Dramatic Increase in Teens’ Smoking Risk With Previous Vaping

Youth whose first use of a tobacco product was electronic cigarettes were more likely to initiate cigarette smoking over 2 years of follow-up in a newly reported study.

Prior e-cigarette use was associated with a more than four-fold greater risk of ever smoking cigarettes and three-fold greater risk of current cigarette use in the prospective cohort study.

Findings from the nationally representative study, published online in JAMA Network Open, add to the growing evidence linking e-cigarette use to an increased risk for initiating cigarette smoking among youth, especially among low-risk teens.

Kaitlyn M. Berry, MPH, of Boston University School of Public Health, and colleagues, concluded that the findings highlight the need for “aggressive regulation” to restrict access to e-cigarettes among teens.

Several recent studies have raised the alarm about an elevated risk of smoking initiation among teen e-cigarette users, including a 2017 meta-analysis that found that teens and young adults who used e-cigarettes had more than three times the odds of later cigarette use and more than four times the odds of current cigarette smoking.

This analysis led the National Academies of Sciences to conclude in a 2018 report that there is “substantial evidence” that e-cigarette use increases the risk for cigarette-smoking tobacco-naive youth.

But in an email exchange with MedPage Today, Berry explained that many of the prior studies may have been subject to methodological limitations because they started with a sample of youth who were never cigarette users, assessed their e-cigarette use at that early time point, and then reviewed their smoking status after a year of follow-up.

“By removing cigarette users at the beginning, this design may overlook youth who started with e-cigarettes and already made the transition to cigarette smoking,” she said. “Additionally, the design may misclassify youth who started vaping between the two time points.”

The design of the new study, which centers around a youth’s very first tobacco product use, allowed the researchers to create what Berry described as “a loose timeline of the order of products used, that, in theory, avoids these potential issues.”

The researchers analyzed data from three waves of the nationally representative Population Assessment of Tobacco and Health (PATH) Study (2013-2016) in their effort to evaluate the association between prior e-cigarette use and use of other non-cigarette tobacco products with later cigarette initiation over a roughly 2-year period.

The sample included 6,123 respondents (49.5% female, 54.1% non-Hispanic white) with a mean age of 13.4 (1.2 years) who were tobacco-naive at baseline.

A total of 8.6% reported e-cigarettes as their first tobacco product, while 5.0% reported using another non-cigarette product first (3.3% reported using cigarettes first).

Cigarette use at wave 3 was higher among prior e-cigarette users (20.5%) compared with youths with no prior tobacco use (3.8%).

Among the other main findings:

• Prior e-cigarette use was associated with more than four times the odds of ever cigarette use (OR 4.09, 95% CI 2.97-5.63) and nearly three times the odds of current cigarette use (OR 2.75, 95% CI 1.60-4.73), compared with no prior tobacco use

• Prior use of other tobacco products was similarly associated with subsequent ever cigarette use (OR 3.84, 95% CI 2.63-5.63) and current cigarette use (OR 3.43, 95% CI 1.88-6.26), compared with no prior tobacco use

• At the population level, the analysis indicated that the fraction of ever cigarette use attributable to prior e-cigarette use was 21.8% (an estimated 178,850 youths) and 15.3% of current cigarette use (43,446 youths) among U.S. youths ages 12 to 15 may be attributable to prior e-cigarette use

Nine variables were used to categorize the respondents into risk groups, including alcohol, marijuana, and prescription drugs without a prescription. The association of prior e-cigarette use with cigarette initiation was found to be strongest among youth categorized as low-risk (OR 8.57, 95% CI 3.87-18.97).

The researchers concluded that this finding “raises concerns that e-cigarettes may re-normalize smoking behaviors and erode decades of progress in reducing smoking among youths.”

Grant funding for the research was provided by the National Institutes of Health, the National Heart, Lung, and Blood Institute, and the National Cancer Institute.

Researcher Andrew Stokes reported receiving research grants from Johnson & Johnson not associated with this study.

• Primary Source

  JAMA Network Open

  Source Reference: Berry KM, et al “Association of electronic cigarette use with subsequent initiation of tobacco cigarettes in US youths” JAMA Netw Open 2019; 2(2): e187794.

https://www.medpagetoday.com/pulmonology/smoking/77779

Novartis eyes blockbuster launches for 2018-20, including Kymriah

As Novartis shakes off its Alcon eye business and the loss of two high-profile executives, chief Vas Narasimhan has outlined the Swiss drugmaker’s roster of 14 blockbuster launches, a bulk of which are expected to win approval between this year and 2020. The drugs included in the list are largely familiar, but the inclusion of the company’s pioneering CAR-T therapy Kymriah, whose adoption has been wobbly due to manufacturing woes, will raise some eyebrows.

In 2017, Novartis spent a hefty $9 billion on R&D, making it one of the top spenders in global biopharma. Investors expect to see the company to now get bang for its buck. Last November, the company used it R&D review to highlight 26 blockbuster contenders in its arsenal and offer a rosy picture of things to come after suffering a few knocks — the FDA rejecting its heart drug, and the company abandoning its attempt at a Rituxan copycat.

Since then, the company has seen good days and bad. On the positive front, its gene therapy for SMA secured the FDA’s priority review, and its sickle cell drug won breakthrough therapy status. The drugmaker also swallowed a cell and gene therapy manufacturer in an attempt to unclog the commercial rollout for Kymriah. In a first for a multinational pharmaceutical company, Novartis’ Sandoz unit tied up with Canadian medical cannabis producer Tilray, a landmark endorsement of the controversial plant. On Wednesday, as part of its full-year 2018 results, the drugmaker said four newer products — including Cosentyx and Entresto — in its roster of medicines achieved blockbuster status in 2018.
On the other end of the scale, Novartis has also suffered a number of setbacks in the last quarter of 2018. For instance, its migraine drug Aimovig — billed as a blockbuster and partnered with Amgen — was refused endorsement by the UK’s NICE, months after the agency declined to give the nod for Kymriah. Two top executives — CAR-T chief David Lebwohl and oncology head Liz Barrett — also left the drugmaker to take top positions in small biotechs. And J&J dealt Novartis a blow when its psoriasis drug Tremfya beat the dominant Cosentyx in a head-to-head study.

2018
AIMOVIG — The migraine drug forms part of a new crop of biologics targeting the CGRP protein that transmits pain signals into the brain. The drug was the first to win approval in 2018, and within months rival treatments from Lilly and Teva were also given regulatory nods. All three have demonstrated similar efficacy and safety in trials. Like its rivals, the drug is priced at $575 per month and has been pegged as a potential blockbuster. Following the NICE setback, reports suggested Aimovig was excluded from pharmacy benefits manager CVS’ formulary in the United States. This will be a blow, but there are other PBMs on the block.
KYMRIAH — The pioneering CAR-T drug was FDA approved amidst great fanfare in 2017, and since then the FDA has expanded its use in the United States and the EC also approved the drug last August. NICE refused to endorse the pricey drug. Meanwhile, rivals such as Gilead’s Yescarta have emerged, and Kymriah sales have suffered due to manufacturing issues. In the fourth quarter, the drug generated a paltry $28 million. However, Novartis is doing its best to shore up manufacturing, having bought cell and gene therapy manufacturer CellforCure.
LUTATHERA — The cancer drug, which came with Novartis’ $4 billion acquisition of Advanced Accelerator Applications in 2017, paid off handsomely in early 2018 after the FDA gave it a quick OK. Novartis reported an 11% jump in oncology revenue in the fourth quarter, driven partly by Lutathera sales of $81 million.
2019
BYL719 — Otherwise known as alpelisib, the PI3K inhibitor nearly doubled progression-free survival in a third of patients with a hard-to treat form of breast cancer last October. Other drugs in this class, including Roche’s taselisib, have largely crashed and burned due to safety concerns.
MAYZENT — Expected to launch this year, the MS drug also known as siponimod is critical for the company as one of its top sellers Gilenya has generic competition looming. Company officials have previously described the drug’s data in glowing terms, and analysts have concurred, offering a $3 billion peak sales projection for the treatment.
RTH258 — The eye drug has been built up as a rival to Regeneron’s flagship blockbuster injection Eylea and CEO Narasimhan has gone so far as to say RTH258 is “consistently superior” to Eylea, after conducting retrospective analyses of late-stage data last year. Eylea has been untouchable for more than a decade, so it is up to Novartis to prove otherwise.
ZOLGENSMA — The gene therapy is currently under FDA review and the agency is expected to announce its decision in May. In its review posted in December, ICER suggested the Zolgensma — with a list price of $2 million — would offer more cost-effective benefit in the long run versus rival Biogen’s Spinraza. However, the Swiss drugmaker has suggested a price of $4 million for the curative therapy, which it acquired via a $8.7 billion takeover of AveXis, may be justified.
2020
COSENTYX — The psoriasis drug that became a blockbuster in 2016 is one of Novartis’ key drugs, and the drugmaker is working on expanding the IL-17A inhibitor’s market by including patients with psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondylarthritis (nrAxSpA). Pivotal data are expected later this year and, if positive, will be followed by a marketing application before the end of this year.
ENTRESTO — The medicine is another top seller for Novartis and is currently approved for HFrEF (formerly known as systolic heart failure) — in these patients the heart muscle does not contract effectively, reducing the level of oxygen-rich blood pumped into to the body. Initially a slow moving product hampered by physicians reluctant to adopt a new therapy and insurers who balked at its price, Entresto is now comfortably a blockbuster product. The drug is now under evaluation for HFpEF (also referred to as diastolic heart failure) — a now larger group of patients whose heart muscle contract normally but ventricles do not relax as they should during ventricular filling. Data from the trial PARAGON-HF are expected in the third quarter of 2019.
INC280 — Otherwise known as capmatinib, the MET inhibitor was licensed to Novartis from Incyte in 2009. Mid-stage data on the drug in certain patients with the most common form of lung cancer (NSCLC), presented last October, showed INC280 induced an ORR of 72% in treatment-naive patients and about 39% in previously treated patients. Novartis is expected to submit a marketing application later this year.
OMB157 — Other than the approved Gilenya and Mayzent — which is currently under review — ofatumumab (OMB157) is another drug Novartis is hoping to use in MS. The drug, already sold as Arzerra, has caused a number of problems for Novartis as a treatment for leukemia — the drugmaker was forced to pull it off the market outside the US as competition heated up. Novartis thinks it can repurpose the drug for MS, an indication for which it is currently being investigated in two Phase III studies.
PDR001 COMBO — PDR001, also called spartalizumab, is Novartis’ PD-1 inhibitor and is being tested in a number of cancers. A late-stage study testing the drug in combination with Novartis’ approved cancer drugs — Tafinlar and Mekinist — in patients with metastatic melanoma is ongoing.
QVM149 — The asthma drug is currently being tested against standard triple combination therapy in a late-stage study in uncontrolled asthmatics — the trial is expected to be completed this year.
SEG101 — Expected to launch in 2020, the sickle cell disease drug has secured the FDA’s breakthrough therapy designation earlier this month. After a delay in 2018, a marketing application for the drug is expected this year.

https://endpts.com/novartis-lays-out-blockbuster-launches-for-2018-2020-with-surprising-inclusion-of-kymriah/

Merck KGaA CEO sees high demand for semiconductor solutions

Merck KGaA CEO Stefan Oschmann told Bloomberg in a television interview that demand for semiconductor solutions is high. The CEO reiterated that the business will return to sustainable growth in 2019, according to Bloomberg.
https://thefly.com/landingPageNews.php?id=2857917

OptumRx to cover migraine drugs from Amgen, Eli Lilly

An OptumRx client note viewed by Reuters reveals that new migraine drugs from Amgen (AMGN) and Eli Lilly (LLY) are listed as preferred treatments on its lists of covered drugs, according to Caroline Humer. Teva Pharmaceutical’s (TEVA) rival drug, Aimovig, is excluded on one list from the PBM owned by UnitedHealth (UNH) and patients can pay more for it in some cases on a second list, Reuters added
https://thefly.com/landingPageNews.php?id=2857923

Crunch time for ImmunoGen as phase 3 readout looms for lead antibody-drug

2019 could be a pivotal year for antibody-drug conjugate specialist ImmunoGen as it tries to draw a line under past challenges with phase 3 data for lead drug mirvetuximab soravtansine.

Within the next few months, ImmunoGen should report the results of its FORWARD I trial of the wholly owned folate receptor alpha-targeting ADC in platinum-resistant ovarian cancer, which aims to displace chemotherapy as the go-to treatment in these patients.

Analysts at Jefferies say they are “leaning positively on the outcome of the trial”, which could lead to an FDA approval in 2020 and—if all goes to plan—U.S. sales of around $774 million in 2032, with another $233 million possible from ex-U.S. royalties.

ImmunoGen has one of the longest histories in the biotech sector, having been incorporated way back in 1981, so it has been a long haul towards sustainable revenues and profits for the company’s investors as it approaches the end of its fourth decade of operations.

The last couple years have also been a little mixed for ImmunoGen’s ADC pipeline, with a late-stage failure of Bayer-partnered mesothelioma drug anetumab ravtansine in 2017 and the loss of Sanofi as a partner for its anti-LAMP1 candidate last year. On the plus side, it also signed new partnering deals with Jazz Pharma and Debiopharm.

Jefferies is expecting data from FORWARD I to read out in the first half of the year, and said the trial will give ImmunoGen more than one shot on goal.

The study is comparing mirvetuximab to the most commonly used second-line chemotherapies—Johnson & Johnson’s Doxil (pegylated liposomal doxorubicin), topotecan and paclitaxel—and the best outcome will be a significant improvement in median progression-free survival (mPFS) for the ADC across the whole patient population.

If that doesn’t happen, ImmunoGen could still move ahead with registration if mirvetuximab is shown to be better than the comparators in a subset of patients with high levels of folate receptor alpha (FRα) expression. FRα is overexpressed on ovarian and several other epithelial cancers, and the majority of the FORWARD I cohort are high expressers.

From data generated with the ADC to date, Jefferies think that it has a reasonable chance of showing a two month or more advance on mPFS which should be enough for FDA approval, given that the current second-line chemotherapies typically only extend life for three to four months.

It is worth noting, however, that a couple of other FRα-targeting drugs have failed at the last hurdle in refractory ovarian cancer, including Merck and Endocyte’s vintafolide and Eisai/Morphotek’s farletuzumab.

Nevertheless, ImmunoGen reported positive preliminary results with mirvetuximab and Merck’s PD-1 inhibitor Keytruda (pembrolizumab) at last year’s ESMO which seemed to indicate a benefit for the combination over the ADC alone, which adds to the optimism about the program.

“We see use in combination in earlier lines of therapy as upside to our estimates,” said the Jefferies analysts.

https://www.fiercebiotech.com/biotech/crunch-time-for-immunogen-as-phase-3-readout-looms-for-lead-adc

Anti-rejection drug rapamycin shows promise in liver cancer

Scientists at the University of Pittsburgh School of Medicine were studying the cells that surround the liver’s central vein when they made a serendipitous discovery. Cells with a mutation in a gene called β-catenin also made high levels of the mTOR protein—a fault that they believe could promote the development of cancer.

Since there are already mTOR inhibitors on the market, including anti-rejection drug rapamycin, they wanted to dig deeper to learn whether those drugs could be repurposed in liver cancer. So they created a mouse model of liver cancer with mutations in the β-catenin and MET genes, creating animals with tumors that are similar to more than 20% of liver cancers in people.

When they fed the mice rapamycin, the tumors shrunk. When they added a MET inhibitor, the cancers almost disappeared completely, the Pitt researchers reported in the journal Cell Metabolism.

Inhibiting mTOR has been tried before in liver cancer but with little success. A 2016 trial in 525 patients with the disease, for example, found little difference in survival between patients given mTOR inhibitor sirolimus after liver transplantation versus patients who received a different sort of anti-rejection drug. The Pitt researchers believe their results argue for a more refined approach, targeting mTOR inhibitors to patients whose liver tumors have both β-catenin mutations and an addiction to the mTOR protein.

By studying the mouse models of liver cancer that they created, the scientists discovered that β-catenin uses an enzyme called glutamine synthase to activate mTOR. “Activating mTOR kicks up the protein-making factories in these cells, giving them the resources to divide and grow,” saidsenior author Satdarshan Monga, M.D., professor of pathology and director of the Pittsburgh Liver Research Center at Pitt, in a statement.

Rapamycin analogs are already approved and on the market to treat a range of cancers, including renal cell carcinoma and HER2-negative breast cancer. The crowding of the market for mTOR inhibitors in oncology may have prompted AstraZeneca’s recent decision to drop its midstage candidate vistusertib, in spite of promising data in a range of cancers.

At the very least, Pitt’s Monga believes his team’s findings argue for an approach whereby liver cancer patients who undergo transplants are given rapamycin as the preferred anti-rejection medicine over other choices.

“Current liver cancer therapies increase the likelihood of survival only by 3 or 4 months, so taking a precision medicine approach to identify the right patient could allow us to repurpose existing drugs to improve treatment success,” he said.

The next step for the Pitt researchers is to plan a clinical trial testing rapamycin as a treatment for liver cancer and as a way to prevent recurrences in patients who have received liver transplants.

https://www.fiercebiotech.com/research/anti-rejection-drug-rapamycin-shows-promise-liver-cancer

J&J Erleada trial stops early on good news, new prostate cancer nod eyed

Johnson & Johnson is counting on Erleada to carry the prostate cancer baton as Zytiga battles generics. And it just got one step closer to a new indication.

Wednesday, the New Jersey drugmaker said investigators had cut short a phase 3 study of Erleada in combination with androgen deprivation therapy in patients with metastatic, castration-sensitive prostate cancer (mCSPC) after the combo showed it could significantly stave off disease progression and extend patients’ lives. Based on the results, an independent data monitoring committee recommended placebo-plus-ADT patients switch over into the Erleada group.

Now, the pharma giant will submit those results for presentation at an upcoming medical meeting, and in the meantime, it’s planning to file for approval in mCSPC this year, it said.

A green light for Erleada would add to its first indication, a nod in nonmetastatic castration-resistant prostate cancer that brought it to the market last February. There, it’s battling Pfizer and Astellas’ Xtandi—also known as Zytiga’s longtime nemesis—which picked up its own go-ahead in July. Despite Erleada’s head start, Xtandi has a sizeable lead in the market, Pfizer said this week, pegging Xtandi’s share at quadruple Erleada’s.

A new approval would also bring in patients from the castration-sensitive group who aren’t currently eligible for Zytiga. The elder drug is OK’d only in high-risk patients, while Erleada’s newest data applies to a broader patient pool.

All in all, analysts expect Erleada to eventually cross the blockbuster barrier but not to show up its predecessor. Barclays analyst Geoff Meacham has projected $1.3 billion in peak sales, which is less than half of the $2.71 billion Zytiga pulled in over the first nine months of 2018.

Meanwhile, looking to dodge the impact of Zytiga generics on Xtandi’s original market—metastatic castration-resistant prostate cancer—Pfizer and Astellas are going after new indications, too. Executives are looking ahead to two key trials in hormone-sensitive prostate cancer, a market Angela Hwang, president of Pfizer’s biopharmaceuticals group, called the one “we’re really excited about.”

https://www.fiercepharma.com/pharma/j-j-s-erleada-trial-stops-early-good-news-setting-up-case-for-new-prostate-cancer-nod