Takeda could rack up $10B in selloffs after Shire buyout

With a crucial shareholder vote looming, Takeda is on an aggressive push to win investor support for a Shire buyout expected to load the company with debt. Now, a top executive says that debt burden could be $10 billion lighter after the deal closes.

Takeda CFO Costa Saroukos told Nikkei the company could sell up to $10 billion worth of “noncore assets” to help fund the buyout, twice as much as had been reported previously. Bloomberg sources said in September that the Japanese company was considering $4 billion to $5 billion in selloffs, potentially including Shire’s eye drug Xiidra.

Last month, the company tagged Shire’s inflammatory bowel disease pipeline med SHP647 as a potential selloff, and Bloomberg reported that Takeda may sell some OTC assets in Europe to help fund the purchase. Meanwhile, Takeda is also sharpening its job-cutting ax to squeeze costs out of the combined company.

With the deal, Takeda will refocus on drugs in gastroenterology, oncology and rare diseases, among other disease areas. Takeda nabbed European approval for the buyout last week, and shareholders are set to vote next week.

And that vote isn’t a rubber stamp. The company needs to secure a two-thirds majority to wrap up the buy, but some insiders worry about the company’s debt and direction after the deal. Kazu Takeda, a member of the founding family who voiced opposition in September, said Takeda “will no longer be a Japanese company” if it closes the deal, according to the Financial Times.

This week, Takeda ex-chairman Kunio Takeda said in a statement to Nikkei that “after performing various analyses on my own and making a thorough assessment, I came to the conclusion that I cannot offer my support.” Dissident shareholders are ginning up “no” votes, hoping to derail the transaction.

Along with the debt, Takeda and Shire also expect to pay nearly $1 billion in banking and legal fees for the merger, Reuters previously reported.

Takeda CEO Christophe Weber has stood firm in the face of resistance, saying the deal will bolster Takeda’s presence in key treatment areas and transform the company into a leader in rare diseases. He said the deal will create “global scale to drive future development,” and touted other benefits.

Takeda unveiled its plan to acquire Shire in May. The buyout would be pharma’s largest M&A deal in years and would vault Takeda into the top 10 rankings of big pharma companies.

As is standard with pharma mergers, it’ll come with layoffs and a big target for cost savings. Already, Takeda has said it’s moving its U.S. headquarters from suburban Chicago to Boston, putting 1,000 jobs in jeopardy. Some employees will receive relocation offers, a spokesperson said. Aside from that, Takeda is moving hundreds of R&D jobs to Boston, and a spokesperson said the company has cut 480 primary care sales representatives.

https://www.fiercepharma.com/pharma/takeda-selloffs-could-total-10b-after-shire-buyout-report

Fresenius, NXStage getting renewed questions from FTC, Capitol Forum says

 Questions about (FMS) $2B acquisition of NxStage (NXTM) have led to a renewed focus by the FTC on the deal’s potential impact on the entry into the home hemodialysis machine market, putting the companies’ plans to close the transaction by the end of the year in jeopardy, The Capitol Forum reports, citing sources familiar with the matter.
https://thefly.com/landingPageNews.php?id=2830645

Drug pricing focus could be catalyst for change in US biosimilar landscape

While biosimilar makers have long established themselves in Europe, only a few copycat versions of biologics have launched in the nascent US market, which is beginning to show signs of maturing, but is complicated by a reimbursement landscape fractured by multiple players. The spotlight on drug pricing, however, may at long last provide the catalyst for change.

Biosimilars were approved in the United States amidst much fanfare in 2015, years after their introduction in Europe, thanks partly to the tactics employed by Big Pharma to evergreen the patent protection of their prized blockbuster biologics in the world’s biggest market for drugs.

AbbVie $ABBV, for instance, has ensured that all but one biosimilar maker will delay launching copycat versions of its flagship Humira — which brought in roughly $12 billion in US sales last year — to 2023 in the United States. The one dissident, who is still wrestling with AbbVie in the courts, is Boehringer Ingelheim.

Earlier this week, the German drugmaker said it had decided to focus all its effort into launching its Humira biosimilar Cyltezo in the United States, and would abandon its entire biosimilar development program elsewhere. Meanwhile AbbVie has not been able to keep biosimilar competition at bay in Europe, where at least four Humira copycats have already been launched, forcing the company to slash the rheumatoid arthritis drug’s price by 80% in European markets to remain competitive.

The few copycats that have launched on the US market out of the 15 that have secured FDA approval have not so far garnered significant market share compared to their European counterparts — largely due to pricing dynamics and reimbursement hurdles. Yet with political pressure reaching full boil on drug pricing in the United States, newer entrants may be forced to temper their pricing strategy, which could entice insurance coverage, and help their makers chip away at the monopoly of established branded biologics.

On Wednesday, Teva $TEVA and Celltrion’s once-rejected biosimilar for Roche’s non-Hodgkin’s lymphoma drug Rituxan was approved by the FDA — but the two partners have not disclosed their pricing plans for the drug, Truxima, or offered a launch date. Sales of Rituxan, one of Roche’s arsenal of cancer blockbusters, have already plummeted in Europe thanks to biosimilar competition. Teva and Celltrion are also gearing up for a US approval for a Herceptin biosimilar, which could deal a further blow to Roche’s $20 billion cancer franchise.

But Roche is convinced that marked difference in biosimilar dynamics between Europe and the United States will persist. Last month, as part of a quarterly earnings conference call, CEO Severin Schwan put on a brave face: “I would put the US in a highly heterogeneous system and…let’s be clear we expect significant entrant of biosimilars, we don’t expect the erosion rate to be similar to Europe at this stage even with some potential additional activities with the administration in the U.S. government.”

But under commissioner Scott Gottlieb, the FDA seems upbeat about the future of biosimilars.

“We’re advancing new policies to make the development of biosimilars more efficient and to enable more opportunities for biosimilar manufacturers to make these products commercially successful and competitive,” Gottlieb said in a statement announcing the Truxima approval. “We’re seeing more biosimilar drugs gain market share as this industry matures.”

In Europe, however, biosimilar competition has begun to hurt makers of branded drugs in a meaningful way. AbbVie, in its recent quarterly earnings call, suggested the pricing pressure they are facing in the Europe from Humira biosimilars is greater than previously anticipated. The company has now forecast a 26-27% erosion in Humira ex-US sales in 2019, from a previous estimate of 18-20%.

As the landscape for biosimilars evolves at a different pace in Europe versus the United States, there is a mixed bag of developments to keep track of, noted Credit Suisse’s Vimal Divan.

On the positive side, the FDA has approved three biosimilars in recent weeks — Truxima, Coherus’ Neulasta biosimilar Udenyca, and Novartis’ version of Humira, Hyrimoz. On the negative side, other than Boehringer’s decision to terminate biosimilar development outside the United States, Merck $MRK has also axed the development of their knockoff of Lantus, and Novartis’ Sandoz unit has stopped their Rituxan biosimilar program in the US.

As it stands, Pfizer and Novartis are best positioned to weather potential biosimilar threats in the coming years, Divan said, noting that the two drugmakers are also developing their own biosimilars, which could help offset some of that risk. Unsurprisingly, the two companies that have the most to lose are AbbVie and Roche.

https://endpts.com/spotlight-on-drug-pricing-could-be-catalyst-for-change-in-us-biosimilar-landscape/

Lundbeck has something to cheer as Rexulti combo shows promise in PTSD

With generics eating into sales of three key drugs and a recent key setback in schizophrenia, new Lundbeck CEO Deborah Dunsire can finally enjoy a bit of good news: the Danish company’s blockbuster antipsychotic brexpiprazole has yielded success in a mid-stage study in patients with PTSD when given in combination with the antidepressant sertraline (Zoloft).

Initiated in 2017, the 12-week placebo-controlled phase II trial enrolled 321 patients and was designed to assess brexpiprazole as monotherapy, sertraline as monotherapy or the two as a combination therapy in adults with PTSD. Brexpiprazole, which is already approved for use in major depression and schizophrenia, is sold as Rexulti and was discovered by Japan’s Otsuka.

Compared to patients that received a placebo, the combination treatment induced a statistically significant (p<0.01) reduction in symptoms, the partners said. However, brexpiprazole alone came up short, with a p>0.35, as did sertraline monotherapy, which fared even worse clocking in a p>0.60.

Although brexpiprazole was well tolerated, there was one death in the placebo group, the companies added on Friday, saying that they planned to meet the FDA to discuss next steps for the program.

Last year, two late-stage studies testing brexpiprazole for agitation triggered by Alzheimer’s dementia threw up mixed data, with one study successful and the other deemed a failure. Meanwhile, late-stage data from two studies evaluating the use of brexpiprazole in manic episodes associated with bipolar disorder is expected in the first quarter of 2019.

Dunsire took over the reigns in July, and was quickly forced to contend with a phase III failure of the company’s schizophrenia drug candidate, Lu AF35700.

https://endpts.com/lundbecks-dunsire-has-something-to-cheer-as-rexulti-combo-shows-promise-in-ptsd/

Prepping for ASH, Aprea Therapeutics gets $57M to fuel Phase 3 p53 cancer study

Seven months ago, Stockholm-based Aprea Therapeutics managed to remain almost completely overlooked at AACR when the biotech unveiled data from a handful of 8 patients with TP53 Mutant Myelodysplastic Syndromes. Scientists said the study demonstrated a 100% overall response rate for their p53 corrector — APR-246 combined with azacitidine.

Six of the patients had a complete response according to investigators.

But while they may have achieved little recognition for the low-profile Phase Ib/II trial, venturing into a p53 arena that has seen multiple setbacks over the years, Aprea’s investors appear to have taken note.

Today the biotech touted a $57 million raise for a drug designed to correct mutant p53 so it can go about its business in killing cells.

Aprea — helmed by CEO Christian Schade — now is planning to use the Series C cash to gear up a pivotal trial for their drug while prepping updated Phase II data for the upcoming ASH conference in San Diego.

The lead investigator for the MDS study is David Sallman from the Moffitt Cancer Center.

Whatever they have coming up must be good, because the biotech attracted quite a crowd of transatlantic investors. Redmile Group led the round, with new investor Rock Springs Capital chipping in alongside existing investors: 5AM Ventures, Versant Ventures, HealthCap, Sectoral Asset Management and Karolinska Development AB.

https://endpts.com/prepping-for-key-ash-presentation-little-aprea-therapeutics-gets-57m-to-fuel-phiii-p53-cancer-study/

Don’t overlook the giant step that Editas is taking today on the CRISPR front

As health officials the world over — and especially in China — breathe fire over Jiankui He’s apparently credible claims that he skated clear of regulators and genetically altered the embryos of two newborns to guard them against HIV, Editas $EDIT today is celebrating a critical milestone in the long, hard journey to launching its first human trial with major implications for the CRISPR field.

The FDA has accepted Editas’ IND for their first gene-editing trial in a handful of patients suffering from an inherited retinal degenerative disease called Leber Congenital Amaurosis type 10.

Normally, that’s not something that gets much attention in the biopharma world these days. As money has pumped into the system, creating a wave of new biotechs, INDs have become routine — even if, as in Editas’ case, it comes with a $25 million milestone payment.

Editas, though, set out fully 5 years ago to widespread acclaim, one of several startups that were inspired by 3 scientists: Feng Zhang, Jennifer Doudna and Emmanuelle Marie Charpentier. Now, after the applause has died down, Editas and its partners at Allergan will finally have their shot to see whether gene editing tech — in this case CRISPR/Cas9 and the newer CRISPR/Cpf1 — can play a big role in correcting severe diseases.

To get here Editas has had to fight off a stiff patent challenge, keep the money pumping in as a public company which necessarily had to spend years in preclinical development, bat back persistent questions about off-target effects and convince regulators that it had everything lined up properly before it shifted from animal studies to humans.

“The FDA’s acceptance of our IND for EDIT-101 is a significant moment in the field of genome editing,” noted CEO Katrine Bosley, “and importantly, a critical milestone for patients, as we are now one step closer to a treatment for LCA10.”

Jiankui He will end the week as one of the most notorious rogue scientists in the world. Editas will be better off financially and one big step closer to a dramatic test case to gauge the near-term potential of what is still a radically new technology. It won’t get as much attention, but in the long run it’s much more important than the headlines coming out of Hong Kong.

https://endpts.com/while-jiankui-he-gets-all-the-attention-dont-overlook-the-giant-step-that-editas-is-taking-today-on-the-crispr-front/

Sneak Peak at Practice-Changing Research From ASH 2018

The largest and top conference for hematologists and blood disease specialists is just about underway here.

While pre-conference activities at the 60th American Society of Hematology (ASH) Annual Meeting — industry-sponsored symposia and ASH-a-Palooza (formerly Trainee Day) — are taking place on Friday, ASH 2018 officially starts early Saturday morning when the scientific program kicks off with simultaneous oral and educational sessions, followed by the first of the poster displays.

An estimated 25,000 people from 115 countries are expected to attend the 4-day conference.

“It’s really shaping up to be a very exciting meeting,” said Aaron Gerds, MD, MS, of the Cleveland Clinic in Ohio and chair of the ASH Committee on Communications, during a press briefing ahead of the meeting. “I know we say this every year, but I anticipate this will be the best annual meeting ever.”

Mark your calendar for an early evening talk with National Cancer Institute (NCI) Director Norman E. Sharpless, MD, who will discuss his vision of big data, workforce development, and basic science at the NCI.

Sunday’s plenary session will feature six studies of the “highest caliber,” selected from nearly 5,000 abstracts covering the latest research on the biology and treatment of hematologic malignancies, blood dyscrasias, clotting disorders, sickle cell anemia, and other diseases and disorders of the blood.

Also on the agenda during the meeting are two afternoon sessions covering new ASH guidelines. On Sunday, attendees can get a preview of the 2019 sickle cell disease guidelines, and on Monday, authors of the just-released venous thromboembolism guidelines will discuss their recommendations.

Monday will also feature a pair of joint symposia from ASH and the FDA on recently approved drugs for hematological disorders.

Key themes and topics at the meeting will be “Big Trials, Big Results,” as the meeting organizers put it, along with sickle cell disease, CAR T-cell therapies, and the future of medicine — a window into what treatment in hematology may look like in the years ahead.

Big Trials, Big Results

The FLYER trial (abstract 781), a de-escalation study in diffuse large B-cell lymphoma (DLBCL) patients with favorable prognosis, topped the list for the “Big Trials, Big Results” theme.

“This is almost certainly going to be practice changing,” said ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins School of Medicine in Baltimore, during the press briefing.

Another practice changer (abstract 6), he said, compared ibrutinib (Imbruvica) alone or with rituximab (Rituxan) to chemoimmunotherapy in untreated, older chronic lymphocytic leukemia (CLL) patients.

“The reason this is important is ibrutinib has been FDA approved for untreated CLL since 2016, but here it’s been compared to chlorambucil, which is not a very effective therapy,” he explained. “The critique of this is it’s never been compared against what we would consider a modern standard of care for CLL.”

Sickle Cell Disease

One of the studies highlighted by ASH President Alexis Thompson, MD, MPH, of the Robert H. Lurie Children’s Hospital of Chicago, reports 2-year outcomes for high-risk sickle cell disease patients who underwent familial haploidentical stem cell transplantation. The researchers found improved quality of life and neurocognition (abstract 162).

“This is actually a really interesting study,” said Thompson, noting that the researchers looked at various outcomes including cardiovascular disease, neurocognitive deficits, processing speed, and emotional and physical functioning.

Another study (abstract 315) examined opioid use and mortality for sickle cell disease patients, who often require high doses. “There does not appear to be an increased association of in-hospital mortality in patients with sickle cell compared to the general population,” she said.

As opioid-related deaths in the U.S. climbed from 1999 to 2013, the researchers found that in-hospital mortality among those with sickle cell disease remained steady. Thompson said the findings should alleviate many concerns about opioid use in these patients.

CAR T-Cell Therapies

“CAR T cells continue to play a prominent role in the management of refractory B-cell malignancies,” said Brodsky.

He pointed to two studies that aimed to reduce toxicity or improve the efficacy of CAR T-cell therapy in relapsed or refractory CLL and B-cell acute lymphoblastic leukemia (ALL). The CLL trial (abstract 299), which he cautioned had just 36 patients, combined CD19-specific CAR T cells with ibrutinib.

“This was well tolerated, and there’s a suggestion at least that the ibrutinib was able to decrease some of the side effects — the cytokine release that is often seen with CAR T-cell therapy — and there may even be evidence that this can actually improve response,” he said. “Early, preliminary, but very exciting.”

In ALL, the checkpoint inhibitor pembrolizumab (Keytruda) was combined with CAR T cells with the goal of preventing relapse and seemed to show benefit in half the patients (abstract 556).

Late-Breaking Abstracts

Among the late breakers is a trial of emapalumab (Gamifant) for primary hemophagocytic lymphohistiocytosis (HLH), which led to FDA approval earlier this month in this setting, the first agent cleared by the agency specifically for HLH.

“Suffice it to say that this drug was very effective in controlling the disease,” Brodsky said. “This is going to have a major impact.”

A phase III study of daratumumab (Darzalex) in newly diagnosed myeloma patients who are ineligible for transplant will be another to watch for. Asked whether the agent may have an advantage over current available first-line therapies in myeloma, Brodsky said that this would be one of the takeaways from the meeting, noting that daratumumab is giving patients deeper responses, longer remissions, and looks to be offering better survival as well.

Other late-breaking abstracts include a look at rivaroxaban thromboprophylaxis in high-risk ambulatory cancer patients on systemic therapy; a phase III trial comparing first-line ibrutinib against chemoimmunotherapy in younger CLL patients; findings on a BCL2mutation that confers resistance to venetoclax (Venclexta) in progressive CLL; and results of the PAUSE study of perioperative management for patients with atrial fibrillation on direct oral anticoagulants.

https://www.medpagetoday.com/meetingcoverage/ashhematology/76614