First Positive Clinical Data for In Vivo Genome Editing in Humans Opens “New Era of Medicine”

Abstract

Researchers from Intellia Therapeutics, Regeneron Pharmaceuticals, and clinical partners have published the first-ever clinical data that strongly support the safety and efficacy of in vivo CRISPR genome editing in humans.

The team of researchers based in the United States, the United Kingdom, and New Zealand showed that the companies' lead in vivo genome editing candidate, NTLA-2001, generated a dose-dependent sustained reduction of protein linked to transthyretin (ATTR) amyloidosis following a single dose in six patients living with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN).

In a study published on June 26 in The New England Journal of Medicine—findings also presented at the 2021 Peripheral Nerve Society Annual Meeting—the researchers reported that a single 0.3 mg/kg dose of NTLA-2001 led to an 87% mean reduction in serum transthyretin (TTR) protein concentration in three of the ATTRv-PN patients by day 28, with individual reductions of 80%, 84%, and 96%.

Standard of care for ATTRv-PN, which requires chronic treatment, typically yields TTR reductions of ∼80%, Intellia and Regeneron said.

A single 0.1 mg/kg dose of NTLA-2001 resulted in a 52% mean reduction in serum TTR protein in the other three ATTRv-PN patients, with individual reductions of 47%, 52%, and 56% by day 28.

NTLA-2001 also generated positive safety data: “Administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR,” the researchers reported in the NEJM study.¹

Intellia President and CEO John Leonard, MD, said that the interim results supported the companies' belief that NTLA-2001 had the potential to halt and reverse ATTR amyloidosis with a single dose.

“Solving the challenge of targeted delivery of CRISPR-Cas9 to the liver, as we have with NTLA-2001, also unlocks the door to treating a wide array of other genetic diseases with our modular platform, and we intend to move quickly to advance and expand our pipeline,” Leonard stated, declaring: “With these data, we believe we are truly opening a new era of medicine.”²

Prime Medicine Raises $315M in Financing

Prime Medicine, which likens its gene editing approach to the search-and-replace function of a word processor with DNA, has emerged from stealth mode by announcing it has completed $315 million in financing.

The financing consisted of a $115 million series A round and a $200 million series B round. Prime said proceeds from the financing will be used to continue building the company, rapidly advance its gene editing therapy candidates toward clinical indications, and expand the capabilities of its platform.

Prime is advancing multiple drug discovery programs targeted at liver, eye, ex vivo hematopoietic stem cell, and neuromuscular indications. By the end of 2021, Prime said, it expects to employ >100 people full time.

The company trains its searching and replacing on disease-causing genetic sequences at their precise location in the genome, without resulting in double-strand DNA breaks that cause unwanted cellular changes. According to the company, its genome editing approach has the potential to address >90% of known disease-causing mutations, and works in a variety of dividing and nondividing primary human cells, as well as in animals.

Prime said its technology is designed to overcome several technical barriers attributed to earlier gene editing technologies—such as off-target edits delivered by many versions of CRISPR genome editing.

“Prime Editing is a transformative technology that we believe will make a significant impact by addressing the fundamental causes of genetic disease,” said Keith Gottesdiener, MD, CEO of Prime Medicine. “We are operating from a position of financial strength, and look forward to further developing the technology and progressing our preclinical programs toward the clinic, with the hope that they may cure or halt the progression of genetic diseases for patients,” Gottesdiener added.³

The technology behind Prime Medicine was first disclosed publicly in October 2019, when David Liu, PhD, and colleagues at the Broad Institute of MIT and Harvard published an article in Nature that laid out a new mechanism for genome editing that did not make double-strand breaks in the target sequence or use a donor DNA template.⁴

In an interview with Human Gene Therapy earlier this year, Liu discussed the importance of prime editing in expanding the percentage of the ∼75,000 known human gene variants associated with genetic disease that are correctable: “The community and our laboratory are working really hard on expanding the scope of prime editing the same way that the community expanded the scope of base editing, to hopefully cover a large majority of that enormous pie chart.”⁵

Fujifilm Plans $850M Expansion of Manufacturing, Development

FUJIFILM will invest ¥90 billion ($850 million) to expand the manufacturing and development capacity of its FUJIFILM Diosynth Biotechnologies contract development and manufacturing organization (CDMO).

The CDMO plans to double cell culture production for biologics—including recombinant vaccines for COVID-19—in the United States. In the United Kingdom, gene therapy production will be increased 10-fold, cell culture capacity will be tripled, and microbial fermentation output at the existing 5,000-L scale facility will be doubled, FUJIFILM said.

The U.K. cell culture expansion will also include current good manufacturing practice (cGMP) capacity for continuous manufacturing, while process and analytical development capacity will also be increased, the company added. Expansions are scheduled to begin operating by late 2023. FUJIFILM said it would disclose further details on the capabilities of the new and expanded facilities upon the conclusion of initial engineering studies.

The newest investment brings to ¥600 billion ($5.5 billion) FUJIFILM's total spending in FUJIFILM Diosynth Biotechnologies since 2011. “FUJIFILM will never stop in its relentless pursuit to develop new technologies and provide the necessary manufacturing capacity to meet the needs of our customers and accelerate the growth of its Bio CDMO business,” said Teiichi Goto, president of FUJIFILM Corporation.⁶

FUJIFILM Diosynth specializes in development and manufacturing of recombinant proteins, vaccines, and large molecules that include monoclonal antibodies, as well as viral products expressed in a variety of microbial, mammalian, and host/virus systems.

Biogen Weighs Next Steps for Failed Choroideremia Therapy…

Biogen is evaluating the next steps for its choroideremia gene therapy candidate timrepigene emparvovec (BIIB111/AAV2-REP1) after it failed a Phase III trial.

Timrepigene emparvovec missed its primary endpoint in the Phase III STAR trial (NCT03496012) of a statistically significant proportion of participants with a ≥15 letter improvement from baseline in best corrected visual acuity at month 12 in the interventional group compared with an untreated control group, as measured by the Early Treatment of Diabetic Retinopathy Study chart.

Timrepigene emparvovec also failed to demonstrate efficacy on key secondary endpoints. Biogen said, adding that it will evaluate the trial's complete data set before confirming next steps for clinical development. Biogen plans to present detailed results of the study at a future scientific forum. Safety results were consistent with previous studies, Biogen added.

STAR was multicenter randomized three-arm parallel-controlled group study that enrolled 169 adult men with a genetically confirmed diagnosis of choroideremia.

“While we are disappointed by the results of the STAR study, we are hopeful that the clinical insights gleaned from this study may help to shape therapeutic innovation for inherited retinal diseases including choroideremia, so that in the future there may be treatment options for the community affected by these debilitating disorders,” said Katherine Dawson, MD, head of the Therapeutics Development Unit at Biogen.⁷

… As Roche Ends Alliance With 4D Molecular Therapeutics in Choroideremia

4D Molecular Therapeutics (4DMT) acknowledged that Roche is terminating a collaboration to develop the gene therapy candidate 4D-110 for choroideremia, effective September 16, “as a result of Roche's assessment of a change in the risk-benefit profile.”⁸

The termination will result in 4DMT regaining full rights to the intravitreally delivered 4D-110. 4DMT said it intended to continue clinical development of 4D-110 based on the totality of data generated to date.

The company released initial clinical safety data from a Phase I trial (NCT04483440) showing that at both dose levels studied, 4D-110 was well tolerated and did not result in any dose-limiting toxicity in six patients followed up between 1 and 9 months. Initial biologic activity data from the Phase I trial is expected in the fourth quarter, following at least 6 months follow-up for all currently enrolled patients and completion of a 90-day transition period with Roche.

“We plan to conclude the Roche-funded clinical trial under the collaboration and subsequently transfer previously treated patients onto a long-term follow-up study to continue monitoring biological activity endpoints and safety,” said Robert Kim, MD, senior vice president of Clinical Research, head of Clinical Ophthalmology at 4DMT.⁸

He added that 4DMT was committed to designing and initiating the next 4D-110 clinical trial, including treatment of earlier-stage patients, as soon as possible after reviewing earlier data with its investigators and the U.S. Food and Drug Administration (FDA).

4DMT and Roche launched their collaboration in 2015, initially agreeing to discover and develop optimized next-generation adeno-associated virus (AAV) vectors for indications with high unmet medical need. Three years later, the companies agreed to codevelop 4D-110 as their first collaboration program.

Kriya Raises $100M Series B

Kriya Therapeutics completed a $100-million Series B financing, with the proceeds intended to help the company to transform the design, development, and manufacturing of gene therapies.

Based in Redwood City, CA, Kriya aims to improve the speed to market of gene therapies—and reduce their cost per dose significantly—through a pair of technology platforms: A computationally enabled proprietary platform for rational vector design (SIRVE™) and a high-efficiency manufacturing platform for scalable and low-cost production (STRIPE™).

Proceeds from the financing will help Kriya develop its core technology platforms, expand its therapeutic pipeline, and advance its current programs in metabolic disease, ophthalmology, and oncology.

The financing was led by Patient Square Capital, with participation from new investors Woodline Partners LP, CAM Capital, Hongkou, Alumni Ventures and others. All existing institutional investors also participated in this round, including QVT, Dexcel Pharma, Foresite Capital, Bluebird Ventures, Transhuman Capital, Narya Capital, Amplo, and JDRF T1D Fund.

“We believe that Kriya is well positioned to deliver transformative improvements in cost, scale and efficiency that will help the gene therapy field achieve its full potential across a range of therapeutic areas,” said Shankar Ramaswamy, MD, cofounder and CEO of Kriya Therapeutics.⁹

Tenaya Therapeutics Plans Initial Public Offering

Tenaya Therapeutics has disclosed plans to the U.S. Securities and Exchange Commission to sell its first public stock through an initial public offering valued at $100 million.

Tenaya, based in South San Francisco, CA, has developed a gene therapy platform that uses AAVs to deliver genes to specific cells in the heart, with the aim of correcting or compensating for functional defects. Tenaya said it can use both known AAV capsids as well as novel capsids identified through its internal capsid engineering capabilities to target cardiomyocytes, cardiac fibroblasts, or other cells important to heart function.

“Our vision is to change the treatment paradigm for heart disease, the leading cause of death in the world, and in doing so improve and extend the lives of millions of individuals and families,” Tenaya stated in its Form S-1 Registration statement.¹⁰

Tenaya has said it plans to file an Investigational New Drug application (IND) to the FDA, or a Clinical Trial Application to the European Medicines Agency (EMA), for its most advanced gene therapy product candidate, TN-201, designed to treat genetic hypertrophic cardiomyopathy caused by Myosin Binding Protein C3 (MYBPC3) gene mutations.

TN-201, now in IND-enabling studies, is designed to deliver a fully functional MYBPC3 gene driven by our proprietary heart-specific promoter to restore normal levels of MYBPC3 protein.

Gene therapy is one of Tenaya's three platforms for discovering novel therapies for heart disease; the others apply cellular regeneration and precision medicine. In March, Tenaya said it completed a $106-million Series C financing, with the proceeds intended to advance its lead gene therapy program toward clinical studies; progress new programs toward IND-enabling studies; expand drug discovery and development capabilities; and invest in cGMP capabilities.

References

Gillmore

, Gane

, Taubel

, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med 2021 DOI: 10.1056/NEJMoa2107454. https://www.nejm.org/doi/full/10.1056/NEJMoa2107454 (last accessed July 10, 2021 ).

Intellia Therapeutics and Regeneron Pharmaceuticals Intellia and Regeneron announce landmark clinical data showing deep reduction in disease-causing protein after single infusion of NTLA-2001, an investigational CRISPR therapy for transthyretin (ATTR) amyloidosis. 2021. https://ir.intelliatx.com/news-releases/news-release-details/intellia-and-regeneron-announce-landmark-clinical-data-showing (last accessed July 10, 2021 ).

Prime Medicine. Prime Medicine launches with $315 million financing to deliver on the promise of prime editing. 2021. https://www.primemedicine.com/media/prime-medicine-launches-to-deliver-on-the-promise-of-gene-editing (last accessed July 15, 2021 ).

Anzalone

, Randolph

, Davis

, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 2019 DOI: 10.1038/s41586-019-1711-4. https://www-nature-com-s.web.bisu.edu.cn/articles/s41586-019-1711-4 (last accessed July 15, 2021 ).

Davies

. Precision chemistry on the genome: interview with David

. Liu. Human Gene Therapy 2021;32:237–242, DOI: 10.1089/hum.2021.29151.int. https://www.liebertpub.com/doi/10.1089/hum.2021.29151.int (last accessed July 15, 2021 ).

FUJIFILM Corporation. $850 million USD (¥90 billion yen) investment in FUJIFILM Diosynth Biotechnologies to add additional development and manufacturing capacity. 2021. https://fujifilmdiosynth.com/about-us/press-releases/850-million-usd-%C2%A590-billion-yen-investment-in-fujifilm-diosynth-biotechnologies-to-add-additional-development-and-manufacturing-capacity/ (last accessed July 10, 2021 ).

Biogen. Biogen announces topline results from phase 3 gene therapy study in choroideremia. 2021. https://investors.biogen.com/news-releases/news-release-details/biogen-announces-topline-results-phase-3-gene-therapy-study (last accessed July 13, 2021 ).

4D Molecular Therapeutics. 4D Molecular Therapeutics announces rare disease ophthalmology product candidate portfolio update, including initial clinical safety and tolerability data for 4D-110 for choroideremia and 4D-125 for XLRP, and termination of Roche collaboration and license. https://4dmt.gcs-web.com/news-releases/news-release-details/4d-molecular-therapeutics-announces-rare-disease-ophthalmology (last accessed July 13, 2021 ).

Kriya Therapeutics . Kriya Therapeutics completes $100 million series B financing to advance its fully integrated platform for designing, developing and manufacturing transformative gene therapies. 2021. https://kriyatherapeutics.com/kriya-therapeutics-series-b-financing/ (last accessed July 15, 2021 ).

10.

U.S. Securities and Exchange Commission . Form S-1 registration statement of Tenaya Therapeutics, Inc. 2021. https://www.sec.gov/Archives/edgar/data/1858848/000119312521212010/d175698ds1.htm#toc175698_548/000119312521212010/d175698ds1.htm#toc175698_5 (last accessed July 13, 2021 ).