Bruce Goldsmith, PhD, Passage Bio president and CEO

Passage Bio is doubling down on its lead clinical program, a gene therapy designed to treat GM1 gangliosidosis, after interim clinical data from a Phase I/II trial showed developmental improvement in two young boys with the late infantile form of the inherited lysosomal storage disorder, after receiving a low dose of PBGM01.

Interim data from the Imagine-1 trial (NCT04713475), presented earlier this month at the 18th Annual WORLDSymposium, showed PBGM01 led to “meaningful” improvement in development milestones and no reported serious adverse events or complications related to intra-cisterna magna (ICM) delivery.

The first patient was 15 months old when dosed with the low dose of 3.3e10 genome copies per gram estimated brain weight (GC/g) but had a developmental age of 11 months. Patient two was 31 months old at gene transfer, but a developmental age of only seven months.

“We were really excited to see that there were gains in developmental milestones in both patients,” Bruce Goldsmith, PhD, Passage Bio’s President and CEO, told GEN Edge. “The reason it’s two patients is, the outcome is to get from this Cohort 1, which is late infantile low dose, to a higher dose of late infantile patients, and a same dose one in an earlier patient population.”

Philadelphia-based Passage Bio develops gene therapies for rare, monogenic CNS disorders through a strategic collaboration and licensing agreement with the University of Pennsylvania’s Gene Therapy Program (GTP) to conduct discovery and IND-enabling preclinical work. A year after it was launched in 2019, the company went public through an initial public offering that raised $227.5 million. Passage Bio’s co-founders include GTP Director and gene therapy pioneer James M. Wilson, MD, PhD.

In late infantile GM1, the disease onset occurs between ages 6–24 months, compared with up to six months in early infantile patients. Passage Bio presented details of the progress made by the two boys dosed with PBGM01. The first patient showed skills improvements after nine months in:

  • Gross motor: From taking a few steps without support to running without falling and showing the abilities to climb off his bed, balance on one foot, and move up and down stairs.
  • Fine motor: From sometimes to always able to squeeze a toy, as well as place a piece in a puzzle and put a coin in a slot.
  • Receptive language: From never to always pointing to (three) named body parts; from never to always pointing to named objects in a book; from rarely to always following one-step commands.
  • Expressive language: From expressing no words with meanings to naming 10 familiar objects and 10–20 words with specific meanings.

Increased beta-gal activity

Patient one’s beta galactosidase (beta-gal) enzyme activity in his cerebrospinal fluid (CSF) increased 1.5-fold over baseline at one month, to 2.7 nmol/mL/3 hr. That improvement was maintained after six months, Goldsmith said. Patient 2’s beta-gal activity rose 4.8-fold during the first month, stabilizing during that six-month period to an increase of 0.6 nmol/mL/3 hr, rising to roughly 2 nmol/mL/3 hr.

Imagine-1 data also showed a favorable safety profile for PBGM01, with 14 adverse events being mild, while two others were moderate. All moderate adverse events were resolved without intervention and were deemed not treatment related, Passage Bio reported.

PBGM01 is designed to treat GM1 gangliosidosis by targeting the lysosomal enzyme β-galactosidase (GLB1). PBGM01 delivers a codon-optimized gene sequence encoding functional beta-gal enzyme, using an AAVhu68 viral vector. The vector is delivered directly to the CSF by a single ICM injection, with the goal of increasing beta-gal enzyme activity levels in both the central nervous system (CNS) and periphery.

During a February 11 conference call with analysts following the WORLDSymposium presentation, Goldsmith outlined next steps for the Imagine-1 trial: Passage Bio will open additional trial sites and expects to release additional data this year from the trial’s second and third of an eventual four cohorts, two patients per cohort. Cohort 2 will consist of two late infantile GM1 patients to be dosed at the high PBGM01 dose of 1.1e11 GC/g. Cohort 3, two early infantile GM1 patients at the low dose.

“We will continue to enroll cohorts 2 and 3, as we are leveraging patient identification efforts to identify additional study participants,” Goldsmith said. “We expect to provide additional data updates during 2022. First we will continue to provide additional biomarker and efficacy data from Cohort 1 and we also plan to produce initial safety and biomarker data from cohorts 2 and 3 in the second half of this year.”

Investors haven’t yet appeared to share the company’s enthusiasm over the PBGM01 data. The day of the WorldSymposium presentation, shares of Passage Bio rose about 4%, to $6.64—only to tumble since, to $3.65 as of February 16, just above the stock’s 52-week low of $3.61; the 52-week high of $22.33 was reached in March 2021.

The positive results presented from Imagine-1 were updated from initial favorable data announced by the company when the trial’s Independent Data Monitoring Committee recommended proceeding with two additional planned patient cohorts on December 17.

On the right track

Geulah Livshits, PhD, a senior research analyst at Chardan covering biotech companies, noted in a December research report that the initial results reflected an observation she made in an earlier report that “[d]irectionally consistent increases in CSF beta-gal activity over each patient’s baseline could signal to us that PBGM01 is on the right track.”

“We think the safety profile here has important positive read-across for the company’s other pipeline programs using ICM delivery,” Livshits added.

PBGM01 is one of three clinical-phase gene therapies being developed by Passage Bio; the other two are PBKR03, which treats Krabbe disease by using an AAVhu68 viral vector to deliver a functional GALC enzyme gene that codes for galactosylceramidase (GAL-C); and PBML04, a treatment for metachromatic leukodystrophy (MLD) and mutations in the enzyme ARSA gene, which encodes the lysosomal enzyme ARSA.

Sometime in “early 2022,” Passage Bio plans to dose the first patient in the Phase I/II GALax-C trial (NCT04771416) of PBKR03. Later this year, the company plans to file an IND application to the FDA for its Phase I/II clinical program for PBML04.

The rest of Passage Bio’s pipeline is in preclinical discovery phases, with five of the eight gene therapy candidates not yet named by the company. Among the named candidates are PBFT02, a frontotemporal dementia candidate that delivers a modified DNA encoding the granulin gene (GRN) to a patient’s cells through an adeno-associated virus 1 (AAV1) viral vector. PBFT02 aims to provide higher-than-normal levels of the progranulin protein (PGRN) to the CNS, to overcome progranulin deficiency in GRN gene mutation carriers.

Passage Bio has also set an “early 2022” timeframe for dosing the first patient in the Phase I/II upliFT-D trial (NCT04747431) evaluating PBFT02 for frontotemporal dementia with granulin mutations.

Also named by the company: PBAL05, an amyotrophic lateral sclerosis (ALS) treatment for patients with a gain-of-function mutation in the C9orf72 gene; and PBCM06, a treatment for Charcot-Marie-Tooth neuropathy type 2a (CMT2a).

Passage Bio says it intends this year to advance PBCM06 as well as the five unnamed candidates, all in the discovery phase. Include a Canavan disease therapy that targets the ASPA gene; a Parkinson’s disease prospect targeting the PRKN gene; a Huntington’s disease treatment; an Alzheimer’s disease therapy targeting an undisclosed gene; and a temporal lobe epilepsy candidate also acting on an undisclosed gene. The latter two programs are the subject of target identification research programs that the company plans to progress.

In December, Passage Bio expanded its pipeline to take in the programs for Canavan and Huntington’s diseases, by exercising two additional options with GTP. The expansion brought to nine the number of program license options exercised out of the total 17 held by the company for additional CNS pipeline candidates.

Passage Bio has executed nine of the 17 options it holds on developing programs based on GTP research. The nine include the company’s three clinical programs, plus another six programs now in research phases.

Seeking differentiation

“The way we think is, for all of these programs, is there a way to differentiate our approach versus other approaches that are out in the environment, whether in academic centers or in clinical studies?” Goldsmith said.

In Huntington’s disease, Passage Bio will explore a pair of approaches—one targeting the HTT protein, the other undisclosed—that it reasons may differentiate the company.

“If we couldn’t find that point of differentiation, and we couldn’t actually achieve that proof of differentiation, we may not continue, because there are other approaches that might be better. So that’s the overall philosophy here—trying to create sustainable value from diversified and differentiated portfolio,” Goldsmith said. “When I say we, with all credit it’s actually Jim Wilson, and his team of experts, in collaboration and consultation with us.”

Though GTP, Passage Bio can access initial research, analytics, vector engineering, and some of the process development that make up the foundation of the company’s manufacturing effort.

In 2020, Passage Bio began expanding its internal manufacturing capabilities to support its lead programs as they advance into the clinic and toward commercialization.

The company started supporting AAV production for its lead gene therapy product candidates at a dedicated manufacturing suite at Catalent Cell & Gene Therapy’s Harmans/BWI campus in Harmans, MD, near Baltimore/Washington International Airport. The Harmans site offers Passage Bio dedicated cGMP capacity to address its end-to-end clinical supply chain.

Last year, Passage Bio began Chemistry, Manufacturing and Controls (CMC) lab operations for its gene therapy programs at the Princeton West Innovation Campus, a former Bristol-Myers Squibb property in Hopewell, NJ. The CMC R&D lab carries out analytical and process development and clinical product testing, in order to support Passage Bio’s strategy of expanding internal manufacturing capabilities to support its lead programs as they advance into the clinic and toward commercialization.

Passage is continuing to add to its manufacturing capabilities. By year’s end, the company plans to create and a pilot manufacturing suite in Hopewell that will offer the company scale-up capability designed to support its R&D pipeline and future development plans.

“It is not going to be GMP qualified, so it will not allow clinical supply. But we will invest now to make sure that if we want to change that and make it GMP qualified, we’ll be able to do that later and mostly around error handling and quality controls,” Goldsmith said. “It should be open by the end of this year.”

Between Philadelphia and Hopewell, Passage Bio has a headcount of 140. “We do expect to add 20 or so people to the analytics and quality group up in the manufacturing labs” at Princeton West Innovation Center,” Goldsmith said.

Passage Bio reported combined cash, cash equivalents, and marketable securities of $316 million at the end of 2021—which according to the company is sufficient enough to fund operations through the end of 2023.

“We never have intended to be acquired. We think that the most important thing is to continue to build on our mission. If it makes sense at some point or other to have partnerships, for example ex-U.S., or looking at some of our pipeline, we may do that. But right now, we think we can move this forward on our own,” Goldsmith said. “The cash we have and the outlook we have are very, very positive.”

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