Old diabetes drug metformin may find yet another role: reversing lung fibrosis

The drug metformin has been used to control blood sugar in many patients with Type 2 diabetes for more than two decades. Now scientists at the University of Alabama, Birmingham, have amassed evidence that the drug’s ability to target cell metabolism could help repair the lung.

The team is investigating therapies for pulmonary fibrosis, a condition that can occur after lung injuries from infections or treatments like chemotherapy. They are particularly interested in finding effective treatments for idiopathic pulmonary fibrosis (IPF), a progressive, fatal disease that can strike out of the blue and affects more than 5 million patients worldwide.

The scientists zeroed in on cells called myofibroblasts, which are responsible for depositing the damaging collagen that proliferates in lung fibrosis. They found that the activity of an enzyme called AMP-activated protein kinase (AMPK) was suppressed in fibrotic areas of tissue samples taken from IPF patients. The metabolisms of those cells went into overdrive, making them less likely to undergo apoptosis, or programmed cell death.

Metformin activates AMPK. In experiments with the tissue samples and lung fibroblasts from mice, the researchers found that metformin reversed lung fibrosis. So they decided to try the diabetes drug in mouse models of lung fibrosis. They started the treatment three weeks after the lungs were damaged—making the lung fibrosis well established—and continued it for the next 5 weeks. That accelerated lung repair.

To confirm their suspicion that AMPK was the key to metformin’s activity in myofibroblasts, they tried the same experiment in mice that lacked the enzyme. Lung fibrosis did not improve in those animals. They published their research in the journal Nature Medicine.

Metformin has long been of interest in the oncology community because observational studies have shown that diabetics who take the drug have a lower risk of cancer than those who don’t. The drug’s effect on AMPK seems to play a role there. Scientists at the University of California, San Diego, discovered that metformin activates a protein pathway that prompts AMPK to build barriers in the body against inflammation and other cancer-causing stressors, for example.

Scientists are also studying the potential of metformin in treating other conditions, including autismand disorders of aging like heart disease.

The University of Alabama researchers believe their study shows that AMPK is a “critical metabolic switch” that shifts the metabolism of lung cells so they can resolve fibrosis, they wrote in their study. “Additionally, we provide proof-of-concept that activation of AMPK by metformin or other pharmacologic agents that activate these pro-resolution pathways may be a useful therapeutic strategy for progressive fibrotic disorders.”

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Henry Schein creates key software joint venture with Internet Brands

Henry Schein Inc. and partner Internet Brands have completed the creation of a joint venture to create and market software for the global dental market, the companies announced Monday.

Analysts have said that practice-management software is crucial in cementing Henry Schein’s supplier relationship with dentists as online providers such as Seattle-based Amazon.com enter the market.

The joint venture, named Henry Schein One, incorporates Henry Schein’s practice-management software for dentists, including Dentrix and Easy Dental, with Internet Brands’ web-based programs such as Demandforce and DentalPlans.com.

Melville-based Henry Schein, which distributes products to clinics and the offices of dentists, physicians and veterinarians, owns more than 70  percent of the joint venture, which is based in American Fork, Utah.

Stanley M. Bergman, chairman and chief executive of Henry Schein, said in an interview Friday that the company began offering dentists Henry Schein branded software in the early 1990s.

That business has grown in importance, he said, with the proliferation of electronic medical records and the need for “interoperability” on computers and mobile devices.

“We want to become the iPad for the dentist,” he said.

James A. Harding, who formerly served as the chief technology officer of Henry Schein, is the joint venture’s chief executive.

If the joint venture had existed in 2017, it would have had sales of about $400 million, with three quarters attributed to Henry Schein.

El Segundo, California-based Internet Brands runs consumer websites in the areas of health, automotive, legal and home and travel, including WebMD and Fodor’s Travel.

Internet Brands is owned by private equity firms KKR & Co., based in Manhattan, and Temasek, based in Singapore.

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Novo Nordisk upped to buy by Bernstein

Novo Nordisk upgraded to Outperform from Market Perform at Bernstein

https://bit.ly/2lRfwzE

Record Year So Far for Massachusetts Biotech IPOs

It’s been a pretty good year for mergers and acquisitions in the biopharma industry, with Takeda Pharmaceutical buying Shire for $62.2 billion, and the year starting with Sanofi buying Bioverativfor $11.6 billion and then Ablynx for $4.8 billion. Celgene acquired Juno Therapeutics for $9 billion, shortly after buying Impact Biomedicines for $1.1 billion.

But the landscape for initial public offerings (IPOs) has been excellent as well, particularly in Massachusetts, which has recorded 13 IPOs since the beginning of the year, raising a combined $1.3 billion. This exceeds by money raised the record in 2014, when 17 Massachusetts biotechs raised $1.2 billion, and the year’s only half over. And there are three biotech companies in Massachusetts that have filed to go public, but hadn’t done so yet. One of those includes Rubius Therapeutics.

The list of Massachusetts biotech companies with IPOs so far this year is listed below.

#1. Cue BioPharma. Headquartered in Cambridge, Mass., Cue focuses on injectable biologics engineered to modulate the immune system to treat cancer, chronic infectious diseases and autoimmune disorders. Its IPO on January 2 raised $66 million.

#2. Unum Therapeutics. Also based in Cambridge, Unum is also working in the immuno-oncology space, developing therapies based on an antibody-coupled T cell receptor. It is differentiated from CAR-T or TCR by not being restricted to a particular target and may have applications in a broad range of cancer types. The company’s IPO raised $69 million on March 29.

#3. Scholar Rock. Of course, based in Cambridge, Scholar Rock is focused on the biology of growth factor activation, targeting growth factors in the disease microenvironment. This has applications in neuromuscular disorders, cancer, fibrosis, and anemia. It raised $75 million on May 24.

#4. RestorBio. Headquartered in Boston, RestorBio is focusing on aging-related diseases. Its lead program, RTB101, focuses on the mechanistic target of rapamycin (mTOR) pathway, an evolutionarily conserved pathway that regulates aging. On January 26, the company raised $85 million.

#5. Evelo Biosciences. Located in Cambridge, Evelo Biosciences focuses on monoclonal microbials for oncology and inflammatory diseases. Its lead product is EDP1066, currently in a clinical trial in inflammatory diseases, such as psoriasis, atopic dermatitis, and ulcerative colitis/Crohn’s colitis. On May 9, the company raised $85 million.

#6. AvroBio. Headquartered in Cambridge, AvroBio is focused on lentiviral-based gene therapies for rare diseases. Its lead gene therapy is AVR-RD-01 for Fabry disease. It also has three more gene therapies for other lysosomal storage disorders. On June 21 it raised $99 million.

#7. Neon Therapeutics. Located in—you guessed it—Cambridge, Neon is working on directing the immune system using neoantigens to treat cancer. Neoantigens are specific genetic mutations that are common in cancer. The company’s June 27 IPO raised $100 million.

#8. Magenta Therapeutics. Magenta is based in Cambridge and is developing therapeutics for bone marrow transplant for patients with autoimmune diseases, blood cancers and genetic diseases. The company’s most advanced clinical product is MGTA-456, a cell therapy in a Phase II clinical trial in patients with inherited metabolic diseases. Magenta raised $100 million on June 21.

#9. Surface Oncology. Based in Cambridge, Surface Oncology, not surprisingly given its name, focuses on cancer. The differentiating factor is its focus on the tumor microenvironment. On June 12, it initiated a Phase I clinical trial of SRF373, a fully human antibody targeting CD73, the second of its immunotherapies to advance into this clinic this year. On April 19, its IPO raised $108 million.

#10. Translate Bio. Headquartered in Lexington, Mass., Translate focuses on messenger RNA (mRNA) to treat diseases caused by protein or gene dysfunction. On June 11, it signed a dealwith Sanofi Pasteur to develop up to five undisclosed infectious disease pathogens. The company raised $122 million on June 28.

#11. Solid Biosciences. Based in Cambridge, Solid is focused on a gene therapy for Duchenne muscular dystrophy (DMD). On June 18, the U.S. Food and Drug Administration (FDA) lifted a clinical hold on the company’s IGNITE DMD Phase I/II clinical trial of SGT-001 for DMD, acknowledging the company had addressed all the questions the agency had in its clinical hold. The company raised $125 million on January 26.

#12. Homology Medicines. Headquartered in Bedford, Mass., Homology is a genetic medicines company focused on rare genetic diseases. Its proprietary platform utilizes its human hematopoietic stem cell-derived adeno-associated virus vectors (AAVHSCs) to deliver genetic medicines either through a gene therapy or nuclease-free gene editing modality for a variety of genetic disorders. Its IPO on March 28 raised $144 million.

#13. Kiniksa Pharmaceuticals. Kiniksa has headquarters in Hamilton, Bermuda and Lexington, Mass. The company’s pipeline includes rilonacept for recurrent pericarditis, mavrilimumab for giant cell arteritis, KPL-716 for prurigo nodularis/atopic dermatitis, KPL-045 for T-cell dependent and B-cell-mediated indications, and KPL-404 for the same as KPL-045. On May 24, its IPO raised $153 million.

https://bit.ly/2IM2egH

Boston Positioning To Become Retail Cannabis Hub Of The East Coast

The West Coast is no stranger to cannabis shops, and the cannabis-oriented industrial space that supports them, but now it is the East Coast’s turn.

The sale of recreational marijuana becomes legal under Massachusetts law on July 1, and retail shops will begin popping up soon afterward. Dank Depot, Flickr “We think it’s hugely consequential — Massachusetts becomes an anchor market on the East Coast,” John Kagia, an analyst at cannabis research firm New Frontier Data, told Bloomberg.

Voters in the commonwealth approved Question 4 in 2016, which legalized the recreational use and sale of cannabis, pending the establishment of a regulatory framework and the issuing of retail licenses, which have been in the works since then.

According to New Frontier Data, cannabis sales in the Bay State are projected to rise from $52M in 2016 — when the only sales were medical marijuana — to $1.07B in 2020, with the vast majority being recreational sales.

The opening of retail shops might be a little slow at first in Massachusetts, as the Cannabis Control Commission awards licenses. There has been a crush of interest in getting licenses.

As of this week, none had been issued, but according to Boston.com, the agency plans to vote soon on issuing the first retail license to Cultivate, a medical marijuana dispensary that opened recently in Leicester.

Vermont, Maine and the District of Columbia have also legalized marijuana, but unlike Massachusetts, do not have a system of regulation in place under which retail shops could be set up.

Marijuana is still unlawful under federal law, but despite U.S. Attorney General Jeff Sessions’ avowed stance against legalization at any level, he has made little progress in putting the cannabis genie back in the bottle, the Wall Street Journal reports.

Even so, the federal prohibition makes it harder for marijuana retailers and growers to do business even in legal states, especially when it comes to gaining access to financing. But there is momentum to change that, with various bills proposed in Congress.

Last month, Sen. Cory Gardner, (R-Colo.) joined Sen. Elizabeth Warren (D-Mass.) in introducing a bill that would bar federal interference in state marijuana policy — and President Donald Trump told the press he would likely support it.

https://bit.ly/2KHW46i

Lilly med provides fast migraine relief without cardiovascular side effects

Lasmiditan, a new type of drug for acute treatment of migraine, provided prompt relief of pain and other bothersome symptoms as soon as an hour after administration, researchers reported here.

About 20% of patients treated with the highest dose of lasmiditan in one of two phase III trials reported being free of headache pain at 1 hour post-treatment, rising to nearly 40% at 2 hours.

The results were presented at the American Headache Society annual meeting.

Lasmiditan could potentially represent the first major innovation for the treatment of acute migraine in two decades. The drug is a serotonin agonist selective for the 5-HT_1F receptor. Triptans activate that receptor, but they are also active at other 5-HT receptor subtypes that are believed to be responsible for these agents’ unwanted cardiovascular effects.

In the current study with lasmiditan, cardiovascular effects were nearly absent.

These phase III results follow the recent approval of the first of another new class of migraine drugs, the calcitonin gene-related peptide (CGRP) inhibitors. Other research presented at the meeting showed that lasmiditan inhibits the release of CGRP from central and peripheral trigeminal nerve terminals in the mouse brain to the same degree as sumatriptan.

“This is an incredibly exciting time to be in the headache field. So much is happening. This is a golden age for people with migraines,” AHS scientific program committee chair Peter Goadsby, MD, PhD, told reporters during an advance media briefing ahead of the meeting.

Sheena Aurora, MD, of lasmiditan’s developer Eli Lilly, presented results from a pair of randomized phase III studies of lasmiditan.

SAMURAI and SPARTAN were randomized, double-blind trials comparing lasmiditan versus placebo for the treatment of acute migraine. Together, the studies included 4,439 participants. More than 80% were women, most were white, and the mean age was approximately 42 years. They had an average of about five migraines per month, one-third experienced aura, and they had moderate migraine-related disability (MIDAS score of 11 or higher). About 20% used prophylactic medications to reduce migraine frequency.

About 80% of patients had at least one risk factor for cardiovascular disease, including family history, smoking, hypertension, hyperlipidemia, and type 2 diabetes. SAMURAI, but not SPARTAN, excluded people with known coronary artery disease, arrhythmias, or uncontrolled hypertension.

In both studies, participants were randomly assigned to receive lasmiditan or placebo within 4 hours after the onset of migraine. Both studies evaluated oral doses of 100 mg and 200 mg, and SPARTAN also included a 50-mg dose. Patients could receive a randomized second dose, if needed, 2 to 24 hours after the first.

In both studies, patients experienced headache pain relief in as little as one hour, with better response rates seen at the higher doses, Aurora reported.

In SAMURAI, about 15% of people taking the 200-mg dose were pain-free at 1 hour after lasmiditan administration, rising to 32.2% at 2 hours in a modified intention-to-treat analysis. The same proportion in SPARTAN taking the highest dose were pain-free at 1 hour, rising to nearly 30% at 1.5 hours and 38.8% at 2 hours. Response rates in the placebo group at 2 hours were 15.3% and 21.3% in the two studies. Participants taking the 50-mg dose did not see a significant advantage over placebo until 2 hours post-administration.

The researchers also looked at relief of the most bothersome symptom as defined by the patient, most often photophobia. In both studies, about 25% of participants taking the highest dose reported being free of this symptom at 1 hour after administration, rising to 40.7% in SAMURAI and 48.7% in SPARTAN at 2 hours. Corresponding 2-hour rates in the placebo arms were 29.5% and 33.5%. Significant separation from the placebo was seen as early as half an hour in the high-dose lasmiditan arm.

Overall, SAMURAI participants reported about 60% headache pain relief and SPARTAN participants reported nearly 65% relief at 2 hours after the first dose of lasmiditan at either 100 mg or 200 mg. Placebo recipients reported about 40% pain relief in both studies.

Treatment with lasmiditan was generally safe and well tolerated. About 40% of patients receiving the 200-mg dose and 36% of those taking 100 mg experienced treatment-emergent adverse events, all mild to moderate. The most common side effects in the 200-mg arm were dizziness (16.3%-18.0%), paresthesia (6.6%-7.9%), somnolence (5.4%-6.5%), fatigue (3.1%-4.8%), and nausea (2.6%-5.3%). Less than 1% experienced cardiovascular adverse events.

An open-label trial called GLADIATOR is now underway to assess the longer-term safety and efficacy of lasmiditan, Aurora said.

Presentation session moderator Andrew Charles, MD, of the David Geffen School of Medicine at UCLA, told MedPage Today, “As a whole, we’re seeing dramatic new approaches from multiple sources. My overall impression is that these are extraordinary times, with new approaches based on new delivery methods and modification of old approaches, but also new molecules.”

The research was funded by Eli Lilly and multiple authors were company employees.

Goadsby reported relationships with numerous companies active in migraine drug development and marketing. Charles reported no relevant disclosures.

• Primary Source

  American Headache Society

  Source Reference: Wietecha L, et al “Phase 3 studies (SAMURAI, SPARTAN) of lasmiditan compared to placebo for acute treatment of migraine” AHS 2018; Abstract IOR-02.

• Secondary Source

  American Headache Society

  Source Reference: Maassen van den Brink A, et al “Lasmiditan inhibits CGRP release in the mouse trigeminovascular system” AHS 2018; Abstract OR-03.

https://bit.ly/2KzkvDb

Many top FDA execs eligible to retire soon

The FDA is looking to strengthen its workforce using new authorities granted under the 21st Century Cures Act, according to a report sent to Congress earlier this month. And they’ll need all the help they can get.

After digging in and reducing the number of open jobs in the past year, FDA leaders say that 40% of senior execs will be eligible to retire next year — leaving the agency susceptible to a major top-level transition period at a time the hunt for top talent has never been more intense.

The Cures Act granted FDA the authority to streamline the hiring process for certain scientific, technical and professional positions, and allows the agency to provide higher salaries to ensure the agency can compete with industry and academia.

“This authority will allow us to better build and maintain the highly talented workforce needed to meet the challenges of today’s rapid advances in science, medicine, and technology,” FDA Commissioner Scott Gottlieb writes in the opening of the report.

According to Gottlieb, FDA has been using the human resources authorities granted under Cures since February 2018 but has “only begun to tap its potential.”

In the years leading up to Cures enactment, FDA struggled to fill hundreds of vacancies in its review divisions, often citing a drawn out hiring process and low salaries compared to industry as major hurdles in attracting new talent, especially in emerging scientific and technical areas.

However, within the last two years the number of vacancies at the Center for Drug Evaluation and Research has come down from more than 900 in May 2016 to 650 in July 2017.

Since Cures‘ passage in 2016, FDA says it has been working towards implementing its new hiring and HR authorities.

According to the agency, some of those efforts include creating a staffing team to identify candidates for “hard-to-fill” scientific positions, developing processes to reduce time to hire to less than 80 days and designing a new alternative pay structure for 38 occupations that is more competitive than under the agency’s earlier authorities.

FDA says it is still working on completing new policies and procedures around hiring but says that it made its first two hires using Cures authorities in early 2018 and expects to fill additional positions in the coming months.

Aside from salary levels and lengthy hiring times, FDA says that its swelling size has contributed to the challenge of filling open positions. In the last decade, FDA says its staff has more than doubled from 8,000 employees to approximately 17,000 today.

“The need to rapidly recruit highly skilled and experienced staff has been a challenge for the agency,” FDA writes.

Another major challenge FDA faces in maintaining its workforce is the sheer number of staff who will become eligible to retire in the coming years.

According to the report, staff turnover is currently around five percent each year, consistent with other federal agencies, but may soon spike as a growing number of staff become eligible for retirement.

As of 2017, FDA says that 13.3% of its staff are eligible to retire, and by 2019 the agency says that more than 40% of senior leadership will be eligible to retire.

In anticipation of the coming departures, FDA says it is working to develop succession planning strategies, though specific strategies have yet to be determined.

https://bit.ly/2NhGNb2