FDA approves new drug to treat heart failure

 

For Immediate Release   The U.S. Food and Drug Administration today approved Entresto (sacubitril/valsartan) tablets for the treatment of heart failure. The drug has been shown to reduce the rate of cardiovascular death and hospitalization related to heart failure. It is a condition in which the heart can't pump enough blood to meet the body's needs. Heart failure generally worsens over time as the heart's pumping action grows weaker. The leading causes of heart failure are diseases that damage the heart, such as heart attacks and high blood pressure. “Heart failure is a leading cause of death and disability in adults,” said Norman Stockbridge, M.D., Ph.D., director of the Division of Cardiovascular and Renal Products in the FDA’s Center for Drug Evaluation and Research. “Treatment can help people with heart failure live longer and enjoy more active lives.”  Entresto was reviewed under the FDA’s priority review program, which provides for expedited review of drugs that are intended to treat a serious disease or condition and may provide a significant improvement over available therapy. It was also granted fast track designation, which supports FDA’s efforts to facilitate the development and expedite the review of drugs to treat serious or life-threatening conditions and fill an unmet medical need. Entresto was studied in a clinical trial of more than 8,000 adults and was shown to reduce the rate of cardiovascular death and hospitalizations related to heart failure compared to another drug, enalapril. Most patients were also receiving currently approved heart failure treatments, including beta-blockers, diuretics, and mineralocorticoid antagonists.  The most common side effects in clinical trial participants being treated with Entresto were low blood pressure (hypotension), high blood potassium levels (hyperkalemia), and poor function of the kidneys (renal impairment). Angioedema (an allergic reaction usually appearing as swelling of the lips or face) was also reported with Entresto; black patients and patients with a prior history of angioedema have a higher risk. Patients should be advised to get emergency medical help right away if they have symptoms of angioedema or trouble breathing while on Entresto. Health care professionals should advise patients not to use Entresto with any drug from the angiotensin converting enzyme (ACE) inhibitor class because the risk of angioedema is increased. When switching between Entresto and an ACE inhibitor, use of the two drugs should be separated by 36 hours. Health care professionals should counsel patients about the risk of harm to an unborn baby. If pregnancy is detected, use of Entresto should be discontinued as soon as possible. Entresto is manufactured by Novartis, based in East Hanover, New Jersey. The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

New cancer drug to begin trials in multiple myeloma patients

 

October 13, 2014

Imperial College London

A new cancer drug has been developed, which researchers plan to trial in multiple myeloma patients by the end of next year. The researchers report how the drug, known as DTP3, kills myeloma cells in laboratory tests in human cells and mice, without causing any toxic side effects, which is the main problem with most other cancer drugs. The new drug works by stopping a key process that allows cancer cells to multiply.

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Scientists at Imperial College London have developed a new cancer drug which they plan to trial in multiple myeloma patients by the end of next year.

In a paper published today in the journal Cancer Cell, the researchers report how the drug, known as DTP3, kills myeloma cells in laboratory tests in human cells and mice, without causing any toxic side effects, which is the main problem with most other cancer drugs. The new drug works by stopping a key process that allows cancer cells to multiply.

The team have been awarded Biomedical Catalyst funding from the Medical Research Council (MRC) to take the drug into a clinical trial in multiple myeloma patients, scheduled to begin in late 2015.

Multiple myeloma is an incurable cancer of the bone marrow, which accounts for nearly two per cent of all cancer deaths.

Professor Guido Franzoso, from the Department of Medicine at Imperial College London, who led the research, said: "Lab studies suggest that DTP3 could have therapeutic benefit for patients with multiple myeloma and potentially several other types of cancer, but we will need to confirm this in our clinical trials, the first of which will start next year."

The new drug was developed by studying the mechanisms that enable cancer cells to outlive their normal lifespan and carry on multiplying. In the 1990s, a protein called nuclear factor kappa B (NF-kB), which plays an important role in inflammation, and the immune and stress response systems, was discovered to be overactive in many types of cancer, and responsible for switching off the normal cellular mechanisms that naturally lead to cell death. This enables the cancer cells to survive.

The pharmaceutical industry and scientists around the world have invested heavily in research into NF-kB inhibitors, but such compounds have not been successfully developed as therapies because they also block the many important processes controlled by NF-kB in healthy cells, causing serious toxic side effects.

The Imperial researchers took a different approach, looking for target genes downstream of NF-kB that might be responsible for its role in cancer specifically.

By studying cells from multiple myeloma patients, they identified a protein complex, named GADD45β/MKK7, that appeared to play a critical role in allowing the cancer cells to survive.

Searching for a safe way to target the NF-kB pathway, they screened over 20,000 molecules and found two that disrupted the protein complex. Further refinements led to the experimental drug, DTP3, which tests showed kills cancer cells very effectively but appears to have no toxicity to normal cells at the doses that eradicate the tumours in mice.

"We had known for many years that NF-kB is very important for cancer cells, but because it is also needed by healthy cells, we did not know how to block it specifically. The discovery that blocking the GADD45β/MKK7 segment of the NF-κB pathway with our DTP3 peptide therapeutic selectively kills myeloma cells could offer a completely new approach to treating patients with certain cancers, such as multiple myeloma," Professor Franzoso said.

A spinout company, Kesios Therapeutics, was formed to commercialise DTP3 and other drug candidates based on Professor Franzoso's research, with support from Imperial Innovations, a technology commercialisation company focused on developing the most promising UK academic research.

"The significant progress made by Professor Franzoso in multiple myeloma is one of the many cancers we believe his signal transduction research could be applied to. To help develop this ground-breaking research further, Imperial Innovations created the spin out Kesios Therapeutics," explained Dayle Hogg from the Healthcare Ventures team at Imperial Innovations.

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Story Source:

The above story is based on materials provided by Imperial College London. Note: Materials may be edited for content and length.

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Journal Reference:

1. Laura Tornatore, Annamaria Sandomenico, Domenico Raimondo, Caroline Low, Alberto Rocci, Cathy Tralau-Stewart, Daria Capece, Daniel D’Andrea, Marco Bua, Eileen Boyle, Mark van Duin, Pietro Zoppoli, Albert Jaxa-Chamiec, Anil K. Thotakura, Julian Dyson, Brian A. Walker, Antonio Leonardi, Angela Chambery, Christoph Driessen, Pieter Sonneveld, Gareth Morgan, Antonio Palumbo, Anna Tramontano, Amin Rahemtulla, Menotti Ruvo, Guido Franzoso. Cancer-Selective Targeting of the NF-κB Survival Pathway with GADD45β/MKK7 Inhibitors. Cancer Cell, 2014; 26 (4): 495 DOI: 10.1016/j.ccr.2014.07.027

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Imperial College London. "New cancer drug to begin trials in multiple myeloma patients." ScienceDaily. ScienceDaily, 13 October 2014. <www.sciencedaily.com/releases/2014/10/141013123034.htm>.

 

Promising cancer drug data helps AstraZeneca in Pfizer fight

 

 

(Reuters) - New data showing an experimental AstraZeneca lung cancer drug shrank tumors in more than half of patients gave the British group fresh ammunition to argue that Pfizer's takeover offer undervalues it substantially.

Britain's second-biggest drugmaker said on Thursday the strong results were among a raft of recent updates that showed accelerating progress in its pipeline of experimental medicines.

AstraZeneca has rejected a $106 billion approach from U.S. rival Pfizer, arguing that it has a bright independent future due to its promising line-up of new drugs. Pfizer is widely expected to return with a sweetened offer in coming days.

"We continue to build our pipeline and we are encouraged by the progress in the development of key assets," Chief Executive Pascal Soriot said in a statement.

Its new lung cancer drug, known as AZD9291, targets a genetic mutation that helps tumors evade current treatments. AstraZeneca believes it could sell as much as $3 billion a year.

Results from an early-stage Phase I trial of the drug, released late on Wednesday, showed AZD9291 shrank tumors in 51 percent of patients. Tumors shrank in 64 percent of patients found to have the mutation, known as T790M, which develops in about half of lung cancers that become resistant to drugs known as epidermal growth factor receptor (EGFR) inhibitors.

Savvas Neophytou, an analyst at brokerage Panmure Gordon, said the results were impressive and "AstraZeneca’s management is right to be excited by the pipeline".

AstraZeneca shares were 0.8 percent higher in slightly lower London market by 1400 GMT.

EGFR drugs, such as Roche's Tarceva and AstraZeneca's own Iressa, are used to treat various solid tumor cancers with mutated or overactive EGFR. Around 15 percent of patients with non-small cell lung cancer, the most common form of the disease, have mutations in the EGFR gene.

But most of them will eventually become resistant to available EGFR inhibitors, said Dr Pasi Janne, professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston and the study's lead investigator.

"The issue of drug resistance has been the bane of chemotherapy treatment of cancer for decades," Dr Peter Yu, president-elect of the American Society of Clinical Oncology (ASCO), said during a press conference.

$45 BLN SALES TARGET

AZD9291 is one of several new drugs flagged by AstraZeneca last week in a bid to convince investors of the strength of its experimental pipeline, which includes several innovative cancer drugs, as well as treatments for diabetes, asthma, rheumatoid arthritis and psoriasis.

Overall, the British company forecasts these new products will help its sales rise 75 percent to $45 billion by 2023. [ID:nL6N0NS337]

The Phase I trial for AZD9291, featured ahead of the annual ASCO meeting later this month, involved 199 patients with advanced non-small cell lung cancer with EGFR mutations whose disease worsened despite treatment with a current EGFR drug.

The most common side effects seen in the trial included diarrhea and rash, but researchers said the level of toxicity was less severe than is seen with available EGFR inhibitors.

AstraZeneca is currently conducting a Phase 2 study of AZD9291 in patients with the T790M mutation at a daily dose of 80 milligram, which it said could enable accelerated regulatory filing in the second half of next year.

AZD9291 has been granted "breakthrough" status by the U.S. Food and Drug Administration as a second-line therapy for non-small cell lung cancer. AstraZeneca will also study the drug as an initial treatment for eligible lung cancer patients.

Investors are keen to get a look at other cancer data from AstraZeneca due to be presented at the ASCO meeting.

The company's MEDI4736 has the potential to become one of the first in a new class of drugs known as anti-PDL1 treatments that fight cancer by boosting the immune system. It is initially being tested as a treatment for non-small cell lung cancer and AstraZeneca said data to date had shown "durable clinical activity and acceptable safety".

AstraZeneca has forecast potential peak sales for MEDI4736 of $6.5 billion, including combination therapies.

An AstraZeneca spokeswoman said updated data from trials of MEDI4736 will be presented at the conference at the end of May.

Data from another of the company's experimental cancer drugs, olaparib for ovarian cancer, will be featured at the ASCO meeting. AstraZeneca has forecast peak olaparib sales of $2 billion, compared with consensus analyst estimates of $1.5 billion to $3 billion.

It has also had encouraging results combining olaparib and another drug called cediranib.

(Editing by Tom Pfeiffer and Erica Billingham)

Experimental Drug Shows Early Promise for Some Cases of Advanced Melanoma

 

 

TUESDAY April 8, 2014, 2014 -- An experimental cancer drug that activates the immune system has shown early promise for advanced cases of melanoma skin cancer, researchers report.

The findings come from an early stage trial of just 31 patients. But experts were cautiously optimistic about what the study showed: The drug's side effects were manageable, and four patients saw their tumors shrink.

That's a small number, but a trial like this is largely aimed at seeing whether a drug is safe and finding a tolerable dose.

"Any time you see some responders in an early study, it's encouraging," said Dr. Jeffrey Weber, a melanoma expert at the Moffitt Cancer Center in Florida, who was not involved in the research.

Much more remains to be learned about the drug -- known for now as IMCgp100. "But," Weber said, "it is good enough to show some activity in an early stage trial. It's definitely worth pursuing."

IMCgp100 is just one of several "immunotherapies" under study for advanced melanoma. The general idea behind immunotherapy is to help the body's immune system do a better job of recognizing and killing off cancer cells.

Melanoma is the rarest, but deadliest, form of skin cancer. Caught early, it's curable with surgery. But once it spreads to distant lymph nodes or other organs -- known as stage 4 melanoma -- the disease is very hard to treat.

In just the past few years, though, researchers have made headway. In 2011, the United States and Europe approved an immunotherapy drug called ipilimumab (Yervoy) -- the first treatment shown to prolong the lives of some patients with advanced melanoma.

Still, only a minority of patients respond to the drug, and it can cause severe side effects -- including life-threatening inflammation of the liver or digestive tract.

So there's an acute need for additional therapies, said Dr. Mark Middleton, who was to present the new findings on Tuesday at the annual meeting of the American Association for Cancer Research, in San Diego.

"The reality is, despite exciting advances in treatment, most of the patients we see with advanced melanoma will die of the disease," said Middleton, of Oxford University in England.

IMCgp100 targets melanoma in two ways: It attaches to a specific, tiny protein found on some melanoma cells, and it activates nearby T-cells to attack the tumor.

The catch is that a patient's cancer must be positive for that protein, called HLA A2 -- which is true in about 45 percent of melanomas, Middleton said.

The 31 patients in this study were all HLA A2-positive, and all but one had stage 4 melanoma. They were split into eight groups and given different doses of IMCgp100. Patients who were able to tolerate the first infusion received six more weekly treatments.

In the end, there were four patients who showed a "partial response" to the drug, which meant their tumors shrunk. One patient continued to see a regression with further treatment, and is still stable after more than 10 months, according to Middleton.

The most common side effects were rash, fever and "tumor flare" -- swelling and tenderness at the site of a tumor. Two of four patients who got the highest drug dose did have an immediate drop in blood pressure, so the researchers have since set the maximum dose below that.

Middleton said his team is now studying the drug in a larger group of patients, and trying to find the most effective regimen.

"The other obvious question is, where would this drug fit in?" Middleton said.

Besides Yervoy and other immunotherapies under development, there are also newer "targeted" drugs that directly attack proteins found on some melanomas -- including drugs called BRAF inhibitors.

Weber said researchers will have to figure out whether combinations of different therapies work better than a single one -- and which patients stand to benefit from a particular combination.

Middleton agreed. "We now have a whole range of therapies coming out, which is exciting," he said. But the difficult part, he added, will be understanding how to best use them.

In the United States, about 76,000 people will be diagnosed with melanoma this year, and 9,700 will die of the disease, according to the American Cancer Society. While melanoma is relatively uncommon, its incidence has been rising for the past few decades, the cancer society notes.

Immunocore, the company developing IMCgp100, funded the current study. Middleton reports no financial interests in the work.

The data and conclusions of research presented at medical meetings should be viewed as preliminary until published in a peer-reviewed journal.

More information

The American Cancer Society has more on melanoma treatments.