Genentech

New Analysis Confirms Hemlibra’s Sustained Efficacy in Controlling Bleeding in Some Children With Hemophilia A

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New Analysis Confirms Hemlibra’s Sustained Efficacy in Controlling Bleeding in Some Children With Hemophilia A

A new analysis of the Phase 3 HAVEN 2 study’s results shows that Genentech’s Hemlibra (emicizumab-kxwh) prophylaxis (preventive treatment) leads to significant reductions in the number of bleeds among hemophilia A children younger than 12 with factor VIII inhibitors.

The results showed that Hemlibra administered on different schedules — once a week, either every two or four weeks — resulted in a clinically meaningful reduction of bleeds.

The results were presented at the 60th American Society of Hematology (ASH) Annual Meeting, Dec. 1-4 in San Diego, California, in a presentation titled, “Emicizumab Prophylaxis Provides Flexible and Effective Bleed Control in Children with Hemophilia Α with Inhibitors: Results from the HAVEN 2 Study.”

“Children with inhibitors are at increased risk of life-threatening bleeds and may experience frequent, repeated bleeding into joints,” Guy Young, MD, director of the Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, said in a press release.

“These updated data from HAVEN 2 showed that the majority of children with hemophilia A with factor VIII inhibitors treated with emicizumab-kxwh [Hemlibra] had zero treated bleeds across three different dosing schedules, reinforcing the ability of this medicine to provide sustained, effective bleed control,” said Young, also a professor at the University of Southern California Keck School of Medicine, Los Angeles.

The HAVEN 2 study (NCT02795767), which enrolled 85 children younger than 12 with hemophilia A and factor VIII inhibitors, tested the efficacy and safety of preventive treatment with Hemlibra delivered either once weekly, every two weeks or every four weeks as subcutaneous (under the skin) injections.

In total, 65 children received the therapy once a week and were followed for a median of 58 weeks. Ten children received Hemlibra every two weeks and 10 received Hemlibra every four weeks, with follow-up of 21.3 weeks and 19.9 weeks respectively.

The results showed that 76.9 percent of the children treated with Hemlibra once weekly experienced zero treated bleeds.

Hemlibra delivered every two and every four weeks led to zero treated bleeds in 90 percent and 60 percent of the children, respectively.

An intra-patient analysis comparing those treated with once-weekly Hemlibra to patients treated with bypassing agents, either preventive or on-demand, showed that Hemlibra led to a 99 percent decrease in the number of treated bleeds.

Bypassing agents, rather than replacing the missing VIII factor, bypass the factors blocked by the patient’s antibodies to help form a normal clot.

Researchers reported no serious adverse effects, specifically blood clots in small vessels (called thrombotic microangiopathy).

“The updated analysis from the HAVEN 2 study supports the potential of Hemlibra to control bleeds at less frequent subcutaneous dosing, providing parents and their children more flexibility to choose a treatment schedule that is right for them,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development.

“Many children with hemophilia A with factor VIII inhibitors have already experienced the benefits of Hemlibra, and with these new positive data, we are confident that this treatment will continue to make a meaningful difference in their lives,” Horning said.

Data from the HAVEN 2 study and from the previous Phase 3 HAVEN 1 (NCT02622321) trial supported Hemlibra’s approval in Taiwan to be administered as a once-weekly subcutaneous injection for hemophilia A patients with factor VIII inhibitors. Hemlibra is marketed in Japan and other countries by Chugai Pharmaceutical, a member of the Roche Group.

“We are pleased that Hemlibra has received regulatory approval for hemophilia A with factor VIII inhibitors now in Taiwan,” said Yasushi Ito, Chugai’s executive vice president, co-head of project & lifecycle management unit. “Chugai will cooperate with Chugai Pharma Taiwan so that Hemlibra may contribute to people with hemophilia A with inhibitors who have limited treatment options.”

Rituximab outperformed steroids in Graves’ ophthalmopathy.

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Despite data presented earlier at the American Thyroid Association Annual Meeting showing that rituximab was not effective in treating Graves’ ophthalmopathy, another presenter here said that the drug does improve disease state when compared with methylprednisolone.

“Response to rituximab was as high as 93%, compared to 69% observed after IV steroid,”Mario Salvi, MD, from the University of Milan in Italy, said. “Preliminary evidence of NOSPECS class 2 signs shows improvement after rituximab.”

Similar to the study presented earlier at the meeting, Salvi said the primary endpoint was a change of two or more points in the clinical activity score (CAS) at 24 weeks. Secondary endpoint was a reduction of disease severity by at least two NOSPECS classes.

Inclusion criteria included euthyroid for at least 6 to 8 weeks and affected by active Graves’ ophthalmopathy. Any previous steroid treatments had to be stopped at least 3 months before study inclusion.

Patients were randomly assigned to IV methylprednisolone (n=16; mean age, 50.4 years) or rituximab (Rituxan, Genentech; n=16; mean age, 51.9 years). In both groups, six patients had received previous steroid treatment. Originally, Salvi said, patients in the rituximab group were receiving 1,000 mg in two doses, but after two adverse reactions, they lowered the dosage to 500 mg. There was no difference between these two treatment dosages at 24 weeks.

At 12 weeks, the difference between the two groups was not significant, but at 24 weeks, 93% of patients in the rituximab group improved, as compared with 69% of the steroid group (P<.02).

“Rituximab was more effective than IV methyprednisolone in inactivating Graves’ orbitopathy, as assessed at 24 weeks,” Salvi said. “Graves’ orbitopathy remained invariably inactive after rituximab during follow-up.”

The researchers are confident in the response seen from methylprednisolone as it is as high as seen in recently published studies, Salvi said.

These results were preliminary and final analysis is expected shortly, he added.

PERSPECTIVE

 

Kenneth D. Burman

·         Both of the studies and each of the investigators did an excellent job in performing their studies. These studies are complex as it is difficult to recruit patients and to monitor them closely.

My initial impression is that the studies were designed differently. The Mayo Clinic study had rituximab as the active agent vs. placebo as the control, whereas the Italian study had rituximab as the active agent vs. intravenous steroids as an active control.

The doses of rituximab were also different. Salvi reduced the dose of rituximab mid-study and the lower dose was 500 mg/day vs. a total of 2,000 mg/day earlier in the study; the Mayo Clinic study used 2,000 mg. Salvi, et al suggested the lower dose was equally efficacious, but this needs to be explored further.

The major controversy relates to the patient population studied and whether the patients had received previous therapy, how recently this therapy had been given, the extent of therapy and the duration of disease. Stan, et al noted that about two-thirds of their patients did not receive treatment prior to the rituximab treatment, while Salvi, et al noted that six patients in each arm of their study had steroid treatment, but not within 3 months of the study.

Salvi, et al did indicate that their patients had progressive disease, which can defined by various scales. The CAS score, which was the sole measure in Salvi’s study, takes into account a multitude of factors. Stan, et al asserted that 24 of his 25 patients were classified as progressive as well. If the disease is progressive and treated early, the effect of immunomudulatory treatment is expected to be more efficacious. It is difficult to know with certainty if both studies analyzed patients at similar time points in the progression of ophthalmopathy.

Rituximab is not approved by the FDA for the treatment of Graves’ ophthalmopathy, The question now arises whether rituximab is effective in the treatment of progressive Graves’ ophthalmopathy given the apparent different results in these two clinical trials. Perhaps, the most appropriate advice is to refer these patients to large, tertiary medical centers that have extensive experience in treating patients with progressive Graves’ ophthalmopathy. Given that most physicians treating Graves’ ophthalmopathy are not experienced with using rituximab, and also give these conflicting results, it seems most prudent to not advise individual physicians to consider using rituximab therapy in this context outside of a tertiary medical center or a clinical trial.

o    Kenneth D. Burman, MD

o    Chief of the Endocrine Section at Washington Hospital Center 
Professor of Medicine 
Georgetown University

 Soure: Endocrine Today

Novartis drug Afinitor® significantly extended time without disease progression in women with HER2 positive advanced breast cancer.

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  • nova
  • Everolimus plus trastuzumab and vinorelbine met primary endpoint of extending PFS compared to placebo plus trastuzumab and vinorelbine after prior therapy[1]
  • Results of Phase III trial, BOLERO-3, first to show potential benefit of everolimus in HER2 positive advanced breast cancer, an aggressive form of the disease[1]
  • Detailed data will be presented at the upcoming ASCO Annual Meeting and shared with regulatory authorities worldwide

Results of a pivotal Phase III trial in women with HER2 positive (HER2+) advanced breast cancer showed that Afinitor® (everolimus) tablets in combination with trastuzumab (Herceptin®*) and vinorelbine significantly extended progression-free survival (PFS) after prior therapy when compared to treatment with placebo plus trastuzumab and vinorelbine,meeting the study’s primary endpoint[1].

Efficacy and safety data from the BOLERO-3 (Breast cancer trials of OraL EveROlimus-3) trial were assessed as part of a prospectively planned analysis. These results will be presented on June 2 at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois[2], as well as at future medical congresses, and shared with regulatory authorities worldwide.

“We are encouraged by the BOLERO-3 results and are committed to helping improve treatment options for the HER2 positive patient population where there remains an unmet need,” said Alessandro Riva, Global Head, Oncology Development & Medical Affairs, Novartis Oncology. “Everolimus works differently than any currently available treatment for HER2 positive breast cancer, and these results support its potential expanded role in advanced breast cancer.”

Everolimus targets the PI3K/AKT/mTOR pathway, which is hyperactivated in many types of cancers[3]. mTOR is a protein that acts as an important regulator of cell division, blood vessel growth and cell metabolism[4]. Data confirm that blocking mTOR is a proven approach to maximize the benefit of existing advanced breast cancer treatments[4].

Everolimus is approved as Afinitor in more than 65 countries including the United States and the countries of the European Union to treat postmenopausal women with hormone receptor-positive, HER2 negative (HR+/HER2 negative) advanced breast cancer in combination with exemestane, after recurrence or progression following a non-steroidal aromatase inhibitor[1]. The specific indications vary by country[1]. HR+/HER2 negative advanced breast cancer is the most common form of the disease[5]. Approximately 70% of all invasive breast cancers are positive for HR expression at the time of diagnosis[6].

*Herceptin® is a registered trademark of Genentech, Inc.

Study design

BOLERO-3 is a Phase III, randomized, double-blind study of everolimus plus trastuzumab and vinorelbine conducted at 159 clinical trial sites globally[1]. The trial included 569 women with HER2 positive locally advanced or metastatic breast cancer who were previously treated with a taxane and were resistant to trastuzumab[1]. Participants were randomized 1:1 to receive either everolimus 5 mg/day orally or placebo, plus weekly vinorelbine 25 mg/m2 IV and weekly trastuzumab 2 mg/kg IV following loading dose of 4 mg/kg[1].

The primary endpoint of the trial is PFS[1]. Secondary endpoints include overall survival, objective response rate, time to deterioration of performance status, changes in quality-of-life scores over time, clinical benefit rate, duration of response, time to response, safety and pharmacokinetics[1].

About advanced breast cancer

Advanced breast cancer comprises metastatic breast cancer (stage IV) and locally advanced breast cancer (stage III)[7]. Metastatic breast cancer is the most serious form of the disease and occurs when the cancer has spread to other parts of the body, such as the brain, bones or liver[7]. Locally advanced breast cancer occurs when the cancer has spread to lymph nodes and/or other tissue in the area of the breast, but not to distant sites in the body[7].

Overactivation of the PI3K/AKT/mTOR pathway has been associated with disease progression in women with advanced breast cancer[4]. Eighty percent of advanced breast cancer is either hormone receptor-positive (HR+) and/or human epidermal growth factor receptor-2 positive (HER2 positive)[1],[8].

HR+ advanced breast cancer is the most common type of advanced breast cancer, with an estimated 220,000 women diagnosed globally each year[1]. HR+ advanced breast cancer is characterized by hormone receptor-positive tumors, a group of cancers that express receptors for certain hormones such as estrogen and progesterone. Cancer cell growth can be driven by these hormones[9].

In HER2 positive advanced breast cancer, overexpression of the HER2 gene activates signaling pathways, such as the mTOR pathway, leading to the uncontrolled growth and division of cancer cells[1],[10]. Globally, an estimated 140,000 women are living with HER2 positive advanced breast cancer[1].

About Afinitor® (everolimus)

Everolimus is approved as Afinitor® in the European Union for the treatment of hormone receptor-positive,HER2 negative (HR+/HER2 negative) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative breast cancer (advanced HR+/HER2 negative breast cancer) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Afinitor (everolimus) tablets is approved in more than 95 countries, including the United States and throughout the European Union, in the oncology settings of advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy, and in the United States and European Union for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin.

Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor® or Votubia®, Certican® and Zortress® and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Important Safety Information about Afinitor (everolimus) tablets

Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections (including sepsis), and kidney failure, which can lead to death. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar, cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed. Fertility in women and men may be affected by treatment with Afinitor/Votubia.

The most common adverse drug reactions (incidence >=10 percent) are mouth ulcers, skin rash, feeling tired or weak, diarrhea, nausea, decreased appetite, infections (including upper respiratory tract infection), low level of red blood cells, abnormal taste, inflammation of lung tissue, weight loss, swelling of extremities or other parts of the body, nose bleeds, itching, vomiting, high level of blood cholesterol, headache, high level of blood sugar, cough, spontaneous bleeding or bruising, and breathlessness. The most common Grade 3-4 adverse drug reactions (incidence >=2 percent) are mouth ulcers, feeling tired or weak, infections, inflammation of lung tissue, diarrhea, spontaneous bleeding or bruising, low white blood cells (a type of blood cell that fights infection), and breathlessness. Cases of hepatitis B reactivation, blood clots in the lung or legs, and menstruation disorders such as absence of periods have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

Source: Novartis newsletter

TERISA: Ranolazine reduced angina in patients with diabetes.

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Results from an international trial demonstrate that ranolazine was safe and effective for patients with type 2 diabetes, coronary artery disease and persistent chronic angina.

Mikhail Kosiborod, MD, from St. Luke’s Mid America Heart Institute and University of Missouri, Kansas City, presented data that showed ranolazine (Ranexa, Gilead) significantly reduced angina frequency and sublingual nitroglycerin use, and as safe and well tolerated.

Following a single blind, 4-week placebo run-in phase, 949 patients were randomly assigned to 8 weeks of ranolazine (1,000 mg twice daily) or matching placebo. The mean age of the patients’ was 64 years; 61% were men; mean diabetes duration was 7.5 years; and mean baseline HbA1c was 7.3%.

“Ranolazine has previously been shown to be effective and may have the additional property of lowering HbA1c,” Kosiborod said at a press conference.

The primary endpoint was number of self-reported angina episodes between weeks 2 and 8. Weekly episodes of angina were reported less in patients assigned ranolazine compared with placebo (3.8 vs. 4.3; P=.008). A secondary endpoint was frequency of sublingual nitroglycerin use during the same study period. Self-reported use was also lower in the ranolazine group (1.7 doses per week vs. 2.1 doses per week; P=0.003).

Data indicate no difference in the incidence of serious adverse events between groups.

The researchers also found that ranolazine was especially effective in patients with worse glucose control.

“If the glucose-lowering action of ranolazine is confirmed in future studies, patients with diabetes and angina may derive a dual benefit from this drug,” Kosiborod stated in a press release.

The TERISA trial was conducted at 104 centers in 14 countries. At baseline, 43% of patients were taking one anti-angina agent and 57 were taking two anti-angina agents. The use of guideline-recommended therapy was high: 87% taking antiplatelet agents, 83% taking statins, 88% taking ACE inhibitors/angiotensin receptor blockers and 90% taking beta-blockers.

Compliance with self-reports in an electronic diary was 98% in both groups, Kosiborod said. – by Samantha Costa

For more information:

Kosiborod M. Late-breaking clinical trials III: Chronic CAD/stable ischemic heart disease. Presented at: American College of Cardiology Scientific Sessions; March 9-11, 2013; San Francisco.

Kosiborod M. J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2013.02.011.

Disclosure: The study was funded by Gilead Sciences. Kosiborod reports consultancy fees/honoraria from Boehringer Ingelheim, CardioMEMS, Genentech, Gilead, Hoffman-La Roche, Kowa Pharmaceuticals, Medtronic Minimed and Sanofi-Aventis, and research grants from Genentech, Gilead, Glumetrics and Medtronic Minimed.

PERSPECTIVE

  • In many European countries, particularly in the countries that participated in this study, there is still more of a conservative approach to the management of patients with angina. They are stable, they use more medications and less interventions than we do in the United States.

Now, there are new criteria for revascularization and we are being encouraged to treat people medically — to treat them properly — if they respond to drugs. In the United States, we might be moving a little more in that direction.

Ranolazine already has been shown to be effective, so the question researchers were looking [to answer] was whether patients with diabetes benefit from this drug. Diabetics, as we know, have problems with reduction in coronary reserve, myocardial issues, diabetic cardiomyopathy, muscle stiffness and more.

The other interesting point is that patients with HbA1c levels greater than 7% had strikingly better effect response than those with HbA1c less than 7%. This becomes very interesting in terms of possible mechanisms exploring other areas.

  • Miguel A. Quinones, MD, MACC
  • Chairman of the ACC, 2013
    Professor of Medicine, Weill Cornell Medical College
    Chairman, Department of Cardiology, The Methodist Hospital
    Methodist DeBakey Heart & Vascular Center

Source: Endocrine Today.