Biopharmacetiucal Approval Trends in 2009 - Biotech approvals were up last year. Is it a sign of a new trend? - BioPharm International


Biopharmacetiucal Approval Trends in 2009
Biotech approvals were up last year. Is it a sign of a new trend?

BioPharm International
Volume 23, Issue 10


The remainder of the article focuses on the 14 products approved for the first time in 2009. This information was drawn from regulatory sources and the web sites of sponsoring companies.3,4 The remaining six products have been considered in previous articles.5–7 Antibodies represented the single largest product class, with six such products (Arzerra, Ilaris, Removab, Acterma, Simponi, and Stelara) gaining approval in 2009. Produced in Sp2/0, NS0, or Chinese hamster ovary (CHO) cell lines, all antibodies are engineered in some way—four are fully human, one is humanized, and one (Removab) is particularly noteworthy in that it is the first bispecific antibody approved for human use.


Removab (catumaxomab) was approved in the EU in April 2009 for the treatment of malignant ascites (fluid accumulation in the peritoneal cavity) in patients displaying EpCAM-positive carcinomas. It remains in clinical trials for the treatment of various additional cancers, both in the EU and US. It is the first bispecific antibody to come on the market, i.e., unlike nativea antibodies, its two antigen-binding regions differ, thereby allowing it to bind to two different antigens. The antibody was developed and is manufactured by Trion Pharma (Munich, Germany), with Fresenius Biotech (Graefelfing, Germany) holding marketing authorization. The antibody comprises a mouse kappa light chain, a rat lambda light chain, a mouse IgG2a heavy chain, and a rat IgG2b heavy chain. The antibody displays two different antigen-binding sites, a mouse-derived epithelial cell adhesion (EpCAM)-binding Fab region and a rat-derived CD3-binding Fab region. EpCAM is overexpressed on the majority of epithelial tumors and the bispecific nature of the antibody effectively brings CD3 expressing T lymphocytes into close proximity with tumor cells. Additionally, the Fc region of the antibody facilitates docking of various immune effector cells (e.g., phagocytes and natural killer cells) which, in combination with the T lymphocytes, can induce tumor cell destruction. The product is administered by intraperitoneal infusion using a constant infusion pump system and the dosing schedule normally entails four separate infusions over 10 days. The main clinical trial investigating safety and efficacy entailed treatment of 258 patients with the product in combination with drainage of fluid from the abdomen versus the use of drainage alone. The main endpoint was lifespan without the need for further drainage. For patients treated with Removab, this averaged at 46 days, as opposed to 11 days in the case of patients treated with drainage alone. The most common side effects noted included lymphopenia (low lymphocyte count), abdominal pain, and digestive upset.

Arzerra (ofatumumab) gained approval in the US and the EU for the treatment of patients with chronic lymphocytic leukemia (CLL), which is refractory to fludarabine (a nucleoside analog) and alemtuzumab (Genzyme's anti-CD52 MAb, Campath). CLL, the most common form of leukemia in the US and EU, is characterized by accumulation of abnormal B-lymphocytes. Its course is highly variable with some patients never requiring treatment. However, approximately one third of sufferers develop an aggressive form from onset, requiring immediate attention. Current and past treatments include the use of alkylating agents and nucleoside analogs, as well as antibodies targeting B-lymphocytes—Campath (alemtuzumab) and Rituxan (rituximab). Arzerra is a 149 kDa fully human (IgG) MAb, generated by transgenic mouse and hybridoma technology, and produced in an NS0 cell line. It targets the CD20 antigen, which is expressed on the surface of both normal and transformed B-lymphocytes, but not on hematopoietic stem cells. Binding of the antibody to the cell surface induces lysis, likely by triggering complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The product is administered by infusion, with a dosage schedule of 12 infusions over a period of 28 weeks. The main clinical study supporting its approval was one trial involving 154 CLL patients, with just over half of patients to other treatments responding to Arzerra. The most common side effects noted included respiratory tract infection, neutropenia, and anemia. Arzerra is manufactured by GlaxoSmithKline (London, UK).

Ilaris (canakinumab) is a recombinant, fully human IgG expressed in Sp2/0 cells with binding specificity for human interleukin-1α (IL-1α). It was approved in both the US and EU for the treatment of Cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in persons four years of age and older. Autoinflammatory syndromes are usually underlined by aberrant regulation of cytokine signaling. CAPS (including FCAS and MWS) encompass one such group of rare autoinflammatory conditions, representing a spectrum of one disease manifesting with varying degrees of severity. The conditions are linked to mutations in a gene coding for a protein known as cryopyrin, which plays a role in the generation of free biologically active interleukin-1α (IL-1α). As a result, overproduction of IL-1α occurs, driving inflammation. General features of these conditions include recurrent fevers, rash, and joint pain. The discovery of the molecular basis of this disease group suggested the blocking of IL-1α activity as a potential treatment. Some CAPS patients have thus been treated with Kineret (anakinra, an IL-1 receptor antagonist approved for the treatment of rheumatoid arthritis since 2001), although that product's short half-life necessitates daily injections. Arcalyst (rilonacept; a soluble IL-1α decoy receptor) was approved for the treatment of CAPS in 2008. The fusion product's antibody Fc portion confers on it an extended half-life, supporting once weekly injections. The cited advantages of Ilaris over other treatments include a treatment schedule of one subcutaneous injection every eight weeks, as well as the inclusion of children in the approved indication. The main clinical study included 35 adults and children with CAPS. None of the patients receiving Ilaris over a 24-week treatment period experienced a relapse of symptoms (a disease flare), whereas 81% of patients receiving a placebo did experience a recurrence of disease symptoms. The most common side effects noted included inflammation of the nose and throat, and vertigo, as well as a potential for an increased risk of serious infection. Ilaris is manufactured by Novartis (Basel, Switzerland).

RoActemra (tocilizumab) is a humanized, 149 kDa antibody that binds specifically to the interleukin 6 receptor, preventing binding of IL-6, and effectively inhibiting the biological activity of this pro-inflammatory cytokine. It gained approval in the EU in January 2009 (and has subsequently been approved in the US in 2010 under the tradename Actemra). It is indicated (either as a monotherapy or in conjunction with disease-modifying anti-rheumatic drugs, such as the antimetabolite methotrexate), for the treatment of rheumatoid arthritis in patients who have had an inadequate response to certain other drugs. It usually is administered once monthly by infusion over 60 minutes. Product safety and efficacy was established by five main studies collectively involving >4,000 patients with moderate to severe rheumatoid arthritis, with the main endpoint measured being a reduction in symptoms of 20% or more, measured using a standard scale for rheumatoid arthritis. When given as an add-on to treatment therapies to which the patient exhibited an inadequate response, administration of RoActemra was between 4 and 9 times more likely to achieve a reduction in measured symptoms when compared to the administration of placebo. The main side effect of note is an increased risk of serious infections. RoActemra is manufactured by Roche (Basel, Switzerland).

Simponi (golimumab) is a 145 kDa fully human (IgG) MAb, generated by transgenic mouse technology, and produced in Sp2/0 cells. It targets human TNF-α, binding to both the soluble and transmembrane forms of this pro-inflammatory cytokine. It is approved in both the US and EU for the treatment of rheumatoid and psoriatic arthritis, as well as ankylosing spondylitis (inflammation in the joints of the spine). Binding to TNF prevents the latter from binding to the TNA receptor, thereby inhibiting TNF activity. It displays a mode of action similar to previously approved anti-TNF biopharmaceuticals (Remicade, Enbrel, Humira, and Cimzia). The product is supplied in the form of prefilled pens and syringes, and is administered subcutaneously once monthly. Safety and efficacy were established by five randomized, double-blind trials involving >2,000 participants, and in all cases treatment with Simponi significantly reduced the incidence and severity of disease symptoms. The most common side effect noted was upper respiratory tract infections. Simponi is manufactured by Centocor Ortho Biotech (Horsham, PA).

Stelara (ustekinumab) is a 149 kDa fully human (IgG) MAb produced in Sp2/0 cells. It specifically binds the p40 subunit of IL-12 and IL-23. It was approved in both the EU and the US in 2009, and is indicated for the treatment of adults with moderate to severe plaque psoriasis under certain conditions. It is administered by subcutaneous injection every 12 weeks. Psoriasis is a relatively common chronic inflammatory skin condition, affecting up to 3% of the general population. It is underlined by migration and over-activation of T lymphocytes in the epidermis, a process that is fueled in part by IL-12 and IL-23. By binding to these interleukins, Stelera prevents them from triggering a biological response. Safety and efficacy were studied in two main randomized, double blind, placebo-controlled studies, involving almost 2,000 adults with moderate to severe psoriasis. The primary endpoint measured was the proportion of sufferers who displayed a minimum response rate (an improvement of at least 75% relative to baseline when using the psoriasis area and sensitivity index). Almost 70% of sufferers receiving Stelara achieved such a response after 12 weeks, as compared to 3% of those receiving a placebo. The main potential side effect is an increased risk of infection. The trials are ongoing and are scheduled to last for up to five years. Stelara is manufactured in the US by Centocor Ortho Biotech (Horsham, PA) and in Europe by Janssen-Cilag (Antwerp, Belgium).

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