A Phase I/II Clinical Trial of Lentiviral Hematopoietic Stem Cell Gene Therapy for Treatment of Developed Metachromatic Leukodystrophy and Adrenoleukodystrophy

Evaluating the safety and efficacy of Lentiviral Hematopoietic Stem Cell Gene Therapy for advanced stage of Metachromatic Leukodystrophy and adrenoleukodystrophy.

Start Date01 Jan 2015

Sponsor / Collaborator

Shenzhen Second People's Hospital

[+2]

100 Clinical Results associated with Nulabeglogene autogedtemcel

100 Translational Medicine associated with Nulabeglogene autogedtemcel

100 Patents (Medical) associated with Nulabeglogene autogedtemcel

Literatures (Medical) associated with Nulabeglogene autogedtemcel

01 Feb 1992·CytotechnologyQ4 · BIOLOGY

Modified CelliGen-packed bed bioreactors for hybridoma cell cultures

Q4 · BIOLOGY

Article

Author: David Freedman ; Avinoam Kadouri ; Corey Jacklin ; Guozheng Wang ; Wenying Zhang ; Lee Eppstein

This study describes two packed bed bioreactor configurations which were used to culture a mouse-mouse hybridoma cell line (ATCC HB-57) which produces an IgG1 monoclonal antibody. The first configuration consists of a packed column which is continuously perfused by recirculating oxygenated media through the column. In the second configuration, the packed bed is contained within a stationary basket which is suspended in the vessel of a CelliGen bioreactor. In this configuration, recirculation of the oxygenated media is provided by the CelliGen Cell Lift impeller. Both configurations are packed with disk carriers made from a non-woven polyester fabric. During the steady-state phase of continuous operation, a cell density of 10(8) cells per cm3 of bed volume was obtained in both bioreactor configurations. The high levels of productivity (0.5 gram MAb per 1 of packed bed per day) obtained in these systems demonstrates that the culture conditions achieved in these packed bed bioreactors are excellent for the continuous propagation of hybridomas using media which contains low levels (1%) of serum as well as serum-free media. These packed bed bioreactors allow good control of pH, dissolved oxygen and temperature. The media flows evenly over the cells and produces very low shear forces. These systems are easy to set up and operate for prolonged periods of time. The potential for scale-up using Fibra-cel carriers is enhanced due to the low pressure drop and low mass transfer resistance, which creates high void fraction approaching 90% in the packed bed.

News (Medical) associated with Nulabeglogene autogedtemcel

08 Mar 2024

·www.businesswire.com

Graphite Bio Declares Special Dividend In Connection with Proposed Merger with Lenz Therapeutics

SOUTH SAN FRANCISCO, Calif.--( BUSINESS WIRE )--Graphite Bio, Inc. (Nasdaq: GRPH) (“Graphite” or the “Company”) today announced that its Board of Directors has declared a special dividend in connection with the previously announced merger (the “Merger”) with Lenz Therapeutics, Inc. (“LENZ”) pursuant to the Agreement and Plan of Merger, dated November 14, 2023 (the “Merger Agreement”). The special dividend, which the Company estimates will be $1.03 per share of Graphite’s common stock, will be payable in cash to the stockholders of record as of March 18, 2024. The exact amount of the special dividend will be calculated after deducting certain cash amounts as set forth in the Merger Agreement. The payment date in respect of such special dividend will be on March 21, 2024. The special dividend will not exceed an amount equal to $60 million, subject to the adjustments set forth in the Merger Agreement. Payment of the special dividend is conditioned upon the closing of the Merger, which Graphite’s stockholders will consider and vote upon at the special meeting of Graphite’s stockholders scheduled for 9:00 a.m. PT on March 14, 2024 with closing expected to occur after market close on March 21, 2024, assuming the transaction is approved by Graphite’s stockholders and the satisfaction or waiver of all conditions under the Merger Agreement. If you need assistance in voting your shares or have questions regarding the special meeting of Graphite’s stockholders, please contact Graphite’s proxy solicitor, MacKenzie Partners, Inc. at (800) 322-2885 (toll-free) or (212) 929-5500 (collect), or email at proxy@mackenziepartners.com . About LENZ LENZ is a late-stage biopharmaceutical company focused on developing and commercializing innovative therapies to improve vision. Its product candidates, LNZ100 and LNZ101, are preservative-free, single-use, once-daily, aceclidine-based eye drops currently in Phase 3 clinical trials for the treatment of presbyopia. Presbyopia impacts an estimated 1.8 billion people globally and 128 million people in the United States. LENZ is headquartered in San Diego, California, and is backed by venture capital investors, including Versant Ventures, RA Capital Management, Alpha Wave Global, Point72, Samsara BioCapital, Sectoral Asset Management and RTW Investments. For more information, visit: LENZ-Tx.com . About Graphite Graphite has historically been a clinical-stage, next-generation gene editing company. In February 2023, Graphite announced its decision to discontinue the development of nulabeglogene autogedtemcel ("nula-cel"), Graphite’s lead product candidate for sickle cell disease, and to initiate a process to explore and review a range of strategic alternatives focused on maximizing stockholder value from Graphite’s product development assets and cash resources. For more information, please visit www.graphitebio.com . Forward-Looking Statements This communication contains “forward-looking statements” within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including but not limited to, express or implied statements regarding the structure, timing and completion of the proposed merger by and between Graphite and LENZ; the combined company’s listing on Nasdaq after the closing of the proposed Merger; expectations regarding the ownership structure of the combined company; the anticipated timing of the closing of the Merger (the “Closing”); the expected executive officers and directors of the combined company; expectations regarding the structure, timing and completion of a concurrent private financing, including investment amounts from investors, timing of closing, expected proceeds and impact on ownership structure; each company’s and the combined company’s expected cash position at the Closing and cash runway of the combined company following the Merger and private financing; the future operations of the combined company, including commercialization activities, timing of launch and buildout of commercial infrastructure; the nature, strategy and focus of the combined company; the development and commercial potential and potential benefits of any product candidates of the combined company, including expectations around market exclusivity and IP protection; the location of the combined company’s corporate headquarters; anticipated clinical drug development activities and related timelines, including the expected timing for announcement of data and other clinical results and potential submission of a New Drug Application for one or more product candidates; and other statements that are not historical fact. All statements other than statements of historical fact contained in this communication are forward-looking statements. These forward-looking statements are made as of the date they were first issued, and were based on the then-current expectations, estimates, forecasts, and projections, as well as the beliefs and assumptions of management. There can be no assurance that future developments affecting Graphite, LENZ, the Merger or the concurrent private financing will be those that have been anticipated. Forward-looking statements are subject to a number of risks and uncertainties, many of which involve factors or circumstances that are beyond Graphite’s control. Graphite’s actual results could differ materially from those stated or implied in forward-looking statements due to a number of factors, including but not limited to (i) the risk that the conditions to the Closing are not satisfied, including the failure to timely obtain stockholder approval for the transaction, if at all; (ii) uncertainties as to the timing of the consummation of the proposed Merger and the ability of each of Graphite and LENZ to consummate the proposed Merger; (iii) risks related to Graphite’s ability to manage its operating expenses and its expenses associated with the proposed Merger pending the Closing; (iv) risks related to the failure or delay in obtaining required approvals from any governmental or quasi-governmental entity necessary to consummate the proposed Merger; (v) the risk that as a result of adjustments to the exchange ratio, Graphite stockholders and LENZ stockholders could own more or less of the combined company than is currently anticipated; (vi) risks related to the market price of Graphite’s common stock relative to the value suggested by the exchange ratio; (vii) unexpected costs, charges or expenses resulting from the transaction; (viii) potential adverse reactions or changes to business relationships resulting from the announcement or completion of the proposed Merger; (ix) the uncertainties associated with LENZ’s product candidates, as well as risks associated with the clinical development and regulatory approval of product candidates, including potential delays in the completion of clinical trials; (x) risks related to the inability of the combined company to obtain sufficient additional capital to continue to advance these product candidates; (xi) uncertainties in obtaining successful clinical results for product candidates and unexpected costs that may result therefrom; (xii) risks related to the failure to realize any value from product candidates being developed and anticipated to be developed in light of inherent risks and difficulties involved in successfully bringing product candidates to market; (xiii) risks associated with the possible failure to realize certain anticipated benefits of the proposed Merger, including with respect to future financial and operating results; (xiv) the risk that the private financing is not consummated upon the Closing; and (xv) the risk that Graphite stockholders receive more or less of the cash dividend than is currently anticipated, among others. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties. These and other risks and uncertainties are more fully described in periodic filings with the SEC, including the factors described in the section titled “Risk Factors” in Graphite’s Annual Report on Form 10-K for the year ended December 31, 2023, filed with the SEC on February 27, 2024, and in other filings that Graphite makes and will make with the SEC in connection with the proposed Merger, including the Proxy Statement/Prospectus described below under “Additional Information and Where to Find It.” You should not place undue reliance on these forward-looking statements, which are made only as of the date hereof or as of the dates indicated in the forward-looking statements. Graphite expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based. This communication does not purport to summarize all of the conditions, risks and other attributes of an investment in Graphite or LENZ. No Offer or Solicitation This communication does not constitute an offer to sell or the solicitation of an offer to buy any securities nor a solicitation of any vote or approval with respect to the proposed transaction or otherwise. No offering of securities shall be made except by means of a prospectus meeting the requirements of Section 10 of the Securities Act, and otherwise in accordance with applicable law. Additional Information and Where to Find It This communication relates to the proposed Merger involving Graphite and LENZ and may be deemed to be solicitation material in respect of the proposed Merger. In connection with the proposed Merger, Graphite has filed relevant materials with the SEC, including a registration statement on Form S-4 (the “Form S-4”), which has been declared effective by the SEC and contains a definitive proxy statement and prospectus (the “Proxy Statement/Prospectus”). This communication is not a substitute for the Form S-4, the Proxy Statement/Prospectus or for any other document that Graphite may file with the SEC and or send to Graphite’s shareholders in connection with the proposed Merger. BEFORE MAKING ANY VOTING DECISION, INVESTORS AND SECURITY HOLDERS OF GRAPHITE ARE URGED TO READ THE FORM S-4, THE PROXY STATEMENT/PROSPECTUS AND OTHER DOCUMENTS FILED WITH THE SEC CAREFULLY AND IN THEIR ENTIRETY WHEN THEY BECOME AVAILABLE BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION ABOUT GRAPHITE, THE PROPOSED MERGER AND RELATED MATTERS. Investors and security holders will be able to obtain free copies of the Form S-4, the Proxy Statement/Prospectus and other documents filed by Graphite with the SEC through the website maintained by the SEC at http://www.sec.gov . Copies of the documents filed by Graphite with the SEC will also be available free of charge on Graphite’s website at www.graphitebio.com , or by contacting Graphite’s Investor Relations at investors@graphitebio.com . Participants in the Solicitation Graphite, LENZ, and their respective directors and certain of their executive officers may be considered participants in the solicitation of proxies from Graphite’s shareholders with respect to the proposed Merger under the rules of the SEC. Information about the directors and executive officers of Graphite is set forth in its Annual Report on Form 10-K for the year ended December 31, 2023, which was filed with the SEC on February 27, 2024 and other documents that may be filed from time to time with the SEC. Additional information regarding the persons who may be deemed participants in the proxy solicitations and a description of their direct and indirect interests, by security holdings or otherwise, have been included in the Form S-4, the Proxy Statement/Prospectus and other relevant materials filed, or to be filed, with the SEC. You may obtain free copies of this document as described above.

Phase 3Acquisition

13 Dec 2023

·www.fiercebiotech.com

After long-running patent battle, Vertex pays $100M to license Editas’ gene-editing tech

Vertex is paying for non-exclusive licensing rights to Editas’ Cas9 tech for ex vivo gene-editing medicines targeting the BCL11A gene in SCD and beta thalassemia, including CRISPR Therapeutics-partnered Casgevy. After receiving the FDA greenlight for its sickle cell disease (SCD) gene therapy, Vertex Pharmaceuticals is paying up to $100 million—plus potential licensing fees—for rights to Editas Medicines’ Cas9 gene-editing tech, a deal that encompasses freshly approved Casgevy. Under the new deal, Vertex secures non-exclusive licensing rights to Editas’ Cas9 tech for ex vivo gene-editing medicines targeting the BCL11A gene in SCD and beta thalassemia, including CRISPR Therapeutics-partnered Casgevy (exagamglogene autotemcel), which just nabbed FDA approval Dec. 8. Besides receiving $50 million in upfront cash, Editas is eligible to receive another $50 million through a contingent payment. Editas didn't disclose what would trigger the other $50 million payment. The biotech also has the chance to receive yearly licensing fees ranging from $10 to $40 million per year through the patent's expiry in 2034, an Editas spokesperson told Fierce Biotech via email. The payment is part of a long-running legal battle brought by two universities and one of the founders of the gene-editing technique, Nobel Prize winner Emmanuelle Charpentier, Ph.D. Alongside fellow Nobel Prize laureate Jennifer Doudna, Ph.D., Charpentier created a type of genetic scissors that can be used to cut any DNA molecule. This was dubbed CRISPR/Cas9 and has been used to create gene-editing therapies by dozens of biotechs, including Editas, which licensed the tech from the Broad Institute of MIT. Last February, the U.S. Patent and Trademark Office ruled in favor of the Broad Institute of MIT and Harvard over Charpentier, the University of California, Berkeley and the University of Vienna. After that decision, Editas became the exclusive licensee of certain CRISPR patents for developing human medicines, including a Cas9 patent estate owned and co-owned by Harvard University, Broad Institute, the Massachusetts Institute of Technology and Rockefeller University. Now, Editas will send a portion of the payments from Vertex to the Broad Institute and Harvard, according to Dec. 12 documents filed with the Securities and Exchange Commission. The legal battle isn’t over yet, though, with Charpentier and two universities officially appealing the decision last spring. "The interference proceeding in front of the Federal Circuit is moving forward as expected," the Editas spokesperson said. "We are waiting for the oral argument to be scheduled and we expect the oral argument will be scheduled early next with a decision following mid-next year." The non-exclusivity aspect of the Editas-Vertex deal means the agreement only covers using the BCL11A gene. New deals would have to be made for other uses. Though the long-term fate of the patents remains unclear, Editas benefits immediately from the Vertex payments, with the deal pushing the biotech’s cash runway into 2026. As of the company's Q3 financial results, Editas previously had enough money to take it into the third quarter of 2025. “We are pleased with the financials—the upfront payments extending our cash runway into and ensuring this game-changing technology can reach more patients in need of transformative medicines,” the Editas spokesperson said. The deal comes after the FDA approval of not one but two gene therapies to treat SCD—Vertex’s and CRISPR Therapeutics’ Casgevy and bluebird bio’s Lyfgenia (lovo-cel). The therapies are long-awaited treatments for the debilitating and life-threatening disease that affects more than 100,000 Americans, most of them Black. This leaves Editas with the tough task of differentiating its own SCD candidate, dubbed renizgamglogene autogedtemcel (reni-cel), from the two approved treatments. The gene-editing biotech has bet a lot on reni-cel, clearing out the majority of its pipeline earlier this year to focus its efforts on the investigational medicine amid unrelenting difficult market conditions. Faced with the likelihood of an exa-cel approval, many other companies—such as Graphite Bio, Sangamo Therapeutics and Intellia-partnered Novartis—shelved their own SCD candidates. In contrast, Editas doubled down on reni-cel, previously dubbed EDIT-301, by funneling more cash into the program to accelerate its trial. On Dec. 11, the Massachusetts-based biotech shared new data from two separate phase 1/2 trials assessing reni-cel among patients with severe SCD or transfusion-dependent beta thalassemia (TDT) at the 65th American Society of Hematology Annual Meeting and Exposition. The gene-editing biotech assessed reni-cel in 11 patients with SCD and six patients with TDT and found that the ex vivo asset showed a safety profile consistent with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant. No serious adverse events tied to reni-cel were reported.

License out/inGene TherapyASH

11 Dec 2023

·www.fiercebiotech.com

ASH: After landmark FDA approvals, Editas still thinks its gene therapy differentiates itself enough from competition

Editas has bet a lot on reni-cell, clearing out the majority of its pipeline earlier this year to focus on the ex vivo gene therapy. On the heels of Friday’s FDA approval of not one but two gene therapies to treat sickle cell disease (SCD), Editas Medicine is sharing another slice of early data for its gene-edited candidate designed to tackle the same condition. The new data span 17 patients who received Edita’s renizgamglogene autogedtemcel (reni-cel), either in a phase 1/2 trial dubbed RUBY for severe SCD or in a separate phase 1/2 trial known as EdiTHAL for transfusion-dependent beta thalassemia (TDT). The results build off a previous dataset shared this summer, incorporating information from 12 more patients, and were presented on Dec. 11 at the 65th American Society of Hematology Annual Meeting and Exposition. The gene-editing biotech assessed lead candidate reni-cel among 11 patients with SCD and six patients with TDT and found that the ex vivo asset showed a safety profile consistent with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant. No serious adverse events tied to reni-cel have been reported. All 11 RUBY patients are free of vaso-occlusive events (VOEs)—debilitating pain episodes—and have maintained normal hemoglobin levels and a fetal hemoglobin level of at least 40% in the five-plus months after treatment. Reni-cel’s data are compared to Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy (exa-cel), another CRISPR-edited therapy that just received FDA approval in the indication. Interim data reported in June showed that 15 of 16 (94%) SCD patients treated with exa-cel didn’t have VOEs for at least 12 consecutive months, which was the primary endpoint measured. The benefits are expected to be lifelong, Vertex and CRISPR have said. Another trial assessing exa-cel among TDT patients, meanwhile, showed that 89% achieved the primary endpoint of transfusion independence for at least 12 consecutive months. The FDA is scheduled to make a decision on exa-cel in that indication by March 30 of next year. Editas has shared that in its EdiTHAL trial, all patients with TDT had an early and robust increase of total hemoglobin, above the transfusion independence threshold of 9 g/dl. “These new and promising data with a larger patient cohort support our belief that reni-cel can be a clinically differentiated, one-time, durable medicine that can provide life-changing clinical benefits to patients with sickle cell disease and beta thalassemia, specifically driving early and robust correction of anemia and sustained increases in fetal hemoglobin,” Baisong Mei, M.D., Ph.D., Editas’ senior vice president and chief medical officer, said in a Dec. 11 release. “We look forward to dosing additional patients and sharing further RUBY and EdiTHAL clinical updates in mid-2024.” Editas has bet a lot on reni-cel, clearing out the majority of its pipeline earlier this year to focus efforts on the investigational medicine amid unrelenting difficult market conditions. Faced with the likelihood of an exa-cel approval, many other companies—such as Graphite Bio, Sangamo Therapeutics and Intellia-partnered Novartis—shelved their SCD candidates. In contrast, Editas doubled down on reni-cel, previously dubbed EDIT-301, funneling more cash into the program to accelerate its trial. Now, Editas faces the tough task of differentiating reni-cel from not just exa-cel, but also bluebird bio’s Lyfgenia (lovo-cel), which was also approved Friday for patients with SCD. The therapies are long-awaited treatments for the debilitating and life-threatening disease that affects more than 100,000 Americans, most of them Black.

Clinical ResultDrug ApprovalASHGene Therapy

100 Deals associated with Nulabeglogene autogedtemcel

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Indication	Highest Phase	Country/Location	Organization	Date
Anemia, Sickle Cell	Phase 2	US	Graphite Bio, Inc.	15 Nov 2021

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASH2023	Phase 1/2	Anemia, Sickle Cell	1	Nula-Cel	rjnddnwhfu(bkwvzykekh) = Hemoglobin electrophoresis demonstrated increased levels of HgbF gmllhglkey (ngawmzatrf ) View more	-	11 Dec 2023

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