SAN DIEGO—With plans to advance 10 drugs into the clinic over the next five years for a variety of disorders, Entos Pharmaceuticals didn’t want to depend on contract manufacturers for the drug substance it will need to deliver those candidates.

So, earlier this year the Canadian-based genetic medicine developer opened a Good Manufacturing Practice (GMP) facility in Carlsbad, CA, near its U.S. home base in San Diego.

The 20,000-square-foot GMP facility is designed to help Entos support IND-enabling studies and clinical trials for its broad pipeline of some 20 wholly owned and partnered programs.

“We wanted to be ready to provide clinical material for those studies through this facility,” Entos CEO John Lewis, PhD, told GEN in an interview at the Biotechnology Innovation Organization (BIO) International Convention, which is expected to draw some 20,000 people to the San Diego Convention Center.

Entos won’t disclose the cost of the Carlsbad facility but did say it has room for expansion. The GMP facility in Carlsbad is about 20 miles from Entos’ U.S. home base at 32,000 square feet at 3040 Science Park Road in San Diego, one of three buildings within The Muse at Torrey Pines, a three-building lab/office campus redeveloped by The RMR Group of Newton, MA.

“We have a single line now running beginning to end. We’re envisioning that we will not add fill-finish to this. We’ll finish in our commercial manufacturing facility,” Lewis said. “I think we have the capacity in this 20,000 square foot space to build at least three parallel lines.”

Entos bases 16 of its approximately 70 employees at the Carlsbad facility—a number that is expected to grow as the site adds capacity to carry out additional GMP manufacturing of DNA- and RNA-based drugs.

Carlsbad is one key component of an eventual global manufacturing strategy intended to address Entos’ need for manufacturing capacity. Another component will emerge when Entos builds a commercial manufacturing facility in Edmonton, Alberta, Canada, where the company is based. The project has won support from Alberta provincial officials, and Entos is hoping for a similar positive response from Canada’s federal government, Lewis said.

PLV drug delivery

Entos focuses on developing next-generation genetic medicines based on its Fusogenix proteolipid vehicle (PLV) drug delivery system, designed to enable the delivery of nucleic acids, intact and unmodified, directly into target cells through direct fusion. The company’s library of Fusogenix PLV formulations can deliver a wide variety of therapeutic nucleic acid types including gene therapy, mRNA, miRNA, RNAi, and CRISPR.

Fusogenix PLVs are formulated with fusion-associated small Transmembrane (FAST) proteins through a platform intended to combine the low-toxicity profile of neutral lipid formulations with the efficacy of the company’s fusogenic protein-mediated delivery technology.

Entos says its Fusogenix PLVs are safe and well tolerated at doses that far exceed standard human efficacious doses; and that the use of FAST proteins ensures highly efficient fusion and intracellular delivery of therapeutic nucleic acid payloads.

Entos’ pipeline includes Covigenix-VAX-001, a COVID-19 DNA vaccine targeting the Spike protein that completed Phase II. That vaccine is being developed by Entos subsidiary Aegis Life, launched in 2020 to develop a novel DNA vaccine differentiated from other SARS-CoV-2 vaccine approaches, using Fusogenix gene delivery technology.

In 2020, Entos selected two lead Covigenix candidates from its prototyping program launched at the onset of the COVID-19 pandemic, based on strong preclinical results demonstrating high immunogenicity, high levels of SARS-CoV-2 neutralizing antibodies, and the potential for no antibody-dependent enhancement (ADE).

It was COVID-19 that compelled Entos to do its own manufacturing since the company couldn’t find contract manufacturing organizations (CMOs) available to help it with its work on Covigenix.

“We had to develop that expertise and manufacturing in-house,” Lewis recalled. “Also, our platform is distinctly different on the manufacturing side because we’re incorporating protein into the formulation. Since we had already developed in-house expertise for manufacturing, but already optimized a pretty slick scalable manufacturing process, we thought it made more sense for us to have clinical grade manufacturing in-house as well.”

Storage, durability challenges

So where does Covigenix fit into a COVID-19 vaccine universe dominated by billion-dollar jabs like Pfizer/BioNTech’s Comirnaty® and Moderna’s Spikevax®—both of which have seen their sales plunge over the past year as demand has waned and new variants force development of new products?

“Obviously the RNA vaccines have been incredibly successful. They’re efficacious. But we see that there are challenges with this platform, with storage and stability. They require deep cold storage, which makes it more challenging to deliver to rural areas and in particularly lower middle-income countries. And we also see a potential issue with durability,” Lewis said. “We think the durability of the RNA vaccines could be improved, particularly in younger individuals.”

“A DNA-based vaccine like Covigenix should provide for greater price stability as well as longer durability given differences in the pharmacokinetics of DNA vs. RNA,” Lewis added.”

In addition to Covigenix-VAX-101, Aegis Life is developing Covigenix-VAX-002, a preclinical vaccine targeting multiple epitopes. VAX-002 is envisioned as a booster that will be headed into a Phase I/II clinical study in the next few weeks.

“The vaccine program will probably read out data in, I would say, mid third quarter,” Lewis said.

Entos is also partnering with OncoSenX in developing OSX-001, a gene therapy targeting cells that are transcriptionally active for p53, which has completed preclinical development.

OSX-001 anchors a group of oncology candidates that includes OSX-002, a preclinical immuno-oncology gene therapy also partnered with OncoSenX; an internal preclinical program targeting cancer metastasis; eight undisclosed cancer programs being pursued with an undisclosed partner; and an unspecified number of vaccines also being developed with an undisclosed partner.

Next clinical candidate

Entos’ probable next candidate to enter the clinic, Lewis said, will address a metabolic disorder—through a single shot gene therapy candidate being developed to treat lipid storage disease.

“The IND-enabling studies are happening now, and we should enter the clinic in about 18 months,” Lewis said.

Entos’ pipeline also features candidates for:

  • Age-related diseases: Entos is partnering with Oisín Biotechnologies to develop a preclinical senolytic therapeutic. Entos is also pursuing three undisclosed programs with an undisclosed partner.
  • Genetic diseases: Several undisclosed programs are being developed internally, Lewis said, though Entos has not offered details.
  • Neurological disorders: Entos said it continues to partner with Eli Lilly to develop candidates for “multiple” neurological indications. “We don’t have any specific dates for when they may hit the clinic, but we’re excited about how that project is going,” Lewis said.

The companies have not furnished specific updates since announcing their collaboration in 2022. Lilly paid Entos $50 million upfront and agreed to pay Entos up to $400 million tied to achieving developmental and commercial milestones, plus royalties upon successful development and commercialization of products.

“We see the opportunity for this kind of technology to be utilized in a wide variety of different gene therapies,” Lewis said. “We’re being strategic about where we go to clinic first because we want to establish safety both through local administration through a vaccine program and systemic administration through our metabolic disease.

“The intent is to be widely deployed in a lot of different fields,” he added.

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