Helen Sabzevari, PhD, Precigen President and CEO

By Alex Philippidis

More than a century after the first reported case was published in 1817, E.V. Ullman first described the viral etiology of recurrent respiratory papillomatosis (RRP) in 1923 by successfully producing papilloma-like growths on his arm, and the arm of his assistant. To generate those growths, Ullman injected cell-free tissue extracts derived from a six-year-old boy’s laryngeal papilloma (LP), as RRP was then called.

In the 100 years that have followed, researchers have confirmed that the papillomas contain the DNA of human papillomavirus (HPV) and have conclusively linked HPV to both adult and juvenile onset LP, with HPV-6 and HPV-11 being the most commonly detected viruses.

Yet, the standard of care for RRP remains repeated surgeries. RRP still lacks an approved treatment—though a Germantown, MD, cell and gene therapy developer is one of at least two companies working to be first to bring such a therapy to market.

Precigen this week presented positive data from the Phase I portion of a first-in-human Phase I/II study (NCT04724980) of its lead pipeline candidate, PRGN-2012, in patients with severe RRP.

At the recommended Phase II dose of 5×1011 particle units, six of 12 patients (50%) receiving PRGN-2012 achieved a complete response by becoming “surgery-free,” no longer needing to be operated on for at least 12 months post-treatment. All complete responders continued to be surgery-free as of the data cutoff, ranging from 440 to 600 days depending on the patient.

The Phase I portion also showed that treatment with PRGN-2012 led to fewer surgeries in 10 out of 12 patients (83%) in the 12 months following treatment compared with the 12 months before, as the therapy induced robust de novo HPV-specific T-cell immune response in RRP patients. PRGN-2012 was well-tolerated with no dose-limiting toxicities and no treatment-related adverse events greater than Grade 2, Precigen researchers reported.

“These data demonstrate the overall favorable safety profile and significant clinical benefit of PRGN-2012 in adult patients with severe RRP,” researchers from Precigen and the NIH’s National Cancer Institute (NCI) concluded in the abstract, “Significant clinical benefit and enhanced T-cell responses with repeated administration of PRGN-2012, a novel gorilla adenoviral vector-based immunotherapy.”

Scott M. Norberg, DO, head of the solid tumor cellular therapy group and assistant research physician at the Center for Immuno-Oncology, within NCI’s Center for Cancer Research, presented the abstract Tuesday at the European Society of Gene & Cell Therapy (ESGTC) 30th Annual Congress in Brussels.

Precigen has completed enrollment in the 23-patient Phase II portion of the study of PRGN-2012, with complete data expected to be reported in the first half of 2024.

DNA plasmids vs. gorilla adenovectors

Precigen is one of at least two companies that are developing RRP therapies by cellular targeting. The other is Inovio Pharmaceuticals, which earlier this year completed a successful Phase I/II trial (NCT04398433) of INO-3107, its lead DNA medicine product candidate. Like PRGN-2012, INO-3107 is designed to treat RRP by eliciting a targeted T cell response against HPV-6 and HPV-11.

In Inovio’s Phase I/II trial, nine of 32 patients (28.1%) required no surgical intervention during or after the dosing window, while 26 of the 32 patients (81.3%) showed a decrease in surgical interventions in the year after INO-3107 administration compared to the prior year.

Inovio’s INO-3107 applies the company’s DNA medicines platform, consisting of precisely designed DNA plasmids, and an investigational delivery vehicle, the CELLECTRA® medical device. Inovio likens its DNA plasmids to software that the body’s cells can download to produce specific proteins to target and fight disease.

Precigen’s PRGN-2012, by contrast is a vaccine that applies an optimized antigen design based on the company’s gorilla adenovector technology. According to Precigen, gorilla adenovectors have numerous therapeutic advantages, including the ability for repeat administration, the inability to replicate in vivo, and the ability to deliver a large genetic payload.

Gorilla adenovectors are among adenoviral vectors designed to deliver vaccine antigens and therapeutic genes efficiently through the company’s AdenoVerse™ platform. PRGN-2012 is designed to elicit immune responses directed against cells infected with HPV type 6 (HPV 6) or HPV type 11 (HPV 11).

“The vectors deliver gorilla adenoviruses that humans have not been exposed to before, so we don’t have pre-immunity to them. Therefore, your immune system has not seen them before, and they don’t mount neutralizing antibodies,” Precigen President and CEO Helen Sabzevari, PhD, a co-author of the study released at ESGCT, told GEN Edge. “You can keep giving these vectors or viruses and every time that you give it, you enhance the immune system, which is not the case for other Ad5s or gene therapies or vaccines that use different viruses, including even chimp.”

Precigen’s study confirmed data first disclosed by the company during its R&D Day in January. Based on that earlier data, the FDA in June granted its Breakthrough Therapy designation to PRGN-2012.

The FDA has also granted Breakthrough Therapy to INO-3107—and in recent months delivered even more welcome news to both companies, by allowing Precigen and Inovio to file Biologics License Applications (BLAs) for accelerated approval without having to conduct additional randomized, placebo-controlled Phase III trials. As a result, both companies can use data from their Phase I/II studies to serve as pivotal data.

Saving three plus years

“You’re looking at least, a minimum of three years of time being saved, if not more,” Sabzevari said. A randomized clinical trial would take much longer because investigators would have a harder time finding patients willing to be randomized to drug or placebo, she added.

However, the FDA requested that both Precigen and Inovio conduct confirmatory studies before submitting their BLAs—something both companies have said they will do. Precigen said its confirmatory is expected to launch in the first half of 2024.

“We’re now focused on streamlining our development plan to support submission of a BLA for accelerated approval. Inovio President and CEO Jacqueline Shea, PhD, said in a statement. “We believe INO-3107 could become a game-changing treatment option for those suffering from RRP.”

Precigen plans to file its BLA for PRGN-2012 in the second half of 2024, Sabzevari said, once it concludes a rolling submission set to start by the end of this year. In addition to Breakthrough Therapy, PRGN-2012 has also received the FDA’s Orphan Drug Designation in patients with RRP.

“We are really moving very rapidly toward the commercialization part and submissions for different parts of the BLA for PRGN-2012,” Sabzebvari said. “We also are looking forward to communicating in early next year first quarter or beginning of second quarter our full clinical data from a pivotal Phase II part of PRGN-2012.”

$1B+ peak annual sales forecast

Precigen has projected a market opportunity of more than $1 billion in peak annual sales for PRGN-2012—and about $2 billion in peak annual sales globally. Commercialization would enable the company to increase its workforce, which now stands at 150.

Precigen rebranded from Intrexon in 2019, tapping its then-head of R&D Sabzevari to run the company. Sabzevari recounted her joining the company, as well as life and career, as a guest on GEN’s “Close to the Edge” video interview series.

More recently, Precigen has projected its cash runway has been stretched into 2025—not counting any future strategic partnerships—following the raising of $72.8 million in net proceeds from a 44 million-share public offering in January; cost-cutting that included reducing contract research costs and completely retiring $200 million in convertible notes—and refocusing its R&D to accelerate PRGN-2012 development.

PRGN-2012 is among treatment candidates for RRP that have been studied in 31 past and current clinical trials stretching back to 1999, according to ClinicalTrials.gov.

Among candidates being studied in current trials:

  • Bevacizumab—The NCI’s Norberg and Melissa (Missy) L. Wheatley are study contacts for a Phase II trial (NCT05797246) evaluating treatment in RRP patients with the targeted cancer therapy marketed as Avastin® by Roche and its Genentech subsidiary.
  • Lenvatinib and Pembrolizumab—Sara I. Pai, MD, PhD, at Massachusetts General Hospital and colleagues are conducting a Phase II study (NCT04645602) assessing the combination therapy in people with HPV-associated RRP. The drugs are marketed by Eisai as Lenvima® and by Merck & Co. as Keytruda®, respectively.

Alex Philippidis is Senior Business Editor of GEN.

SIDEBAR

Precigen’s Six Clinical Candidates

Of Precigen’s six clinical-phase pipeline candidates, two are based on gorilla adenovectors—PRGN-2012 (see above), and PRGN-2009, a first-in-class, off-the-shelf immunotherapy designed to activate the immune system to recognize and target HPV+ solid tumor cancers.

“This is a gorilla adenovirus that we have genetically engineered in such a way that it targets all the major epitopes of HPV 16 and 18, plus some proprietary epitopes that we have found,” Precigen President and CEO Helen Sabzevari, PhD, told GEN Edge.

Two of Precigen’s platforms, UltraCAR-T and AdenoVerse™ Immunotherapy [Precigen]

PRGN-2009 combines AdenoVerse with UltraVector®, a second Precigen platform. UltraVector applies advanced DNA construction technologies and computational models to design and assemble genetic components into complex gene expression programs. PRGN-2009 is being developed through a Cooperative Research and Development Agreement (CRADA) with NCI.

In June at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Precigen presented positive clinical data (Abstract# 2628) from the Phase I portion of a Phase I/II trial (NCT04432597) assessing PRGN-2009, alone and in combination with bintrafusp alfa, an investigational anti-PDL1/TGF-Beta Trap checkpoint inhibitor, in patients with recurrent/metastatic (R/M) HPV-associated cancers.

Study data showed that combining PRGN-2009 with checkpoint inhibition resulted in a favorable safety profile and a 30% objective response rate (ORR), with prolonged duration of responses in patients with heavily pre-treated HPV-associated cancers, including those who were checkpoint blockade resistant.

“They were deep responses with a very durable response, well over a year—year and a half,” Sabzevari said.

By year’s end, she added, Precigen expects to announce the start of Phase II study for PRGN-2009 in second-line cervical cancer. The company and FDA have come to agreement on a commercial manufacturing path for PRGN-2009.

Three of Precigen’s six clinical candidates are multigenic, autologous chimeric antigen receptor T-cell (CAR-T) cell therapies based on its UltraCAR-T platform. The platform uses Precigen’s advanced non-viral Sleeping Beauty system to simultaneously express an antigen-specific CAR to specifically target tumor cells, plus membrane-bound interleukin-15 (mbIL15) for enhanced in vivo expansion and persistence, and a “kill switch” activator designed to conditionally eliminate CAR-T cells for a potentially improved safety profile.

The UltraCAR-T candidates are:

  • PRGN-3005—Ovarian cancer treatment targeting the unshed portion of MUC16, plus mbIL15 and a kill switch. Precigen presented positive Phase I trial (NCT03907527) data in patients with advanced platinum resistant ovarian cancer at ASCO 2023. A Phase Ib dose expansion study is ongoing.
  • PRGN-3006—Acute myeloid leukemia (AML) treatment targeting CD33, plus mbIL15 and a kill switch. Precigen has reported positive data from a Phase I trial (NCT03927261) including a 27% objective response rate in heavily pre-treated relapsed or refractory AML patients infused once after lymphodepletion. A Phase Ib dose expansion study is ongoing, with interim data expected in 2024.
  • PRGN-3007—A treatment for advanced ROR1+ blood and solid tumors targeting receptor tyrosine kinase-like orphan receptor 1 (ROR1), mbIL15, a kill switch, and a novel mechanism for the intrinsic blockade of PD-1 gene expression. Based on a next-gen version of the UltraCAR-T platform, PRGN-3007 is in the Phase I dose escalation portion of a Phase I/Ib trial (NCT05694364).

Precigen’s other clinical candidate, the type 1 diabetes (T1D) treatment AG019, uses the company’s ActoBiotics platform to deliver the autoantigen human Proinsulin (hPINS) and human Interleukin-10 (hIL-10) in order to induce antigen-specific immune tolerance to prevent, delay or reverse T1D. AG019 completed a Phase I/II trial (NCT03751007) in 2021.

“What we have done with that in the past year or so, is preparing discussions with the FDA for a pivotal trial,” Sabzevari said.

She said limited funds have prevented Precigen from advancing AG019 into Phase III—but that could change if the company can find a collaboration partner. Talks are ongoing with several potential co-developers.

AG019 is an oral treatment and does not require infusion —something Sabzevari said will enable the drug to stand out from competitors like Provention Bio’s anti-CD3 antibody Tzield® (teplizumab-mzwv), approved in November 2022 as the first drug capable of delaying the onset of stage 3 type 1 diabetes in adults and older children ages eight and up with stage 2 T1D.

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