Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

Adeline Siew, PhD

Eli Lilly reported that enzastaurin did not meet the primary endpoint in a Phase III study, which evaluated the agent as a monotherapy for the prevention of relapse in patients with diffuse large B-cell lymphoma (DLBCL). Clinical data showed that treatment with enzastaurin did not significantly increase disease-free survival compared to placebo. Safety data were consistent with previous studies, with no new safety findings. Lilly will present data from this study at an upcoming scientific meeting. 

Lilly has decided to stop development of enzastaurin. The company's investigational oral small molecule is a serine/threonine kinase inhibitor of the PKC beta and AKT pathways. Termination will result in a second-quarter charge to the company's R&D expenses of approximately $30 million. Lilly's previously-issued financial guidance for 2013 remains unchanged. 

"We are disappointed in the results that we're announcing today," said Richard Gaynor, M.D., vice president, product development and medical affairs for Lilly Oncology, in the company's 

. "However, our oncology pipeline is still one of the most robust across the industry containing more than 20 molecules, including two Phase III molecules in five different tumor types." 

Articles

Eli Lilly reported that enzastaurin did not meet the primary endpoint in a Phase III study, which evaluated the agent as a monotherapy for the prevention of relapse in patients with diffuse large B-cell lymphoma (DLBCL).

Lilly's Enzastaurin Disappoints in Phase III Trial

Amgen and Zhejiang Beta Pharma have signed an agreement to form a joint venture to commercialize Amgen's Vectibix (panitumumab) in the Chinese market. The aim is to quickly and efficiently deliver Vectibix to patients in China. Vectibix is a fully human anti-epidermal growth factor receptor (EGFR) antibody approved by FDA for the treatment of metastatic colorectal cancer. 

Founded in 2003, Zhejiang Beta Pharma is headquartered in Hang-Zhou with R&D operations in Beijing. It has fully integrated capabilities that include GMP manufacture, sales and marketing. Zhejiang Beta Pharma's expertise in the development and commercialization of molecularly targeted therapies as well as its oncology sales network in China will be of benefit to this joint venture. The company's capabilities complement Amgen's global expertise in the development and manufacturing of human therapeutics. 

The joint venture will be named Amgen-Beta Pharmaceuticals, with the Chinese partner owning 51% of the venture while Amgen keeps 49%. According to the 

, its establishment is subject to the satisfaction of certain closing conditions, including the approval of relevant government authorities in China. 

"This joint venture brings us one step closer to providing Chinese patients with Amgen's medicines and supports our strategy of expanding in key, fast-growing markets," said Anthony C. Hooper, executive vice president at Amgen, in a 

"Our partnership with Amgen will be of long-term strategic significance not only for Zhejiang Province, but also for the whole medical community in China," said Lieming Ding, chairman of Zhejiang Beta Pharma.  "We share Amgen's passion for developing molecularly targeted therapies for unmet medical needs, and are confident that together we can help many Chinese patients who suffer from colorectal cancer."  

Amgen and Zhejiang Beta Pharma have signed an agreement to form a joint venture to commercialize Amgen's Vectibix (panitumumab) in the Chinese market. The aim is to quickly and efficiently deliver Vectibix to patients in China. Vectibix is a fully human anti-epidermal growth factor receptor (EGFR) antibody approved by FDA for the treatment of metastatic colorectal cancer.

Amgen Forms New Joint Venture to Commercialize Vectibix in China

Takeda and US vaccines maker Inviragen jointly announced that they have entered into a definitive agreement for Takeda to acquire Inviragen for an upfront payment of US$35 million and future payments of up to US$215 million upon achievement of key commercial milestones, linked to the progress of clinical development. 

Inviragen is a privately-held biopharmaceutical company with headquarters in Fort Collins, CO, and facilities in Madison, WI as well as Singapore. The company’s expertise is in developing innovative vaccines for emerging infectious diseases, including dengue and hand, foot and mouth disease (HFMD). 

Inviragen’s lead candidate, DENVax, is a four-strain recombinant viral vaccine for the prevention of dengue infection. Phase II trials are currently being conducted to evaluate an administration schedule of two doses of DENVax over 90 days. Inviragen also has in its pipeline, a vaccine candidate to protect against hand, foot and mouth disease (HFMD) caused by enterovirus 71 (EV71), which has completed Phase I clinical testing, and a recombinant vaccine candidate against chikungunya, which is currently undergoing preclinical evaluation. 

The acquisition will not only expand Takeda’s vaccine pipeline but also enhance its core vaccine R&D capabilities with Inviragen’s vaccine development center in Singapore, a region where vaccines have the greatest impact. 

 "Takeda has taken another major step toward its goal of establishing a world-class global vaccine business by acquiring Inviragen and its advanced vaccine candidate against dengue, a serious mosquito-borne illness that threatens nearly half of the world’s population," said Rajeev Venkayya, M.D., executive vice president and head of Takeda’s vaccine business division in a 

. "Today’s announcement reinforces Takeda’s commitment to develop innovative vaccines to fight some of the world’s most important infectious diseases." 

 "The acquisition of Inviragen supports Takeda’s overall research and development programs, long-term growth strategy and commitment to improve health through innovation and new technology," said Tadataka Yamada, M.D., Takeda’s chief medical and scientific officer and member of the Takeda board of directors. "Coming less than a year after the acquisition of LigoCyte with the world’s leading norovirus vaccine candidate, this illustrates Takeda’s commitment to its global vaccine business and global public health."

Takeda will integrate the Inviragen team into the company’s vaccine business division. The deal is expected to close in the next few weeks, pending the satisfaction of customary closing conditions. 

Takeda and US vaccines maker Inviragen jointly announced that they have entered into a definitive agreement for Takeda to acquire Inviragen for an upfront payment of US$35 million and future payments of up to US$215 million upon achievement of key commercial milestones, linked to the progress of clinical development.

Takeda to Acquire Inviragen for up to $250 Million

In its commitment to transparency, GlaxoSmithKline (GSK) has outlined plans to share detailed data from its clinical trials. GSK is to establish a new 

 that will enable researchers to request access to anonymised patient level data. 

This move marks the first step towards the ultimate aim of the clinical research community developing a broader system where researchers can access data from clinical trials conducted by multiple organisations. It is hoped that data sharing in such a way will help advance scientific research, increase understanding of new and current medicines and ultimately improve patient care. 

Researchers will be able request access by providing a scientific protocol with a commitment to publish their findings. External independent experts appointed by GSK to advise on the development of the system will be the initial review panel, responsible for assessing research proposals made through the system.  Access to the data from GSK’s studies will be granted on a password protected website to protect research participants’ privacy and to ensure that the data are used for the approved scientific purpose.   

 "When people volunteer for clinical trials, they expect that the results will be used to help others. We are absolutely committed to sharing data so that researchers can examine the details more closely, do their own analyses and learn more about medicines and how they can best be used. Consistent with good scientific practice, researchers will be required to submit a research plan and to commit to transparency in the publication of their work, " said Patrick Vallance, GSK’s president of pharmaceuticals R&D, in a 

 "We are the first organisation to develop a system for sharing detailed clinical data in this way. Now we want to see this initiative transition to a broader independent model that brings together data from multiple organisations. We are keen for this to progress and hope such a system can be put in place by a third party in the public or charitable sector as soon as possible, " Vallance added.   

GSK has already begun discussions with interested parties to encourage the development of such a system. Studies will be listed on the online system once a medicine has been approved or terminated from development and the study has been accepted for publication. Studies that do not progress to publication will also be available.  Global studies conducted since 2007 have already been included in the system and those dating back to the formation of GSK in December 2000 will be added over the next two years. 

In its commitment to transparency, GlaxoSmithKline (GSK) has outlined plans to share detailed data from its clinical trials. GSK is to establish a new online system that will enable researchers to request access to anonymised patient level data.

GSK Announces Plans to Share Clinical Trial Data

Lyophilization, or freeze drying, is an important manufacturing step widely used to increase the stability of pharmaceutical and biological products. Developed during the 1940s, lyophilization produces a dry product that can be readily reconstituted to its original form by adding water when required (1). It prolongs product shelf life by inhibiting chemical, microbiological, and physical degradation pathways that occur in the presence of moisture, particularly where long periods of storage and transit prior to use are involved (1, 2).  

PHOTO 24/MARIA TOUTOUDAKI/GETTY IMAGES; DAN WARD			

The lyophilization process consists of three main stages—freezing (solidification), primary drying (ice sublimation), and secondary drying (moisture desorption)—and usually takes several days to complete. Multiple vials containing a liquid drug formulation are loaded on temperature-controlled shelves within a sterile chamber and cooled to low temperatures until completely solidified (2). After that, chamber pressure is reduced and shelf temperature is raised to remove the frozen solvent through sublimation. The remaining unfrozen solvent that is chemically bound to the solid product is removed by a desorption process (3). The drying process is concluded by stoppering the vials in the chamber, generally under a subambient pressure of inert gas. The final dry product, called a cake, usually occupies approx-imately the same volume as the initial liquid fill because of its high porosity (2). "To ensure that high quality products are consistently produced, it is crucial to be able to control and provide repeatability of the lyophilization cycles," says Joseph Brower, technology manager at IMA Life North America.

The freezing step is one of the most important steps in lyophilization because it determines the texture of the frozen material and consequently, the final morphological characteristics of the freeze-dried material and its biological activity stability (4). "Proper freezing creates the foundation for efficient and consistent freeze-drying cycles," says T.N. Thompson, president of Millrock Technology, a company that develops freeze drying/lyophilization systems for laboratory applications and cGMP production. 

The three steps in the freezing process are nucleation, crystallization of the freeze concentrate, and for the maximal freeze concentrate, either freeze separation in eutectic products or concentration in amorphous products. The parameters of the freezing protocol directly affect pore size distribution and pore connectivity of the porous network of the freeze-dried matrix. The ice-crystal morphology determines both mass and heat transfer rates through the dry layer and as a result, freezing parameters have a strong influence on the total duration of the primary and secondary drying steps (4).

During the freezing phase of a typical freeze-drying cycle, the nucleation process of which the first solid domains are formed occurs randomly in the vials. "In an uncontrolled environment, due to the lack of nucleation sites in pure systems, the formulation solution must be cooled down to temperatures that are significantly lower than the equilibrium freezing point (i.e., supercooled) to initialize formation of ice crystals," Brower explains. 

The contents of individual vials often nucleate or begin freezing over a broad range of temperatures, "usually spanning 10–15 °C below the formulation's thermo-dynamic freezing point in a laboratory freeze dryer and 20 °C or greater in a cGMP Class 100 production dryer," says Mark Shon, vice-president of sales and marketing at SP Scientific. This supercooling phenomenon creates significant vial-to-vial heterogeneity in the solid microstructure, which significantly affects the subsequent drying processes. "To accommodate this heterogeneity, today's best practice is to design lyophilization processes for the worst-case scenarios; however, this strategy can result in excessively long drying cycles, broad product specifications, longer process development times, and nonoptimal product preservation," comments Cheryl Thierfelder, Praxair's business development manager.

It has long been recognized that one of the most important goals during the freezing step of lyophilization is to produce a uniform batch, which is a challenge due to the stochastic nature of nucleation. The random nature of nucleation, however, makes it difficult to control the nucleation temperature and maintain it within the desirable supercooling range. 

The nucleation behavior can affect several lyophilization process steps and product attributes. "The implications of uncontrolled nucleation are several-fold," says Shon. "First, since every vial can nucleate at a slightly different time and temperature, true vial-to-vial uniformity is really not achievable. We have seen a vial nucleate at -7 °C and another vial (of the same type with the same product) nucleate an hour later at -18 °C. These vials are now very different. They will dry at different rates and have a different pore structure, different cake structure, and different specific surface area." 

Nucleation of freezing strongly influences the size of the resulting ice crystals. Studies have demonstrated that colder nucleation (i.e., higher degree of supercooling) generally produces smaller and more numerous ice crystals, which leave behind smaller pores upon sublimation in primary drying. "These smaller pores present a greater resistance to subsequent sublimation of the remaining ice. As a result, primary drying is slowed by cold nucleation temperatures," explains Thierfelder. "The longer cycles stemming from uncontrolled nucleation require increased investment in lyophilization capacity and higher operating costs. It also means greater risk as the product sits in a vulnerable multiday batch operation."

On the other hand, a lower degree of supercooling produces larger ice crystals that result in large pores during drying, reduced resistance to mass flow, and shorter drying times. "Studies have shown that primary drying times  were extended 1–3% for every 1 °C change in ice-nucleation temperature (5, 6). Therefore, by reducing the degree of supercooling from, for example, 15 °C to 5 °C for uncontrolled and controlled nucleation respectively, the primary drying time can potentially be decreased by 10–30%, which is significant given the fact that primary drying may take days," says Brower.

"Reduction in primary drying time is one of the significant benefits of controlled nucleation," Shon adds. "A number of research groups have reported as much as a 40% reduction in primary drying times (7–9). This can have a significant financial impact on production as throughput can be significantly increased without increasing the number of expensive production dryers."     Besides influencing the size of ice crystals, the nucleation behavior can also affect product yield in various ways. For example, previous research has shown that proteins tend to aggregate on the surface of ice (10–14). Colder nucleation tends to produce smaller ice crystals, which possess larger surface areas; therefore, colder nucleation creates increased aggregation stress on sensitive proteins. 

Another potential source of yield loss in lyophilization arises from vial cracking. "The exact mechanisms for vial cracking are not well understood, but the problem seems to occur when certain formulation components are improperly frozen into metastable states that rearrange upon heating in primary drying, and sometimes this rearrangement creates sufficient force to crack the glass container," Thierfelder explains. "The temperature at which nucleation occurs affects the kinetics of the freezing process and can influence vial-cracking phenomena." 

Uncontrolled nucleation can adversely affect product quality. "No matter how well engineered your process controls or how uniform your freeze-dryer's heat-transfer environment might be, vial-to-vial uniformity is impossible to achieve in the absence of controlled nucleation," Thierfelder notes. "The vials will nucleate at random temperatures and times, and therefore, have separate temperature histories, which will impart different properties to the freeze-dried product." Nucleation and freezing also affect the cosmetic properties of cakes with effects such as glazing, cake cracking, and stratification often resulting from problems during the freezing step. "Overall, it should be recognized that the traditional lack of control over nucleation behavior is poorly aligned with FDA's current emphasis on quality by design," Thierfelder adds. 

A successful lyophilization cycle is defined by dried products that are visually and functionally acceptable, and chemically and biologically stable, with a short reconstitution time. "Although ice nucleation is an important parameter for achieving homogeneous product and optimized cycles, there have been very few attempts to achieve it at a commercial scale until recently," observes Brower. The standard practice has been to use an annealing cycle, which involves raising the product tempe-rature after freezing to a temperature above glass transition, and then holding it. This method results in the formation of larger ice crystals at the expense of smaller ones, and helps minimize the variability in drying behavior (15). Brower, however, points out that the benefits of shorter drying times may be offset by the additional time required for the annealing cycle. Moreover, annealing fails to address the root cause of variable ice structure, which is the lack of a uniform ice-nucleation temperature, and can only help to mitigate a flawed condition (15).

Controlled ice nucleation involves cooling the entire batch of vials to a given selected temperature that is below the equilibrium freezing point but above the temperature at which spontaneous heterogeneous nucleation may occur (16). Nucleation is then induced by seeding the vials with ice crystals or by depressurizing the freeze-dryer chamber. 

Controlled nucleation makes it possible to achieve uniform ice-crystal formation within a vial as well as between vials in the same batch at a minimum degree of supercooling. "This means more consistent and larger ice crystal sizes resulting in the most open product structure and faster drying," says Brower. "It also allows faster reconstitution of the product prior to use."

The two main techniques for controlling nucleation are ice fog (e.g., Millrock's FreezeBooster nucleation technology and Linde's Veriseq nucleation technology) and depressurization (ControLyo technology, developed by Praxair). "The method of controlled nucleation, whether by injecting ice crystals or depressurization, has no material difference on the initial ice structure," says Thompson. "The key to successful crystal formation is a common starting point and the control of crystal growth after the nucleation event."

In the ice-fog technique, the vials are first cooled to the desired temperature below the equilibrium freezing point and the pressure is reduced to approximately 50 Torr. Cold nitrogen gas is then introduced (through a liquid nitrogen heat exchanger) into the chamber. The cold gas in the humid chamber forms an ice fog, which is forced into the vials to seed ice crystallization in the supercooled solution (16). In short, ice fog generates "seed" crystals that fall into the vials creating the "nucleus" around which ice crystals form during nucleation. 

On the other hand, the depressurization technique involves reducing the product temperature in all vials to a selected value, followed by pressurization of the freeze-dryer chamber with an inert gas such as nitrogen or argon. When thermal equilibrium has been achieved, the excess pressure is released rapidly (i.e., depressurization), causing ice crystals to form at the top of the solution and propagate throughout the vial within seconds (16). With this method, ice formation is induced at essentially the same time for all vials in the batch, in contrast to the ice-fog technique where the vials are nucleated within a minute or two. 

Thompson, however, points out that a consistent crystal structure in the vial and across the batch is not produced by merely controlling the shelf temperature at a specific ramp rate. "Controlled nucleation provides a method to create a consistent starting point for crystal formation, but by itself only provides moderate improvement of crystal structure. Controlled nucleation needs to be combined with controlled crystal formation to produce the most homogeneous and efficient crystal structure inside the vial and throughout the batch," Thompson explains. Once controlled nucleation has occurred, a method for measuring and controlling the crystal growth is needed.

Millrock's patented FreezeBooster controlled nucleation technology combined with the company's patent pending AccuFlux technology is an ice-fog approach that allows the crystal structure to be consistently created, monitored, and controlled. According to Thompson, the combined methods of FreezeBooster and AccuFlux produce a consistent and repeatable ice formation resulting in a highly uniform finished product with reduced primary drying times.

"To reduce drying times and produce a consistent product, control of the entire freezing process is required," explains Thompson. "Millrock's AccuFlux technology enables crystal growth to be monitored and controlled even though the temperature of the product is not changing. It provides the tool necessary to accurately and repeatedly transfer protocols from the laboratory to production. It also provides a tool for simulating production protocols in the laboratory, which is useful for determining production problems." 

The Veriseq nucleation technology, developed by Linde Gases in cooperation with IMA Life North America, offers a commercially viable technique for cryogenically generating a uniform dispersion of microscopic ice crystals as a result of contact between liquid nitrogen (produced from sterile-filtered gaseous nitrogen) and steam in a mixing device outside the lyophilization chamber. Upon introduction into precooled vials containing the product to be freeze dried, these ice-fog crystals serve as nucleation sites, which cause rapid and uniform nucleation of the product in a vial as well as between vials of the same batch at very low degrees of supercooling.

"A key challenge for the commercial implementation of Veriseq nucleation technology was to generate sufficient amount of ice-fog and ensure its penetration inside the vials given various lyophilizer volumes," observes Brower. "Efficient ice-fog generation and distribution were achieved using the ejector assembly, providing an extremely efficient way of quickly forming the ice fog and circulating it throughout the freeze chamber."

A recent case study involved the use of Veriseq nucleation technology on a product that required a long (120-hour) lyophilization cycle (17). Conservative cycle parameters had to be employed because of the thickness and concentration of the frozen material. Attempts to reduce cycle time by adding more heat to the process resulted in broken containers. By using Veriseq nucleation technology to increase the crystal size, it was possible to accelerate drying with no breakage and reduce cycle time to 80 hours (17).

For successful controlled nucleation, each vial of product must experience the same conditions at the same time. "ControLyo technology is based on pressure and each vial, regardless of shelf location or tray position, experiences exactly the same conditions at exactly the same time," says Thierfelder. "For this reason, ControLyo technology is successfully used from laboratory to manufacturing scale." 

ControLyo Nucleation On-Demand technology was developed by Praxair and licensed to SP Scientific exclusively for use on dryers with shelf areas of less than 1.0 m

  and nonexclusively on larger dryers. This technology allows users to select the temperature at which they want to nucleate. The selected temperature must be below the true freezing point of the product and above the temperature at which stochastic nucleation starts. Thierfelder explains that by selecting a temperature above the stochastic nucleation temperature, supercooling can be minimized, the freeze-drying chamber can remain warmer, and overall energy consumption and cycle time can be reduced. 

"SP Scientific introduced the Lyostar 3 pilot freeze dryer with ControLyo technology approximately three years ago. It was the first commercially available freeze dryer with the capability to control nucleation," says Shon. 

"ControLyo technology provides advantages in product quality and yield as well as in manufacturing cost and capacity," says Thierfelder. Benefits that have been observed include: 					

 Nucleation at warmer temperate creates larger ice crystals with reduced resistance to mass transfer and decreases drying time. Cycle time reductions of up to 40% have been reported (7–9).

Nucleation behavior can have a pronounced effect on the cosmetic quality and structure of the final freeze-dried product. Cake cosmetic defects such as cracks, stratification, glazing, and color heterogeneity in many cases owe their origin to problems in freezing. Controlled nucleation may be a useful tool for adjusting freezing behavior to optimize cake elegance.

 Larger ice crystals also result in lower overall ice crystal surface area. Protein aggregation (i.e., clumping of short strands of proteins) tends to occur on the surface of ice crystals and is synonymous with yield loss and potential adverse effects. ControLyo users have reported a reduction in protein aggregation (14). 

Some lyophilized products have an amorphous structure and some have a crystalline structure. Others, such as those formulated with mannitol, can freeze in either an amorphous or crystalline structure. Upon initial freezing, certain products with the ability to form amorphous or crystalline structures will orient in an amorphous structure. During an annealing cycle (i.e., freeze, warm, and refreeze), the product is forced into its crystalline structure. In the absence of annealing, some products may randomly transition during processing, resulting in vial cracking. Vial cracking is costly and disruptive. In general, it has been observed that cracking problems can be substantially mitigated using ControLyo technology to induce nucleation at warmer temperatures (18). 

"A number of studies have been conducted where we have scaled-up ControLyo technology to a production dryer," says Shon. "It does not require that the dryer be manufactured with the capability to perform the controlled nucleation." Shon explains that it is relatively easy to retrofit a commercial freeze dryer that has steam-in-place (SIP) capability with the manifolds and controls to do the pressurization/depressurization required for ControLyo technology. "In the largest scale-up study to date, we collaborated with Fresinius-Kabi and performed a retrofit on a 28-m

 production dryer (19). The dryer was fully loaded with 100 mL, 50 mL, 30 mL, and 20 mL vials with 5% mannitol solution. Nucleation was controlled and every vial was visually inspected to confirm complete nucleation. In total, 8701 vials were nucleated (19)." 

1. ABB website, "Freeze Drying in the Pharmaceutical Industry," 

4. A. Hottot, S. Vessot, and J. Andrieu, 

6. J.A. Searles, J. F. Carpenter, and T.W. Randolph, 

8. P. Startzel, M. Gieseler, and H. Gieseler, "Rational Freeze-Drying Cycle Optimization Using Two Innovative Technologies: SMART Freeze-Dryer and ControLyo Nucleation On-Demand," presentation at the Controlled Release Society Germany Local Chapter Meeting (Wuerzburg, Mar., 2012).

9. G.A. Sacha and R. Sever, "Controlled Nucleation in Lyophilization: The Effects on Lyophilization Time and Physical Appearance of Lyophilized Pharmaceutical Excipients," presentation at the CPPR Freeze Drying of Pharmaceuticals & Biologicals Conference (Breckenridge, CO, Aug., 2012). 

Lyophilization technologies for controlled nucleation.

Controlling Ice Nucleation During the Freezing Step of Lyophilization

 that FDA has approved Actemra (tocilizumab) for the treatment of polyarticular juvenile idiopathic arthritis (PJIA) in children aged two years and older. Actemra can be given as monotherapy or in combination with methotrexate. 

 This approval marks the second Actemra indication in children and is the first FDA approval for the treatment of PJIA in approximately five years. The expanded indication for Actemra was based on positive Phase III results of the CHERISH study in children with PJIA, which demonstrated that Actemra-treated patients experienced clinically meaningful improvement in signs and symptoms of PJIA.  

 PJIA is a form of juvenile idiopathic arthritis (JIA), characterised by inflammation in five or more joints, usually affecting the hands and feet. Approximately 100 in every 100,000 children suffer from JIA, with PJIA accounting for approximately 30%. 

 "Polyarticular juvenile idiopathic arthritis is a rare, debilitating condition in children that worsens over time," said Hal Barron, MD, chief medical officer and head of global product development, in a 

. "We are pleased to offer Actemra to doctors and parents of children aged two or older as an important medicine to help improve the signs and symptoms of this often painful disease." 

 Actemra is the first humanised interleukin-6 (IL-6) receptor antagonist approved for the treatment of adult patients with moderate to severe rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs). The clinical development program for RA included five Phase III clinical studies, which enrolled more than 4000 RA patients from 41 countries, including the US. Actemra is also approved for the treatment of active systemic juvenile idiopathic arthritis (SJIA). 

Genentech announced that FDA has approved Actemra (tocilizumab) for the treatment of polyarticular juvenile idiopathic arthritis (PJIA) in children aged two years and older.