FDA staff largely unfazed by CV signal in Amgen osteoporosis drug trials

FDA staff braved the snow and the federal shutdown to post their review of Amgen’s once-rejected osteoporosis drug on Monday, underscoring that the efficacy of the drug in postmenopausal women had been established, and suggesting that the CV signal observed in two trials may not be a significant worry.

The review comes days after Amgen and partner UCB secured Japanese approval for the drug, romosozumab, and precedes a meeting of independent experts on Wednesday who will make their recommendation on the approvability of the drug in the United States. Romosozumab — which is to be sold under the brand name Evenity — functions predominantly as a bone anabolic agent that stimulates bone growth.

The monoclonal antibody was tested in three late-stage studies: the 7,180-patient FRAME study in postmenopausal women with osteoporosis, which tested the drug against a placebo; the 4,093-patient ARCH study in postmenopausal women in osteoporosis, which tested the drug against an osteoporosis drug originally made by Merck called alendronate; and the 245-patient BRIDGE study in men with osteoporosis, which tested the drug against a placebo.

All three pivotal studies showed the drug was effective, but the ARCH and BRIDGE trial demonstrated a signal of cardiovascular-related serious adverse events, which led to the FDA issuing a complete response letter to the companies, after they had applied for approval in postmenopausal women with osteoporosis. Taking into account the CV signal and feedback from the FDA about the paucity of anabolic agents, the duo re-submitted an application to market drug last year, but for a narrower patient population: postmenopausal women with osteoporosis who carry a high risk of fracture. They also proposed a boxed warning as well as a precaution for cardiovascular risk on the drug’s label, if approved. Meanwhile, the drug is under review in Europe.

Globally, 1 in 3 women over age 50 will experience osteoporotic fractures, according to the International Osteoporosis Foundation.

In its review, FDA staff agreed that the effectiveness of romosozumab for the treatment of postmenopausal osteoporosis had been established, but questioned whether the CV signal seen in ARCH and BRIDGE were generalizable to the US population, given that enrolled patients from the US only accounted for 1.8% of the ARCH study, and 1.4% of the BRIDGE study. In their suggested questions for independent panel, the agency’s reviewers did not stress the CV issue.

“The docs read mostly benign and discussion/voting questions are not as critical on CV risk, supporting a favorable panel vote on Wed (1/16) and an eventual approval later in H1:19,” Jefferies analysts wrote in a note, adding that Lilly’s osteoporosis drug Forteo carries a black box warning highlighting the risk of cancer and still rakes in about $2 billion.

The drug “represents a modest $500 million worldwide upside opportunity not widely accounted by consensus, and the drug has shown strong efficacy (beating Fosamax by 48-50%) along with an acceptable safety profile. The prior safety signal seen in the smaller of two key Phase III studies (ARCH vs FRAME) seems more spurious than concerning to us,” they noted.

https://endpts.com/fda-staff-largely-unfazed-by-cv-signal-in-amgen-osteoporosis-drug-trials/

January 2019 Life Science IPOs

January 2019 IPO Filings and Pricings, Updated 1/14/19

_{Know of an IPO since Jan. 1, 2019 that we missed? Email us at news@biospace.com.} 

Related: Check out BioSpace’s October list, November list, and December list.

DATE	COMPANY NAME	AMOUNT (USD)	COMPANY HQ	RESEARCH FOCUS
1/11/19	Cirius Therapeutics	$86M Filed	San Diego, CA	Innovative therapies for the treatment of liver and metabolic diseases
1/11/19	Kaleido Biosciences	$100M Filed	Lexington, MA	Modulate the metabolic output and profile of the body’s microbiome
1/7/19	Alector	$150M Filed	San Francisco, CA	Develop therapies that empower the immune system to cure neurodegeneration
1/7/19	Anchiano Therapeutics	$35M Filed	Jerusalem, Israel	Genetic therapy for early-stage bladder cancer
1/4/19	Poseida Therapeutics	$115M Priced	San Diego, CA	CAR-T products to treat hematological malignancies and solid tumors
1/4/19	China SXT Pharmaceuticals	$10.2M Priced	Taizhou, China	Research, development, manufacture, marketing and sales of Traditional Chinese Medicine Pieces

https://www.biospace.com/article/biospace-s-list-of-january-2019-life-science-ipos/

Intuitive’s Q4 results overshadowed positive China news, says Piper Jaffray

Overshadowed last week by Intuitive Surgical’s “strong” preliminary Q4 results and 2019 procedure guidance were several positive updates in China, Piper Jaffray analyst JP McKim tells investors in a research note. These included the successful completion of a 63 patient SP trial by Hong Kong University, which highlighted the ability of the system to access hard to reach places and reduced incision, says the analyst. Further, he points out Intuitive’s Xi system in China was cleared in December and that the company is now direct through its joint venture Intuitive-Fosun not only for Ion but for da Vinci products as well. McKim expects a ramp in Intuitive Surgical’s placements throughout 2019 in China, which he believes should “further fuel above average” procedure growth in 2019 and 2020. The analyst reiterates an Overweight rating on Intuitive Surgical with a $625 price target.

https://thefly.com/landingPageNews.php?id=2848448

Vivus gains on published Qsymia CV data

Thinly traded nano cap VIVUS (NASDAQ:VVUS) is up 6% premarket on light volume on the news that results from a retrospective study assessing the cardiovascular safety of Qsymia (phentermine and topiramate extended-release) will be published in the February 1 issue of The Journal of Clinical Endocrinology & Metabolism.

The results, based on medical claims databases, showed that the combined risk of major adverse cardiovascular events (MACE) was not elevated in patients receiving Qsymia, or concurrently taking both phentermine and topiramate, compared to former users of these medications. There were only three MACE events over 3,245 person-years of follow-up, too few to draw definitive conclusions.

https://seekingalpha.com/news/3422649-vivus-6-percent-premarket-published-qsymia-cv-data

GE Healthcare partners with Vanderbilt on AI immunotherapy diagnostics

GE Healthcare is teaming up with Vanderbilt University Medical Center to develop more precise cancer immunotherapy diagnostics that use artificial intelligence to predict both efficacy and potential side effects.

The five-year partnership will aim to produce multiple diagnostic tools, using anonymized demographic, genomic, tumor, cellular, proteomic and imaging data from thousands of VUMC cancer patients.

“This partnership is a great example of the increasing convergence of the tools, technologies and data used by therapy innovators and healthcare providers,” said GE Healthcare’s president and CEO, Kieran Murphy.

The two aim to make the first analytics application prototype available by the end of 2019.

“Immunotherapy offers tremendous promise but given the current unpredictability of some patients’ reactions to treatments, it is also associated with increased morbidity and cost,” added Jeff Balser, president and CEO of Vanderbilt University Medical Center and dean of the Vanderbilt University School of Medicine.

In addition, GE Healthcare and the university plan to develop new positron emission tomography (PET) tracers to help physicians stratify cancer patients for clinical trials and avoid the recruitment of inappropriate study participants.

The two also hope the PET tracers will ultimately be used to monitor the efficacy of immunotherapies in everyday practice, with proof-of-concept being established by the end of 2020.

Meanwhile, GE Healthcare will also collaborate with the Vanderbilt-Ingram Cancer Center and its stem cell transplant facility to improve productivity, efficiency and cost of cell processing operations through automation, digitizing workflows and industrializing operations.

In late 2018, GE Healthcare signed on to build an AI-powered command center for the Bradford Royal Infirmary, an National Health Service teaching hospital in the U.K., which aims to use real-time information and analytics to direct patient care delivery and allocate resources. Its goal is to increase the number of patients who are admitted, transferred and discharged within four hours from its emergency department, which sees 350 to 400 patients per day.

https://www.fiercebiotech.com/medtech/ge-healthcare-partners-vanderbilt-ai-based-immunotherapy-guidance-and-diagnostics

Biotechs still scramble for IPOs: Kaleido, Cirius file amid government shutdown

We saw a flurry of initial public offering activity in the lead-up to the J.P. Morgan Healthcare Conference, but it seems as the dust settles on another chaotic week, biotechs are not standing still.

At the start of this year’s meeting in San Francisco, three early-through-late-stage biotechs wanted nearly $300 million between them. At the end of the week, two more have joined them: Kaleido Biosciences and Cirius Therapeutics.

But there may be a wait on these biotechs’ hands, given the ongoing partial U.S. government shutdown, which has cut the number of staffers at the SEC (PDF). But all five have at least got their paperwork in.

Massachusetts-based Kaleido, which wants a beefy $100 million IPO for its midstage work on microbiome therapies to treat rare genetic disorders. Just six months ago, the biotech got off a $101 million series C.

The Flagship Pioneering-founded company only came out of stealth in September 2017, with $65 million and the goal of developing new chemistries that direct the human microbiome and its various bacteria.

Whereas previous gut-bacteria-targeting strategies have focused on adding or subtracting certain microbes from the mix, Kaleido is looking to treat and shape the microbiome as a single human organ, which metabolizes nutrients and interacts with other parts of the body through biochemical signals.

The company hopes to manage the microbiome’s total metabolic output to treat diseases across multiple areas, including rare genetic disorders.

Kaleido’s discovery platform performs automated, high-throughput screening of the company’s libraries of novel molecules against human ex vivo microbiomes, allowing early testing of both healthy and patient volunteers.

In October 2017, the biotech penned an agreement with the genomics platform company CoreBiome to provide high-scale microbiome sequencing on tens of thousands of microbiome samples, combining physiological data, metabolomics and screening assays.

Since its founding in 2015, the quiet biotech has conducted at least 10 pre-IND studies including safety and tolerability studies in human subjects.

The most advanced products in Kaleido’s pipeline include treatments for high levels of ammonia in the blood linked to urea cycle disorders or hepatic encephalopathy. Other disease targets include drug-resistant bacterial infections, renal disease, diarrhea, cardiovascular disease, immuno-oncology and diabetes.

It plans to list on the Nasdaq under the symbol “KLDO.”

And then there’s Cirius, which wants $86 million toward its work on liver and metabolic diseases.

The San Diego-based company, founded back in 2015, plans to list on the Nasdaq under the symbol “CSTX.”

One known as Octeta Therapeutics, the company has undergone a transformation in recent years with new leadership, location and a new name coming in April 2017. The NASH biotech is hoping to cash in on the potentially large fatty liver market, although it has some tough competition from across nearly every biopharma company.

But Cirius’ metabolism-modifying approach differs from—and is potentially complementary to—the mechanisms of action of NASH assets in the clinic at other companies, opening the door to combination therapies that could help it in market terms in the future.

The IPO cash will go toward its lead product candidate, MSDC-0602K, a once-daily, oral small molecule for NASH with liver scarring. It’s currently in a phase 2b test in just over 400 patients.

Back in October, the company reported positive interim results from the first 328 subjects reaching their six-month follow-up visit, which “demonstrated improvements in liver enzymes and glycemic control,” the biotech notes in its SEC-1 filing.

“The overall rate of treatment emergent adverse events was similar across placebo and all dose cohorts, and we saw no signal for peripheral edema, a safety concern associated with first generation thiazolidinediones, or TZDs. We expect to report final data from this clinical trial in the second half of 2019.”

https://www.fiercebiotech.com/biotech/after-jpm-biotechs-still-scrambling-for-ipos-as-kaleido-cirius-file-amid-government

Swiss team halts breast cancer metastasis by fooling cells into becoming fat

What if doctors could stop breast cancer from spreading by turning tumor cells into something harmless, like fat? That question led scientists at the University of Basel to a combination of two FDA-approved drugs that, in mice, transformed breast cancer cells into fat cells—and prevented the tumors from growing and spreading.

The combo treatment consisted of GlaxoSmithKline’s diabetes drug Avandia (rosiglitazone) and Novartis’ cancer treatment Mekinist (trametinib). “As far as we can tell from long-term culture experiments, the cancer cells-turned-fat cells remain fat cells and do not revert back to breast cancer cells,” said Gerhard Christofori, a professor of biochemistry at the University of Basel, in a statement.

The key to the Swiss scientists’ experiment was their ability to exploit a developmental phase during which cancer cells are amenable to turning into many different types of cells. When cancer cells enter that stage, called epithelial-mesenchymal transition, they become more like stem cells, but they also promote metastasis.

The researchers gave doses of Avandia and Mekinist to mice that had human breast cancer cells implanted into them. The drugs slowed the growth of the primary tumors and prevented the cancer from spreading. They published their findings in the journal Cancer Cell.

Breast cancer is the second most common form of the disease after skin cancer, according to the American Society of Clinical Oncology, and about 5% of patients already have metastatic disease when they are diagnosed. Women with metastatic breast cancer have a five-year survival rate of just 27%.

Mekinist is currently approved in combination with Tafinlar to treat patients with BRAF-mutated melanoma or non-small cell lung cancer. Several studies of Mekinist in combination with a variety of other treatments in breast cancer are ongoing.

As for Avandia, it was once a $3-billion-a-year hit in diabetes, but controversies over potential cardiovascular risks drove sales down to $183 million in 2011, just before generic competitors entered the market. In 2015, the FDA said that after years of monitoring side effect reports on the drug, it was lifting all prescribing restrictions.

The University of Basel researchers believe the combination of Mekinist and Avandia forces enough cancer cells to differentiate into fat that the primary tumor is no longer able to resist conventional chemotherapy. Their next step is to try their fat-conversion approach along with chemotherapy, and to see if the combinations work in other cancers as well.

Said Christofori said in a release from the University of Basel, “This innovative therapeutic approach could be used in combination with conventional chemotherapy to suppress both primary tumor growth and the formation of deadly metastases.”

https://www.fiercebiotech.com/research/swiss-team-stops-breast-cancer-metastasis-by-fooling-cells-into-becoming-fat