Susan Haigney

Retrofitting Facilities for Cell and Gene Therapy Production

In his episode of Ask the Expert, Peter Walters, Fellow of Advanced Therapies at CRB Group, discusses the retrofitting of older and/or solid-dosage facilities into sustainable cell and gene therapy manufacturing facilities. According to Walters, cell and gene therapy facilities can be made very lean and sustainable, with some being 100% electric.“A lot of that has to do with the fact that there isn't a huge utility draw for that process,” says Walters. “A lot of those materials are going to be typically purchased and either made off site and brought in, or are made on site, but are low water usage, low utility usage.”

Walters says that, when retrofitting a facility, air handling, air locking, and personnel flows are factors to consider. “Cell therapy facilities tend to have at least a handful of spaces that want to be very high classified, and so you're [going to] need not only the air handling—ability to push a lot of air through those spaces in a very clean manner—but the air locking to get the material segregation movements [and] the personnel flows to get into those highly classified spaces. As we talk about gene therapy, sometimes viral vector spaces want to be BSL [biosafety level] spaces. They want to have certain levels of segregation. It's not uncommon to see vector facilities that have [a] two-corridor system; one dedicated to the supply of materials and one dedicated to outgoing waste and outgoing materials, and that helps drive segregation of flows and materials through your facility. It can be difficult to find a facility that's set up in such a way [as] to facilitate an easy retrofit.”

Click the video above to watch Walters answer the following question:

We wish to retrofit our solid-dosage facility into a sustainable facility for cell and gene therapy commercialization. What kind of cost should we expect?

Peter Walters is Fellow of Advanced Therapies at CRB Group.

Welcome to the Ask the Expert video series. This series is an extension of the PharmTech Group’s long-running print column in which industry experts answer common quality and regulatory questions from the industry. This new video series will expand on topic areas to include development and manufacturing concerns to help those working in the industry better understand bio/pharmaceutical requirements. Have a question you would like answered? Send it to 

, and it may appear in a future episode or print column.

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In this episode of the Ask the Expert video series, Peter Walters, Fellow of Advanced Therapies at CRB Group, discusses how facilities used for solid dosage manufacturing may be retrofitted into sustainable cell and gene therapy production facilities.

Science laboratory test tubes, laboratory equipment | Image Credit: © BillionPhotos.com - © BillionPhotos.com - stock.adobe.com

FDA has approved a vaccine to prevent lower respiratory tract disease resulting from the respiratory syncytial virus (RSV) in adults 18 to 59 years of age who are at increased risk, Pfizer announced on Oct. 22, 2024. The bivalent RSV prefusion F vaccine, Abrysvo, has a broader indication to include those younger than 60 and is the only RSV vaccine approved in pregnant people who are at 32 through 36 weeks of gestation, and infants from birth to six months of age, according to the company (1).

“In the prefusion state, the RSV fusion protein (F) is a major target of neutralizing antibodies, serving as the basis of Pfizer’s RSV vaccine. Variations in the F protein sequence among RSV-A and RSV-B subgroups are clustered in a key antigenic site, a target for potent neutralizing antibodies,” stated the company (1).

According to Pfizer, FDA made its decision based on results from a Phase III clinical trial(NCT05842967), MONeT (RSV I M munizati ON Study for Adul T s at Higher Risk of Severe Illness), which looked at the safety and efficacy in adults with certain chronic medical conditions, such as asthma and diabetes.

“Immunocompromised adults, such as patients with cancer or autoimmune disorders, have a substantially increased risk of experiencing severe complications from RSV, yet there are currently no vaccines approved for those aged 18 to 59 in the [United States],” said Annaliesa Anderson, Pfizer senior vice president and chief scientific officer for vaccine research and development, in an August 2024 press release about the results (2). “We are encouraged by the positive top-line data from this study, which provide important evidence that Abrysvo has the potential to address a significant unmet need in this vulnerable population.”

“RSV represents a significant threat to younger adults with certain chronic conditions. After decades of vaccine research by the scientific community and Pfizer, we now have the opportunity to help alleviate the burden of RSV in this high-risk adult population,” said Aamir Malik, chief US commercial officer and executive vice president, Pfizer, in a press release (1). “With this approval, we are proud that Abrysvo is now the only RSV vaccine indicated for adults aged 18 to 49 at increased risk for the disease, expanding on its existing indications for older adults and pregnant women.”

Abrysvo was also granted marketing authorization in the European Union by the European Commission in August 2023 for older adults and maternal immunization (3).

“The approval of ABRYSVO in Europe marks significant progress in the scientific community's efforts to provide meaningful protection against RSV, a common respiratory virus that could potentially be severe and even life-threatening, especially for infants and older adults,” said Anderson, at the time (3). “Last year’s significant number of newborns, children, and adults being hospitalized across Europe demonstrated the immense need for protection against severe RSV cases. The approval of the vaccine for both older adults and infants through maternal immunization is a triumph for public health and we hope to see a tremendous impact for future seasons.”

Pfizer.U.S. FDA Approves Pfizer’s RSV Vaccine Abrysvo for Adults Aged 18 to 59 at Increased Risk for Disease. Press Release. Oct. 22, 2024.

Pfizer. Pfizer Announces Top-Line Results of Abrysvo for RSV in Immunocompromised Adults. Press Release. Aug. 12, 2024.

Pfizer. European Commission Approves Pfizer’s Abrysvo to Help Protect Infants through Maternal Immunization and Older Adults from RSV. Press Release. Aug. 24, 2023.

Articles

Pfizer’s bivalent RSV prefusion F vaccine has been approved to prevent lower respiratory tract disease resulting from the respiratory syncytial virus in adults 18 to 59 years of age who are at increased risk.


FDA Approves RSV Vaccine

On Oct. 18, 2024, REGiMMUNE and Kiji Therapeutics announced the two companies are intending to merge, creating a specialty company, REGiMMUNE/Kiji TX, for regulatory T cells (Tregs) targeting drugs for multiple modalities and indications. The two companies’ complementary portfolios will be used to create the new Treg biotech to address unmet needs by the modulation of the Treg function.

Treg function has been increased by both companies in different ways; REGiMMUNE has regulated the role of the Treg with a molecule enhancer to increase Treg function, and Kiji TX uses next-generation multigene engineered cell therapy IL10 enhancers to increase Treg anti-autoimmune functions. To reduce or eliminate Treg function, REGiMMUNE uses monoclonal antibodies. By combining these technologies, the companies hope to create an international Treg specialist that will focus on immune-oncology and autoimmunity.

REGiMMUNE/Kiji TX will target its pipeline on four therapies. “It will establish proof of concept with gene engineered mesenchymal stem cells (KJ01) in graft-versus-host disease (GvHD), and prepare for clinical entry in the second half of 2025, develop its iPSC platform (KJ02) for inflammatory bowel disease (IBD), psoriasis and CNS disorders, define clinical readiness with a Treg depleting/inhibiting monoclonal antibody (RGI6004) and advance clinical development with the launch of a Phase III clinical trial with a clinical stage small molecule Treg enhancer targeting GvHD (RG2001),” the companies stated in a press release (1).

“Tregs have proved themselves to be a leading promising modality in the cell and gene therapy field, both therapeutically and commercially. As a result of this potential, we have collectively created a global Treg specialist super-company to realize this potential,” said Miguel Forte, CEO, Kiji TX, in the release. “We will also be able to combine several fields, including small molecule, CGT and monoclonal antibodies to use Tregs to their full potential. These approaches are off-the-shelf and allogeneic, with a competitive advantage over autologous or patient matched Treg approaches currently in development in the sector. The new company now has a variety of options, including an IPO by mid-2025 in the Taiwan Stock Exchange. This will enable REGiMMUNE/Kiji TX to develop our multiple therapeutic pipeline in-house, as well as partnering for co-development or out-licensing.”

“Modulating Treg function in both directions has significant potential in a variety of conditions with major commercial benefits. Creating the new Treg specialist REGiMMUNE/Kiji TX will result in a company that will have the resources to achieve this potential. With a planned IPO in 2025, we will be able to combine leading modalities to develop therapies for conditions involving significant numbers of patients globally,” said Kenzo Kosuda, CEO, REGiMMUNE, in the release. “The global reach of the company and experience of the senior management also enables us to explore development across the globe to match the therapeutic potential and size of the market that is open to us.”

REGiMMUNE Limited, a clinical-stage biopharmaceutical company based in Taiwan, specializes in immunotherapies by harnessing Tregs for immune diseases and cancer. Kiji Therapeutics specializes in next-generation IPSC-MSC engineered cell therapy for inflammatory diseases. Kiji TX is developing superior potency multi-gene engineered stem cell therapies.

1. Kiji Therapeutics and REGiMMUNE. REGiMMUNE and Kiji Therapeutics Announce Intention to Merge. Press Release. Oct. 18, 2024.

The merger will create a specialty company, REGiMMUNE/Kiji TX, for regulatory T cells.

REGiMMUNE and Kiji Therapeutics to Merge

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The European Medicines Agency announced on Oct. 18, 2024 that its Committee for Medicinal Products for Human Use (CHMP) has recommended 10 new medicines for marketing approval, including five new drugs, one orphan drug, two biosimilars, and two generic drugs (1). This brings the total of new medicines receiving positive opinions to 89 in 2024. Extensions for indications were also granted to six drugs.

Two vaccines, Fluad and Flucelax, were approved for immunization against influenza. Fluad is a surface antigen, inactivated, adjuvanted vaccine for use in adults 50 years of age and older. Flucelvax, which is a surface antigen, inactivated and prepared in cell cultures, may be used in adults and children, two years of age and older.

Alhemo (concizumab) for routine prophylaxis of bleeding in patients with haemophilia A or B with inhibitors

Korjuny (catumaxomab) to treat intraperitoneal malignant ascites, “a build-up of fluid containing cancer cells in the abdomen of cancer patients,” according to EMA.

Siiltibcy (rdESAT-6/rCFP-10) to diagnosis 

Wainzua (eplontersen), designated an orphan drug, to treat adults with hereditary transthyretin-mediated amyloidosis

Buprenorphine Neuraxpharm (buprenorphine) to treat opioid addiction.

In addition, two biosimilars, Absimky (ustekinumab) and Imuldosa (ustekinumab), were granted positive opinions for the treatment of plaque psoriasis in children and adults, psoriatic arthritis, Crohn’s disease, and ulcerative colitis. The generic drug, Eltrombopag Viatris (eltrombopag), was also recommended for the treatment of children and adults with primary immune thrombocytopenia and thrombocytopenia associated with chronic hepatitis C.

CHMP also recommended extending indications for Cerdelga (eliglustat), Hepcludex (bulevirtide), Kevzara (sarilumab), Kisqali (ribociclib), Tevimbra (tislelizumab), and Yselty (linzagolix choline). Updates to the COVID-19 vaccines Nuvaxovid and Bimervax were also given positive opinions.

At the meeting, CHMP also stated that it is confirming its recommendation, originally issued in June 2024, to refuse authorization for Masitinib AB Science (masitinib) for the treatment of amyotrophic lateral sclerosis after re-examination of the application.

“At the time of the initial evaluation, the agency considered that the study data were not reliable, as findings from good clinical practice inspections coordinated by EMA and other regulatory authorities had identified issues with the conduct of the study that could not be sufficiently addressed by the company. In addition, the benefits of Masitinib AB Science could not be convincingly demonstrated; the study found no difference between the medicine and placebo in the main measure of effectiveness for the total study population and had several methodological issues. These concerns did not change after re-examination of the data provided and following consultation of a group of experts in neurology, as well as patient representatives. In reaching its final decision, the agency also considered information shared by patient organizations (so-called third-party interventions). Therefore, the Agency maintained its opinion that the benefits of Masitinib AB Science did not outweigh its risks and recommended refusing marketing authorization,” the agency stated on its website (2).

 Two drug applications were withdrawn from consideration. Apremilast Viatris (apremilast), to treat plaque psoriasis, active psoriatic arthritis, and mouth ulcers caused by Behçet’s disease, was withdrawn because the agency found that the data provided did not match bioequivalence conclusions. The epilepsy drug, Epixram (levetiracetam), was withdrawn because of a change in the company’s regulatory strategy.

EMA. Meeting Highlights from the Committee for Medicinal Products for Human Use (CHMP) 14–17 October 2024. Press Release. Oct. 18, 2024.

The agency’s CHMP recommended drugs to treatments for hemophilia, two biosimilars for psoriasis, and two flu vaccines at their October meeting.

Several Medicines Recommended by EMA’s CHMP in October

The European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) reconfirmed its rejection of the conditional marketing authorization of Translarna (ataluren) after reexamination of the data, the agency announced on Oct. 18, 2024. EMA stated in a press release that the effectiveness of the drug, used to treat Duchenne muscular dystrophy in patients two years of age and older, has not been confirmed (1).

CHMP’s initial negative opinion was issued in September 2023 and confirmed after a previous reexamination in January 2024. The European Commission requested that EMA revisit the opinion in June 2024 to review real-world data and the views of a scientific advisory group. Another reexamination was requested by the sponsor company. CHMP then reviewed results from study 041, patient registry data, and new analysis provided by the company.

According to CHMP, study 041, which looked at the effect of Translarna on a specific subgroup of patients with a progressive decline in the ability to walk, showed “that the distance patients could walk in six minutes after 18 months of treatment decreased by about 82 meters in the Translarna group compared with 90 meters in the placebo (dummy treatment) group; however, this difference was not statistically significant, meaning that it may be due to chance,” the agency stated in the press release. “Similarly, when looking at the decline in motor functions after about 18 months as measured using a standard scale called North Star Ambulatory Assessment (NSAA), the difference between patients treated with Translarna and those who received placebo was also not statistically significant. The CHMP therefore concluded that study 041 had failed to confirm the effectiveness of the medicine.”

Data from two patient registries, STRIDE and CINRG DNHS, were also studied. STRIDE patients were treated with the drug for 5.5 years and patients from CINRG DNHS were not treated with the drug. Results from the registries suggested a delay in the loss of the ability to walk with those treated with the drug; however, CHMP stated that differences between the registries and biases made the comparison inconclusive. Data also did not outweigh the negative results of two post-authorization studies, according to CHMP.The mechanism of action for the drug was also not confirmed, according to the agency.

“Throughout its review of Translarna, the CHMP consulted parents of boys and men with Duchenne muscular dystrophy of different ages. They were invited to meetings as patient experts along with other experts, including neurologists, to describe what it is like to live with this disease, and they spoke directly to the CHMP on several occasions. The patients’ and parents’ perspectives have been sought and captured at every stage of the evaluation of this medicine. The Committee also considered all third-party information received from parents and caregivers of boys affected by Duchenne muscular dystrophy, patient organizations, healthcare professional organizations, and treating doctors.”

“The CHMP acknowledges the high unmet medical need for an effective treatment for patients with Duchenne muscular dystrophy. However, based on all the evidence accumulated, it concluded that the effectiveness of Translarna has not been confirmed in patients with Duchenne muscular dystrophy caused by a nonsense mutation, including those who were expected to have a better response to treatment,” the agency stated in the press release.

EMA. Translarna: EMA Re-confirms Non-renewal of Authorization of Duchenne Muscular Dystrophy Medicine. Press Release. Oct. 18, 2024.

The agency has reconfirmed its recommendation to not give positive opinion to Translarna (ataluren) after a reexamination of the available data.

EMA Denies Authorization of Duchenne Muscular Dystrophy Treatment, Again

Tech Transfer Considerations

® spoke with Ahmed Youssef, senior manager, USP Process Development at Ascend, to get his input on how tech transfer may be complicated when dealing with emerging therapies, such as antibody-drug conjugates, cell and gene therapies, and patient-centric treatments. Youssef pointed to timing as being key for technology transfer.

“It takes an innovator around 12 to 24 months to make a product ready, tech transfer it, [and] complete the safety studies for it,” says Youssef. “But there could be other solutions that could be offered in the background that could make this more efficient, faster, and more attractive to product developers.”

When it comes to sponsors and contract organizations working together to ensure a secure tech transfer, Youssef says the contract development and manufacturing organization (CDMO) should shoulder the responsibility. “A good CDMO [should] have structured communication, because communication is key … when you're talking to your business partner. We always build that in a more collaborative environment,” says Youssef. “[A CDMO needs] to protect the IP rights of their clients, their partners, as well as good documentation practices, in addition to a solid IT department. All of that gives the assurance to the security of the data and the security of the transfer information between the CDMO and their partner.”

Youssef also gave his insights on how sponsors can benefit when contractors offer end-to-end services. “If you mean by end-to-end, the whole process, you know, without the whole offering, from the start of plasmid manufacturing till commercial manufacturing of the batches, and then the fill and finish and release, understand that the advantage would be that you're running all of that under one MSA [master supply agreement], one big MSA,” said Youssef.

Click the video above to watch the interview.

Ahmed Youssef, senior manager, USP Process Development at Ascend, provides insight on tech transfer when developing and manufacturing emerging therapies and new modalities.