PepGen Inc. (NASDAQ:PEPG) is a clinical-stage biotechnology company at the forefront of developing innovative oligonucleotide therapies to transform the treatment of severe neuromuscular and neurological diseases. The company's proprietary Enhanced Delivery Oligonucleotide (EDO) platform has enabled the advancement of two lead clinical programs targeting Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1), both of which have the potential to be disease-modifying.
In 2023, PepGen made significant strides in its clinical development efforts, initiating the first inpatient trials evaluating its EDO-based product candidates. The company's lead program, PGN-EDO51, is designed for the treatment of DMD patients amenable to an exon 51-skipping approach, which represents approximately 13% of the DMD population. PepGen's second clinical program, PGN-EDODM1, targets the underlying cause of DM1, a debilitating neuromuscular disorder for which there are currently no approved disease-modifying treatments.
Financials
For the full year 2023, PepGen reported a net loss of $78.6 million and no revenue, reflecting the company's focus on advancing its clinical pipeline. Research and development expenses for the year totaled $68.1 million, as the company continued to invest in the development of its lead DMD and DM1 programs. General and administrative expenses were $16.6 million for the full year.
The company's cash position remains strong, with $110.4 million in cash and cash equivalents as of December 31, 2023. Subsequent to the end of the year, PepGen successfully completed an underwritten stock offering in February 2024, raising approximately $80 million in gross proceeds. Based on the company's current operating plans, the combined cash and cash equivalents, including the proceeds from the recent offering, are expected to fund operations into 2026.
Advancing the DMD Program: CONNECT1 and CONNECT2
PepGen's lead DMD program, PGN-EDO51, is currently being evaluated in two Phase 2 clinical trials: CONNECT1 and CONNECT2. CONNECT1 is an open-label, multiple ascending dose study designed to assess the safety, exon skipping, and dystrophin production of PGN-EDO51 in DMD patients. The company has completed enrollment for the first cohort, which received a 5 mg/kg dose of PGN-EDO51, and plans to escalate to the 10 mg/kg dose cohort pending review of the safety data.
Importantly, PepGen expects the 5 mg/kg dose of PGN-EDO51 to achieve greater than 1% of normal dystrophin levels above background in DMD patients, based on the company's internal modeling and extrapolation from previous clinical data. For the 10 mg/kg dose, PepGen's projections suggest the potential to achieve greater than 9% of normal dystrophin levels, which would be the highest level of dystrophin production reported for an exon-skipping therapy to date.
In parallel, PepGen received clearance from the UK's Medicines and Healthcare products Regulatory Agency (MHRA) to initiate the CONNECT2 study, a Phase 2, multinational, randomized, double-blind, placebo-controlled trial evaluating multiple dose levels of PGN-EDO51 in DMD patients. The company expects to begin dosing the first cohort at the 5 mg/kg dose level in the third quarter of 2024, with plans to expand the trial to additional geographies, including the US, subject to regulatory approvals.
The combined data package from the CONNECT1 and CONNECT2 trials is designed to support a potential accelerated approval pathway for PGN-EDO51, subject to alignment with regulatory authorities.
Advancing the DM1 Program: FREEDOM-DM1 and FREEDOM2-DM1
In the DM1 space, PepGen's PGN-EDODM1 program recently received Fast Track designation from the FDA, underscoring the significant unmet need and the potential of this investigational therapy. The company has initiated the FREEDOM-DM1 study, a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose trial evaluating the safety, splicing correction, and functional outcome measures of PGN-EDODM1 in DM1 patients.
PepGen expects the 5 mg/kg and 10 mg/kg dose levels evaluated in FREEDOM-DM1 to be pharmacologically active, with the potential for the 10 mg/kg dose to exhibit meaningful splicing correction and myotonia correction. The company anticipates reporting preliminary data from the 5 mg/kg cohort in the second half of 2024.
Building on the FREEDOM-DM1 study, PepGen plans to open the FREEDOM2-DM1 trial, a placebo-controlled multiple ascending dose study in DM1 patients, in the second half of 2024. This trial is designed to further evaluate the safety and efficacy of PGN-EDODM1 and support potential regulatory approvals.
Advancing the Preclinical Pipeline
In addition to its clinical-stage programs, PepGen continues to advance its preclinical pipeline, including PGN-EDO53, a candidate designed to target exon 53 skipping in DMD, which has demonstrated robust exon skipping in non-human primate studies. The company plans to initiate IND- and CTA-enabling studies for PGN-EDO53 in 2024.
Risks and Challenges
As a clinical-stage biotechnology company, PepGen faces several risks and challenges common to the industry, including the inherent uncertainties of drug development, the need for successful clinical trials, regulatory approvals, and the ability to secure adequate funding to support its operations and pipeline advancement. The company's success will also depend on its ability to navigate the competitive landscape in both DMD and DM1, where other novel therapies are in development.
Outlook
PepGen has made significant progress in advancing its EDO-based oligonucleotide therapies for severe neuromuscular and neurological diseases. The company's lead DMD and DM1 programs have demonstrated promising preclinical and early clinical results, and PepGen is well-positioned to continue its momentum in 2024 and beyond.
With multiple data readouts expected in the coming year, including preliminary results from the CONNECT1 and FREEDOM-DM1 trials, PepGen is poised to provide important updates on the potential of its innovative therapies. The company's strong financial position, following its recent equity offering, further supports its ability to execute on its clinical development strategy and drive value for shareholders.
Conclusion
As PepGen continues to advance its pipeline and navigate the regulatory landscape, the company's commitment to transforming the treatment of devastating diseases like DMD and DM1 will be closely watched by the investment community. With a robust clinical program, a differentiated technology platform, and a seasoned management team, PepGen remains an intriguing player in the oligonucleotide therapeutics space.