A Phase 3, Double-blind, Placebo-controlled, Randomized Withdrawal Study to Evaluate the Efficacy and Safety of SYNB1934 in Patients With PKU (SYNPHENY-3)

SYNB1934-CP-003 was designed as a 3-part, adaptive study consisting of a dose-escalating, open-label period (DEP; Part 1) of up to 15 weeks, followed by a 4-week, double-blind, placebo-controlled, randomized withdrawal period (RWP; Part 2), and an open-label extension (OLE; Part 3) of up to 36 months

Start Date05 Jul 2023

Sponsor / Collaborator

Synlogic, Inc.

NCT04984525 / CompletedPhase 1

A Phase 1, Dose-escalation, Placebo- and Active-Controlled Crossover Study to Assess the Safety, Tolerability, and Pharmacodynamics of SYNB1934 and the Effect of Concomitant Proton Pump Inhibitor Administration in Healthy Volunteers

This Phase 1, first-in-human, multiple dose-escalation, randomized, double-blinded, placebo-controlled study is evaluating SYNB1934 in healthy volunteers (HV). Eligible subjects receive investigational product (IP) and undergo safety monitoring, evaluations, and subsequent follow-up after IP administration.

Start Date02 Jul 2021

Sponsor / Collaborator

Synlogic, Inc.

NCT04534842 / CompletedPhase 2

An Open-label Study of the Efficacy and Safety of SYNB1618 and SYNB1934 in Patients With Phenylketonuria (SynPheny-1)

This Phase 2 study in patients with phenylketonuria (PKU) will be an open-label, dual-arm study of either a SYNB1618 or SYNB1934 dose-ramp regimen. All evaluations and assessments throughout this study may be conducted either at the clinical site or by a home healthcare professional at an alternative location (e.g., patient's home, hotel).

Start Date25 Aug 2020

Sponsor / Collaborator

Synlogic, Inc.

100 Clinical Results associated with SYNB-1934

100 Translational Medicine associated with SYNB-1934

100 Patents (Medical) associated with SYNB-1934

Literatures (Medical) associated with SYNB-1934

01 Oct 2023·Nature metabolism

Efficacy and safety of a synthetic biotic for treatment of phenylketonuria: a phase 2 clinical trial.

Article

Author: McWhorter, Nicole ; Phillips, John A ; Grange, Dorothy K ; Humphreys, Kristina ; Searle, Shawn ; Diaz, George A ; Brennan, Aoife M ; Denney, William S ; Thomas, Janet A ; Vockley, Jerry ; Ernst, Sharon L ; Sondheimer, Neal ; Zori, Roberto ; Ginevic, Ilona ; Kurtz, Caroline ; Northrup, Hope ; Puurunen, Marja ; Harding, Cary

Despite available treatment options, many patients with phenylketonuria (PKU) cannot achieve target plasma phenylalanine (Phe) levels¹. We previously modified Escherichia coli Nissle 1917 to metabolize Phe in the gut after oral administration (SYNB1618) and designed a second strain (SYNB1934) with enhanced activity of phenylalanine ammonia lyase^2,3. In a 14-day open-label dose-escalation study (Synpheny-1, NCT04534842 ), we test a primary endpoint of change from baseline in labeled Phe (D5-Phe AUC_0-24; D5-Phe area under the curve (AUC) over 24 hours after D5-Phe administration) in plasma after D5-Phe challenge in adult participants with screening Phe of greater than 600 µM. Secondary endpoints were the change from baseline in fasting plasma Phe and the incidence of treatment-emergent adverse events. A total of 20 participants (ten male and ten female) were enrolled and 15 completed the study treatment. Here, we show that both strains lower Phe levels in participants with PKU: D5-Phe AUC_0-24 was reduced by 43% from baseline with SYNB1934 and by 34% from baseline with SYNB1618. SYNB1934 led to a decrease in fasting plasma Phe of 40% (95% CI, -52, -24). There were no serious adverse events or infections. Four participants discontinued because of adverse events, and one withdrew during the baseline period. We show that synthetic biotics can metabolize Phe in the gut, lower post-prandial plasma Phe levels and lower fasting plasma Phe in patients with PKU.

Nature CommunicationsQ1 · CROSS-FIELD

Improvement of a synthetic live bacterial therapeutic for phenylketonuria with biosensor-enabled enzyme engineering

Q1 · CROSS-FIELD

ArticleOA

Author: Isabella, Vincent M ; Monahan, Catherine E ; Greisen, Per Jr ; Castillo, Mary Joan ; Mirabella, Teodelinda ; Momin, Munira ; Renaud, Lauren ; Abin-Fuentes, Andres ; Spoonamore, James ; Fitch, Lauren E ; Weile, Carl J ; Callihan, Isolde ; Adolfsen, Kristin J ; Lawrence, Adam G ; Weng, Lindong ; Konieczka, Jay H

AbstractIn phenylketonuria (PKU) patients, a genetic defect in the enzyme phenylalanine hydroxylase (PAH) leads to elevated systemic phenylalanine (Phe), which can result in severe neurological impairment. As a treatment for PKU, Escherichia coli Nissle (EcN) strain SYNB1618 was developed under Synlogic’s Synthetic Biotic™ platform to degrade Phe from within the gastrointestinal (GI) tract. This clinical-stage engineered strain expresses the Phe-metabolizing enzyme phenylalanine ammonia lyase (PAL), catalyzing the deamination of Phe to the non-toxic product trans-cinnamate (TCA). In the present work, we generate a more potent EcN-based PKU strain through optimization of whole cell PAL activity, using biosensor-based high-throughput screening of mutant PAL libraries. A lead enzyme candidate from this screen is used in the construction of SYNB1934, a chromosomally integrated strain containing the additional Phe-metabolizing and biosafety features found in SYNB1618. Head-to-head, SYNB1934 demonstrates an approximate two-fold increase in in vivo PAL activity compared to SYNB1618.

News (Medical) associated with SYNB-1934

01 Aug 2024

·www.pharmaceutical-technology.com

Otsuka snaps up Jnana with its phenylketonuria drug for $800m

Otsuka will gain Jnana’s lead candidate JNT-517 for treating phenylketonuria (PKU), along with its drug discovery RAPID chemoproteomics platform. Image Credit: Ratana21 / Shutterstock. Otsuka Pharmaceutical is looking to acquire US-based Jnana Therapeutics in a deal worth up to approximately $1.1bn. The Japanese company will pay Jnana’s shareholders $800m through its US subsidiary, Otsuka America. Jnana will also be in line to receive up to $325m in milestone-based payments. The deal is expected to close in Q3 this year. Otsuka plans for Jnana to operate as its subsidiary following the acquisition. To achieve this, it plans to merge Jnana with a special purpose company, established under Otsuka America, with the Jnana remaining as the surviving company. Jnana’s lead asset is JNT-517 being developed to treat phenylketonuria (PKU), a rare inherited metabolic disorder that causes an amino acid called phenylalanine to build up in the body. JNT-517 inhibits SLC6A19 or solute carrier family 6 member 19, a transmembrane protein that regulates phenylalanine absorption and reuptake in the small intestine and kidney. In June, Jnana reported positive topline data from a Phase I trial (NCT05781399) evaluating JNT-517 in 64 healthy individuals. The therapy was safe and well tolerated at all dose levels, with no serious adverse events. The company plans to start a registrational trial for JNT-517 next year. See Also: AbCellera and Lilly broadens antibody discovery partnership NICE recommends BeiGene’s MZL tablet for NHS use The deal will also give Otsuka access to Jnana’s drug discovery technology, the RAPID chemoproteomics platform. The platform has been successful in identifying therapies against various cancers, and immune-mediated and neurological targets, with Jnana signing two drug discovery deals with Roche. There are a limited number of therapies in development to treat PKU. PTC Therapeutics has found success with sepiapterin, which was studied in a positive Phase III AFFINITY trial (NCT06302348). The placebo-controlled portion of the study included 98 patients with PKU who achieved a mean phenylalanine reduction of 63% when treated with sepiapterin. However, this area has also seen some disappointments. Synlogic was not that successful with its PKU therapy SYNB1934, which was designed to reduce phenylalanine levels in the gastrointestinal (GI) tract. In February, Synlogic had to terminate SYNB1934’s development after an interim data review found that the Phase III Synpheny-3 trial (NCT05764239) was unlikely to meet the primary endpoint. Following that news, the company laid off more than 90% of its staff.

Phase 3Clinical ResultPhase 1AcquisitionPhase 2

09 Feb 2024

·www.fiercebiotech.com

Synlogic reaches end of line, laying off 90% of staff and ceasing operations after phase 3 fail

Synlogic had already slimmed down its pipeline and workforce in 2022, leaving its future heavily reliant on labafenogene marselecobac’s success. Synlogic’s dreams have gone up in smoke on the news that a pivotal phase 3 study of its lead phenylketonuria (PKU) drug is on track to miss its primary endpoint. The Massachusetts-based biotech launched the 150-patient global Synpheny-3 trial of labafenogene marselecobac—which is designed to target and consume an amino acid called phenylalanine in the gastrointestinal tract—in June 2023. Top-line data had been expected in the first half of 2025. As recently as early January, CEO Aoife Brennan sounded optimistic about the trial. In a Jan. 4 look ahead, Brennan suggested that the data monitoring committee review of initial study data was set to be a “key milestone” that would help ensure 2024 was another “momentous” year for the company that could usher in an expansion of the trial into adolescent PKU patients. The committee’s review was indeed momentous for the company, but not in the way Brennan intended. Instead, they “indicated the trial was unlikely to meet its primary endpoint,” Synlogic revealed in a postmarket release Feb. 8. The decision was not based on concerns regarding the safety nor the tolerability of the drug, which is also known as SYNB1934, the biotech pointed out. As a result, the company will cease operations and lay off more than 90% of its workforce this month. The remaining employees will be involved with discontinuing the Synpheny-3 study across trial sites and assisting in a “strategic review” of the company “to enhance shareholder value.” Synlogic entered 2024 with cash, equivalents and short-term investments totaling $47.7 million. “It is with a heavy heart that we share this news, and our resulting decision to end Synpheny-3,” said Brennan, who will also be stepping down. “Based on the program’s progress and data to date, we had expected the study to demonstrate the potential for SYNB1934 to provide an important new treatment option for those affected by PKU.” The company had already slimmed down its pipeline and workforce in 2022, leaving its future heavily reliant on the success of labafenogene marselecobac. PTC Therapeutics appeared to have more success last year in a phase 3 trial in PKU. However, the design of the study meant analysts remained unsure about the strength of PTC’s hand and whether its drug sepiapterin could rival BioMarin’s approved PKU drug Kuvan. Since then, PTC’s approval application for sepiapterin has been brushed aside by the FDA, which demanded an additional mouse study.

Phase 3Drug Approval

08 Feb 2024

·firstwordpharma.com

Synlogic shutters operations after ending phenylketonuria trial

Shares in Synlogic cratered Thursday, sinking as much as 55% in after-hours trade following the company's decision to pull the plug on a Phase III study of its lead asset labafenogene marselecobac (SYNB1934) as a potential treatment for phenylketonuria.The company is now weighing a menu of options for its future, including a possible acquisition, merger, sale of assets or dissolution, but in the meantime is closing down operations, and laying off almost all of its staff. The majority of impacted positions will end this month. About 10% of workers will be retained to help with its strategic review and assist in the discontinuation of the Synpheny-3 study.Synpheny-3 got under way last June, and Synlogic noted at the time that it incorporated feedback regarding its design from global regulatory agencies, including the FDA. The global study was expected to recruit approximately 150 patients with baseline plasma phenylalanine (Phe) levels of >360 μM, and tested three doses. The primary endpoint was change in plasma Phe levels.Trial unlikely to succeedHowever, an internal review conducted in advance of an upcoming independent data monitoring committee (DMC) assessment, indicated the trial was unlikely to meet its primary endpoint. Synlogic said its decision was not based on any safety or tolerability concerns. Labafenogene marselecobac is a synthetic biotic designed from natural probiotic single strain bacteria engineered using Synlogic's synthetic biology and microbiome platform.The company's other pipeline projects include SYNB1353 and SYNB8802, both at the cusp of entering Phase II for classical homocystinuria and enteric hyperoxaluria, respectively, according to its website. It was also working on the preclinical gout treatment SYNB2081, and two other undisclosed candidates for cystinuria and inflammatory bowel disease.

Phase 3Phase 2Microbial therapyClinical Trial Failure

100 Deals associated with SYNB-1934

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Phenylketonurias	Phase 3	CA	Synlogic, Inc.	05 Jul 2023
Phenylketonurias	Phase 3	TR	Synlogic, Inc.	05 Jul 2023
Phenylketonurias	Phase 3	GE	Synlogic, Inc.	05 Jul 2023
Phenylketonurias	Phase 3	US	Synlogic, Inc.	05 Jul 2023

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05764239 (SYNPHENY-3, CTgov)	Phase 3	Phenylketonurias	35	SYNB1934v1 (DEP (Part 1, SYNB1934v1))	muxaowfkuz(suvelfoakp) = qhcwjizsyn otmorampnj (lwgnwdqpmg, eogzmyiinm - trjaxnveke) View more	-	20 Jun 2024
				SYNB1934v1 (RWP (Part 2, SYNB1934v1))	muxaowfkuz(suvelfoakp) = xgdcceygvs otmorampnj (lwgnwdqpmg, oqxxwuqfnb - nhwfiggtnk) View more

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