Hemophilia B Treatment Refixia Passes Key EU Regulatory Hurdle

Hemophilia B Treatment Refixia Nears European Union Approval
Novo Nordisk’s hemophilia B treatment Refixia has cleared a major hurdle toward European Union approval.

An arm of the European Medicines Agency (EMA) known as the Committee for Medicinal Products for Human Use (CHMP) has recommended approving Refixin for preventing and treating patients 12 years and older with hemophilia B, or congenital factor IX deficiency. The European Commission will make the final decision on approval.

The EU designated Refixia (nonacog beta pegol, N9-GP) an orphan drug on May 15, 2009. The EMA said in a press release that the new recommendation covers Refixia as a powder and solvent for injection. The doses it covers include 500 IU, 1000 IU and 2000 IU.

Nonacog beta pegol, the active ingredient in Refixia, is a recombinant coagulation factor IX. It replaces the missing factor IX in patients with hemophilia B, helping the blood to clot and providing temporary bleeding control.

CHMP’s Refixia recommendation was based on the results of a Phase 3 clinical trial that enrolled 115 children and adults with moderately severe to severe hemophilia B.

Novo Nordisk reported in January 2016 that trial investigators found Refixia effective in preventing and treating bleeding episodes, and controlling bleeding in surgery. The treatment was well-tolerated, with no safety problems, the investigators said.

Refixia’s half-life was five times longer than that of other factor IX products, the trial results showed.  Participants achieved a higher level of factor IX in their blood than with other products, even with less frequent doses of Refixia. A drug’s half-life is the amount of time it takes for its effectiveness to drop in half.

The trial also found that 40 IU/kg of Refixia once per week kept patients’ factor IX levels above 15 percent, and reduced their median annualized bleeding rate (ABR) to 1.0. In addition, the treatment showed potential in preventing joint bleeding, and in improving patients’ quality of life.

“We are excited about the positive opinion obtained for Refixia, Mads Krogsgaard Thomsen, executive vice president and chief scientific officer of Novo Nordisk, said in a press release. It represents a significant milestone in our efforts to expand the treatment options for patients with haemophilia. We believe Refixia with its strong clinical profile provides hemophilia B patients better protection against bleeds, even into damaged joints, and an overall improved quality of life.”


Green Light for Cancer Immunotherapies in Europe

The European Medicines Agency (EMA) has recommended granting marketing authorization for three cancer immunotherapies ― pembrolizumab (Keytruda, Merck & Co, Inc) for melanoma, nivolumab (Opdivo, Bristol-Myers Squibb Company) for lung cancer, and dinutuximab (Unituxin, United Therapeutics Corporation) for neuroblastoma.

In addition, the EMA recommended approval for the additional indication of Waldenstrӧm’s macroglobulinaemia for ibrutinib (Imbruvica, Pharmacyclics, Inc, Janssen Biotech, Inc) and also for a generic version of bortezomib (Bortezomib Accord, Accord Healthcare) for use in the treatment of multiple myeloma and mantle cell lymphoma.

Pembrolizumab for Advanced Melanoma

Pembrolizumab will be the second drug that acts as a programmed death inhibitor for the treatment of advanced melanoma in Europe, joining nivolumab, which was recommended for approval for this indication just a few weeks ago. Both drugs are already approved in the United States for use in advanced melanoma.

The data supporting the recommendation for approval come from one uncontrolled study and early results from two ongoing randomized, controlled trials, one comparing pembrolizumab with standard chemotherapy, and the other comparing pembrolizumab with ipilimumab (Yervoy, Bristol-Myers Squibb Company), another immunotherapy but with a slightly different mechanism of action.

The Committee for Medicinal Products for Human Use (CHMP) says the data so far have demonstrated the efficacy of pembrolizumab in adults with unresectable or metastatic melanoma, both in patients who had and in those who had not previously received ipilimumab. The committee also looked at safety information from more than 1000 patients enrolled in clinical studies and regarded the safety profile to be manageable.

Nivolumab for Lung Cancer

Nivolumb was recommended for approval for use in the treatment of squamous non–small cell lung cancer (NSCLC) when the disease is advanced and the patient has already been treated with chemotherapy. It is the first immunotherapy to be approved for use in lung cancer, and was welcomed by experts when this approval was announced in the United States.

In Europe, for this indication the product will have the trade name Nivolumab BMS, whereas for the treatment of melanoma, it will be marketed as Opvido, the tradename used in other countries.

The CHMP notes that this recommendation for approval is based on data from a phase 3 trial in 272 patients with squamous NSCLC in whom chemotherapy had failed. These patients were randomly assigned to receive either nivolumab or chemotherapy with docetaxel. This study found that nivolumab improved overall survival compared with docetaxel (median, 9.2 months, compared with 6.0 months). After 12 months, 42% of patients treated with nivolumab were still alive compared with 24% of patients treated with docetaxel, the CHMP notes. Details of this study are due to be presented next week at the annual meeting American Society of Clinical Oncology.

There were also further data from an uncontrolled study involving 117 patients with squamous NSCLC who had undergone at least two previous chemotherapy treatments and who were then treated with nivolumab, the CHMP noted.

Dinutuximab for Neuroblastoma

Dinutuximab was recommended for approval for use in the treatment of high-risk neuroblastoma in children who had already responded to an induction treatment with chemotherapy, followed by myeloablative therapy and autologous stem-cell transplant. The product should be administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin.

The product was recently approved in the United States.

Neuroblastoma is a rare cancer, so dinutuximab has orphan drug designation for this indication. The tumor forms from immature nerve cells and is usually seen as a lump in the abdomen or around the spine. It typically occurs in children younger than 5 years, the EMA explained in a press release. In many cases, it is present at birth, but the diagnosis is made only later, when the cancer has already spread to other parts of the body, and the child begins to show symptoms of the disease.

Dinutuximab is a monoclonal antibody designed to recognize and attach to disialoganglioside (GD2), an antigen that is present in high amounts on the surface of neuroblastoma cells but in lower amounts in normal cells. When the product attaches to the neuroblastoma cells, it marks them as targets for the body’s immune system, which is then expected to attack the cancer cells and thereby reverse or slow down the progression of the disease, the EMA explained.

The recommendation for approval was based on data from a clinical trial in children with high-risk neuroblastoma who had already responded to chemotherapy (showing at least a partial response) and were further treated with myeloablative therapy and autologous stem-cell transplant. The study randomly assigned 230 patients to receive dinutuximab combined with GM-CSF and IL-2 and oral isotretinoin, or isotretinoin alone.

After 2 years, 66% of patients receiving the dinutuximab combination were alive and free from recurrence or tumor growth, compared with 48% of patients treated with isotretinoin alone.

Dinutuximab “provides a much-needed treatment option to prolong survival” of patients who are considered to have high-risk neuroblastoma, the agency commented.

The most common side effects of dinutuximab are pain, allergic reactions, and hypotension. Because the protein targeted by the product is also present on normal nerve cells, its use may cause irritation and severe pain of the nerve cells, so pain relief is recommended both before and during treatment. Despite prophylaxis, two thirds of children experience pain, and about 40% experience severe pain.

The CHMP recommended that the safety profile be further assessed post authorization, and the agency required the company to include this in their risk management plan for dinutuximab.

Ibrutinib for Rare Lymphoma

An indication extension was recommended for ibutinib (Imbruvica, Pharmacyclics, Inc, Janssen Biotech, Inc). This drug is already approved for use in chronic lymphocytic leukemia and mantle cell lymphoma. The new indication covers its use in Waldenstrӧm’s macroglobulinemia (also known as lymphoplasmacytic lymphoma), a type of non-Hodgkin’s lymphoma. Ibrutinib will be the first drug for the treatment of this rare blood cancer. It has orphan drug designation for this indication.

Waldenstrӧm’s macroglobulinemia is characterized by an excess of abnormal B lymphocytes and plasma cells in the bone marrow and sometimes in other organs, the EMA explains. These abnormal cells produce large amounts of an immunoglobulin M (IgM), which can make the blood thicker than normal. This cancer usually begins in people older than 60 years. Five years after diagnosis, between 36% and 87% of patients are still alive, depending on their individual risk factors.

Ibrutinib offers a novel strategy in the treatment of malignancies involving B lymphocytes. It acts as an inhibitor of Bruton’s tyrosine kinase (Btk), which has a key role in the survival of B lymphocytes and their migration to the organs where these cells normally divide. By blocking Btk, ibrutinib decreases survival and migration of B lymphocytes, thereby delaying the progression of the cancer, the agency explains.

The recommendation for approval is based on the results of a phase 2 study in 63 patients with previously treated Waldenstrӧm’s macroglobulinemia. Around 90% of the patients treated with ibrutinib responded positively to the treatment, and approximately 80% of patients were alive without disease progression after 18 months.

The adverse events reported during the clinical trial were similar to those observed in the already approved indications of ibrutinib, the agency noted. They include neutropenia and thrombocytopenia.

Generic Bortezomib for Multiple Myeloma

In addition, the EMA recommended for approval a generic version of bortezomib (Bortezomib Accord, Accord Healthcare) for the treatment of multiple myeloma and mantle cell lymphoma.

Bortezomib Accord is a generic version of Velcade (Takeda/Millennium), which has been authorized for use in the European Union since April 2004, the agency noted. “Studies have demonstrated the satisfactory quality,” it added, stating that because Bortezomib Accord is administered intravenously and is 100% bioavailable, a bioequivalence study vs the reference product Velcade was not required.

When EMA and FDA decisions conflict: differences in patients or in regulation?.

Are Americans more resistant to the risks and more likely to benefit from certain drugs than Europeans or, on the contrary, is the European Medicines Agency (EMA) more resistant than the US Food and Drug Administration (FDA) to the drug industry’s desire to get approval for drugs with unique risks but without compensating benefits?

This question arises because the FDA has recently approved two diet drugs, heralded by the agency as “the first drugs for long-term weight management that FDA has approved in 13 years”1 but rejected by the EMA. In both cases FDA advisory committees earlier rejected approval but later supported the FDA’s and the companies’ desire for approval. Similarly, the FDA has also failed to ban the diabetes drug rosiglitazone (Avandia), banned three years ago by the EMA.2

In June 2012 the FDA approved lorcaserin (marketed in the United States as Belviq). The weight loss drugs dexfenfluramine and fenfluramine were banned in 1997 because of many post-approval cases of heart valve damage, attributed to adverse effects on the 2B serotonin heart receptor.3 Lorcaserin has minimal 2B serotonin receptor activity, but the FDA approved the drug despite a 16% increase in heart valve damage in randomized trials, not statistically significant but with an upper confidence interval of 67%.4 The reduction in weight loss, beyond that of placebo, was 3% to 3.7%.5 The chairman of the FDA advisory committee reviewing the drug stated, “There’s probably not sufficient data at this time to rule out a clinically meaningful increase in the risk for valvular heart disease.” The cardiologist Sanjay Kaul, a committee member who voted against approval, said, “Given the totality of evidence, the potential benefits of lorcaserin do not, in my opinion, outweigh the potential risks when used long term in a population of overweight and obese individuals.”6

Despite its approval of the drug, the FDA required the company to do post-marketing randomized trials to better evaluate cardiovascular risk, including heart valve damage.7

Before the EMA had formally rejected the application for lorcaserin, but after withdrawal of the marketing application by the drug’s sponsor, Arena, the EMA stated that “at the time of the withdrawal the CHMP [the EMA’s Committee for Medicinal Products for Human Use] . . . was of the provisional opinion that Belviq could not have been approved for weight control in obese and overweight patients” because “the benefits of Belviq did not outweigh its risks.” The committee’s safety concerns included “the potential risk of psychiatric disorders (such as depression) and valvulopathy.”8

Shortly after it approved lorcaserin, the FDA approved a combination of phentermine and topiramate (now marketed as Qsymia in the US) despite concerns about its cardiovascular risk. In studies the proportion of patients with pulse increases exceeding 10 beats per minute, a risk factor for cardiovascular disease,9 was significantly higher in the high dose Qsymia group than in the placebo group.10 In patients in the mid-dose Qsymia group, the incidence of arrhythmia related adverse events was 4.2%, compared with 1.8% in the placebo group.11 Metabolic acidosis—significantly higher in patients taking Qsymia—can be a risk factor for cardiac arrhythmias.12 Metabolic acidosis resulted in increased nephrolithiasis: 22 cases in the Qsymia groups, five in the placebo group.13 Cognitive related adverse events, including memory impairment and reduced concentration or attention, occurred in 1.7% of placebo patients and 5.6% of mid-dose Qsymia patients.14

An FDA analysis of serious adverse cardiovascular outcomes in randomized clinical trials of Qsymia found six events in 743 patients taking Qsymia but none in 227 placebo patients. These events included myocardial infarction or acute coronary syndrome in four patients.15 However, patients in the mid-dose Qsymia groups in the randomized trials lost 6.7% more weight than patients in the placebo groups.16

When Qsymia was approved in July 2012, the FDA hailed it as another treatment option but decided that a study was needed to clarify the risks of major adverse cardiac events such as heart attack and stroke—but only after it was on the market. The FDA also required training of prescribers and certification of pharmacies and a patient leaflet giving important safety information.17

The EMA rejected Qsymia for the second time in February 2013, noting that “the main studies showed clinically relevant weight loss following treatment with Qsiva [the European name for Qsymia]” but that it had “concerns about the medicine’s long-term effects on the heart and blood vessels” and “about the long-term psychiatric effects (depression and anxiety were reported in the studies) and cognitive effects (such as problems with memory and attention).”18 It concluded that “the benefits of Qsiva did not outweigh its risks and recommended that it be refused marketing authorisation.”18

Thus, two more diet drugs, following in the footsteps of the now banned phenylpropanolamine, dexfenfluramine, sibutramine and others, were found by the EMA to be too dangerous to be used for weight loss but are considered by the FDA to be “safe enough” for Americans.

This safe diet drug delusion recalls the editorial by the UK endocrinologist Gareth Williams after sibutramine was removed from the European market by the EMA but was, unfortunately, still available for many more months in the US until it was banned. He wrote, “The fate of sibutramine reminds us how little antiobesity drugs have had to offer—at best, a reduction of a few per cent in the total burden of excess weight carried until death. With energy homoeostasis so deeply enmeshed in physiology, it has always seemed unlikely that a magic bullet could ever switch off food intake without hitting something vital.”19

This is not to say that the EMA is perfect but rather that its recent record on drugs such as these puts the FDA to shame. It is not the resistance of Americans to the risks of these drugs but the intermittently dangerous malleability of the FDA that is the problem in the cases discussed here.

Source: BMJ

What are biosimilars and are they important?


All prescribers will be familiar with the issues associated with the use of branded and generic ‘chemical’ medicines.1 For biological products (e.g. epoetin, filgrastim), a biosmilar medicine is a new biological product that is similar to a medicine that has already been authorised to be marketed in the EU (the biological reference medicine).2 Six biosimilar medicinal products are currently marketed in the UK—three versions of filgrastim (▼Nivestim, ▼Tevagrastim and Zarzio),3–5 two versions of epoetin (Binocrit and Retacrit)6,7 and one version of somatropin (Omnitrope).8 Applications for biosimilar versions of follitropin alfa and infliximab are under evaluation by the European Medicine’s Agency (EMA) Committee for Medicinal Products for Human Use.9 In the future there may also be biosimilar versions of insulins, recombinant vaccines, interferons and monoclonal antibodies such as rituximab and trastuzumab.10 It is estimated that about 50% of the current UK market for biological medicines by spend may be subject to biosimilar competition by 2019. In this article, we will consider the background to developing biosimilar medicines, how and why they differ from traditional generic medicines in their licensing requirements and the issues that may arise as they are introduced to clinical practice.

Source: BMJ