Pfizer has signaled its intent to expand its already significant presence in messenger RNA (mRNA) by launching collaborations with four companies to develop more therapies and vaccines based on the technology.

The four collaborations include an up-to-$1.35 billion partnership with base editing developer Beam Therapeutics, alliances with Codex DNA and Acuitas Therapeutics, all announced Monday; and a third mRNA vaccine partnership with BioNTech, its partner in developing the blockbuster COVID-19 vaccine COMIRNATY®, announced last week.

Pfizer and Beam have inked a four-year research collaboration, with a possible one-year extension, designed to apply Beam’s in vivo delivery technologies toward base editing programs to develop three undisclosed targets for rare genetic diseases of the liver, muscle, and central nervous system. The technologies are intended to deliver base editors to target organs using mRNA and lipid nanoparticles (LNPs).

“At Pfizer, we believe in the powerful potential of mRNA and LNP technologies to address the greatest unmet needs for patients, as evidenced by the beneficial impact our mRNA/LNP-based COVID-19 vaccine is having on the pandemic,” Mikael Dolsten, MD, PhD, Pfizer’s CSO and president, worldwide research, development and medical, said in a statement.

“We have a strong history in developing gene replacement therapies for rare diseases, and we see this collaboration with Beam as an opportunity to advance the next generation of gene editing therapies—an exciting scientific frontier—potentially leading to transformation for people living with rare genetic diseases,” Dolsten added.

Under the terms of their collaboration agreement, Beam will conduct all research activities through development candidate selection for the three targets, which are not included in Beam’s existing programs.

Pfizer retains an exclusive option for worldwide licenses to each development candidate. For each option that Pfizer exercises, it will oversee all development activities, as well as potential regulatory approvals and commercialization, for that program.

At the end of Phase I/II studies, upon paying an unspecified option exercise fee, Beam has a right to opt into a global co-development and co-commercialization agreement focused on one program licensed under the collaboration. Under that agreement, Pfizer would shoulder 65% of development and commercialization costs and enjoy 65% of net profits, with the other 35% of both going to Beam.

“This collaboration will provide a unique opportunity to create potentially transformative base editing programs for indications with critical unmet needs, leveraging our proprietary base editing technology and expanding delivery capabilities,” Beam CEO John Evans stated. “We look forward to working together with Pfizer to advance these technologies and potentially expand our impact for people suffering from serious diseases.”

$300M upfront

Pfizer has agreed to pay Beam $300 million upfront. Should Pfizer exercise its opt-in license rights for all three targets, the pharma giant would pay Beam up to $1.05 billion in payments tied to achieving development, regulatory, and commercial milestones. Beam is also eligible to receive royalties on global net sales for each licensed program.

“Our initial impression is that the terms of the collaboration are favorable for Beam,” Rick Bienkowski, PhD, a vice president, equity research with SVB Leerink focused on genetic medicines, wrote today in a research note. “The buy-in of a large pharma partner reflects positively on Beam’s base editing technology, and the large upfront cash payment will reinforce Beam’s balance sheet with non-dilutive capital (to approximately $1.2B in pro forma cash and cash equivalents) while potential milestones and royalties can add longer-term value.”

“We believe this collaboration supports our core thesis that Beam’s base editing technology holds enormous scarcity value and will continue to enable partnerships under favorable terms for the company,” Bienkowski added.

Michael Yee, analyst with Jefferies, and four colleagues observed in a research note that Pfizer has become the first “big pharma” company to partner with a drug developer using a genome-editing approach.

“We understand [Pfizer] directly came to Beam and initiated discussions to partner single base pair editing programs,” Yee and colleagues wrote, adding that the Pfizer collaboration “adds early validation to Beam’s preclinical data and technology and potential over the next few years.”

They noted that the partnership can draw upon strengths that include:

  • Pfizer’s in vivo delivery expertise from its COVID-19 vaccine work and sizeable manufacturing capacity for LNP
  • Beam’s cash balance, which as a result of the Pfizer collaboration has grown to about $1.2 billion.
  • Beam’s proprietary LNP and new LNPs acquired with its up-to-$440 million purchase of Guide Therapeutics last year.

“Beam is working on new tissue-targeted LNPs to CNS and muscle and can leverage the investments from the [Pfizer] work into more programs Beam is working on coming down the pipe,” Yee and colleagues wrote.

Investors, however, seemed less wowed about the Pfizer collaborations, as the company’s share price inched up about 1% in trading Monday, to $56.24 from Friday’s close of $55.72. Beam shares dipped 2.7% to $68.46 from $70.36 on Friday.

Beam was founded in 2017 by Harvard University chemist David Liu, PhD, who developed the underlying technology behind base editing with research led by then-postdocs Alexis Komor, PhD, and Nicole Gaudelli, PhD.

Together with friends and colleagues Feng Zhang, PhD, and Keith Joung, MD, Liu co-founded Beam Therapeutics to commercialize base editing. Beam went public in 2020 through an initial public offering that ultimately raised $188.3 million in net proceeds.

“One and done” approach

Speaking on GEN’s Close to the Edge” video interview series last summer, Evans noted that the potential of base editing rested in its “one-and-done” approach to precision medicine. Last year, the company published promising results in The CRISPR Journal on a redesigned family of base editors to alter the single base mutated in sickle-cell disease.

Beam Therapeutics is one of three companies whose partnerships Pfizer announced Monday, coinciding with the start of the virtual J.P. Morgan 40th Healthcare Conference.

Pfizer has also agreed to access and further develop Codex DNA’s short oligo ligation assembly (SOLA) novel enzymatic DNA synthesis (EDS) technology for potential use by Pfizer in its mRNA-based vaccines and other biopharma products. Under a strategic collaboration and licensing agreement, Pfizer agreed to pay Codex DNA an undisclosed upfront payment, plus potentially more than $100 million in payments tied to achieving “near-term” technical milestones.

In partnering with Codex DNA, Pfizer reasons that Codex’s technology may reduce production time from several weeks to days by eliminating several front-end steps in the mRNA production process, namely by moving from biologic to synthetic DNA assembly.

San Diego-based Codex DNA is a synthetic biology company that went public in June 2021, raising $112.5 million in net proceeds through its IPO. The company’s products aim to enable researchers to rapidly, accurately, and reproducibly build or “write” high-quality synthetic DNA and mRNA that is ready to use in many downstream markets. Codex DNA markets the BioXp™ system, a fully automated benchtop end-to-end automated workstation designed to provide a turnkey, end-to-end solution for generating synthetic DNA and mRNA starting from DNA sequence.

Last year, Codex DNA was among “Up & Comers” highlighted in GEN’s A-List of Top 10 Synthetic Biology Companies.

Pfizer also entered into a development and option agreement with Acuitas Therapeutics granting the pharma giant an option to license, on a nonexclusive basis, Acuitas’ LNP technology for up to 10 targets for vaccine or therapeutic development. The value of the agreement and other financial terms were not disclosed.

Surmounting two challenges

Through their collaboration, Pfizer aims to surmount two challenges to mRNA use in drugs and vaccines. One is the difficulty mRNA has passing through the cell wall. Another is “naked” mRNA’s vulnerability to significant degradation or attack by the immune system before reaching desired cells. Pfizer and Acuitas assert that engineered LNPs allow more efficient intracellular delivery of mRNA vaccines and drugs to the cytoplasm.

Vancouver, BC-based Acuitas develops LNPs designed to protect mRNA and transport it into the cells of patients.

The collaborations with Beam, as well as the alliances with Codex DNA and Acuitas, come roughly a year after Pfizer joined BioNTech in launching COMIRNATY (also known as BNT162b2), which uses Acuitas’ LNP technology.

COMIRNATY generated a combined $24.277 billion in sales for Pfizer in direct sales and revenues from its alliance with BioNTech during the first three quarters of 2021. BioNTech reported another €13.303 billion ($15.067 billion) in COVID-19 vaccine revenues.

Pfizer has projected COMIRNATY revenues of approximately $36 billion in 2021, and about $29 billion for this year. BioNTech has forecast between €16 billion to €17 billion in revenues this year ($18 billion to $19 billion).

Last week, Pfizer and BioNTech signed a third mRNA vaccine collaboration by agreeing to accelerate the development of a first mRNA-based vaccine for the prevention of shingles (herpes zoster virus, or HZV)—two years after joining to develop COMIRNATY and four years after partnering on an influenza mRNA vaccine.

The companies have agreed to apply a proprietary antigen technology identified by Pfizer’s scientists and BioNTech’s proprietary mRNA platform technology used in the companies’ COVID-19 vaccine. Pfizer and BioNTech plan to launch clinical trials in the second half of this year, and have agreed to share development costs, as well as gross profits from commercialization.

Pfizer has agreed to pay BioNTech $225 million upfront, including $75 million cash and an equity investment of $150 million—while BioNTech agreed to pay Pfizer $25 million for use of its proprietary antigen technology. BioNTech is eligible to receive up to $200 million in regulatory and sales milestone payments.

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