaborators in Barcelona, led by Dr. Laura Audi, identified a patient that had a loss of androgenprecursor. After genetic and biochemical laboratory tests, the Spanish team was able to confirm a novel mutation in the gene CYP17A1. “I immediately realized that this was not some ordinary mutation but is located at the center of CYP17A1 protein where sex hormones bind,” says Pandey.

Further studies in Bern showed that sex hormones could no longer attach properly at the center of the defective enzyme. Biochemical studies in Bern also found that mutated gene results in a defective CYP17A1 protein which is responsible for production of androgen precursor DHEA. Pandey hopes that knowledge from this study will lead to the development of better drugs for the treatment of prostate cancer and polycystic ovary syndrome.

Successful International teamwork in translational medicine

This research is an example of translational medicine showing the collaboration of the bedside to laboratory research. “This could not have been achieved by either team alone,” Pandey emphasizes. The Audi group in Barcelona provided their decades of experience and competence in genetics and pathology and laboratories of Christa E Flück and Amit V Pandey at the University Children’s hospital Bern used their experience in advanced recombinant protein production, molecular biology of sex steroids, and bioinformatics to understand the complexities of androgen production in humans. “These research results exemplify what can be achieved with close collaboration between multidisciplinary teams,” says Pandey.

More information: Mónica Fernández-Cancio et al. Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency, Pharmaceuticals (2018). DOI: 10.3390/ph11020037

https://bit.ly/2L1LpzZ

Paving way for personalized obesity treatments

Research by scientists at King’s College London into the role the gut plays in processing and distributing fat could pave the way for the development of personalized treatments for obesity and other chronic diseases within the next decade. The research is published in Nature Genetics.

In the largest study of its kind, scientists analyzed the fecal metabolome (the community of chemicals produced by gut microbes in the feces) of 500 pairs of twins to build up a picture of how the gut governs these processes and distributes fat. The King’s team also assessed how much of that activity is genetic and how much is determined by environmental factors.

The analysis of stool samples identified biomarkers for the build-up of internal fat around the waist. It’s well known that this visceral fat is strongly associated with the development of conditions including type 2 diabetes, heart disease and obesity.

By understanding how microbial chemicals lead to the development of fat around the waist in some, but not all the twins, the King’s team hopes to also advance the understanding of the very similar mechanisms that drive the development of obesity.

An analysis of fecal metabolites (chemical molecules in stool produced by microbes) found that less than a fifth (17.9 percent) of gut processes could be attributed to hereditary factors, but 67.7 percent of gut activity was found to be influenced by environmental factors, mainly a person’s regular diet.

This means that important changes can be made to the way an individual’s gut processes and distributes fat by altering both their diet and microbial interactions in their gut.

On the back of the study researchers have built a gut metabolome bank that can help other scientists engineer bespoke and ideal gut environments that efficiently process and distribute fat. The study has also generated the first comprehensive database of which microbes are associated with which chemical metabolites in the gut. This can help other scientists to understand how bacteria in the gut affect human health.

Lead investigator Dr Cristina Menni from King’s College London said: ‘This study has really accelerated our understanding of the interplay between what we eat, the way it is processed in the gut and the development of fat in the body, but also immunity and inflammation. By analyzing the fecal metabolome, we have been able to get a snapshot of both the health of the body and the complex processes taking place in the gut.’

Head of the King’s College London’s Twin Research Group Professor Tim Spector said: ‘This exciting work in our twins shows the importance to our health and weight of the thousands of chemicals that gut microbes produce in response to food. Knowing that they are largely controlled by what we eat rather than our genes is great news, and opens up many ways to use food as medicine. In the future these chemicals could even be used in smart toilets or as smart toilet paper.’

Dr Jonas Zierer, first author of the study added: ‘This new knowledge means we can alter the gut environment and confront the challenge of obesity from a new angle that is related to modifiable factors such as diet and the microbes in the gut. This is exciting, because unlike our genes and our innate risk to develop fat around the belly, the gut microbes can be modified with probiotics, with drugs or with high fiber diets.’

Source: https://www.kcl.ac.uk/

https://bit.ly/2IYtWYv

Patients with low-back pain benefit from early physical therapy

Patients with low-back pain are better off seeing a physical therapist first, according to a study of 150,000 insurance claims.

The study, published in Health Services Research, found that those who saw a physical therapist at the first point of care had an 89 percent lower probability of receiving an opioid prescription, a 28 percent lower probability of having advanced imaging services, and a 15 percent lower probability of an emergency department visit – but a 19 percent higher probability of hospitalization.

The authors noted that a higher probability of hospitalization is not necessarily a bad outcome if physical therapists are appropriately referring patients to specialized care when low back pain does not resolve by addressing potential musculoskeletal causes first.

These patients also had significantly lower out-of-pocket costs.

“Given our findings in light of the national opioid crisis, state policymakers, insurers, and providers may want to review current policies and reduce barriers to early and frequent access to physical therapists as well as to educate patients about the potential benefits of seeing a physical therapist first,” said lead author Dr. Bianca Frogner, associate professor of family medicine and director of the University of Washington Center for Health Workforce Studies.

Frogner said individuals in all 50 states have the right to seek some level of care from a physical therapist without seeking a physician referral, however, many do not take advantage of this option. She said this may be because some insurance companies have further requirements for payment.

About 80 percent of adults experience back pain at some point during their lifetime, according to the National Institutes of Health.

Currently, patients with low-back pain are given painkillers, x rays and, in some cases, told to rest, said Frogner. She said said seeing a physical therapist first and given exercise is a more evidence-based approach.

Using an insurance claims dataset provided by the Health Care Cost Institute, the researchers reviewed five years of data of patients newly diagnosed with low back pain who had received no treatment in the past six months. The claims were based in six states: Washington, Wyoming, Alaska, Montana, Idaho and Oregon.

The research involved the UW School of Medicine in Seattle and The George Washington University in Washington, D.C.

“This study shows the importance of interprofessional collaboration when studying complex problems such as low-back pain. We found important relationships among physical therapy intervention, utilization, and cost of services and the effect on opioid prescriptions,” said Dr. Ken Harwood, lead investigator for The George Washington University.

Source:

https://www.uwmedicine.org/

https://bit.ly/2J7PKEv

FDA OKs new uses for Novartis combo for thyroid cancer

The Food and Drug Administration (FDA) approved Tafinlar (dabrafenib) and Mekinist (trametinib), administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body (metastatic), and has a type of abnormal gene, BRAF V600E (BRAF V600E mutation-positive).

The FDA granted Priority Review and Breakthrough Therapy designation for this indication. Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases, was also granted for this indication.

The FDA granted this approval to Novartis Pharmaceuticals Corporation.

“This is the first FDA-approved treatment for patients with this aggressive form of thyroid cancer, and the third cancer with this specific gene mutation that this drug combination has been approved to treat,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients.”

Thyroid cancer is a disease in which cancer cells form in the tissues of the thyroid gland. Anaplastic thyroid cancer is a rare, aggressive type of thyroid cancer. The National Institutes of Health estimates there will be 53,990 new cases of thyroid cancer and an estimated 2,060 deaths from the disease in the United States in 2018. Anaplastic thyroid cancer accounts for about 1 to 2 percent of all thyroid cancers.

Both Tafinlar and Mekinist are also approved for use, alone or in combination, to treat BRAF V600 mutation-positive metastatic melanoma. Additionally, Tafinlar and Mekinist are approved for use, in combination, to treat BRAF V600E mutation-positive, metastatic non-small cell lung cancer.

The efficacy of Tafinlar and Mekinist in treating ATC was shown in an open-label clinical trial of patients with rare cancers with the BRAF V600E mutation. Data from trials in BRAF V600E mutation-positive, metastatic melanoma or lung cancer and results in other BRAF V600E mutation-positive rare cancers provided confidence in the results seen in patients with ATC. The trial measured the percent of patients with a complete or partial reduction in tumor size (overall response rate). Of 23 evaluable patients, 57 percent experienced a partial response and 4 percent experienced a complete response; in nine (64 percent) of the 14 patients with responses, there were no significant tumor growths for six months or longer.

The side effects of Tafinlar and Mekinist in patients with ATC are consistent with those seen in other cancers when the two drugs are used together. Common side effects include fever (pyrexia), rash, chills, headache, joint pain (arthralgia), cough, fatigue, nausea, vomiting, diarrhea, myalgia (muscle pain), dry skin, decreased appetite, edema, hemorrhage, high blood pressure (hypertension) and difficulty breathing (dyspnea).

https://bit.ly/2IRcZU0

bluebird cash, links lend investment edge

Bellicum Pharmaceuticals (NASDAQ:BLCM) and bluebird bio (NASDAQ:BLUE) are both clinical-stage biotechs that are developing cutting-edge therapies to treat cancer and other diseases. But the fortunes of these two biotechs have been very different over the last 12 months. Bellicum stock is down 37% during the period, while Bluebird's share price has soared more than 125%.
What do each of these biotech stocks have to offer investors now? And which is the smarter pick? Here's how Bellicum and Bluebird compare.

The case for Bellicum

With a clinical-stage biotech like Bellicum, the investing thesis for the stock boils down to what the potential is for the company's pipeline candidates. Bellicum's lead candidate is BPX-501, a T-cell therapy that is given to patients after hematopoietic stem cell transplantation (HSCT) from another donor.
Stem cell transplants can be a lifesaver for some patients with blood cancer and other diseases, but they also come with the risk of infections and graft-versus-host disease (GvHD), where donor stem cells attack the patient's cells. BPX-501 includes T-cells that help fight blood disorders but are genetically modified with a "safety switch" that shut down the T-cells if GvHD or other complications occur.
Bellicum is evaluating BPX-501 in a phase 3 clinical study being conducted in Europe with pediatric patients undergoing HSCT. The biotech expects to report data from this study by late 2018 and plans to file for regulatory approval in Europe next year, assuming the results are positive.
In January, the FDA placed a clinical hold on Bellicum's clinical study of BPX-501 in the U.S. This clinical hold came after three cases of abnormal brain function were reported in patients taking BPX-501. However, the FDA lifted the clinical hold in April after Bellicum agreed to implement an amended study protocol for patient monitoring for potential adverse neurological events.
Bellicum's pipeline also includes three other programs. BPX-601 is a chimeric antigen receptor T-cell (CAR-T) therapy targeting solid tumors expressing prostate stem cell antigen (PSCA), which is a cancer antigen expressed in prostate, pancreatic, bladder, esophagus, and gastric cancers. BPX-701 is a T-cell receptor (TCR) therapy for treating several blood diseases. The company also has a CAR-T program targeting CD19, an antigen expressed by B-cells.
All of these other programs, though, are in early-stage clinical studies. For now, Bellicum's fortunes rest largely on BPX-501.
The biotech completed a stock offering in April that raised $69 million before commissions and other expenses. This amount combined with Bellicum's cash stockpile of $88 million at the end of Q1 should allow the company to fund operations through the end of 2019.

The case for Bluebird

How does Bluebird's pipeline stack up against Bellicum's? The biotech's lead candidate is gene therapy LentiGlobin. Bluebird plans to file for European approval of the drug in the second half of this year for treating transfusion-dependent beta-thalassemia, a rare blood disorder.
With LentiGlobin, a functional human beta-globin gene is inserted into a patient's hematopoietic stem cells outside the body. These modified stem cells are then transplanted back into the patient's blood via infusion.
Another promising gene therapy in Bluebird's pipeline is Lenti-D, which is being evaluated in a phase 2/3 clinical study targeting treatment of cerebral adrenoleukodystrophy (CALD), a rare genetic metabolic disorder. Lenti-D works in a similar fashion as LentiGlobin, except instead of the beta-globin gene, a functioning copy of the ABCD1 gene is inserted into stem cells.
Bluebird also claims a couple of promising CAR-T therapies targeting treatment of multiple myeloma -- bb2121 and bb21217. Celgene is partnering with the biotech on both programs. The big biotech exercised its option in March to co-market bb2121 in the U.S. and exclusively market the drug outside of the U.S., pending approval down the road.
Thanks in large part to funds received from Celgene, Bluebird is sitting pretty when it comes to cash. The biotech reported a whopping $1.57 billion in cash, cash equivalents, and marketable securities in its first-quarter update.

 

Better buy

One of these clinical-stage biotechs is closer to potentially winning approval for its lead candidate. This same biotech also has a deeper pipeline. It claims a tight relationship with a much larger partner. And it's loaded with cash.
That biotech, obviously, is Bluebird. However, with a market cap topping $9 billion, there's a lot of growth baked into Bluebird's share price. Bellicum's market cap is less than $340 million. Good news for Bellicum should provide a bigger catalyst than Bluebird would experience.
So which is the better buy? My view is that Bluebird has the edge, even with its steep valuation. I think that LentiGlobin, Lenti-D, and bb2121 have blockbuster sales potential. Bluebird could stumble if it experiences any pipeline setbacks, but I think the stock should be a winner over the long run.
https://bit.ly/2ISDcgY

Lilly’s cancer business loses its chief just as it’s leaning on oncology for growth

Eli Lilly is leaning on oncology as a key pillar for growth going forward, but with news that its president of the business, Sue Mahony, Ph.D., is retiring, the drugmaker will need to find new leadership for the unit.

Sue Mahony (Eli Lilly)

During her 18 years at Lilly, Mahony has ascended the ranks—earning a spot on the executive committee—and helped see the drugmaker through some big changes. She managed the launch of breast cancer med Verzenio last year and the integration of ImClone, picked up in 2008 for $6.5 billion, Lilly said.

She’s also managed the company’s Canadian operations, and worked in development, marketing and management, according to the drugmaker. Mahony led the company’s recent oncology refocus and was previously senior vice president of human resources and diversity. In that role, she helped the company reorganize into business units in 2009.

“We make medicines that help patients with cancer live longer,” Mahony said in a statement. “What a privilege it’s been to wake up each morning with that as my life’s work.”

Lilly said it will look internally and externally for a successor. Mahony’s last day with the drugmaker is Aug. 31.

Along with many other top players in pharma, Lilly has poured big resources into cancer in recent years, hoping success in the field can help drive growth. In a presentation late last year, Eli Lilly CEO David Ricks said recent launches in cancer—Verzenio, Cyramza and Lartruvo—will help drive the company forward, along with diabetes offerings and drugs for autoimmune diseases.

Before joining the company in 2000, Mahony held various commercial roles in Europe at Amgen, Bristol-Myers Squibb and Schering-Plough, according to Lilly.

The leadership transition at Lilly Oncology comes as several important meds at the drugmaker fall off the patent cliff. Blockbuster erectile dysfunction med Cialis is expected to face cheap rivals in September, and ADHD med Strattera is already under generic assault. The company last year announced 3,500 layoffs to save $500 million in annual expenses, with many coming from early retirements.

https://bit.ly/2xsXBYT

Array to update on Phase 3 of melanoma trial at ASCO June 4

Array BioPharma Inc. (Nasdaq: ARRY) announced that it will present data from the Phase 3 COLUMBUS trial of encorafenib and binimetinib in advanced BRAF-mutant melanoma in an oral presentation on June 4, 2018, at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.

“Binimetinib and encorafenib is the first targeted therapy to demonstrate over 30 months median overall survival in a Phase 3 trial and we look forward to presenting the results from the COLUMBUS trial at ASCO,” said Ron Squarer, Chief Executive Officer. “With nearly 15 months median progression-free survival and an attractive tolerability profile, these data underscore the potential of this combination to become an important new treatment option for patients with BRAF-mutant advanced, unresectable or metastatic melanoma.”

As previously announced, the most common Grade 3/4 adverse events (AEs) seen in more than 5% of patients were increased gamma-glutamyltransferase (GGT) (9%), increased creatine phosphokinase (7%), and hypertension (6%) in the encorafenib plus binimetinib group.

Oral Presentation:
Title:	Overall Survival in COLUMBUS: A Phase 3 Trial of Encorafenib (ENCO) Plus Binimetinib (BINI) vs Vemurafenib (VEM) or ENCO in BRAF-Mutant Melanoma
Presenter:	Reinhard Dummer, M.D.
Abstract:	Abstract #223875/Publication #9504
Session:	Melanoma/Skin Cancers
Date:	Monday, June 4, 2018
Time:	9:12 a.m. – 9:24 a.m. Central Time (10:12 a.m. – 10:24 a.m. Eastern Time)
Location:	Arie Crown Theater

The abstract can be accessed through the ASCO website, http://abstract.asco.org/, beginning May 16, 2018, at 5:00 p.m. Eastern Time. Following the presentation on June 4, the slides will be available as a PDF on Array’s website at http://www.arraybiopharma.com.

Array will host an encore webcast presentation of the COLUMBUS trial data.

Encore Webcast:
Date:	Monday, June 4, 2018
Time:	11:15 a.m. Central Time (12:15 p.m. Eastern Time)
Toll-Free:	(844) 464-3927
Toll:	(765) 507-2598
Pass Code:	9615719

Webcast, including replay and conference call slides: https://edge.media-server.com/m6/p/8juh6tcn

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