Introduction: Alpha-Gal Syndrome

Alpha-gal syndrome (AGS) is an allergy to red meat and other products made from mammals. In addition to red meat allergy, AGS can also manifest as frequent and deadly-if-untreated anaphylactic reactions to a variety of foods.

AGS can result from being bitten by a lone star tick. The tick bite transmits alpha-gal, or galactose-alpha-1,3,-galactose—a sugar which is a disaccharide—into the body of the bitten person. In some people, alpha-gal triggers an immunoglobulin E (IgE) mediated immune system reaction that later results in allergic reactions, which can be severe, to red meat and certain products made from mammals.

Interestingly, AGS sufferers can also display allergic reactions to the cancer drug Erbitux—a monoclonal antibody epidermal growth factor receptor inhibitor indicated for metastatic colorectal cancer, metastatic non-small cell lung cancer, and head and neck cancer. The Mayo Clinic notes that there is “no treatment other than avoiding red meat and other products made from mammals.” A recent U.S. Food and Drug Administration (FDA) announcement may herald the beginning of a form of relief—and new therapies—for AGS sufferers.

Approval of Intentional Genomic Alternation in GalSafe® Pigs

The FDA recently announced it approved an intentional genomic alteration (IGA) in a line of domestic pigs—GalSafe pigs. The FDA notes that GalSafe pigs themselves “are not a drug and are not subject to FDA approval.” Rather, “the intentional genomic alteration (the pPL657 rDNA construct), which is contained in the GalSafe® pigs, is the regulated article subject to FDA approval.” GalSafe pigs have been genetically altered to eliminate alpha-gal on the surface of the pig’s cells. The agency’s approval represents the “first ever approval of an animal biotechnology product for both food and as a potential source for biomedical use...”

The proprietary name for the approved product is “pPL657 rDNA Construct in Domestic Pigs” which was approved under new animal drug application, or NADA, # 141-542. The FDA defines a new animal drug—in part—as “any drug intended for use in animals other than man, including any drug intended for use in animal feed but not including the animal feed...” Under the Federal Food, Drug and Cosmetic Act, a new animal drug may not be sold into interstate commerce unless it is the subject of an approved new animal drug application...“

GalSafe pigs “may potentially provide a source of porcine-based materials to produce human medical products that are free of detectable alpha-gal sugar.” The announcement states that GalSafe pigs could be used to produce heparin (a blood thinning drug) and that “[t]issues and organs from GalSafe pigs could potentially address the issue of immune rejection in patients receiving xenotransplants,” noting that “alpha-gal sugar is believed to be a cause of rejection in patients.”

Underlying Technology

The FDA’s freedom of information summary (the summary) accompanying the announcement is of interest for what it discloses as well as for the details it leaves out—a possible lesson for those considering filing Freedom of Information Act (FOIA) requests.

The summary notes that GalSafe pigs contain “an intentional genomic alteration (IGA) that was accomplished by inserting an additional piece of genetic material, known as recombinant DNA (rDNA) into their genome” and that “the pPL657 rDNA construct disrupts the glycoprotein glactosyltransferase alpha-1,3 (GGTA1) gene.” GGTA1 “normally codes for the enzyme that is responsible for the production of the alpha-gal sugar...”

More specifically, the summary recites:

• A targeting vector was generated that was comprised of the pPL657 rDNA construct and a vector backbone. The pPL657 rDNA construct which integrated into the genome consisted of the DNA sequence used to disrupt the GGTA1 gene and the sequence of the neomycin phosphotransferase (nptII) gene, an antimicrobial resistance marker. The presence of the nptII in the genome required a more thorough hazard analysis...DNA sequence analysis of the pPL657 rDNA construct showed that it was consistent with the intended design. The vector backbone consists of DNA sequences that were used to propagate the rDNA construct in the laboratory during the assembly process but which were not integrated into the animal’s genome, as confirmed by DNA sequence analysis.

Approval Considerations

In determining if the pPL657 rDNA construct was safe and effective, and therefore approvable as a new animal drug, the FDA examined:

1. Stable integration of the rDNA construct across multiple generations;
2. Stability of the pig genotype across multiple generations;
3. Enzyme-linked immunosorbent assay (ELISA), tissue histology, and flow cytometry studies which each independently validated undetectable endogenous alpha-gal sugar residues on food and biological derivatives from the pigs;
4. Human food safety for the general population;
5. Toxicology of the nptII gene in the pPL657 rDNA construct;
6. Potential microbial food safety issues which could arise from the nptII gene and its expressed protein (aminoglycoside-3’-phosphotransferase). This expressed protein, an enzyme, catalyzes the phosphorylation of aminoglycoside antimicrobial drugs, including neomycin, and confers resistance to those drugs in bacteria that contain the gene.

Labeling of Food Products

The summary notes that the “U.S. Department of Agriculture has regulatory oversight over the labeling and processing of food products” made from GalSafe pigs.

Patent Term Extension Considerations

Newly approved animal drugs that are first commercially marketed, if they meet all of the statutory requirements, may be eligible for patent term extension (PTE). PTE can, with certain limitations on patent claim scope, extend the life of a patent by up to five years. While we draw no conclusions on eligibility of the recently approved construct for PTE, we note that PTE for new animal drug recombinant DNA products can be idiosyncratic.

For example, under the patent term extension statute, products eligible for patent term extension include: “a new animal drug...which is not primarily manufactured using recombinant DNA, recombinant RNA, hybridoma technology, or other processes involving site specific genetic manipulation techniques...“ (Emphasis added.)

At the same time, however, the patent term extension statute also recites that patent term extension can apply “in the case of a patent which claims a method of manufacturing the product which primarily uses recombinant DNA technology in the manufacture of the product...” (Emphasis added.)

Conclusion

The FDA’s approval of the intentional genomic alteration (the pPL657 rDNA construct) opens the way for GalSafe pigs to be used as food, for tissue and organ transplant purposes, and to manufacture certain medications. The approval, which is characterized by the FDA as “a first-of-its-kind intentional genomic alteration (IGA) in a line of domestic pigs...which may be used for food or human therapeutics” is significant as an approval milestone, as well as for the potential unlocked by the approval.