Development of Glatopa® (Glatiramer Acetate): The First FDA-Approved Generic Disease-Modifying Therapy for Relapsing Forms of Multiple Sclerosis.

The multiple sclerosis (MS) treatment landscape in the United States has changed dramatically over the past decade. While many disease-modifying therapies (DMTs) have been approved by the US Food and Drug Administration (FDA) for the treatment of relapsing forms of MS, DMT costs continue to rise. The availability of generics and biosimilars in the MS-treatment landscape is unlikely to have a major impact on clinical benefit. However, their availability will provide alternative treatment options and potentially lower costs through competition, thus increasing the affordability of and access to these drugs. In April 2015, the first generic version of the complex drug glatiramer acetate (Glatopa® 20 mg/mL) injection was approved in the United States as a fully substitutable generic for all approved indications of the 20 mg/mL branded glatiramer acetate (Copaxone®) dosage form. Despite glatiramer acetate's complex nature-being a chemically synthesized (ie, nonbiologic) mixture of peptides-the approval occurred without conducting any clinical trials. Rather, extensive structural and functional characterization was performed to demonstrate therapeutic equivalence to the innovator drug. The approval of Glatopa signifies an important milestone in the US MS-treatment landscape, with the hope that the introduction of generic DMTs and eventually biosimilar DMTs will lead to future improvements in the affordability and access of these much-needed treatments for MS.

Demonstration of equivalence of a generic glatiramer acetate (Glatopa™).

Glatiramer acetate (GA) has been available under the brand name Copaxone® for nearly two decades. Recently, the US Food and Drug Administration (FDA) approved the first generic GA, Glatopa™, as fully substitutable for all indications for which Copaxone 20mg is approved; Glatopa also represents the first FDA-approved "AP-rated," substitutable generic for treating patients with MS. Glatiramer acetate is a complex mixture of polypeptides and, consequently, its characterization presented challenges not generally encountered in drug development. Despite its complexity, and without requiring any clinical data, approval was accomplished through an Abbreviated New Drug Application in which equivalence to Copaxone was evaluated across four criteria: starting materials and basic chemistry; structural signatures for polymerization, depolymerization, and purification; physicochemical properties; and biological and immunological properties. This article describes the rigorous overall scientific approach used to successfully establish equivalence between Glatopa and Copaxone, and presents key representative data from several of the comprehensive sets of physicochemical (structural) and biological (functional) assays that were conducted.

Structural Aspects of Rubidium Ion Selectivity by Tribenzo-21-crown-7(1)(a).

The structural origins of the selectivity of rubidium ion over other alkali metal ions by tribenzo-21-crown-7 is investigated from single-crystal X-ray diffraction: data for Cs(tribenzo-21-crown-7)(NO(3)), monoclinic, P2(1)/c, a = 9.598(2) Å, b = 23.466(3) Å, c = 23.973(5) Å, beta = 93.31(1) degrees, V = 5390(2) Å(3), Z = 8; data for [Rb(4,4'-bis-tert-butylbenzo,benzo-21-crown-7)(dioxane)(1.5)(H(2)O)(0.18)][Cl].(dioxane)1.82(H(2)O), triclinic, P&onemacr;, a = 11.687(3) Å, b = 12.800(4) Å, c = 17.680(3) Å, alpha = 75.31(2) degrees, beta = 80.01(2) degrees, gamma = 69.09(2) degrees, V = 2379.8(10) Å(3), Z = 2; data for Na(4,4'-bis-tert-butylbenzo,benzo-21-crown-7)ReO(4).0.5(i-PrOH), monoclinic, P2(1)/c, a = 24.300(5) Å, b = 14.066(3) Å, c = 22.676(5) Å, beta = 108.06(3) degrees, V = 7369(3) Å(3), Z = 8; data for and 4,4'-bis-tert-butylbenzo,benzo-21-crown-7, monoclinic, P2(1)/n, a = 16.427(2) Å, b = 11.3675(9) Å, c = 33.137(3) Å, beta = 94.469(8) degrees, V = 6169.0(10) Å(3), Z = 8. The structures reported here are the first reported for a tribenzo-21-crown-7, and the alkali metal ion complexes are the first reported structures of these ions with any 21-crown-7 ether. Different crown conformations are observed for each structure. Molecular mechanics calculations were performed on all conformers, and the results are related to the observed extraction selectivity for rubidium.

Radiolabeled divalent peptidomimetic vitronectin receptor antagonists as potential tumor radiotherapeutic and imaging agents.

The integrin receptor alphavbeta3 is overexpressed on the endothelial cells of growing tumors and on some tumor cells themselves. A radiolabeled alphavbeta3 antagonists belonging to the quinolin-4-one class of peptidomimetics (TA138) was previously shown to exhibit high affinity for integrin alphavbeta3 and high selectivity versus other integrin receptors. 111In-TA138 exhibited high tumor uptake in the c-neu Oncomouse mammary adenocarcinoma model and produced excellent scintigraphic images. This study describes the synthesis of eight divalent versions of TA138 and their evaluation as potential tumor radiotherapeutic agents. The two main variables in this study were the length of the spacer bridging the biotargeting moieties and the total negative charge of the molecules imparted by the cysteic acid pharmacokinetic modifiers. Receptor affinity was evaluated in a panel of integrin receptor affinity assays, and biodistribution studies using the 111In-labeled derivatives were carried out in the c-neu Oncomouse model. All divalent agents maintained the high receptor affinity and selectivity of TA138, and six of the eight 111In derivatives exhibited blood clearance that was faster than 111In-TA138 at 24 h postinjection (PI). All divalent agents exhibited tumor uptake and retention at 24 h PI that was higher than 111In-TA138. Tumor/organ ratios were improved for most of the divalent agents at 24 h PI in critical nontarget organs marrow, kidney, and liver, with the agents having intermediate-length spacers (29-43 A) showing the largest improvement. As an example, 111In-15 showed tumor uptake of 14.3% ID/g at 24 h PI and tumor/organ ratios as follows: marrow, 3.24; kidney, 7.29; liver, 8.51. A comparison of therapeutic indices for 90Y-TA138 and 177Lu-15 indicate an improved therapeutic index for the divalent agent. The implications for radiotherapeutic applications and the mechanism of this multivalent effect are discussed.