Ginkgo Strengthens Cell and Gene Therapy Services with Circularis, Altar

 Massachusetts-based Ginkgo Bioworks opened its wallet Tuesday and snapped up Circularis and Altar to strengthen its cell and gene therapy programs and bolster its manufacturing capabilities.

Financial terms of both deals were not disclosed. 

Anna Marie Wagner, senior vice president of corporate development at Ginkgo Bioworks, told BioSpace that the company is always on the lookout for new technologies that will enhance its own capabilities to deliver for its clients. She said the technologies at both Altar and Circularis were “obvious fits” for Ginkgo.

“Altar specifically supplements our strong rational gene editing approaches with a more robust directed evolution pipeline, allowing us to better take advantage of biology that we don’t yet understand. Circularis adds richer capabilities to our emerging cell and gene therapy focus area and we are excited about the growth we are seeing in that space,” Wagner said.

Circularis' circular RNA

Through this deal, Ginkgo Bioworks gains Circularis' circular RNA (circRNA) capabilities and a promoter screening platform which are expected to boost cell and gene therapy treatments for rare diseases. 

In its announcement, Ginkgo stated the Circularis platform allows ultra-high-throughput screening of promoters and other enhancers, improving therapeutic potential and the company's capabilities for its gene therapy partnerships. 

Over the past several years, Ginkgo has expanded its presence in the cell and gene therapy space, mainly through an adeno-associated virus capsid manufacturing partnership forged last year with Biogen. 

Circularis' circular RNA platform will enable Ginkgo to identify novel promoters that have the appropriate strength and tissue-specificity to meet customer modality needs, the company announced. Ginkgo said the promoter libraries will provide customers that develop gene therapies "a solution that works across any range of cell or organism models." 

For cell therapy developers, the Circularis platform is expected to provide Ginkgo with the ability to identify "context-specific promoters," such as those that modulate gene expression in the tumor microenvironment.

“Circularis is developing cutting edge circular RNA technology, and we expect a growing number of therapies to be based on circular RNA in the coming years, given the advantages circRNA can provide over other nucleic acid approaches, such as mRNA. Additionally, their promoter screening platform allows for ultra-high-throughput screening of promoters and other enhancers to accelerate our work across cell and gene therapy,” Wagner said.

Altar's Adaptive Evolution Platform

The acquisition of French biotech company Altar was sparked by that company's development of a proprietary adaptive evolution platform that Ginkgo has worked with in the past.

In its announcement, Ginkgo said a "fleet of Altar's automated adaptive laboratory evolution (ALE) instruments will be integrated into Ginkgo's Foundry" in order to serve the company's customers across multiple industries, including health care. Altar's technology can sustainably adapt microorganisms to conditions demanded by industrial companies for commercial-scale projects. 

Incorporating Altar's ALE platform into Ginkgo's own strain engineering capabilities will enable routine engineering of target phenotypes the company's clients require, according to Ginkgo. Ginkgo's existing suite of test workflows will characterize and further validate those strains. 

In a brief statement, Nikos Reppas, senior director of foundry technology at Ginkgo, expressed excitement about the addition of Altar's ALE technology. He said Altar's capabilities will boost Ginkgo Bioworks' own ability to serve its clients. 

"As the range of programs we work on continues to expand, it is imperative that we have the best tools in rational design as well as the ability to leverage the inherent diversity and creativity that emerges from evolutionary processes," Reppas said in a statement. 

Those aren't the only partnerships the company has forged. In August, Ginkgo gained an epidemiological data infrastructure asset from Baktus, Inc. that is expected to bolster the company's growing biosecurity platform.

Additionally, the deal will allow the company to offer expanded epidemic tracking, modeling, and forecasting capabilities to its clients. Ginkgo announced at the time it will integrate multiple ongoing epidemiological analysis projects and a team of epidemiological data experts into its biosecurity and public health initiative, Concentric by Ginkgo.

https://www.biospace.com/article/ginkgo-bioworks-snaps-up-celularis-and-altar-to-strengthen-cell-and-gene-therapy-services/

Wells Fargo Assumes Alaunos Therapeutics at Overweight

 Price Target of $3

https://www.benzinga.com/news/22/10/29133279/wells-fargo-assumes-alaunos-therapeutics-at-overweight-announces-price-target-of-3

Natera: Prospera™ Kidney dd-cfDNA Test Outperforms DSA in Predicting Antibody Mediated Rejection

  Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA (cfDNA) testing, today announced the publication of the latest data from the Trifecta study in Transplantation, found here. The investigators found that in predicting antibody mediated rejection (AMR), donor-derived cell-free DNA (dd-cfDNA) testing with the Prospera Kidney test was superior to the current standard of care, donor-specific antibody (DSA) testing.

In the study, both components of the Prospera two-threshold algorithm, dd-cfDNA donor fraction (AUC 0.84) and estimated amount of dd-cfDNA (AUC 0.85), outperformed DSA (AUC 0.66) in identifying AMR. Societal guidelines currently recommend DSA testing as standard practice for monitoring AMR, highlighting a compelling consideration for the broader use of dd-cfDNA in kidney transplantation.

This manuscript is the latest out of the Trifecta study, led by principal investigator Phil Halloran, M.D., Ph.D., director of the Alberta Transplant Applied Genomics Centre. The investigators assessed dd-cfDNA donor fraction, estimated amount of dd-cfDNA and DSA-status for 280 samples from kidney transplant recipients matched to kidney biopsies evaluated by both RNA-based molecular pathology (Molecular Microscope® Diagnostic System, "MMDX") and histology (Banff Classification of Allograft Pathology, 2019).

https://finance.yahoo.com/news/trifecta-study-demonstrates-prospera-kidney-123300186.html

Abeona Completes Patient Follow-up in Pivotal Phase 3 Study

 Topline VIITAL™ study results expected within the next month

Abeona Therapeutics Inc. (Nasdaq: ABEO) today announced that the last patient has completed their 6-month follow-up visit in Abeona’s pivotal Phase 3 VIITAL™ study of its investigational autologous, engineered cell therapy, EB-101, in patients with recessive dystrophic epidermolysis bullosa (RDEB).

“Completion of the last patient’s 6-month follow-up visit marks a key milestone that enables us to report key findings from our Phase 3 VIITAL™ study of EB-101 in RDEB,” said Vish Seshadri, Chief Executive Officer of Abeona. “We thank the patients, their families, and the clinical investigators, and plan to report topline results from this pivotal study within the next month.”

Abeona has been verifying and preparing the data in real time to ensure that an efficient database lock can be completed within two to three weeks from the last patient’s final visit. Abeona expects the VIITAL™ study, if positive, to serve as the basis for seeking approval by the U.S. Food and Drug Administration (FDA) of EB-101 for the treatment of patients with RDEB.

https://finance.yahoo.com/news/abeona-therapeutics-announces-completion-patient-113000264.html

Aeglea: Partial hold on homocystinuria program

 Aeglea BioTherapeutics, Inc. (NASDAQ:AGLE), a clinical-stage biotechnology company developing a new generation of human enzyme therapeutics as innovative solutions for rare metabolic diseases, today announced that dosing in the third cohort of the Phase 1/2 clinical trial of pegtarviliase for the treatment of Classical Homocystinuria is underway. Patients in this cohort are receiving 1.35 mg/kg of pegtarviliase once weekly administered via subcutaneous injection; patients in cohorts 1 and 2 received doses of 0.15 mg/kg and 0.45 mg/kg, respectively.

Additionally, the company received a letter from the U.S. Food and Drug Administration (FDA) responding to a recently submitted protocol amendment for the Phase 1/2 clinical trial of pegtarviliase for the treatment of Classical Homocystinuria. The protocol amendment, among other things, requested the inclusion of adolescent patients at clinical trial sites in the U.S. The FDA stated the protocol did not provide adequate justification and evidence to support the prospect of direct clinical benefit for pediatric patients and placed the trial on partial clinical hold for the enrollment of patients less than 18 years of age under this Investigational New Drug (IND) at this time. The company intends to address the feedback from the FDA and aims to satisfy the requirements for prospective benefit for future inclusion of pediatric patients under the IND, including in a potential pivotal trial.

The company believes that the letter will have no impact on the planned enrollment and dosing of patients aged 18 years and older in the U.S. or patients aged 12 years and older in the UK and Australia. Enrollment in the trial remains on track and Aeglea continues to expect to announce data in the fourth quarter of 2022, including data from cohort 3. The primary endpoint of the Phase 1/2 open-label trial is safety and tolerability. Three to four patients will be enrolled in each cohort and treated with four once weekly doses of pegtarviliase.

https://finance.yahoo.com/news/aeglea-biotherapeutics-provides-clinical-progress-110100397.html

Illumina upped to Outperform from Market Perform by Leerink

 Target to $270 from $220

https://finviz.com/quote.ashx?t=ILMN

Synlogic’s CSO Outlines Risks and Opportunities in Emerging Synthetic Biotics Space

 The field of synthetic biotics is so new there are only a handful of scientific articles using either that term or ‘engineered living therapeutics.’ Basically, this discipline integrates biology and engineering principles so researchers can use codes to design therapeutics just like their IT counterparts use code to design computer applications.

“The idea is that you, potentially, can apply those principles to bacteria to program or design them to be coded to perform specific functions,” said Dave Hava, Ph.D., CSO at Synlogic, in an interview with BioSpace. “We’re trying to take a probiotic organism – something that’s safe and that there’s lots of human experience with – and apply synthetic biology approaches to engineer that probiotic organism to do something it’s not originally designed to do.”

The result is bacteria into which different genes, enzymes or transporters are introduced to create a therapeutic function.

A Fledgling Space

Only a few companies are active in this space.

Senti Biosciences, founded by one of Synlogic’s founders, Tim Lu, M.D., Ph.D., is one. That firm, which has not yet entered clinical development, uses a synthetic biology approach with mammalian cells. Its two most advanced programs focus on acute myeloid leukemia and hepatocellular carcinoma.

South San Francisco-based Novome Biotechnologies focuses on gut diseases. Rather than probiotics or mammalian cells, it uses colonizing bacteria. Novome has one program in the clinic for enteric hyperoxaluria (EH). 

“It’s a different approach (than ours) with some different risks,” Hava said.

Of these companies, Synlogic appears to be the furthest along. It has three programs in the clinic, including one that is preparing for Phase III initiation next year. Therapeutic applications are focused on rare metabolic and immunological diseases including phenylketonuria (PKU), homocystinuria, EH and gout, in which probiotics are programmed to break down metabolites in the GI tract.

“Our lead clinical program is for PKU,” Hava said. “Patients with PKU can’t break down phenylalanine, an amino acid that’s in much of what we eat. Phenylalanine is absorbed from the GI tract. Having high levels in your blood and, ultimately, in your central nervous system, leads to cognitive decline over time.

“You can’t make an antibody or small molecule against phenylalanine to block it, so by engineering the bacteria to find it and convert it into something that’s not toxic, you effectively remove it from the system. Pac-Man (the 1980s video game) is a good analogy.”

This approach can be used against multiple diseases in which metabolites are involved, either as monotherapies or adjuvants depending on the disease.

“For PKU, there are two approved drugs on the market, but they only serve about 20 percent of the population,” Hava said. For them, Synlogic’s lead program, SYNB1934, could be an adjuvant therapy.

The remaining 80 percent manage their condition using dietary restrictions. “In those patients, what we’re doing with synthetic biotics will be meaningful as a standalone therapeutic.”

SYNB1934 is expected to begin a Phase III trial in the first half of 2023.

HCU and EH, two other conditions Synlogic is targeting, “have no real standard-of-care therapy,” Hava said. So, there is opportunity to address unmet needs as a monotherapy, he noted.

CRISPR Minimizes Risk 

Since the use of probiotics as living therapeutics was first proposed 15 to 20 years ago, the field has been immersed in basic research and tool building as researchers learned what did or did not work. The ability to easily manipulate bacterial DNA and genetics using multiple different techniques (like CRISPR) was an important milestone that removed much of the risk.

As advanced technologies were being developed, scientists’ understanding of the impact of the microbiome on human disease grew substantially, specifically regarding insights into the impact of microbial and dietary metabolites on human disease.

Recent research provides insights into how the imbalance of organisms in the gut (called dysbiosis) contributes to the development of hypertension and how nutritional and pharmacological interventions can help. An earlier paper explored dysbiosis in stroke and cognitive impairment.

Another important development is an improved understanding of the science by regulators, including what they will require in filings to prove the therapeutics are safe and effective.

“The PKU trial that completed Phase II and that will begin its Phase III next year blazed a path we can leverage for other programs,” Hava said.

“When you’re developing a new modality, there’s a lot of platform risk, technical risk and biological risk,” he continued. Therefore, in entering this still emerging field, Synlogic identified areas that already were well-validated and could possibly benefit from a synthetic biotics approach.

For example, “We know that phenylalanine is a bad actor and that if you restrict it by giving patients protein shakes that don’t contain thymine, you can lower phenylalanine and prevent its absorption,” Hava said. “We know that if we do that, patients will do better. That kind of dietary restriction gives us a strong validation that by getting rid of phenylalanine or preventing its absorption we have a good shot at treating the disease.”

The question, then, was whether researchers could do that with synthetic biotics, he said. “Our Phase II data suggests our approach is working. It’s producing the biomarkers we think it should produce and it is lowering phenylalanine levels in patients.”

Synthetic Biotics Gains Traction and Validation

The idea is gaining traction. Synlogic has entered into a partnership with Roche for a program geared toward inflammatory bowel disease. Last year, the company collaborated on a program with the U.S. Air Force, the National Research Council, Oak Ridge Institute for Science and Education and the Henry M. Jackson Foundation to characterize an engineered live bacterial therapeutic to treat PKU in a human gut-on-a-chip.

The coming year should bring additional validation. Within the next 12 months, Hava said he expects three clinical data readouts.

“The biggest of those is our PKU program, expected by the end of Q4 2022,” he said.

A readout also is expected later this year for the enteric hyperoxaluria program (SYNB8802) showing – he hopes – proof of concept for kidney stone formation. Phase I data from the HCU program (SYNB1353) also is expected.

https://www.biospace.com/article/synologic-s-cso-outlines-risks-and-opportunities-in-fledgling-synthetic-biotics-space-/