Status: approved; marketed

Organizations involved:

Sigma-Tau Pharmaceuticals – Manuf.; R&D; Tech.; World mark.

Enzon, Inc. – R&D; Tech; Former

Research Corporation Technologies Inc. – Tech.

Oxis International Inc. – Tech.

Description: Adagen is an aqueous formulation of pegademase bovine or bovine (cow) adenosine deaminase (ADA) enzyme conjugated with polyethylene oxide (polyethylene glycol; PEG) polymer strands. ADA is a glycoprotein primarily consisting of acidic amino acids including galactoseamine and glucoseamine. The adenosine deaminase enzyme is obtained from calf intestine from an unspecified source(s), presumably from U.S. calves or calves from countries not experiencing outbreaks of BSE. Unconjugated ADA has a molecular weight of 32,500-33,000 Dalton (32.5-33 kDa), and an optimum pH of 6.3. Pegademase is produced by covalently coupling ADA enzyme to multiple strands of mono-meth-oxy--poly(ethylene glycol) with a molecular weight of ~5,000 (5 kDa), resulting in resulting in monomethoxypolyethylene glycol succinimidyl L-adenosine deaminase (pedademase). The PEG methoxy group reacts with the terminal amino group of lysine residues of ADA, resulting in covalent attachment of the PEG chains (pegylation). Coupling of ADA with PEG significantly increases the circulating half-life of the enzyme, reduces immunogenicity, and improves other pharmacodynamic properties. Pegylation of ADA increases the molecule’s circulating life to over six days, and masks the ADA to avoid immunogenic reactions.

Adagen was the first successful application of enzyme replacement therapy for an inherited disease.

Adagen is packaged in 15 mL single-use vials (in packages of 4). Each mL of Adagen contains pegademase bovine, 250 units; monobasic sodium phosphate, USP, 1.20 mg; dibasic sodium phosphate, USP, 5.58 mg; sodium chloride, USP, 8.50 mg; and Water for Injection, USP, q.s. to 10 mL. The product is stored at 2-8˚C (refrigerated).

Nomenclature: Adenosine Deaminase, PEG- [BIO]; Adagen Injection [TR]; pegademase bovine [FDA USAN]; deaminase, adenosine, cattle, reaction product with succinic anhydride, esters with polyethylene glycol mon-methyl ether [CAS]; 9026-93-1 [CAS RN]; PEG-- adenosine deaminase [SY]; adenosine deaminase, mono-methoxypolyethylene glycol suc-cinimidyl L- [SY]; EC 3.5.4.4 [EC]

Biological.: Adenosine deaminase (ADA) is a catabolic glycoprotein enzyme ubiquitous in mammalian tissue. ADA catalyzes deamination of adenosine and 2’-deoxyadenosine to inosine and 2-deoxyinosine, respectively, plus ammonia, i.e., Adenosine + H2O –> Inosine + NH3. One unit of ADA converts one micromole (1 µM) of adenosine to inosine per minute at 25˚C, pH of 7.4 (see Clin. Chim. Acta, vol. 75, p. 75, 1973).

ADA is required for proper functioning of the immune system, including both B- and T-lymphocytes (B- and T-cells). Adagen enzyme replacement therapy for ADA deficiency-type severe combined immunodeficiency (SCID), an inherited disease, provides a life-saving alternative for patients for whom compatible bone marrow transplant is not available, and for patients too ill or at too high risk to undergo bone marrow transplantation. Untreated, ADA-deficient children generally die before age two. With Adagen treatment, ADA-deficient SCID patients can lead normal, active lives. SCID patients who are unable to receive successful bone marrow transplants are expected to require Adagen injections for the rest of their lives.

The ADA enzyme functionality of Adagen replaces missing levels of endogenous ADA, leading to increased production of T- and B-cells and increased immunity, including increased resistance to opportunistic infections. Injections of unmodified bovine ADA are not effective for treatment, because of the unmodified enzyme’s short circulating life (less than 30 minutes), there is a danger of immunogenic reactions to the bovine-sourced enzyme, and almost daily injections are required.

Enzon Inc.’s proprietary PEG Modification or PEG Process involves pegylation or the chemically attachment of PEG strand(s) to proteins (or other therapeutic compounds), generally those that are difficult to deliver and/or induce immune responses. Advantages of a pegylated protein, compared to the unconjugated protein, can include: (i) extended circulating life, (ii) reduced incidence of allergic reactions, (iii) reduced dosages with corresponding lower toxicity without diminished efficacy, (iv) increased agent stability, and (v) enhanced drug solubility. PEG, itself, is a relatively non-reactive and non-toxic polymer that has been designated by FDA as a GRAS (Generally Regarded As Safe) compound and is widely used in food and drug products.

Attachment of PEG side chains covers up or disguises the protein and reduces its recognition by the immune system, thereby generally lowering potential immunogenicity. PEG side chains sterically hinders the recognition of antigenic determinants, while generally maintaining activity of the attached protein. PEG strands essentially cover up or disguise the protein, reducing access by proteolytic enzymes, significantly slowing in vivo metabolism and clearance of the active enzyme, and reduce recognition by the immune system. Pegylation also increases the molecular size of the protein so that it is not as easily cleared through glomerular filtration (removed for excretion by the kidneys), leading to a longer circulating half-life.

Companies.: Adagen was developed and is manufactured and marketed by Enzon, Inc., CBER/FDA est. no. 1171. The product was originally manufactured at the company’s South Plainfield, NJ, facilities. In Feb. 2007, Enzon announced plans to consolidate its manufacturing operations in Indianapolis, IN, and the discontinuation of all manufacturing at its South Plainfield, NJ, facility.

Unmodified bovine ADA enzyme for Adagen is manufactured and purchased from an undisclosed company through a supply contract.

In Nov. 2009, Enzon divested its specialty non-recombinant specialty products (Oncaspar, Adagen, DepoCyt, and Abelcet) to Sigma-Tau Pharmaceuticals, sigma-tau Group. Enzon receive potential milestone payments of up to $27 million and royalties of 5%-10% on incremental net sales above a 2009 baseline amount from these products through 2014.

FDA class: Drug NDA

Approvals: Date = 19900321, first approval, NDA; orphan designation (expired 3/1997))

Indications: [full text of the "INDICATIONS AND USAGE” section from product insert/labeling]:

ADAGEN (pegademinase bovine) injection is indicated for enzyme replacement therapy for adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency (SCID) who are not suitable candidates for – or have failed – bone marrow transplantation. ADAGEN (pegademinase bovine) injection is recommended for use in infants from birth or in children at any age at the time of diagnosis. ADAGEN (pegade-mi-nase bovine) injection is not intended as a replacement for HLA identical bone marrow transplant therapy. ADAGEN (pegademinase bovine) injection is also not intended to replace continued medical supervision and the initiation of appropriate diagnostic tests and therapy (e.g., antibiotics, nutrition, oxygen, gamma-globulin) as indicated for intercurrent illnesses.

Status: Adagen is approved in various countries worldwide, and is available on a named patient (compassionate use) basis in various European and many other countries where it has not received full approval (including where the market is too small to justify seeking formal approval). There has been no centralized EU approval.

Tech. transfer: PEG conjugation technology for Adagen was exclusively licensed by Enzon from Research Corporation Technologies (RCT), including U.S. patent 4,179,337 (cited on the product insert/labeling). Enzon has developed considerable intellectual property and proprietary knowledge that goes beyond the technology licensed from RCT.

Enzon received a nonexclusive license from Oxis International Inc. in August 1997 for use of four U.S. pegylation patents – U.S. 5,006,333; 5,080,891; 5,283,317; and 5,648,478. These patents concern linkage of low molecular weight forms of PEG to proteins and peptides. Oxis received an up-front payment, and receives maintenance, (sub)licensing fees, and unspecified royalties.

Enzon also markets another product using this earlier or 1st-generation, straight chain (non-branched) PEG technology – PEG-asparaginase (Oncaspar). A different, 2nd-generation, branched chain, pegylation technology from Enzon is used for peginterferon alfa-2b (PEG-Intron) from Schering-Plough Corp., and other pegylation technology is used for peginterferon alfa-2a (Pegasys) from Hoffmann-La Roche. Enzon does not foresee its first-generation PEG Process being used for development of new products.

Disease: Adagen is used as an enzyme replacement therapy for a ADA-deficiency type Severe Combined Immunodeficiency Disease (SCID), commonly known as “Bubble Boy” disease (since severe patients are sometimes restricted to hospitalization and living within a plastic isolation bubble or tent). SCID is a rare genetic (inherited) disease due to an inborn error in purine metabolism that causes a severe or total failure of the immune system. One type of SCID is caused by a deficiency of functional adenosine deaminase (ADA) enzyme. SCID results in children being born without fully functioning immune systems, leaving them susceptible to a wide range of infectious diseases. Children with SCID are unprotected from even the most minor infections, and must often be hospitalized and isolated for their own survival. ADA-deficient SCID occurs in about one-third of all SCID patients, and is estimated to occur in less than one in one million births, i.e., it is very much an orphan disease.

Medical: Adagen is generally administered on a bi-weekly or weekly basis. ADA deficiency-type SCID patients generally receive Adagen for the rest of their lives (unless they receive a successful bone marrow transplant).

Currently, bone marrow transplantation from an HLA-identical sibling donor is the first-line treatment of choice for ADA-deficient SCID. Prior to Adagen, the only treatments for ADA-deficient SCID involved either a bone marrow transplant to replace the marrow that produces white blood cells that, in turn, produce ADA, or monthly infusions of red blood cells (erythrocytes). However, a bone marrow transplant may not always be effective. Adagen has been shown to be safer and more effective than monthly red blood cell transfusions. Unmodified ADA enzyme is not an alternative, since it is quickly metabolized, making almost daily injections necessary, and may induce immunological rejection of the bovine enzyme.

Adagen is administered to patients undergoing experimental gene therapies to correct ADA-deficient SCID.

Market: Total Adagen sales were $25.3 in 2006, $20.4 million in 2005, and $17.1 million in 2004 (fiscal year ending June 30). Sales appear to be rather steady with slow growth, e.g., Adagen sales in the fiscal year 1999 were $11.25 million.

Adagen is very much an orphan product. Less than 100 patients worldwide at any time receive Adagen.

The 2007 Average Wholesale Price (AWP) is $3,050.00/1.5 mL, 250 U/mL vial ($2,940.00 in 2005; $2,600.00 in 2004) (Red Book, 2007).

The average annual cost for treatment is reported to be about $130,000/year (a low-end estimate)

Adagen is reimbursed by private insurance payers, including HMOs and state and federal medical assistance programs. Enzon reports that payment for Adagen has never been refused. Enzon has retained Reimbursement Dynamics, Inc. to work directly with patients’ insurers to maximize coverage and reimbursement for Adagen.

R&D: Researchers at NIH are developing and testing a gene therapy for treatment of ADA-deficient SCID. To date, treated patients have not been able to halt Adagen treatment, and the trials have been inconclusive.