Merck KGaA has advanced further into gene editing-based drug development with its deal this week that outlicenses to Vertex Pharmaceuticals a pair of DNA-dependent protein kinase (DNA-PK) inhibitors—one clinical, the other preclinical—for use in gene editing applications in six genetic disease indications.

The licensing agreement, whose value was not disclosed, covers M9831 (formerly VX-984) and an additional preclinical compound—two of four compounds that Merck KGaA licensed from Vertex in 2017 for $230 million upfront.

At the time, Merck KGaA said it took on the programs in order to strengthen its own existing oncology pipeline in the fields of DNA damage and repair and immuno-oncology.

M9831 and the preclinical compound are now part of Merck KGaA’s portfolio of DNA Damage Response (DDR) inhibitors. M9831 was the subject of a Phase I clinical trial (NCT02644278) completed last year, a first-in-human study designed to assess the safety, tolerability, and pharmacokinetic/pharmacodynamic profile of the candidate in combination with pegylated liposomal doxorubicin (PLD) chemotherapy.

Merck KGaA said yesterday it is investigating four DDR molecules, including two ATR inhibitors, an ATM inhibitor, and an investigational small-molecule of DNA-PK.

The company reasons that DNA-PK could potentially enhance the efficacy of many commonly used DNA-damaging agents such as radiotherapy and chemotherapy. Merck KGaA also cited preclinical studies that it said showed DNA-PK inhibitors can enhance CRISPR/Cas9-mediated gene editing.

“We are rapidly advancing our leading-edge DDR portfolio in oncology and are delighted to see the potential benefit of DNA-PK in genetic diseases through the enhancement of CRISPR/Cas9-mediated gene editing,” Belén Garijo, member of the executive board and CEO Healthcare, Merck KGaA, said in a statement.

Merck KGaA did not detail the six indications covered by the latest deal with Vertex—but did disclose that they did not include cancer by stating that it retained rights to M9831 and the preclinical compound “in all other disease areas, including oncology, with the ability to develop both these compounds in-house, or to license them to future partners in the gene editing field.”

Latest foray into gene editing

The licensing deal with Vertex is Merck KGaA’s latest foray into gene editing with drug development in mind.

Last month, the company’s Life Sciences business had launched a strategic alliance with genOway by licensing to the French biotechnology exclusive rights to Merck KGaA’s foundational genome-editing patents to produce and sell rodent models designed to allow nonprofit and for-profit scientists to use Merck’s CRISPR/Cas9 technology.

Under that alliance, whose value was not disclosed, genOway also agreed to develop a network of sublicensees in both model creation-and-distribution and preclinical services for all potential applications worldwide, with a “strong” focus in the U.S., Asia, and Europe.

“We have together come up with the idea of using our CRISPR-Cas9 technology and our understanding of gene editing to develop rodent models that are even more indicative and more representative of humans. That motivated the deal,” Udit Batra, PhD, member of the executive board and CEO, Life Science business of Merck KGaA, told GEN earlier this month in San Francisco, where he was attending the recent J.P. Morgan Healthcare Conference.

“This will help us in the application of technology to develop an improve toxicology studies to get more and more medicines faster through the clinic. It’s an affirmation of our capabilities in gene editing,” Batra said.

He also articulated Merck KGaA’s areas of emphasis in gene editing via CRISPR-Cas9. They include developing more specific methods of cutting and replacing relevant parts of the genome while avoiding off-target impacts; and developing better cell lines that more closely mimic human cells for in vitro toxicology studies—for example, using gene editing to modify Madin-Darby Canine Kidney (MDCK) cells to look more like the human gut, or to enhance bioproduction.

The Life Science business of Merck KGaA, which operates as MilliporeSigma in the U.S. and Canada, has been granted CRISPR-related patents in Europe and in Australia, among other regions of the world, and has applications for patents in the U.S.

“Could be pretty interesting”

“If you think of the commercial value of gene editing, it comes from research licenses, and it comes from commercial licenses for therapeutic applications, which down the line could be pretty interesting,” Batra said.

He said Merck’s technology would be applicable as other Cas systems emerge. “You will need all of these in your armamentarium. There is a place for zinc fingers, there is a place for Cas9, there’s a place for the other Cas-es, as well as the technology develops.”

The latest licensing deal also deepens Vertex’ presence in gene-editing drug development. The company is partnering with CRISPR Therapeutics on CTX001, which is in development for both β-thalassemia and sickle cell disease.

As of Monday, the companies were recruiting patients for the first clinical trial of a CRISPR-based therapy sponsored by U.S. companies, a Phase I/II study (NCT03655678) designed to assess the safety and efficacy of the CRISPR-Cas9 modified CD34+ human hematopoietic stem and progenitor cells using CTX001 in transfusion dependent β-thalassemia.

On January 10, Vertex and CRISPR Therapeutics said the FDA had granted its Fast Track Designation for CTX001 for sickle cell disease—the subject of another Phase I/II trial by the companies (NCT03745287), which was recruiting patients as of January 18.