Feliza Mirasol is the science editor for 

Feliza Mirasol

FDA has approved Ultomiris (ravulizumab-cwvz), making it the first and only long-acting C5 complement inhibitor in the United States for treating adult patients with anti-aquaporin-4 (AQP4) antibody-positive (Ab+) neuromyelitis optica spectrum disorder (NMOSD). AstraZeneca announced the approval on March 25, 2024.

The approval was based on positive results from a Phase III trial (CHAMPION-NMOSD) that showed Ultomiris met the primary endpoint of time to first on-trial relapse. Zero relapses were observed among patients treated with Ultomiris. The median treatment duration was 73 weeks with a relapse risk reduction of 98.6%.

Sean J. Pittock, the director of the Mayo Clinic's Center for Multiple Sclerosis and Autoimmune Neurology and of Mayo's Neuroimmunology Laboratory and lead primary investigator in the Phase III trial, said in the press release that, “C5 inhibition has been proven to offer efficacy in reducing the risk of NMOSD relapses by blocking the complement system, a part of the immune system, from attacking healthy cells in the spinal cord, optic nerve, and brain. With today’s FDA approval, patients now have the option of a long-acting C5 inhibitor treatment that showed zero relapses in the pivotal CHAMPION-NMOSD trial, supporting the primary goal of relapse prevention in treating NMOSD.” 

Sean J. Pittock, MD, director, Center for Multiple Sclerosis and Autoimmune Neurology and Neuroimmunology Laboratory, Mayo Clinic. Lead primary investigator in the CHAMPION-NMOSD trial. Image courtesy of Mayo Clinic.

Ultomiris is also approved for certain adults with NMOSD in Japan and the European Union, while regulatory reviews in additional countries remain ongoing.

NMOSD is known to be a rare and debilitating autoimmune disease. It affects the central nervous system, including the spine and optic nerves. Most people living with the disease experience unpredictable relapses, which involve a new onset of neurologic symptoms or the worsening of existing neurologic symptoms. These relapses tend to be severe and recurrent and carry the risk of causing permanent disability. Approximately 6000 adults in the US are estimated to be affected by NMOSD, according to AstraZeneca in the press release.

“Alexion has been at the forefront of innovation in NMOSD, striving to offer patients a future without fear of life-altering or even fatal relapses. Building on the established efficacy of C5 inhibition for people living with AQP4 Ab+ NMOSD, we are proud to deliver a transformative, long-acting treatment option that has the potential to eliminate relapses with a convenient dosing schedule every eight weeks. We are grateful to the NMOSD community for their ongoing collaboration and input, which enables us to advance science for rare diseases,” said Marc Dunoyer, chief executive officer, Alexion, the group within AstraZeneca focused on rare diseases, in the press release.

The rare disease group was created following the completion of AstraZeneca’s approximately $13.3 billion acquisition of Alexion Pharmaceuticals in 2021 (1). With the acquisition, AstraZeneca strengthened its scientific presence in immunology, allowing the company to address the significant unmet medical need in the rare diseases sector. Alexion’s focus is on research in novel molecules aimed toward development of therapeutics for hematology, nephrology, neurology, metabolic disorders, cardiology, and ophthalmology.

1. AstraZeneca. Acquisition of Alexion Completed. Press Release, July 21, 2021.

Articles

FDA has approved AstraZeneca's Ultomiris, marking the first and only long-acting C5 complement inhibitor for patients with NMOSD.

AstraZeneca Gains FDA Nod for Ultomiris, a Treatment for Managing NMOSD

AbbVie has entered into a definitive agreement to acquire Landos Biopharma, a clinical-stage biopharmaceutical company focusing on autoimmune diseases, following an earlier approval of ELAHERE (mirvetuximab soravtansine-gynx), a new antibody-drug conjugate (ADC) for treating ovarian cancer, by FDA, the company announced on March 25, 2024.

Under the Landos agreement, AbbVie will acquire Landos for $20.42 per share, an aggregate value of approximately $137.5 million, in cash upon closing. The deal also includes one non-tradable contingent value right per share at a value of up to $11.14 per share (approximately an additional $75 million in aggregate), dependent on achieving a clinical development milestone. The transaction is expected to close in the second quarter of 2024

The Landos acquisition includes a lead asset, NX-13, an oral nucleotide oligomerization domain-like receptor family member X1 (NLRX1) agonist with a bimodal mechanism of action (MOA) that is anti-inflammatory and that facilitates epithelial repair. NX-13 is in a Phase II clinical trial (NEXUS ) in the United States and Europe for treating ulcerative colitis (UC). According to AbbVie in a company press release, “NLRX1 regulates immunometabolism and inflammation, and its activation impacts multiple mechanisms of inflammatory bowel disease (IBD) pathogenesis.”

"This announcement is a testament to Landos' talented team and their commitment to our mission of creating oral treatments that can address a therapeutic gap," said Gregory Oakes, president and chief executive officer, Landos, in the press release. "NX-13 and its bimodal MOA have the potential to provide a novel approach to the treatment of ulcerative colitis and Crohn's disease. With AbbVie's therapeutic area leadership and expertise in global development, they are the right company to further advance NX-13."

The March 22, 2024 full approval granted by FDA for ELAHERE, meanwhile, advances the field of ADC therapeutics. ELAHERE is now indicated for treating adult patients with folate receptor-alpha (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. The indication is specifically for those patients who have received one to three prior systemic treatment regimens.

, which came to AbbVie with its acquisition of ImmunoGen in February 2024 (1), was first granted 

 by FDA in November 2022 (2). Full approval was based on a confirmatory Phase III trial (MIRASOL), whose data showed that treatment with ELAHERE resulted in an overall survival benefit and a reduced risk of cancer progression by 35%, according to a company press release.

"The full FDA approval of ELAHERE for eligible patients with ovarian cancer represents the culmination of years of work by the ImmunoGen team. ELAHERE is the first and only antibody-drug conjugate (ADC) approved in the US for this difficult-to-treat malignancy," said Roopal Thakkar, senior vice-president, chief medical officer, global therapeutics, AbbVie, in the press release

"As the first treatment to show a statistically significant overall survival benefit in patients with platinum-resistant ovarian cancer, ELAHERE provides an effective new option for patients with folate receptor alpha positive tumors. These patients previously had very limited options and ELAHERE changes that," said Kathleen Moore, deputy director and associate director of clinical research at the Stephenson Cancer Center of The University of Oklahoma and MIRASOL principal investigator.

A marketing authorization application for the ADC in Europe has been accepted by the European Medicines Agency, and regulatory submissions are also under review in multiple other countries.

1. AbbVie. AbbVie Completes Acquisition of ImmunoGen. Press Release, Feb. 12, 2024.
2. FDA. 

FDA Grants Accelerated Approval to Mirvetuximab Soravtansine-Gynx for FRα Positive, Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer

The Landos acquisition adds a lead asset in autoimmune and inflammatory disease to AbbVie's portfolio, while the company's ADC, ELAHERE, gets full FDA approval. 

AbbVie Gains Landos Biopharma and Full FDA Approval for ADC Product

Editor's note: this story was originally published in BioPharmInternational.com.

Roche has entered into an agreement to sell its large-scale biologics manufacturing site in Vacaville, Calif., to Lonza for $1.2 billion, Lonza announced on March 20, 2024. Lonza plans to invest approximately CHF 500 million (US$557 million) to upgrade the facility and enhance capabilities at the site for next-generation mammalian biologics.

The deal is expected to close in the second half of 2024, subject to customary closing conditions. The Vacaville site will be integrated into Lonza’s Biologics division upon closing and will be included in Lonza’s network of existing mammalian manufacturing sites in Visp, Switzerland; Slough, United Kingdom; Tuas, Singapore; Portsmouth, NH; and Porriño, Spain (1).

“The Vacaville site is a highly valuable strategic acquisition that will make capacity immediately available for our customers and unlock future growth for our Biologics division. It will support us in providing a commercialization path to existing customers and incremental large-scale commercial capacity to our partners,” said Jean-Christophe Hyvert, president, Biologics, Lonza, in a company press release.

Lonza will supply the products currently manufactured by Roche at the Vacaville site in the medium term as it phases out those products over time to serve alternative customers. With a total bioreactor capacity of approximately 330,000 L, Lonza expects the Vacaville acquisition to significantly increase its large-scale biologics manufacturing capacity, allowing it to meet demand for commercial mammalian contract manufacturing from customers with existing commercial products. The facility will also serve molecules within Lonza’s network that are currently on the path to commercialization.

The facility’s capacity makes it one of the largest biologics manufacturing sites in the world by volume, according to the Lonza company press release. Because demand for commercial-scale capacity for biologics is expected to remain high across the contract development and manufacturing organization industry as the result of anticipated approvals for innovative new therapies, the acquisition puts Lonza in a position to offer immediate access to significant new capacity in the United States. The move also creates a significant West Coast commercial manufacturing presence, which complements Lonza’s existing biologics site on the East Coast (Portsmouth, NH). The US sites also complement Lonza’s manufacturing network across Europe and Asia.

“Demand for biologics manufacturing capacity by volume is projected to reach nearly 4400 kL, a five-year growth rate of nearly 11.5% per year (just over 2500 kL in 2022). Global biologics manufacturing capacity will increase to nearly 8400 kL by 2027 from nearly 6500 kL in 2023,” according to the 2023 CPHI annual report (2).

“We have deep and long-standing industrial expertise in delivering commercial-scale manufacturing services for our customers’ therapies. In combining this with the strong legacy of the Vacaville facility, its highly skilled colleague community, and its proven track record on quality, we are excited to take our leading large-scale mammalian offering to its next chapter of growth,” Hyvert said in the press release.

Under the transaction, Lonza will offer positions to the approximately 750 Genentech employees working at the Vacaville facility.

1. Lonza. Mammalian Biopharmaceutical Services. 

 (accessed March 25, 2024).
2. Ecker, D. M.; Seymour, P. Supply and Demand Trends: 2022-2027 Mammalian Biomanufacturing Industry Overview. In 

The Vacaville, Calif., site acquisition gives Lonza one of the largest biologics manufacturing sites for mammalian cell-based therapies worldwide.

Roche Sells Large-Scale Biologics Manufacturing Site in US to Lonza for $1.2 Billion

Editor's note: this story was originally published on 

Belgium-based contract development and manufacturing organization (CDMO) White Raven and Cytiva announced on March 19, 2024, that White Raven is installing Cytiva's SA25 Aseptic Filling Workcell at its fill/finish site. This installation completes White Raven’s drug product platform and will increase its manufacturing efficiency. The site is expected to be good manufacturing practice (GMP)-compliant with the new system by the end of 2024.

SA25 is an integrated gloveless robotic isolator that eliminates the need for operator intervention, according to a company press release. The system is designed to provide an optimal aseptic process and comprises a standardized flexible filler that is capable of producing vials, syringes, and cartridges in batch sizes ranging from 100 to up to 20,000 units. The system has a fill-volume range of 0.2 mL – 50 mL. Because it is a closed robotic system, it reduces the risk of product contamination. It also allows for changeover between drug formats within a 45-minute timeframe.

Ludovic Brellier, president, Biotechnology Integrated Solutions and Business Operations, Cytiva. Image courtesy of Cytiva.

“White Raven recognizes that by replacing a human operator with a robotic gloveless isolator, they can remove the biggest risk for contamination—ensuring they are taking the right steps to protect customers’ high value drug products. The need for greater standardized solutions to improve this process is a trend we are seeing across the industry,” Ludovic Brellier, president of Biotechnology Integrated Solutions and Business Operations, Cytiva, says.

White Raven offers a range of formulation services adapted to clinical batches and is capable of working with mixing volumes as low as 50 mL and up to 20 L. The CDMO also offers GMP formulation and aseptic filling of injectable drugs for pre-clinical, clinical, and orphan drugs. White Raven employs single-use consumables over the full aseptic filling process to also reduce contamination risk.

The company is part of Cytiva’s aseptic filling user group, which is a group that works closely with Cytiva to collaborate on best practices, such as system validation and operations. White Raven expects the installed workcell to complete a site acceptance test by mid-2024, prepping the site for GMP readiness by end of the year.

Considerations for improving aseptic operations in the bio/pharma industry are an ongoing exercise for manufacturers. Automation technologies have been a major solution in this area. However, in one sense, automated aseptic processes can be seen as “often playing catch up to the new tools that are being developed,” according to Dan Strange, chief technology officer at Cellular Origins, in a 

 video interview (1). “These consumables and equipment … have been fundamentally designed for manual processes … and that's very hard to automate. It's … straightforward for a manual operator to automate, but it's hard for traditional automated systems to handle that,” Strange noted in the interview.

Drug Digest: Improving Aseptic Processing and Manufacturing Needs

CDMO White Raven aims to reduce contamination risk and gain the capability to handle multiple product formats with the installation of Cytiva’s SA25 Aseptic Filling Workcell.

White Raven to Increase Manufacturing Efficiency with Cytiva’s Aseptic Filling Workcell

FDA has approved Lenmeldy (atidarsagene autotemcel) from Orchard Therapeutics, making it the first approved gene therapy for treating children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy (MLD) in the United States. Following the March 18, 2024, approval, AGC Biologics announced that it will be manufacturing the therapy at its Milan, Italy, site.

According to a FDA press release, MLD is a debilitating, rare genetic disease that affects the brain and nervous system caused by a deficiency of the arylsulfatase A (ARSA) enzyme. This deficiency leads to a buildup of sulfatides in the cells, which causes damage to the central and peripheral nervous system, leading to a loss of motor and cognitive function and early death. MLD is estimated to affect one in every 40,000 individuals in the US, and there is no cure for it. Currently, treatment typically focuses on supportive care and management of symptoms.

Peter Marks, director, FDA’s Center for Biologics Evaluation and Research (CBER). Image courtesy of FDA.

“This is the first FDA-approved treatment option for children who have this rare genetic disease,” said Peter Marks, director of FDA’s Center for Biologics Evaluation and Research (CBER), in the press release. “We remain committed to advancing scientific and regulatory principles that enable the efficient development and review of safe, effective and innovative products that have the potential to change patients’ lives.”

Lenmeldy, derived from the patient’s own hematopoietic stem cells (HSCs), is a one-time, individualized single-dose infusion. The patient’s HSCs are collected and genetically modified to include functional copies of the ARSA gene. The modified cells are then transplanted back into the patient where they engraft within the bone marrow and supply the body with ARSA enzyme-producing myeloid cells. The enzyme helps break down the build-up of sulfatides and may stop the progression of MLD. Prior to treatment with Lenmeldy, patients must undergo high-dose chemotherapy to removes cells from the bone marrow that can then be replaced with the modified HSCs, according to the FDA release.

“This approval represents important progress in the advancement and availability of effective treatments, including gene therapies, for rare diseases,” said Nicole Verdun, director of the Office of Therapeutic Products in CBER. 

Nicole Verdun, director, Office of Therapeutic Products, CBER. Image courtesy of FDA.

The application for Lenmeldy received priority review, orphan drug, rare pediatric disease, and regenerative medicine advanced therapy designations.

Following Lenmeldy’s approval, contract development and manufacturing organization (CDMO), AGC Biologics, announced that its Milan, Italy, site has received clearances from both US and European regulators and can now use approved commercial processes to supply patients with the gene therapy. The company will begin commercial manufacturing for the lentiviral vector and genetically modified cell drug product (DP) for Lenmeldy at the site.

“It is wonderful to see Orchard Therapeutics reach this goal. This accomplishment is a strong proof point of our commitment at AGC Biologics to collaborating directly with developers to meet rigorous regulatory standards and achieve the best possible results for our partners,” said Patricio Massera, CEO, AGC Biologics, in a March 18, 2024 company press release.

According to the company press release, the Milan site has become the only CDMO site to receive FDA clearance to commercially produce this gene therapy for US patients. AGC Biologics stated in the release that the FDA approval is “the culmination of a partnership that started in 2018 with Orchard Therapeutics, which also includes guiding the product through commercial approval by the European Commission (EC) in 2021 [under the European brand name Libmeldy] (1). AGC Biologics’ Milan site is uniquely connected to this product’s full lifecycle, as the facility and our scientific teams partnered with each company that owned this treatment’s IP [intellectual property] over the [p]ast 20 years to help advance it from research and development stages to this DP commercial milestone.”

Luca Alberici, general manager of AGC Biologics Milan, stated in the release, “We congratulate Orchard for reaching this important stage. Our team has had the privilege of supplying every clinical milestone for Lenmeldy and are glad to see it reach FDA approval. I am proud of the work of the Milan team.This demonstrates our unique ability to collaborate on technical processes to deliver groundbreaking treatments to patients worldwide. This approval makes our site one of the rare few in the viral vector and genetically modified cells field that has commercial manufacturing authorization from two of the world’s leading regulatory authorities."

"AGC Biologics has played a pivotal role as a strategic partner throughout the clinical development and commercial scale-up of atidarsagene autotemcel, which helped facilitate regulatory approvals in Europe and the US," added Nicoletta Loggia, chief technical officer of Orchard Therapeutics, in the company press release. "Utilizing our … commercial HSC gene therapy manufacturing platform, we have consistently met the demands for drug product production since the European launch in early 2021. This has enabled us to provide treatment to patients from three continents, including Europe on a commercial basis, the Middle East through treatment abroad programs, and the US, under compassionate use. With the recent US approval, we are excited to further expand access to this vital therapy for eligible children with early-onset MLD."

1. Orchard Therapeutics. Orchard Therapeutics Receives EC Approval for Libmeldy for the Treatment of Early-Onset Metachromatic Leukodystrophy (MLD). Press Release, Dec. 21, 2020.

FDA's approval makes Orchard Therapeutics' Lenmeldy (atidarsagene autotemcel) the first gene therapy approved to treat pediatric metachromatic leukodystrophy in the US.

FDA Greenlights Orchard Therapeutics' Gene Therapy for Children's MLD; AGC Biologics Selected for Manufacturing

On March 13, 2024, Japan=based Ricoh Company, a digital services company, and Ireland-based ERS Genomics announced that they have entered into a non-exclusive licensing agreement in the United States and Japan that gives Ricoh access to clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) genome editing technology patents managed by ERS Genomics.

CRISPR/Cas9 has been shown to be a breakthrough gene editing technology as it enables relatively easy modification of targeted genome sequences. It has become an essential tool in drug discovery research and has application across other fields, according to Ricoh in a company press release. The CRISPR technology is “

” that UK Medicines and Healthcare products Regulatory Agency’s (MHRA’s) approval of Casgevy in November 2023 “caused quite a stir in both the medical and pharmaceutical worlds” (1,2). Alongside FDA’s approval of Casgevy in December 2023, the regulatory authorities’ approvals mark a significant 

 in the biopharma industry (3,4). Casgevy is the first therapeutic based on CRISPR/Cas9 gene-editing technology to be approved by regulatory authorities anywhere in the world (4).

As part of Ricoh’s strategy with its recent moves, the company is aiming to predict the mechanism of action of drug candidates for patients with varied genetic backgrounds. The goal is to improve the speed and efficiency with which messenger RNA (mRNA) is designed; the company plans to achieve this goal by combining certain core technologies with the CRISPR/Cas9 genome editing technology. In 2022, the company completed the acquisition of Baltimore, Md.-based Elixirgen Scientific (5), whose core technologies enable the rapid and efficient differentiation of human induced pluripotent stem cells as well as the design, production, and management of mRNA.

By manipulating the genetic editing of cells to enhance or diminish specific functions, it thus becomes possible to create highly reliable disease models, including models for rare diseases. Ricoh expects that such an advancement will lead to shorter drug development timelines and increased success rates, according to the company press release. Meanwhile, following through on its acquisition of Elixirgen Scientific, Ricoh has been expanding the application areas for that company’s technology through its expertise in digital and artificial intelligence technologies.

New Medicines, Markets, and Manufacture: CRISPR for Sickle Cell Disease and β-thalassemia

 online, Nov. 30, 2023.
2. Vertex Pharmaceuticals. Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, CASGEVY (exagamglogene autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. Press Release, Nov. 16, 2023.
3. FDA. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. Press Release, Dec. 8, 2023.
4. Mirasol, F. 

Milestone Approval to Steady Stream, Gene Editing Revs Up

 (2), 16–19,25.
5. Ricoh. Ricoh to Strengthen Support for Drug Discovery Services Using mRNA. Press Release, May 17, 2022.

Ricoh aims to create novel disease models for R&D using ERS Genomics’ CRISPR/Cas9 genome editing technology.