Hemophilia therapies drive outpatient pharmacy costs for publicly insured children

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Swenson SM, et al. JAMA. 2015;doi:10.1001/jama.2015.7169.

July 29, 2015  From: HemOncToday

Medications for the treatment of hemophilia are a considerable driver of outpatient pharmacy expenditures for publicly insured children with serious chronic conditions, according to study results.

An analysis of outpatient pharmacy products in California between 2010 and 2012 showed antihemophilic agents accounted for more than 40% of the costs, even though they were only used to treat 0.4% of the population studied.

Sonja M. Swenson, BA, the research coordinator at the Center for Health Policy and Center for Primary Care and Outcomes Research at Stanford University, and colleagues retrospectively analyzed paid insurance claims for 34,330 children aged 0 to 21 years in California.

The investigators determined outpatient pharmacy expenditures totaled $475.7 million, and this accounted 20% of total health care expenditures.

Per-child pharmacy expenditures ranged from 16 cents to $56.84 million, for an average of $13,857 per child (median, $791; interquartile range, [IQR] = 127-5,873).

“Our study underscores the potential effect of new, expensive but efficacious pharmaceuticals on the public insurance programs for children with chronic illness,” the researchers wrote. “These findings may inform efforts to enhance value in these programs, particularly as new insurance frameworks, such as accountable care organizations, are considered.”

Blood formation, coagulants and thrombosis agents accounted for 41.9% of the expenditures. Antihemophilic factor, a protein that necessitates blood clotting and is deficient in patients with hemophilia, made up 98% of that group, or 40.9% of all pharmacy expenditures.

Children with an antihemophilic factor paid claim accounted for 0.4% of the entire cohort.

The average per-child expenditure for antihemophilic factor was $1.34 million. For those children with antihemophilic factor claims who were enrolled for the entire 3 years of the analysis, the average annual expenditure was $634,054 (median, $152,280; IQR = 19,434-393,000).

As a comparison, the next largest percentage of total pharmacy expenditures was 9.2% for central nervous system drugs, with a per-child average of $1,869.

“Antihemophilic factor is highly efficacious and essential in caring for children with children with hemophilia putting pressure on public programs to seek improved pricing mechanisms for antihemophilic factor and other highly efficacious, high-cost medications,” Swenson and colleagues wrote.

Limitations for this analysis included a lack of clinical data, lack of in-patient pharmacy data and the study’s cross-sectional design. Also, researchers excluded children enrolled in managed care, and data were limited to 3 years.

The investigators indicated that a state-to-state examination may provide further insights. The average annual expenditure for children with anthemophilic factor claims over 3 years significantly surpassed North Carolina’s Medicaid program, which was $233,968 in fiscal year 2012, as well as Medicaid programs in 10 other states.

“Public programs for children with serious chronic illness vary between states, and care should be taken in making direct program comparisons,” Swenson and colleagues wrote. “Greater transparency of use and costs, and cross-state collaboration, may increase health care value as states revise programs.” – by Anthony SanFilippo

Disclosure: The researchers report no relevant financial disclosures.


Ethanol locks reduce central venous catheter-associated bloodstream infections in children with cancer

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Hemophilia patients with a port-a-cath typically use Heparin to “lock” at the end of the infusion.  The following article give an alternative to Heparin for patients with bloodstream infections. Please talk to your Doctor to see if this is a viable option for you or your child (we are not medical professionals).

From: Schoot RA, et al. Eur J Cancer. 2015;doi:10.1016/j.ejca.2015.06.126.

July 27th, 2015

Ethanol locks prevented central venous catheter-associated bloodstream infections in pediatric patients with cancer, according to the results of a randomized trial.

“The use of central venous catheters (CVC) is indispensable in the modern-day treatment of children with cancer,” Marianne D. van de Wetering, PhD, MMed, FCP(SA), pediatric oncologist at Emma Children’s Hospital Academic Medical Centre in Amsterdam, and colleagues wrote. “Despite improved international guidelines on CVC placement and catheter care, CVC colonization is still an important problem in such patients. Colonized CVCs can cause CVC-associated bloodstream infections (CABSI), with reported infection rates between 0.1 and 2.3 CABSIs per 1,000 catheter days.”

The use of ethanol locks can potentially eliminate pathogens colonizing CVCs with minimal microbial resistance, according to study background.

Van de Wetering and colleagues conducted a randomized controlled trial to determine whether 2-hour, 70% ethanol locks could reduce CABSI in pediatric patients with cancer.

The trial comprised 307 patients aged 1 to 18 years with newly inserted CVCs. Patients received 2-hour ethanol locks (1.5 mL or 3 mL, 70%; n = 153) or heparin locks (1.5 mL or 3 mL, 100 IU/mL; n = 154) as needed, with maximum frequency once weekly.

Seventy patients discontinued the study prematurely. Significantly more patients in the ethanol arm withdrew their informed consent (20 vs. 8; P = .031).

Time to CABSI or death due to CABSI served as the primary endpoints.

The researchers observed a CABSI in 10% (n = 16) of patients in the ethanol arm vs. 19% (n = 29) in the heparin arm. Further, patients in the ethanol arm experienced fewer CABSI per 1,000 catheter days (0.77 vs. 1.46; P = .039).

No patients died from CABSI, and patients in the ethanol arm experienced a reduction of gram–positive CABSIs (8 vs. 21; P = .012). Further, fewer CVC removals due to CABSI occurred among patients on ethanol locks (P = .077).

No suspected and unexpected serious adverse reactions occurred. More patients in the ethanol arm than heparin arm reported nausea (P =.03), taste alteration (P < .001), dizziness (P = .001) and blushing (P < .001); however, adverse event symptoms remained transient and did not exceed grade 2. Serious adverse events occurred at similar rates in both arms (ethanol, n = 65; heparin, n = 67).

The researchers acknowledged several limitations of their study, including poor trial accrual and inequality of the number of patients who withdrew consent following randomization.

“We therefore recommend the implementation of prophylactic ethanol locks in current pediatric oncology practice with the following caveats,” van de Wetering and colleagues concluded. “Firstly, as some patients may have withdrawn from the study because of adverse events, patients should be well informed as to the potential side effects and their transient nature. Secondly, as the diagnosis of CABSI in pediatric oncology patients remains a challenge, for future studies we recommend standard definitions for CABSI applicable to pediatric patients, such as the use of differential time to positivity. Lastly, while shorter lock durations would be more convenient for patients and their families, shorter dwell times/even ethanol flushes, should be compared to 2-hour locks for efficacy.” – by Cameron Kelsall

Disclosure: van de Wetering reports no relevant financial disclosures. One researcher reports an employment role with F. Hoffman-La Roche Ltd.

Find Original article here.

Alnylam Reports New Positive Clinical Data for ALN-AT3, a Subcutaneously Administered, Investigational RNAi Therapeutic Targeting Antithrombin (AT) for the Treatment of Hemophilia and Rare Bleeding Disorders

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– New Interim Data from Ongoing Phase 1 Study in Hemophilia Subjects Demonstrate an up to 86% AT Knockdown and a Re-Balancing of Hemostasis with Normalization of Thrombin Generation up to a Mean Increase of 350% and Marked Improvements in Whole Blood Clotting –

– In Exploratory Post Hoc Analysis, Reduced Bleeding Events Associated with AT Knockdown, with a Maximum Bleed-Free Interval of 114 Days –

– ALN-AT3 Administration Remains Generally Well Tolerated, Including No Clinically Significant Increases in D-Dimer –

– Based on Promising Results, Company Now Expects to Advance ALN-AT3 into Pivotal Studies in Mid-2016 –

CAMBRIDGE, Mass.–(BUSINESS WIRE)– Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, today announced that new positive data from its ongoing Phase 1 clinical trial with ALN-AT3 – an investigational RNAi therapeutic for the treatment of hemophilia and rare bleeding disorders (RBD) – were reported in an oral presentation at the International Society on Thrombosis and Haemostasis (ISTH) 2015 Congress being held June 20 – 25, 2015 in Toronto, Ontario, Canada. Additional study results from 12 hemophilia A and B subjects demonstrated that subcutaneous administration of ALN-AT3 achieved potent and dose-dependent knockdown of AT of up to 86%. AT knockdown was highly durable, with effects lasting over two months after the last dose, supporting further evaluation of a once-monthly subcutaneous dose regimen. In addition, AT knockdown was associated with statistically significant increases in thrombin generation with a mean increase of up to 350% and marked improvements in whole blood clotting; these results demonstrate a re-balancing of hemostasis in severe hemophilia subjects. In an exploratory post-hoc analysis, a reduced frequency of bleeding was observed at higher AT knockdown levels including a maximum bleed-free interval of 114 days. Importantly, ALN-AT3 was found to be generally well tolerated, including no clinically significant increases in D-dimer, a biomarker of pathologic clot formation. Based on these data, the company expects to accelerate the advancement of ALN-AT3 with pivotal studies planned to begin in mid-2016.

“With the potential for infrequent subcutaneous dose administration and possible correction of disease phenotype, we believe that ALN-AT3 represents an innovative investigational medicine for the treatment of hemophilia and rare bleeding disorders. We regard these new results from our ongoing Phase 1 study as very promising, as they demonstrate clinical activity for ALN-AT3 toward AT knockdown and a re-balancing of hemostasis with a normalization of thrombin generation and improved whole blood clot formation. Moreover, we’re encouraged by results from an exploratory analysis of effects on bleeding, where we’ve observed a reduced estimated annualized bleeding rate (ABR) at higher levels of AT knockdown. Importantly, ALN-AT3 has continued to be generally well tolerated in the study, including no clinically significant increases in D-dimer levels,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer at Alnylam. “Based on these results and upon completion of the Phase 1 study, we now intend to proceed to pivotal Phase 3 studies of ALN-AT3 that we expect to start in mid-2016. In addition, we plan to initiate an open-label extension study later this year for subjects from the Phase 1 study, and we expect to present data from that study on an ongoing basis at least once per year beginning in 2016. In the meantime, we also look forward to presenting additional data from our ongoing Phase 1 study, including results from hemophilia subjects receiving a once-monthly subcutaneous dose regimen, later this year.”

“New therapeutic options are needed to manage bleeding in hemophilia and other rare bleeding disorders. This is particularly important for patients who experience multiple annual bleeds when receiving replacement factor ‘on demand’ or patients who have developed inhibitory antibodies. I believe that the availability of a subcutaneously administered therapeutic with a long duration of action – such as a once-monthly regimen – that is shown to be safe and effective would represent a marked improvement over currently available approaches for prophylaxis,” said Claude Negrier, M.D., Ph.D, Professor of Medicine at the Claude Bernard University and Chairman of the Hematology Division at Edouard Herriot University Hospital and Louis Pradel Cardiology Hospital in Lyon, France. “I am very encouraged by the continued tolerability and new clinical activity results emerging from the ongoing Phase 1 study of ALN-AT3. Indeed, the ability of ALN-AT3 to potentially increase thrombin generation in severe hemophilia subjects toward normal levels is an important finding, and this appears to be associated with improvements in whole blood clotting and bleeding frequency. I believe that these new findings support the continued advancement of this novel investigational therapeutic agent.”

The ongoing Phase 1 trial of ALN-AT3 is being conducted in Bulgaria, Russia, Switzerland, and the U.K. as a single- and multi-dose, dose-escalation study comprised of three parts. Part A – which is complete – was a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study (n=4 per cohort; 3:1 randomization of ALN-AT3: placebo) in healthy volunteer subjects. This part of the study was completed after the first dose cohort received a single subcutaneous dose of ALN-AT3 at 30 micrograms per kilogram (mcg/kg). Part B of the study – which is now complete – was an open-label, multi-dose, dose-escalation study that enrolled 12 subjects with severe hemophilia A or B. Subjects in Part B received 3 weekly subcutaneous doses of ALN-AT3 at doses of 15, 45, or 75 mcg/kg with a volume per injection ranging from 0.2 to 0.7 mL. Part C of the study – which is ongoing – is an open-label, multi-dose, dose escalation study of up to 12 subjects with moderate or severe hemophilia A or B in which subjects are receiving 3 monthly subcutaneous doses of ALN-AT3. The initial dose cohort of Part C has received ALN-AT3 at a dose of 225 mcg/kg (volume less than 1mL), which is equivalent to the cumulative dose level from 3 weekly doses of 75 mcg/kg that was found to be generally well tolerated in Part B. The primary objective of Parts B and C of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in thrombin generation at pharmacologic doses of ALN-AT3. For subjects enrolled at select sites in the U.K. and Switzerland, the effects of ALN-AT3 are also being monitored by ROTEM® thromboelastometry, which measures clotting time and clot strength in whole blood following a physiologic coagulation stimulus. In addition, exploratory analyses of bleeding are being performed. In the U.K., enrollment has been aided by the Southern Academic Coagulation Consortium (SACC).

New results were presented from 12 hemophilia subjects in Part B of the ongoing Phase 1 study in an oral presentation at ISTH and include all available data as of the data cut-off date of June 2, 2015. Subcutaneous doses of ALN-AT3 resulted in potent, dose-dependent and statistically significant knockdown of plasma AT of up to 86%. At the top dose of 75 mcg/kg (n=3), the mean maximum AT knockdown was 59 ± 7% (p less than 0.05), with nadir levels achieved between days 28 and 42. AT knockdown was found to be highly durable, with effects lasting over two months after the last dose. For example, at the 45 mcg/kg dose, mean AT knockdown was 36 ± 11% at day 70.

AT knockdown with ALN-AT3 was associated with statistically significant increases in thrombin generation and improvements in whole blood clot formation, providing continued evidence for a re-balancing of hemostasis and potential correction of the hemophilia phenotype in severe hemophilia subjects. The association between levels of AT knockdown and thrombin generation was assessed in a post hoc exploratory analysis in which AT knockdown was categorized into tertiles. In the highest tertile (greater than 66% AT knockdown), ALN-AT3 administration resulted in mean increases in thrombin generation of 350 ± 239% (p less than 0.05). In this same tertile, the observed level of thrombin generation (120 ± 81 nM peak thrombin) was comparable to levels observed in healthy volunteers (120 ± 33 nM peak thrombin) from Part A of the Phase 1 study, demonstrating an apparent normalization of thrombin generation. Thrombin generation is known to be a biomarker for bleeding frequency and severity in people with hemophilia (Dargaud, et al., Thromb Haemost; 93, 475-480 (2005)).

Additional evaluation of the effects of ALN-AT3 employed the use of ROTEM® thromboelastometry in 3 severe hemophilia subjects in which ALN-AT3 administration resulted in statistically significant, AT knockdown-dependent improvements in whole blood clot formation, including a shortening of clot formation time (CFT). At day 35, the CFT for all 3 subjects was significantly shorter than on day 1, with an over three-fold shortening of CFT from 1166 ± 614 sec to 323 ± 46 sec (p less than 0.05).

While the Phase 1 study was not designed to evaluate the effects of ALN-AT3 on bleeding, an exploratory post hoc analysis was performed by examining the frequency of on-study bleeding events in all subjects in Part B of the study. During the period of time when subjects had AT knockdown less than 33%, a total of 33 bleeding events were reported, and the mean estimated annualized bleeding rate (ABR) was 22 ± 5; this ABR is generally consistent with values reported in prospective clinical trials for hemophilia subjects treated “on-demand” with factor replacement. The mean estimated ABR was reduced to 14 ± 5 at levels of AT knockdown between 33 and 66% and was reduced yet further to a mean estimated ABR of zero during the period of time when AT knockdown exceeded 66%. The reduced ABR associated with increased AT knockdown was statistically significant (p less than 0.001 based on negative binomial regression model). The maximum bleed-free interval for any given subject was 114 days, observed in a subject who achieved an up to 86% level of AT knockdown. This subject with severe hemophilia had a self-reported ABR of over 20 bleeds per year prior to entering the ALN-AT3 Phase 1 study.

AT Knockdown
Less than 33% 33-66% Greater than 66%
Subjects (N) 12 9 2
Cumulative Days 509 414 106
Peak Thrombin Generation (nM, Mean +/- SD) 18 ± 8 35 ± 24 120 ± 81
% Increase in Peak Thrombin Generation (Mean +/- SD) 25 ± 72% 69 ± 92% 350 ± 239%
Cumulative Bleeds 33 18 0
Estimated Annualized Bleeding Rate (ABR) (Mean +/- SEM) 22 ± 5 14 ± 5 0

*p less than 0.05, compared with AT knockdown less than 33%
**p less than 0.001, based on negative binomial regression model

As of the current data cut off, ALN-AT3 continues to be generally well tolerated in all subjects. There have been no serious adverse events, no discontinuations, and no significant changes in physical exams, vital signs, or electrocardiography. One subject experienced mild injection site pain lasting two minutes, but otherwise there were no injection site reactions. Further, there have been no clinically significant changes in any laboratory parameter, including liver function tests, hematology, and coagulation measures. There have been no clinically significant increases in D-dimer, a marker of pathologic clot formation, and no thromboembolic events. The most common adverse event observed in hemophilia subjects was the occurrence of mild to moderate bleeds unrelated to study drug. All bleeds were successfully managed with replacement factor administration, with no adverse events associated with factor administration.

Based on these promising results, Alnylam plans to advance directly to pivotal studies for ALN-AT3 and is providing new guidance that it intends to start a pivotal Phase 3 clinical trial in mid-2016. The company also intends to open a Phase 1 open label extension (OLE) study in late 2015 to provide hemophilia subjects enrolled in the Phase 1 study the opportunity for continued dosing; Alnylam intends to report data from the Phase 1 OLE at least once per year with initial data expected in 2016. Finally, the company still plans on presenting additional data from the ongoing Phase 1 study in late 2015.

Alnylam scientists and collaborators also are presenting new pre-clinical data on ALN-AT3 at the ISTH meeting. Earlier this morning, the company presented data from an oral presentation entitled “Antithrombin Reduction Improves Coagulation in Rare Bleeding Disorder Plasma.” Specifically, ex vivo AT depletion was demonstrated to result in increased thrombin generation in plasma from donors with deficiencies in factors V, VII, and XI. These new pre-clinical data support the clinical evaluation of ALN-AT3 in these rare bleeding disorders. Additional data reports from the meeting will be made available on the company’s website following their presentation.

Genzyme Alliance
In January 2014, Alnylam and Genzyme, a Sanofi company, formed an alliance to accelerate and expand the development and commercialization of RNAi therapeutics across the world. The alliance is structured as a multi-product geographic alliance in the field of rare diseases. Alnylam retains product rights in North America and Western Europe, while Genzyme obtained the right to access certain programs in Alnylam’s current and future Genetic Medicines pipeline, including ALN-AT3, in the rest of the world. In certain defined instances, Genzyme has co-development/co-commercialization and/or global product rights. Genzyme has the right, under specified circumstances, to elect to co-develop and co-promote ALN-AT3, with Alnylam maintaining development and commercialization control. Genzyme’s rights are structured as an opt-in that is triggered upon achievement of human proof-of-principle.

Conference Call Information
Alnylam management will discuss these new interim Phase 1 results with ALN-AT3 in a webcast conference call on Tuesday, June 23 at 4:30 p.m. ET. A slide presentation will also be available on the Investors page of the company’s website, www.alnylam.com, to accompany the conference call. To access the call, please dial 877-312-7507 (domestic) or 631-813-4828 (international) five minutes prior to the start time and refer to conference ID 64377549. A replay of the call will be available beginning at 7:30 p.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 64377549.

About Hemophilia and Rare Bleeding Disorders
Hemophiliacs are hereditary disorders caused by genetic deficiencies of various blood clotting factors, resulting in recurrent bleeds into joints, muscles, and other major internal organs. Hemophilia A is defined by loss-of-function mutations in Factor VIII, and there are greater than 40,000 registered persons in the U.S. and E.U. with Hemophilia A. Hemophilia B, defined by loss-of-function mutations in Factor IX, affects greater than 9,500 registered persons in the U.S. and E.U. Other Rare Bleeding Disorders (RBD) are defined by congenital deficiencies of other blood coagulation factors, including Factors II, V, VII, X, and XI, and there are about 1,000 persons worldwide with a severe bleeding phenotype. Standard treatment for persons living with hemophilia involves replacement of the missing clotting factor either as prophylaxis or on-demand therapy. However, as many as one third of people with severe hemophilia A will develop an antibody to their replacement factor – a very serious complication; persons in this ‘inhibitor’ subset become refractory to standard replacement therapy. There exists a small subset of persons living with hemophilia who have co-inherited a prothrombotic mutation, such as Factor V Leiden, antithrombin deficiency, protein C deficiency, and prothrombin G20210A. People who have co-inherited these prothrombotic mutations are characterized as having a later onset of disease, lower risk of bleeding, and reduced requirements for Factor VIII or Factor IX treatment as part of their disease management. There exists a significant need for novel therapeutics to treat people living with hemophilia.

About Antithrombin (AT)
Antithrombin (AT, also known as “antithrombin III” and “SERPINC1”) is a liver expressed plasma protein and member of the “serpin” family of proteins that acts as an important endogenous anticoagulant by inactivating Factor Xa and thrombin. AT plays a key role in normal hemostasis, which has evolved to balance the need to control blood loss through clotting with the need to prevent pathologic thrombosis through anticoagulation. In hemophilia, the loss of certain procoagulant factors (Factor VIII and Factor IX, in the case of hemophilia A and B, respectively) results in an imbalance of the hemostatic system toward a bleeding phenotype. In contrast, in thrombophilia (e.g., Factor V Leiden, protein C deficiency, antithrombin deficiency, amongst others), certain mutations result in an imbalance in the hemostatic system toward a thrombotic phenotype. Since co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, inhibition of AT defines a novel strategy for improving hemostasis.

About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-GalNAc Conjugates
GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. This delivery platform is being employed in nearly all of Alnylam’s pipeline programs, including programs in clinical development.

About RNAi
RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals
Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines. Alnylam’s pipeline of investigational RNAi therapeutics is focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic Disease, with a pipeline of RNAi therapeutics toward genetically validated, liver-expressed disease targets for unmet needs in cardiovascular and metabolic diseases; and Hepatic Infectious Disease, with a pipeline of RNAi therapeutics that address the major global health challenges of hepatic infectious diseases. In early 2015, Alnylam launched its “Alnylam 2020” guidance for the advancement and commercialization of RNAi therapeutics as a whole new class of innovative medicines. Specifically, by the end of 2020, Alnylam expects to achieve a company profile with 3 marketed products, 10 RNAi therapeutic clinical programs – including 4 in late stages of development – across its 3 STArs. The company’s demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world’s top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, Cell, New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information about Alnylam’s pipeline of investigational RNAi therapeutics, please visit www.alnylam.com.

Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam’s future expectations, plans and prospects, including without limitation, Alnylam’s views with respect to the potential for RNAi therapeutics, including ALN-AT3 for the treatment of hemophilia and rare bleeding disorders and the potential clinical activity and durability of ALN-AT3, expectations regarding the reporting of data from clinical studies, in particular the ongoing Phase 1 clinical trial of ALN-AT3, as well as the Phase 1 OLE for ALN-AT3, expectations regarding the initiation of pivotal Phase 3 studies for ALN-AT3, expectations regarding its STAr pipeline growth strategy, and its plans regarding commercialization of RNAi therapeutics, including ALN-AT3, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Alnylam’s ability to discover and develop novel drug candidates and delivery approaches, successfully demonstrate the efficacy and safety of its drug candidates, the pre-clinical and clinical results for its product candidates, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials, obtaining, maintaining and protecting intellectual property, Alnylam’s ability to enforce its patents against infringers and defend its patent portfolio against challenges from third parties, obtaining regulatory approval for products, competition from others using technology similar to Alnylam’s and others developing products for similar uses, Alnylam’s ability to manage operating expenses, Alnylam’s ability to obtain additional funding to support its business activities and establish and maintain strategic business alliances and new business initiatives, Alnylam’s dependence on third parties for development, manufacture, marketing, sales and distribution of products, the outcome of litigation, and unexpected expenditures, as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation to update any forward-looking statements.

Alnylam Pharmaceuticals, Inc.
Michael Mason, 617-551-8327
Vice President, Finance and Treasurer
Liz Bryan (Media), 202-955-6222 x2526

Source: Alnylam Pharmaceuticals, Inc.

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Lettuce Pills May Help Treat Haemophilia

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Dec 16, 2014 |By Elie Dolgin

The food in Anita’s bowl is not your average dog chow. Although the dish contains pellets and wet food, there is also a sprinkling of green powder—the product of a trailblazing experiment to address a potentially lethal complication of haemophilia treatment. Anita, so named because her red coat reminded breeders of the character from the animated film One Hundred and One Dalmatians, is a keagle (a mix of a beagle and a Cairn terrier) with haemophilia B.

Like people with this rare genetic disorder, Anita is naturally deficient in factor IX, a protein that helps the blood to form clots. When treated with replacement coagulation proteins, the dog naturally develops antibodies, or inhibitors, against the therapy—a problem that is also seen in some 5% of humans with haemophilia B. In these people, the immune system identifies the therapeutic protein as dangerous, causing the body to stop accepting the protein as a normal part of the blood, and destroys it before it can stop the bleeding. Continuing to take factor-replacement therapies can result in life-threatening allergic reactions, such as anaphylaxis.

The problem is even worse with haemophilia A, a disease that is four times more common than haemophilia B and in which the missing link in the coagulation chain is a protein called factor VIII. Around 30% of people with haemophilia A develop antibodies against replacement factor VIII.

Therapies are available to eliminate these antibodies. Some people, for example, undergo an intensive treatment called immune tolerance induction therapy, which involves regular intravenous administration of coagulation factors. But this is time consuming and costly (around US$1 million for an average five-year-old patient), and the treatment works in only about three-quarters of patients. “The challenges of treating haemophilia with inhibitors are just staggering,” says Timothy Nichols, director of the Francis Owen Blood Research Laboratory at the University of North Carolina at Chapel Hill, which maintains the colony of haemophiliac dogs to which Anita belongs.

Inducing immune tolerance in people who have developed inhibitors is one approach. But avoiding the problem altogether would be even better. “If you can prevent antibody formation in the first place, by finding some way of producing immunological tolerance that gets around that type of protocol, that would be a major advantage,” says David Lillicrap, a clinician and researcher who specializes in bleeding disorders at Queen’s University in Kingston, Ontario, Canada.

The green powder in Anita’s dish might do just that. The oral treatment is a concentrate of freeze-dried lettuce-leaf cells, each containing around 10,000 chloroplasts—the organelles responsible for photosynthesis—that have been genetically engineered to produce factor IX. These proteins cannot themselves be used to prevent bleeding episodes, because the cellular machinery found in plants cannot package the human clotting factors into the biologically active form. What they can do, however, is prevent the immune system from mounting an attack against subsequent therapy.

The researchers behind the bioengineered lettuce have shown that inhibitor formation and severe allergic reactions can be prevented in mice by feeding the animals with a product based on these plants. If the strategy also works in Anita and her kennel mates—and ultimately in humans—it could form the basis of the first product to protect against the immune responses associated with haemophilia treatment.

Anita is one of only two dogs to have received the bioengineered lettuce. “So far, it’s going very well,” says lead researcher Henry Daniell, director of translational research at the University of Pennsylvania School of Dental Medicine in Philadelphia.

An act of tolerance
In 2006, Lillicrap demonstrated that a simple oral treatment could train the immune system not to produce inhibitors. Working with a mouse model of haemophilia A, he and his colleagues gave the mice a purified fragment of the human factor VIII protein, through the nose or mouth. The researchers found that the treatment afforded some protection against antibody development after factor VIII replacement therapy. But the approach did not deliver sufficient amounts of the factor to immune cells in the gut or nasal passage to fully quash inhibitor formation.

Daniell came up with an improved delivery system. He focused first on haemophilia B. Adapting a technique that he had previously developed to delay the onset of type 1 diabetes, Daniell and his group genetically modified tobacco plants to express human factor IX in their chloroplasts. (Daniell has since switched to using lettuce.)

Chloroplast DNA is separate from the genome DNA in the plant nucleus, and the large numbers of these tiny organelles in the cell allow huge volumes of the coagulation protein to accumulate in each tobacco leaf. Once ingested, the plant cell wall protects the coagulation protein from being destroyed by stomach acid. Gut microorganisms farther down the digestive tract then chew away at the cell wall, releasing the clotting-factor protein.

To target the proteins to the immune system, Daniell then attached a second protein that has high binding affinity for a receptor found on the inside of the human gut. With this fused construct tethered to the intestinal wall, the coagulation protein could be absorbed into the body and processed by the specialized cells in the immune system that induce tolerance.

Working with Roland Herzog, a molecular biologist at the University of Florida in Gainesville, Daniell then tested the plant-based product in animal models. In 2010, they showed that oral delivery of factor IX expressed in chloroplasts in this way led to almost undetectable inhibitor levels in mice, and no sign of anaphylactic shock. “The mice are healthy, they show no allergic responses and they don’t form the inhibitors,” Herzog says. “That’s pretty exciting.”

Daniell then modified the tobacco leaves to express factor VIII and shipped powders of the leaves to Herzog. Earlier this year, the two researchers and their teams documented suppression of inhibitor formation and even reversal of pre-existing inhibitors in mouse models of haemophilia A.

Inhibitory control
Other strategies being pursued to prevent the formation of inhibitors of clotting-factor therapy include immunosuppressants and drugs that deplete specific immune cells. However, these therapies have many side effects, including increased susceptibility to infection.

A potentially safer option comes from Selecta Biosciences, a company in Watertown, Massachusetts. Selecta has developed a nanoparticle delivery system in which an immune-modifying compound is contained in biodegradable plastic particles just 150 nanometres across. When injected together with factor VIII into mouse models of haemophilia A, the nanoparticles deliver their payload to cells in the lymphoid tissue that are responsible for initiating immune responses. These cells, in turn, instruct factor-VIII–specific immune cells to become tolerant to the coagulation protein, resulting in suppression of misdirected antibody responses to the replacement therapy—all without affecting the rest of the immune system.

Green power: from leaf to powder to capsule.
Credit: Kwang-Chul Kwon, Jin Su & Henry
Daniell, Univ. Pennsylvania

David Scott and his colleagues at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, teamed up with Selecta to show that inhibitors remained undetectable for at least six months after treatment with the nanoparticle formulation. “This underscores the point that we’re actually teaching the immune system to become tolerant to factor VIII,” says Selecta’s chief scientific officer, Takashi Kei Kishimoto.

The nanotechnology approach that is being tested for inhibitor control could also improve the haemophilia treatment that is now at the cutting edge of clinical research: gene therapy. Using the standard gene-therapy approach, researchers have shown that they can achieve long-term expression of factor IX in adults with haemophilia B at sufficiently high levels to convert the bleeding disorder into a mild disease (see page S6). There has so far been no reported evidence of inhibitor formation in the small number of human participants in clinical trials for this viral therapy.

Still, the standard form of liver-targeted gene therapy carries a range of potential complications, including the risk of harmful mutations and of the body mounting an immune response against the viral vectors used to carry the correct forms of the defective genes responsible for haemophilia. That is why several research groups are attempting to replace viral vectors with nanoparticles that can deliver gene therapies as ‘DNA pills’.

Pill protection
DNA pills combine DNA plasmids—circular pieces of bacterial DNA containing the gene encoding either factor VIII or factor IX—with nanoparticles made of chitosan, a tough polymeric carbohydrate found in the exoskeleton of crustaceans. Chitosan protects the therapeutic gene product and chaperones it through the gut. “The oral route has significant appeal,” says Gonzalo Hortelano, a gene-therapy researcher at McMaster University in Hamilton, Canada. “The key is to achieve a system of delivery that’s persistent, effective and completely safe.”

Independent studies by Hortelano’s group and other research teams in Germany and the United States have shown that this oral gene therapy does not activate the immune system. Indeed, exposure of the protein produced by the nanoparticle-based gene therapy to the gut mucosa prevents inhibitor development and restores clotting-factor activity in mouse models of both haemophilia A and B. “This approach really could hold big benefit for patients,” says Jörg Schüttrumpf, a transfusion-medicine specialist who led one of the studies performed at the German Red Cross Blood Donor Service in Frankfurt.

Kam Leong, a biomedical engineer at Columbia University in New York City whose team was the first to demonstrate success with this approach in mice, has even tried feeding the chitosan–DNA nanoparticles to dogs with haemophilia A. Leong found some evidence of gene transfer and a reduction in inhibitors in the animals. But bleeding times were not reduced, which would be expected if sufficient levels of factor VIII were being produced. “It is still a very inefficient process,” Leong says, “so it requires continued optimization.”

Although the ideal remains a gene therapy that both corrects the disease and offers immune tolerance, some scientists have focused on treating inhibitor formation, without worrying about fixing the disease. Under this strategy, people would still need to take factor-replacement therapies, but they could do so without fear of inhibitor development.

With this in mind, independent teams led by Scott and Herzog took the conventional viral-vector approach to inducing tolerance through gene therapy. But rather than delivering the entire gene for the clotting-factor proteins to cells, as most gene therapies do, the researchers used the viruses to engineer immune-regulating B cells to express a fragment of the clotting factor fused to an immune molecule called an immunoglobulin. This led to long-lived tolerance in mouse models of haemophilia A and B.

Pursuing such gene-therapy approaches offers a degree of bet hedging, says Herzog. “Each strategy has potential advantages and disadvantages,” he points out, “and we do not really know yet what will work or may work best in people.” With so many therapeutic tactics moving through the preclinical pipeline, scientists and clinicians remain hopeful that at least one will ultimately succeed, eliminating the problem of inhibitor formation for people with haemophilia altogether.

MORE TO EXPLORE1. Verma, D. et al. Proc. Natl Acad. Sci. USA 107, 7101-7106 (2010).

2. Sherman, A. et al. Blood 124, 1659-1668 (2014).

3. Rawle, F.E. et al. J. Thromb. Haemost. 4, 2172-2179 (2006).

4. Ruhlman, T., Ahangari, R., Devine, A., Samsam, M. & Daniell, H. Plant Biotechnol. J. 5, 495-510 (2007).

5. Zhang, A.-H.A. et al. Blood 122, 2337 (2013).

6. High, K.A. Blood 120, 4482-4487 (2012).

7. Bowman, K., Sarkar, R., Raut, S. & Leong, K.W. J. Control. Release 132, 252-259 (2008).

8. Dhadwar, S.S., Kiernan, J., Wen, J. & Hortelano, G. J. Thromb. Haemost. 8, 2743-2750 (2010).

9. Quade-Lyssy, P. et al. J. Thromb. Haemost. 12, 932-942 (2014).

10. Lei, T.C. & Scott, D.W. Blood 105, 4865-4870 (2005).

11. Wang, X. et al. Mol. Ther. 22, 1139-1150 (2014).

This article was originally published with the title “Immunology: Oral solutions.”

For original article, click here.

CSL Behring Submits Biologics License Application for FDA Approval of Recombinant Fusion Protein Linking Coagulation Factor IX with Recombinant Albumin (rIX-FP) for Hemophilia B Patients

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KING OF PRUSSIA, Pa. — 16 December 2014

CSL Behring announced today it has submitted a biologics license application (BLA) to the United States Food and Drug Administration (FDA) for the marketing authorization of its long-acting fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP). Once approved by the FDA, rIX-FP (Coagulation Factor IX {Recombinant}, Albumin Fusion Protein) will provide people with hemophilia B and their physicians a long-acting treatment option with dosing intervals up to 14 days.

“As we mentioned at our recent R&D investor briefing, submission of our BLA to the FDA for rIX-FP is a significant milestone for CSL Behring’s recombinant factor IX development program and moves us one step closer to bringing this innovative therapy to hemophilia B patients in the U.S.,” said Dr. Andrew Cuthbertson, Chief Scientific Officer and R&D Director, CSL Limited. “Our strong partnership with and commitment from the hemophilia community led us to develop rIX-FP based on novel recombinant albumin fusion technology. This technology has led to a long-acting treatment candidate that continues our legacy of improving the well-being of patients with bleeding disorders and other rare diseases.”

About PROLONG-9FP Clinical Development Program

CSL Behring’s BLA is based on the results from the PROLONG-9FP Phase II/III (patients ages 12 to 61 years) study. The Phase II/III pivotal study was an open-label, multicenter, safety, pharmacokinetic (PK) and efficacy study of rIX-FP in previously treated patients with severe hemophilia B (FIX ≤ 2%).

This study was designed to compare the change in frequency of spontaneous bleeding events between on-demand treatment and a weekly prophylaxis regimen in patients previously receiving only on-demand treatment; and the number of patients developing inhibitors against factor IX as primary outcome measures. The study evaluated multiple prophylaxis regimens, including 7-day and 14-day intervals. A sub-study evaluated the prevention and control of bleeding in patients with hemophilia B undergoing a surgical procedure.

Study design details for rIX-FP (CSL654) are available at www.clinicaltrials.gov.

About rIX-FP

CSL Behring engineered rIX-FP to extend the half-life of recombinant factor IX through genetic fusion with recombinant albumin. CSL Behring selected recombinant albumin as its recombinant genetic fusion partner for its coagulation factor proteins due to its long physiological half-life. In addition, recombinant albumin has been shown to have a good tolerability profile, low potential for immunogenic reactions and a well-known mechanism of clearance. The cleavable linker connecting recombinant factor IX and recombinant albumin has been specifically designed to preserve the native function of the coagulation factor in the fusion protein, while benefiting from recombinant albumin’s long physiological half-life.

In 2012, the FDA granted Orphan Drug Designation for rIX-FP for the treatment and prophylaxis of bleeding episodes in patients with hemophilia B. The designation includes routine prophylaxis treatment, control and prevention of bleeding episodes, and prevention and control of bleeding in perioperative settings. The FDA’s Orphan Drug Designation program provides orphan status to unique drugs and biologics defined as those intended for the safe and effective treatment or prevention of rare diseases that affect fewer than 200,000 people in the U.S. Orphan designation qualifies the sponsor of the product for important tax credits, elimination of FDA license application fees and certain marketing incentives.

About Hemophilia B

Hemophilia B (congenital factor IX deficiency) is characterized by deficient or defective factor IX and affects approximately 1 in 25,000 to 50,000 people. Hemophilia B is a congenital bleeding disorder characterized by prolonged or spontaneous bleeding, especially into the muscles, joints, or internal organs. Nearly all hemophilia B patients are male.

About CSL Behring

CSL Behring is a leader in the plasma protein therapeutics industry. Committed to saving lives and improving the quality of life for people with rare and serious diseases, the company manufactures and markets a range of plasma-derived and recombinant therapies worldwide.

CSL Behring therapies are used around the world to treat coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease, and neurological disorders in certain markets. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic disease of the newborn.

CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a global biopharmaceutical company and a member of the CSL Group of companies. The parent company, CSL Limited (ASX:CSL), is headquartered in Melbourne, Australia. For more information, visit http://www.cslbehring.com.

Baxter Provides Progress Update on Gene Therapy Program, Including Phase I/II Clinical Trial of BAX 335, Investigational Gene Therapy for Hemophilia B

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DEERFIELD, Ill., FEBRUARY 12, 2015 – Baxter International Inc. (NYSE:BAX) today provided an update on its gene therapy program, including progress on the Phase I/II open-label clinical trial assessing the safety and optimal dosing level of BAX 335, an investigational factor IX (FIX) gene therapy treatment for hemophilia B, during a sponsored symposium at the 8th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) in Helsinki, Finland.

The trial is assessing the safety of ascending doses of BAX 335 to determine the optimal single dose in up to 16 adult patients with hemophilia B at treatment centers in the United States. The primary endpoint is the safety of a single dose of BAX 335 administered intravenously. Secondary endpoints include evaluation of the optimal dose to achieve stable therapeutic plasma FIX activity, as well as pharmacokinetics and immune response to treatment.

As of the end of 2014, a total of six patients in three dosing cohorts have been treated in the trial with evidence of a dose-related response. No patients have developed FIX inhibitors to date. In the two highest dose cohorts, FIX activity levels around 10 percent or above have been observed in two patients, who also experienced no bleeding events. One of these patients showed elevated levels of liver enzymes indicative of an immune response, which is being treated with oral corticosteroids, per protocol. Immune responses have been reported in previous studies with gene therapy technology. Additional patients are being screened and more information on the trial is available at www.clinicaltrials.gov , by using Identifier #01687608.

“We continue to make steady progress in advancing our hemophilia B program with this technology and look forward to better understanding the applicability of this technology platform in hemophilia A patients as well,” said John Orloff, MD, vice president and global head of research and development at Baxter BioScience. “With the potential to redefine the treatment of hemophilia, this gene therapy technology is a central part of our R&D focus as we prepare to become an independent company this year,”

Patients with hemophilia B lack the ability to produce clotting factor IX and are treated with plasma-derived or recombinant factor IX today. BAX 335 is designed to provide a mechanism for the patient’s own liver to begin producing factor IX over an extended period following a single dose of the genetically engineered treatment.

In April 2014, Baxter announced the acquisition of Chatham Therapeutics, LLC, an affiliate of Asklepios BioPharmaceutical, Inc. (AskBio), and its developmental gene therapy programs. Chatham’s Biological Nano Particles (BNP), an advanced recombinant adeno-associated virus- (rAAV-) based gene therapy technology, has shown potential therapeutic benefit in early studies. In addition to the research in hemophilia B, Baxter is also advancing plans to evaluate the gene therapy technology in the treatment of hemophilia A.

About Hemophilia B
Hemophilia B is the second most common type of hemophilia (also known as Christmas disease) and is the result of insufficient amounts of clotting factor IX, a naturally occurring protein in blood that controls bleeding. Approximately 26,000 people worldwide, including more than 4,000 in the U.S., have been diagnosed with hemophilia B. Hemophilia B is often a debilitating, chronic disease with complications that include bleeding episodes, hemophilic arthropathy (bleeding into a joint) and hospitalization.

About Baxter in Hemophilia
Baxter has more than 60 years of scientific experience in supporting the treatment needs of patients with hemophilia and has introduced a number of therapeutic firsts. Baxter has the broadest portfolio of hemophilia treatments and is able to meet individualized patient therapeutic needs by providing a range of options at each treatment stage. The company’s work focuses on optimizing hemophilia care and improving the lives of people worldwide living with bleeding disorders.

About Baxter International Inc.
Baxter International Inc., through its subsidiaries, develops, manufactures and markets products that save and sustain the lives of people with hemophilia, immune disorders, cancer, infectious diseases, kidney disease, trauma and other chronic and acute medical conditions. As a global, diversified healthcare company, Baxter applies a unique combination of expertise in medical devices, pharmaceuticals and biotechnology to create products that advance patient care worldwide.

This release includes forward-looking statements concerning a Phase I/II open-label clinical trial of BAX 335, as well as plans to separate Baxter’s biopharmaceutical and medical products businesses and related research and development strategies. These statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those in the forward-looking statements: clinical trial results; satisfaction of regulatory and other requirements; actions of regulatory bodies and other governmental authorities; changes in laws and regulations; product quality or patient safety issues; and other risks identified in Baxter’s most recent filing on Form 10-K and other SEC filings, all of which are available on Baxter’s website.Baxter does not undertake to update its forward-looking statements.

For original press release, click here.

Weekly prophylaxis with nonacog beta pegol safe, effective for hemophilia B

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Collins PW. Blood. 2014;doi:10.1182/blood-2014-05-573055.

Nonacog beta pegol effectively treated bleeding episodes and was associated with low annualized bleeding rates in patients with hemophilia B, according to study results.

From www.healio.com October 31, 2014

Peter W. Collins, MD, of the Arthur Bloom Hemophilia Center at Cardiff University in the United Kingdom, and colleagues sought to evaluate the safety and efficacy of nonacog beta pegol (N9-GP, Novo Nordisk) — a recombinant glycoPEGylated Factor IX with an extended half-life — in 74 previously treated patients with hemophilia B.

Thirty patients received with 10 IU/kg weekly for 52 weeks, and 29 patients received 40 IU/kg weekly for 52 weeks. The other 15 patients received on-demand treatment for 28 weeks.

The mean number of exposure days was 54 days in the weekly prophylaxis arms and 14 days in the on-demand arm.

Fifty-five patients (74%) experienced a combined 345 bleeding episodes; of these, 202 occurred in the weekly prophylaxis arms and 143 occurred in the on-demand treatment arm. Most bleeding episodes (78.5%) occurred in joints. Researchers classified 65.8% episodes as spontaneous and 33.6% as traumatic.

Researchers calculated a 92.2% (95% CI, 86.9-95.4) success rate for treating bleeding episodes. A greater proportion of bleeding episodes resolved after one injection of nonacog beta pegol in the 40 IU/kg arm (98.6%) than in the 10 IU/kg arm (84.1%) and the on-demand treatment arm (83.9%).

Fifty-two percent of patients in the 40 IU/kg arm did not require treatment for any bleeding episodes, compared with 17% of patients in the 10 IU/kg arm and 7% of patients in the on-demand arm. The median annualized bleeding rate also was lower in the 40 IU/kg arm (1.04; interquartile range [IQR], 0-4) than in the 10 IU/kg arm (2.93; IQR, 0.99-6.02) and the on-demand arm (15.58; IQR, 9.56-26.47).

Researchers used the EuroQOL-5 Dimensions visual analogue scale to assess health-related quality of life in each study arm. Patients in the 40 IU/kg arm experienced the greatest improvements in quality of life, from a median score of 75 (range, 35-100) at baseline to 90 (range, 60-100) at the end of the trial.

Sixty patients (81%) experienced a combined 215 adverse events. The most commonly reported adverse events were nasopharyngitis (13.5%), influenza (10.8%) and upper respiratory tract infection (10.8%).

No patients developed an inhibitor, and researchers reported no deaths, thromboembolic events or allergic reactions related to treatment.

“Nonacog beta pegol was effective for the treatment of bleeding episodes in both prophylaxis and on-demand patients,” Collins and colleagues wrote. “Low bleeding rates were observed in patients on prophylaxis and are likely related to high trough levels due to the extended half-life of nonacog beta pegol. These data suggest that once-weekly prophylaxis with nonacog beta pegol may provide a new and safe alternative for the prevention and treatment of bleeding episodes in patients with Hemophilia B.”

Disclosure: The study was funded in part by Novo Nordisk A/S. The researchers report honoraria and research funding from, advisory/consultant roles with and employment with Baxter, Bayer, Biogen Idec, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Sanquin and Swedish Orphan Biovitrum.

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