Sangamo Therapeutics will partner with Pfizer to develop a potential gene therapy to treat amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) linked to mutations of the C9ORF72 gene, the companies said today.

The collaboration could yield up to $162 million-plus for Sangamo, which would contribute its zinc finger protein transcription factors (ZFP-TFs) technology to the partnership.

The companies are seeking to address part of a spectrum of neurodegenerative disorders caused by mutations in the C9ORF72 gene that involve hundreds of additional repetitions of a six-base pair sequence of DNA. The mutations ultimately lead to the deterioration of motor neurons in the case of ALS, or neurons in the frontal and temporal lobes in the case of FTLD.

The C9ORF72 mutation is linked to approximately one-third of cases of familial ALS, according to Sangamo and Pfizer.

Sangamo's ZFP-TF technology involves introducing an engineered ZFP designed to identify and bind to a precise sequence of DNA. Once bound to the target sequence of DNA, a transcriptional repressor domain attached to the ZFP suppresses expression of the gene.

Through their collaboration, Sangamo and Pfizer have agreed to investigate allele-specific ZFP-TFs with the potential to differentiate the mutant C9ORF72 allele from the wild-type allele, as well as to specifically downregulate expression of the mutant form of the gene.

The new gene therapy collaboration is the second for Sangamo and Pfizer. Last year, the companies signed an exclusive global collaboration and license agreement to develop and commercialize gene therapy programs for hemophilia A—including SB-525, one of Sangamo’s four lead product candidates, which is under study in a Phase I/II trial launched in August after the FDA granted Orphan Drug designation and cleared the gene therapy for clinical trials. The clinical trial has enrolled its second patient in the last few months, the companies said.

SB-525 uses a recombinant adeno-associated virus (rAAV) to deliver a human Factor VIII cDNA construct and proprietary synthetic liver-specific promoter to the nucleus of liver cells with a single infusion. The therapy is being investigated as a single-treatment strategy intended to provide continuous, therapeutic expression of Factor VIII protein.

“Precision and Flexibility”

“The precision and flexibility of zinc finger proteins enables targeting of virtually any genetic mutation. Collaboration with the right partner for a given therapeutic application is a key component of our corporate strategy and enables us to pursue the vast opportunity set of our platform,” Sangamo CEO Sandy Macrae, M.B., Ch.B., Ph.D., said in a statement.

Pfizer is one of three biopharmas with which Sangamo has partnered on development of ZFP-TFs for central nervous system (CNS) diseases; the others are Shire, with which Sangamo is collaborating in Huntington's disease, and Bioverativ, which is teaming up with Sangamo in hemoglobinopathies, including beta thalassemia and sickle cell disease.

Sangamo’s other lead candidates are also in Phase I/II studies that have recently recruited patients, including:

  • SB-FIX for hemophilia B, which uses ZFN-mediated in vivo genome editing to place a normal functioning copy of the Factor IX gene under the control of the strong albumin promoter in the patient’s liver;
  • SB-318 for mucopolysaccharidosis type I (MPS I; Scheie, Hurler-Scheie, and Hurler syndromes), which uses ZFN-mediated in vivo genome editing to place a normal functioning copy of the IDUA (alpha-L-iduronidase) gene under the control of the strong albumin promoter in the patient’s liver;
  • SB-913 in mucopolysaccharidosis type II (MPS II; Hunter syndrome), which uses ZFN-mediated in vivo genome editing to place a normal functioning copy of the IDS (iduronate 2-sulfatase) gene under the control of the strong albumin promoter in the patient’s liver.

Separately, Sangamo is developing ZFP-TFs to downregulate the expression of tau, a protein associated with Alzheimer's disease and frontotemporal dementia (FTD). Sangamo has said its strategy for the tau program is to seek a development and commercialization partner upon completion of preclinical studies.

Tweaking Development Process

Sangamo, which has studied zinc finger nucleases for two decades, is the primary patent holder for the technology. In recent years, Sangamo has tweaked its process to shorten its development timeline for zinc finger nucleases and make it less laborious—helping address a key criticism of the technology that it requires far more time and skill to develop a high-quality gene-snipping product compared with CRISPR.

Edward Rebar, Ph.D., vice president of technology at Sangamo, told GEN recently that while lead development cycle times could run up to three months, and the total time to identify the final therapeutic ZFN would typically take a year, current lead development cycles have been shortened to as few as 10 days, during which constructs are designed, assembled, and tested in cells. The total time required to produce a final therapeutic ZFN has been shortened to three months, he added.

According to a Sangamo regulatory filing, Pfizer has agreed to pay Sangamo $12 million upfront; up to $60 million if a licensed product achieves specified preclinical development, clinical development, and first commercial sale milestones; and up to $90 million if annual worldwide net sales of licensed products reach specified levels.

Pfizer also agreed to pay Sangamo royalties that will be an escalating tiered, mid- to high-single-digit percentage of the annual worldwide net sales of licensed products—subject to reduction due to patent expiration, entry of biosimilar products to the market, and payments made under certain licenses for third party intellectual property.

Each company has agreed to oversee the cost of its performance of the research program, with Pfizer to be operationally and financially responsible for subsequent development, manufacturing, and commercialization of licensed products.

The companies’ collaboration will terminate “if Sangamo’s work under the research program does not result in the identification of any ZFP-TFs that satisfy preagreed criteria by a specified date, or if Pfizer does not conduct certain preclinical testing by a specified date,” the Sangamo filing stated, without disclosing dates.

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