New way to possibly eliminate clogged arteries

Researchers have proposed a unique study in humans to reduce the early onset of atherosclerosis, the buildup of the artery-clogging plaque that can lead to heart attacks and strokes.

The report, published Oct. 4 in the Journal of the American Heart Association, reviews a host of previous research and proposes a new clinical trial to reduce apolipoprotein B, also called apo B lipoproteins, in young and middle-age adults. Over the past few decades, research has pointed to this group of blood proteins, which includes LDL, or “bad cholesterol,” as the main culprit in the beginnings of atherosclerosis.

“Lowering them may have a big impact on making atherosclerosis go away,” said study lead author Dr. Jennifer Robinson, a professor of epidemiology and director of the Prevention Intervention Center at the University of Iowa. “If this works, you could completely eliminate heart attacks and strokes within a generation, because you can’t have a heart attack or stroke unless you have atherosclerosis.”

The proposed trial, CURing Early ATHEROsclerosis, or CURE ATHERO, would set out to determine if atherosclerosis in high-risk adults aged 25 to 55 might be reversed by using medicines called statins and PCSK9 inhibitors over the course of three years.

“The idea is to get the cholesterol very low for a short period of time, let all the early cholesterol buildup dissolve, and let the arteries heal,” Robinson said, adding that this approach has worked well in animal studies. “Then patients might need to be retreated every decade or two if the atherosclerosis begins to develop again.”

Lipoproteins are tiny, complex particles that transport fat and cholesterol through the blood. “There are a lot of different types of lipoproteins, but the ones that have apolipoprotein B on them are the ones that cause atherosclerosis,” said Dr. John Wilkins, a cardiologist and assistant professor at Northwestern University Feinberg School of Medicine.

Wilkins, who wasn’t involved in the report, called the proposal a “very compelling idea” that might show whether older adults can avoid heart attacks and strokes by making sure they have low LDL and apo B levels earlier in their lives.

“It’s a very important question that we really need to answer, because we have therapies now to lower apo B lipoproteins and LDL cholesterol,” said Wilkins, who has conducted research on apo B lipoproteins.

“We know that people who have low LDL cholesterol for genetic reasons have a very low risk of having cardiovascular events, so if we can replicate one of these genetic states and get people’s LDL cholesterol really low in early adulthood, perhaps these people won’t have downstream complications like heart attack and stroke,” Wilkins added.

The proposed trial would face certain challenges, including reluctance among young, seemingly healthy adults to take medication, Wilkins said. Another possible obstacle is the length of the study.

“Atherosclerosis develops over decades. It’s going to be very difficult to conclusively link a treatment strategy in people in their 30s or 40s to a reduction in risk 20 or 30 years later,” Wilkins said. “You would have to treat people and then follow them for 20 to 30 years, and that type of study design just isn’t practical.”

Doctors aren’t currently advised to test patients’ apo B levels, Robinson said, because routine LDL cholesterol tests and other measures already give doctors information to assess cardiovascular risk.

But she said she hopes the proposed trial will show that lowering apo B levels early in life will help people who are genetically inclined to have high cholesterol, as well as those with health problems caused by a poor diet, obesity and lack of exercise.

“People should do as much as they can with lifestyle, but it’s really hard to have a healthy lifestyle in modern society,” Robinson said.

A clinical trial could pave the way for a new generation of therapies to fight heart attacks and strokes, she said.

“Once you know what causes something, you can come up with a hammer for it and eliminate it. We’re not the first ones to think of this idea. This would be the culminating study of decades of research by thousands of people. But I’m excited about this, and I think it’s really time to pursue this hypothesis.”

 Explore further: Statins save lives of people with high levels of LDL cholesterol

https://medicalxpress.com/news/2018-10-possibly-clogged-arteries.html

Blackstone bags Clarus, gains growing Phase 3 niche in fast changing biopharma

Blackstone likes life sciences. And now it’s diving in deep.

The private equity giant has completed a deal to buy Clarus, a busy life sciences investor with an extensive history of gambling on late-stage drug development.

With $2.6 billion under management, Clarus is a peanut on Blackstone’s $440 billion plate. But with $19 billion in healthcare deals completed and a vast portfolio of biotech facility space on its books, Blackstone has the resources to go much bigger in a field that has been exploding with new activity over the last few years.
Clarus managing director and co-founder Nick Galakatos will now become head of Blackstone Life Sciences, bringing his portfolio of 50 life sciences companies with him.

Clarus has been a keen player in late-stage rounds, a highly competitive field where investors like to scale down risk as much as possible. That strategy was on display just days ago, when Clarus spearheaded a $150 million raise for Galera so it could complete a pivotal Phase III study on GC4419, which targets the toxic effect of radiation therapy as superoxide swiftly builds up in patients, afflicting the sensitive tissue in their mouths.

The big opportunity for Blackstone, though, is to do more of the specialty Phase III deals that Clarus has been inking with Big Pharma and Big Biotech, funding Phase III studies that can’t fit into their budgets or the bandwidth of their R&D groups — taking the risk and getting a payback through a mix of cash milestones and royalty streams.

These are deals you rarely hear about in detail.

“We think there’s a significant unmet need on the part of Big Pharma… to develop more of their R&D pipeline,” says Joe Baratta, head of private equity at Blackstone.

Clarus raised a $910 million fund for this niche last fall, and Blackstone has the assets necessary to go deeper.

“For the most part the R&D budget of the major pharma companies is constrained,” Galakatos told me last fall. “They have a very exciting pipeline and frankly they cannot fund their existing budget.”

In a call with reporters today, Galakatos says they’ve done a string of a dozen deals like this ranging from $50 million to $300 million, noting that late-stage development costs have doubled in the past 10 years.

Their arrival comes as the industry is undergoing a transformation. Instead of being picked off one by one by Big Pharma, more companies — like Alnylam or Agios — are pursuing a future in which they remain independent companies with commercial operations. As these companies grow into mid-cap companies, they’ll need significant amounts of money to make the changeover, more likely to see an advantage in doing development deals the new Blackstone operation has in mind.

Blackstone evidently plans to be ready to work for that business.

“This is a unique moment where rapid advancements in science and technology are creating unprecedented innovation and unparalleled impact on human health,” noted Jon Gray, Blackstone’s CEO. “Private capital can play an important role in accelerating the lengthy clinical development process to help bring vital, but underfunded, drugs to market. Building on the foundation of the world-class Clarus team, Blackstone Life Sciences is uniquely suited to provide much needed capital and expertise to this sector.”

https://endpts.com/blackstone-bags-biotech-backer-clarus-and-stakes-out-a-leading-place-for-itself-in-a-rapidly-changing-biopharma-industry/

JPMorgan sees opportunity to buy Constellation Brands shares after earnings

JPMorgan sees opportunity to buy Constellation Brands shares after earnings. JPMorgan analyst Andrea said that Constellation Brands’ (STZ) better than expected Q2 EPS was driven by stronger top-line growth, better operating profit growth and a favorable tax rate. The company’s updated FY19 EPS view of $9.60-$9.75, when adjusted for 25c-30c dilution from its increased investment in Canopy Growth (CGC), compares to Teixeira’s $9.26 estimate heading into the quarter and the consensus forecast of $9.30, she noted. The analyst, who sees an opportunity to buy Constellation shares following the report, keeps an Overweight rating on the stock, which is up nearly 5% to $220.65 in afternoon trading.
https://thefly.com/landingPageNews.php?id=2799997

Lilly’s breast cancer drug Verzenio approved in EU

Eli Lilly’s Verzenio breast cancer drug has been approved in Europe, as the pharma prepares to compete with established rivals from Pfizer and Novartis.

Verzenio (abemaciclib) is a CDK4 and 6 inhibitor, and has been approved by the European Commission in women living with HR+, HER2- advanced breast cancer, in combination with an aromatase inhibitor or fulvestrant.

The drug can be used in women who have not received endocrine therapy, or women who have received this form of therapy.

Already approved in the US since last year, Verzenio will compete with Pfizer’s Ibrance (palbociclib), and Novartis’ Kisqali (ribociclib), which are in the same class of drugs, which work by interrupting the cycle of cell growth in tumours.

Ibrance is now Pfizer’s biggest selling cancer drug, with sales approaching $2 billion in the first six months of this year, although sales of Novartis’ Kisqali are far behind as the drug was second to the market.

Whether Eli Lilly’s drug will make any inroads remains to be seen, and there was no word from US pharma about pricing in Europe.

However in the US it has a list price before any discounts or rebates of about $10,948 per month.

Dr Arash Tahbaz, Senior Medical Director, Eli Lilly and Company UK and Northern Europe, said: “Despite advancements in medicine, metastatic or advanced breast cancer remains a difficult-to-treat, diverse disease with a range of characteristics that can present differently in each individual.

“This marketing authorisation recognises the potential clinical benefit abemaciclib offers and represents continued progress towards helping more people living with this devastating disease.”

The approval is based on the efficacy and safety demonstrated in the global MONARCH 2 and MONARCH 3 clinical trials. MONARCH 2 was a Phase 3, randomised, double blind, placebo-controlled trial evaluating abemaciclib in combination with fulvestrant that enrolled 669 patients with HR+, HER2- metastatic breast cancer who progressed while on endocrine therapy.

The most commonly occurring adverse reactions observed with abemaciclib are diarrhoea, infections, neutropenia, anaemia, fatigue, nausea, vomiting and decreased appetite.

https://pharmaphorum.com/news/lillys-breast-cancer-drug-verzenio-approved-in-eu/

Weight Loss Drug Helped Prevent Diabetes in Overweight People

In overweight and obese patients with type 2 diabetes, lorcaserin (Belviq) helped improve blood glucose levels, according to the CAMELLIA-TIMI 61 trial.

After 1 year of 10 mg, twice-daily treatment, patients saw a significant 0.33% (95% CI 0.29-0.38%, P<0.0001) drop in mean HbA1c level compared with those receiving placebo, reported Erin Bohula, MD, DPhil, of Brigham and Women’s Hospital in Boston, and colleagues.

There was also a 19% risk reduction seen for incident type 2 diabetes among those who had prediabetes at baseline (HR 0.81, 95% CI 0.66-0.99, P=0.038), as well as a 23% risk reduction among those free of diabetes at baseline (HR 0.77, 0.63-0.94, P=0.012).

“We can’t say for sure there’s more than one potential mechanism [behind the glycemic benefit], although my suspicion is that much of it is related to weight loss,” Bohula stated during a press conference of the findings at the annual meeting of the European Association for the Study of Diabetes (EASD). The results were also simultaneously published in The Lancet.

Lorcaserin was originally FDA approved back in 2012 for chronic weight management as an adjunct therapy to lifestyle modification, although the drug is not available in Europe.

In the multicenter trial, lorcaserin only somewhat helped those with prediabetes achieve a normal glucose range, although this did not reach significance (HR 1.20, 0.97-1.49, P=0.093).

Not surprisingly, the patients who received lorcaserin also had a significant amount of weight loss compared with placebo, seen across all groups of diabetes status (P<0.0001 for all):

• Diabetes: loss of 5.7 lb (95% CI 5.1-6.4 lb) [2.6 kg, 2.3-2.9 kg]
• Prediabetes: loss of 6.2 lb (95% CI 5.5-7.1 lb) [2.8 kg, 2.5-3.2]
• Normoglycemia: loss of 7.3 lb (95% CI 5.7-8.8 lb) [3.3 kg, 2.6-4.0 kg]

A total of 12,000 adults age 40 and older were included in the trial: 6,816 patients with diabetes, 3,991 who were identified as having prediabetes — defined as an A1c between 5.7% to <6.5% — and 1,193 with normoglycemia. All participants had a body mass index of 27+ at baseline with established atherosclerotic cardiovascular disease or other cardiovascular-related risk factors. All patients were encouraged to be involved in a weight management program that was freely available to them, but there was no further treatment given beyond the drug. The participants were then followed for a median 3.3 years.

Questions about Clinical Significance

In an accompanying commentary, Xabier Unamuno, MSc, and Gema Frühbeck, MD, PhD, of the University of Navarra in Pamplona, Spain, were somewhat wary of the findings: “From the endocrinologist’s point of view, both the design of the study and its results are somewhat puzzling — namely, in terms of the magnitude of the effect of lorcaserin and the anti-diabetes management of the patients.” Although there was statistically significant net weight loss seen across all groups, it was only moderate at best and “might not be clinically significant.”

Unamuno and Frühbeck said that ultimately, clinicians may find this weight loss “disappointing, especially if it does not lower the risk of cardiovascular disease,” as was seen in the trial’s previously reported cardiovascular outcomes, presented earlier this year at European Society of Cardiology.

The commentary noted that because not everyone will respond to lorcaserin, physicians may instead consider initially prescribing it only on a temporary basis of around 6-12 months in order to distinguish responders from non-responders. “It is difficult to quantify the risk of chronic use versus meaningful clinical improvement. Treatment on an intermittent basis, to maximize the benefits of the first months, might be considered.”

During the press conference, Bohula also noted that the renal outcomes — microalbuminuria, eGFR, and chronic kidney disease progression — from the trial will be presented later this year at the American Heart Association (AHA) meeting in November.

The trial was funded by Eisai.

Bohula reported financial relationships with Servier, Merck, Lexicon, Medscape, Academic CME, MD Conference Express, Paradigm, Novartis, Amgen, and AstraZeneca, as well as grants from the Natoinal Institutes of Health.

Unamuno and Frühbeck reported grants from the Spanish Health Institute ISCIII, Subdirección General de Evaluación and Fondos FEDER, and CIBEROBN.

• Primary Source

  The Lancet

  Source Reference: Bohula E, et al “Effect of lorcaserin on prevention and remission of type 2 diabetes in overweight and obese patients (CAMELLIA-TIMI 61): a randomised, placebo-controlled trial” The Lancet 2018; DOI: 10.1016/S0140-6736(18)32328-6.

• Secondary Source

  The Lancet

  Source Reference: Unamuno X, Frühbeck G “Lorcaserin: balancing efficacy with potential risks” The Lanceet 2018; DOI: 10.1016/S0140-6736(18)32460-7.

https://www.medpagetoday.com/meetingcoverage/easd/75502

Mallinckrodt selloff on Praxair FDA approval seen as overreaction

Shares of Mallinckrodt (MNK) are sliding following the FDA approval of an abbreviated new drug application for Praxair’s (PX) Noxivent. Commenting on the news, Stifel analyst Annabel Samimy argued that the stock selloff is an overreaction as its competitor will face high commercial hurdles to displace the INOmax System and noted that consensus estimates have reflected potential commercial competition for well over a year. Voicing a similar opinion, her peer at BMO added that there are several important factors to consider that would appear to mitigate the generic risks and make the situation manageable for Mallinckrodt. SELLOFF AN OVERREACTION: Noxivent’s filing as a generic has given investors pause that the gas will be used as a substitute to Mallinckrodt’s nitrous oxide in the INOmax System, the leading nitric oxide vasodilator for respiratory failure in term/near-term infants, Stifel’s Samimy said in a research note. The analyst pointed out, however, that Noxivent cannot be interchanged with the nitric oxide gas used in the INOmax System, and thus far, she has not seen a 510(k) approval from the FDA for Praxair’s device. Furthermore, Samimy highlighted that the pending Praxair system will be another branded competitor and not a generic substitute as the Street reaction implies. The pending approval of this ANDA was well known, she contended, adding that she believes estimates have reflected potential competition for well over a year. Overall, the analyst sees the stock move as an “overreaction to a known event” and believes Mallinckrodt is well-positioned to defend its share. Samimy reiterated a Hold rating and $30 price target on the latter’s shares. Also commenting on Praixar’s Noxivent news, BMO Capital analyst Gary Nachman said in a research note of his own that the generic was expected to be approved at some point, although the timing was uncertain. Moreover, the analyst highlighted that there are several important factors to consider that would appear to mitigate the generic risk and make this situation manageable for Mallinckrodt. Praxair will need its device to be approved in order to have a generic version of INOmax, he noted, adding that he fully expects the device to be approved sometime soon. Additionally, the analyst pointed out that litigation is still ongoing with Mallinckrodt’s appeal of the decision that favored Praxair regarding the INOmax patents, with the former indicating that the appeal is expected to be resolved sometime in the first half of 2019. A Praxair generic launch before then would be “at risk,” Nachman argued. The analyst believes “this is a very challenging market” with many natural barriers including all the support that Mallinckrodt provides the neonatal intensive care units at hospitals. Nachman reiterated an Outperform rating and $37 price target on Mallinckrodt. PRAXAIR APPROVAL REINFORCES OVERHANG: Noting that INOmax is Mallinckrodt’s second largest product, representing approximately $131M of sales in the second quarter, Wells Fargo analyst David Maris told investors that the approval of a generic version of its gas was something that was expected, although the exact timing was unexpected. The analyst pointed out that he was already modelling a slowdown in growth in 2019 for Mallinckrodt but is not modelling “a major loss” of market share. Overall, Maris believes that the Praxair approval “certainly reinforces an overhang issue” and brings market share risk closer to reality, and as such will likely have a negative impact on the shares. He reiterated a Market Perform rating and $30 price target on Mallinckrodt’s shares. PRICE ACTION: In afternoon trading, shares of Mallinckrodt have plunged over 18% to $25.43.

https://thefly.com/landingPageNews.php?id=2799995

Disgruntled Takeda alumni demand a window into $62B Shire buy

It’s no secret that Takeda’s pending Shire megadeal has plenty of critics, and some of them have penned a letter to company president Christophe Weber demanding behind-the-scenes information and documents to justify the buy.

The group of about 130 shareholders, including alumni of the Japanese drugmaker, requested that Weber serve up details on how Takeda plans to pay down the debt it’ll incur with the $62 billion acquisition. It also wants to know why Takeda offered a 65% premium for the rare-disease-focused target, and it’s asking for board-meeting minutes and executive statements, too, Nikkei Asian Review reports.

Dubbing itself, “Thinking about Takeda’s Bright Future,” the group gave Takeda an Oct. 31 response deadline.

Takeda’s deal first faced opposition well before the two parties shook hands. In March, the company’s shares plummeted after it revealed its interest in Shire, in part because of questions surrounding the hefty debt necessary to pull the deal off.

And since Takeda and Shire inked their pact back in May, more critics have joined the chorus. A descendent of Takeda’s founder publicly voiced his disapproval, predicting the takeover would prove detrimental to the Japanese drugmaker’s business. “Hasty decisions on big deals should be avoided. It will lead to disaster if there are large-scale mergers and acquisitions without careful consideration,” he said in September.

This isn’t the first time this particular shareholder group—which owns about 1% of the company, Nikkei says—has tried to pump the brakes on the Shire deal, either, Nikkei notes. During a June shareholder meeting, the group proposed a rule requiring that acquisitions of more than 1 trillion yen ($8.78 billion) win shareholder approval first. But the proposal garnered less than 10% support from shareholders.

Takeda has defended its buyout decision and particularly worked to ward off concerns about its lagging hemophilia business. At a June meeting, Weber reassured investors that Takeda had already factored next-gen competition from Roche into its financial models for the company after Shire joins the fold.

https://www.fiercepharma.com/pharma/disgruntled-takeda-alums-demand-key-details-62b-shire-buy