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The US Pharmacopeia (USP) announced on July 26, 2024 that its Microbiology Expert Committee has approved the inclusion of Chapter <86> Bacterial Endotoxins Test Using Recombinant Reagents into the

 United States Pharmacopeia–National Formulary (USP–NF). 

The chapter permits the use of non-animal-derived reagents for endotoxin testing; the finalized chapter will be published for early adoption in November 2024 before becoming official in May 2025. The new chapter is part of USP’s commitment to expanding the use of animal-free methods and materials.

Endotoxins may cause irreversible side effects and even death in severe cases at sufficient concentrations in the bloodstream (1). Bacterial endotoxins are found in the outer cell membrane of Gram-negative organisms and are known to be one of the most potent toxins. “These toxins are harmless outside of the body and in the alimentary canal. They are extremely potent, however, once introduced in the bloodstream or intrathecally,” Allen L. Burgenson, Testing Solutions, Lonza Pharma & Biotech, said (1).

“Bacterial endotoxins (also referred to as pyrogens) have the capacity to induce a high fever,” said John Dubczak, general manager, Microbial Solutions, Charles River Laboratories (1). “A large enough dose of endotoxin can lead to lung and kidney failure, intravascular coagulation, and a systemic inflammatory response that can lead to septic shock and death.”

Therefore, endotoxin testing is an important part of the quality and safety steps taken in the manufacture of certain sterile pharmaceutical products. Techniques for bacterial endotoxin testing using non-animal derived reagents are provided in the new chapter. Specifically, the new chapter discusses methods using both recombinant cascade (rCR) and recombinant Factor C (rFC) reagents. It also gives information on how to incorporate the methods into quality testing.These new techniques are in addition to those found in Chapter <85> Bacterial Endotoxins.

“Chapter <86>is intended to provide manufacturers with the information needed to use non-animal derived reagents. Manufacturers that currently use limulus amebocyte lysate (LAL) for endotoxin testing can continue to do so and Chapter <86> has no impact on them,” USP said in a press release (2).

One of the main endotoxin tests, LAL assay “works via the reaction of the LAL reagent-an aqueous extract of blood cells from the horseshoe crab-with bacterial endotoxins and lipopolysaccharides” (1). While the LAL test is an animal-derived test, and the animal itself is not tested upon, the desire to reduce animal use in testing has influenced the pharma industry, which resulted in the LAL test replacing the previous standard Rabbit Pyrogen Test. The LAL test is an animal-derived test, meaning the animal itself is not tested upon (1). This change prevented the use of hundreds of thousands of rabbits per year. There has also been a commitment to conserve the horseshoe crab. “Work has included sustainability partnerships to enhance the horseshoe crab population along the mid-Atlantic shores,” said Victoria Watson, laboratory manager, Microbiology at Wickham Labs. “Such projects have focused on increasing the survival rate of the horseshoe crab in early stages of life. Eggs are collected, and the crabs are grown in predation-free, controlled environments then released into their natural environment when older and stronger” (1).

Thomas, F. Putting Endotoxins to the Test. 

https://www.pharmtech.com/view/putting-endotoxins-test

USP. Expert Committee Approves Endotoxin Testing Using Non-animal Derived Reagents. Press Release. July 26, 2024.

Articles

The US Pharmacopeia’s Microbiology Expert Committee approved the inclusion of a chapter into the United States Pharmacopeia–National Formulary that allows the use of non-animal-derived reagents for endotoxin testing.

USP Permits Use of Non-Animal-Derived Reagents for Endotoxin Testing

Feliza Mirasol is the science editor for 

Scorpius Holdings, an integrated contract development and manufacturing organization (CDMO), is prepared to launch its first current good manufacturing practice (CGMP) mammalian manufacturing campaign at its manufacturing facility in San Antonio, Texas, in the 2024 third quarter. The launch follows the company's expansion efforts for its biomanufacturing capabilities, especially in the area of mammalian cell culture for advanced biopharmaceuticals, according to a July 24, 2024 press release.

The company previously started up CGMP operations at its microbial manufacturing facilities, and the start of mammalian CGMP manufacturing campaigns signifies a strategic company milestone in its CDMO operations. The San Antonio site hosts a dedicated mammalian cell culture facility with CGMP-compliant controlled cleanrooms that can be tailored to allow for adaptable manufacturing solutions, according to a company press release.

“I am extremely proud of what our team has accomplished in a short period of time. Our manufacturing and quality teams have worked exceptionally hard to get our mammalian facilities operational in less than two years, well ahead of the typical timing for such complex buildouts. Scorpius is now extremely well-positioned to support a wide range of early stage clinical programs," said Jeff Wolf, CEO of Scorpius, in the press release.

The facility’s design includes cleanrooms with mobile equipment, which enables customizable configurations for the specific needs of individual projects. Scorpius has secured bookings for additional CGMP activities in the mammalian facility for 2025, according to Wolf in the press release.

The San Antonio site underwent significant expansion in May 2024 as Scorpius grew its operational footprint. The expansion included new storage space and a testing facility. Warehouse space was increased more than sevenfold, from approximately 3000 ft2 to approximately 22,000 ft2 with the expansion. The warehouse includes specialized storage areas with temperature control between -20 °C and -80 °C for raw materials as well as spaces designated for contained sampling and quality control testing. The facility will also accommodate bulk drug substance storage to ensure that products are stored under optimal conditions throughout the development and production cycles. (1).

The expanded facility will include a robust stability program meant to bolster Scorpius' service offerings by allowing the company to provide in-house stability storage capabilities. The company intends to foster smooth transitions into onsite testing with the enhanced in-house stability storage.

"These new capabilities enable us to offer our clients continuity through their supply chain and meet their needs from process development through drug substance release. This strategic expansion reflects our commitment to excellence and our dedication to supporting our clients’ overall needs," Wolf said in a May 20, 2024 company press release.

1. Scorpius Holdings. Scorpius Holdings Announces Major Expansion in San Antonio with New State-of-the-Art Storage and Testing Facility. Press Release, May 20, 2024.

Scorpius Holdings is set to launch its first CGMP manufacturing campaign at its San Antonio, Texas, facility for mammalian cell culture in the 2024 third quarter.

Scorpius Holdings Prepares for Mammalian CGMP Manufacturing Campaign Launch in Texas Facility

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

Communication between the manufacturing plant and retail stores. | Image Credit: © Cagkan - stock.adobe.com

SpotSee, a Dallas, Texas-based company that manufactures visual indicators and other types of monitoring devices for a wide range of industries, announced in a press release on July 24, 2024 that its HemoTemp II Blood Bag Temperature Indicator and HemoTemp II Activator had both received an accreditation of “Standards-Compliant” from the Association for the Advancement of Blood & Biotherapies (AABB) (1).

“The AABB is recognized worldwide as a symbol of authority and distinction,” the press release said. “The organization is committed to its core objectives of providing high standards of safety for patients, donors, and facilities. AABB member institutions displaying the AABB accreditation logo are recognized globally for providing quality products and services.”

In the case of the two HemoTemp II products, a thorough review by AABB gave them high marks for quality in equipment and both process and document control, according to SpotSee (1).

“SpotSee sensors are carefully designed with quality in mind,” Tony Fonk, SpotSee president and CEO, said in the press release. “Earning this accreditation and seal of approval communicates to the public that our life science products are trustworthy, reliable, and of the highest quality.”

The blood bag temperature indicator, which is an FDA-approved medical device, is a liquid crystal combination irreversible blood temperature indicator and reversible thermometer for the measurement of blood during transit, and also storage outside the blood bank (1). According to SpotSee, the reversible portion acts like a blood bag thermometer, while the irreversible part warns the user if the blood’s core temperature has exceeded an approximate range of 6 ºC to 10 ºC.

“After activation, the irreversible portion will change color from blue to a non-blue color as the blood temperature increases and as time passes,” SpotSee explains further on the indicator’s product page (2). “Once the indicator has lost its blue color, it will not return to its original color even if the blood unit is re-cooled. This ensures the user of the time and temperature history of the unit.”

A tan color indicates that the temperature is in the lower portion of the desired range, while green signifies it is in the middle (2).

The activator, meanwhile, a block module heater, provides uniform temperature for the purpose of reliably and accurately activating a sensor also bearing the HemoTemp II name (1).

HemoTemp II is the proprietary brand name of SpotSee’s line of blood bag indicators and activators, as seen on a page on the SpotSee website devoted to the company’s offerings of temperature-related products (2). The blood bag temperature indicators are sold in packs of 40, or a larger order consisting of a case of five boxes of 40 indicators each.

SpotSee said that the indicator should not be used as the “sole indication of clinical acceptability of blood for patient infusion,” but rather a tool in the overall kit of a blood temperature monitoring program.

1. SpotSee. “SpotSee’s HemoTemp II Receives Standards Accreditation From AABB.” Press Release. July 24, 2024.
2. SpotSee. Blood Bag Indicators and Activators. 

shop.spotsee.io/temperature_indicators/blood_indicators

The HemoTemp II Blood Bag Temperature Indicator, which is an FDA-approved medical device, and the HemoTemp II Activator both were given the “Standards-Compliant” seal.

Two SpotSee Products Receive AABB Standards Accreditation

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At its meeting held July 22–25, 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) gave positive opinions or granted marketing authorizations to 14 medicines, EMA said in a press release issued July 26 (1).

One negative opinion was given for a drug for the intended treatment of Alzheimer’s disease; 11 others received extensions of their various therapeutic indications.

Anzupgo (delgocitinib), which treats moderate to severe chronic hand eczema in adults for who topical corticosteroids were ineffective, was granted a marketing authorization. So too were Vyloy (zolbetuximab), treating a form of stomach cancer known as gastric or gastroesophageal junction adenocarcinoma, and Iqirvo (elafibranor), given a conditional authorization for the treatment of primary biliary cholangitis, which is a chronic, progressive autoimmune disease that can cause liver damage, according to CHMP (1).

Additionally, the following three were given positive opinions:

Kayfanda (odevixibat) was issued a positive opinion under exceptional circumstances, for treatment of cholestatic pruritis in patients with Alagille syndrome—a rare and life-threatening genetic disorder with numerous clinical manifestations

Loqtorzi (toripalimab), for treating nasopharyngeal and esophageal squamous cell carcinomas

Vevizye (ciclosporin), which treats adult patients with moderate to severe dry eye disease that has not improved with treatment with tear substitutes (1).

Johnson & Johnson was one of the first companies to respond to the CHMP announcement, as its Yuvanci (macitentan/tadalafil) was given a positive opinion for treatment of pulmonary arterial hypertension (PAH) (2).

“PAH is a devastating disease affecting people of all ages and the burden the condition places on the daily lives of people living with it should not be underestimated,” Tamara Werner-Kiechle, MD, of Johnson & Johnson Innovative Medicine, said in a press release.

Six biosimilar medicines received positive opinions: Eksunbi, Fymskina, and Otulfi (all ustekinumab), for treatment of plaque psoriasis (both adult and pediatric), psoriatic arthritis, ulcerative colitis, and Crohn’s disease; Ituxredi (rituximab), for treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis; Ranibizumab Midas (ranibizumab), for treatment of neovascular or “wet” age-related macular degeneration and other visual impairment issues; and Tuznue (trastuzumab), for treatment of breast and gastric cancers (1).

Extensions of therapeutic indications were given to Arexvy, Braftovi, Edurant, Keytruda, Mektovi, Opsumit, Padcev, Rybrevant, Slenyto, Spevigo and Tecentriq (1).

The negative opinion was given to Leqembi (lecanemab), which is intended to treat Alzheimer’s disease. CHMP did not grant a marketing authorization for Leqembi because it did not consider the effects of the drug in delaying cognitive decline to outweigh the risk of serious side effects, including frequent amyloid-related imaging abnormalities, which may involve swelling and potential bleeding in the brain (1).

1. EMA. Meeting Highlights from the Committee for Medicinal Products for Human Use (CHMP) 22–25 July 2024. Press Release. July 26, 2024.
2. Janssen-Cilag International NV. Johnson & Johnson Receives Positive CHMP Opinion for Yuvanci (Single Tablet Combination Therapy [STCT] of Macitentan and Tadalafil) for Treatment of Patients with Pulmonary Arterial Hypertension (PAH). Press Release. July 26, 2024.

An additional 11 medicines were recommended for extension of therapeutic indications, while one negative opinion was issued.

CHMP Recommends 14 Medicines for Approval at July Meeting

Oncology company BeiGene has opened its new biologics manufacturing facility at the Princeton West Innovation Campus in Hopewell, NJ. The $800 million facility represents the company’s flagship facility in the United States and also houses a clinical R&D center. The investment is part of the company's strategic goal to expand its integrated manufacturing and R&D footprint in the US, according to a July 23, 2024 company press release.

BeiGene has more than 30 molecules at clinical- or commercial-stage development. The new 42-acre facility gives the company flexibility to scale production of these drug candidates presently and in the future to meet cancer patient needs. The Hopewell site comprises approximately 400,000 ft2 of space dedicated to commercial-stage biologic manufacturing capacity and includes additional space to expand over time as BeiGene’s pipeline matures.

The facility strengthens BeiGene’s late-stage research and clinical development capabilities. The company’s oncology pipeline addresses 80% of global cancers using modalities such as targeted degraders and antibody drug conjugates as well as monoclonal antibodies and traditional small molecules. The new facility enables the company to produce at scale, which reduces costs and ensures supply chain resiliency. The company aims to avoid global disruptions, protect capacity, and rapidly adapt to the latest innovative modalities, according to a company press release.

“BeiGene has experienced unprecedented global growth, and the addition of our facility at the Princeton West Innovation Campus adds manufacturing and clinical development capabilities that will further strengthen our differentiated strategy, which leverages speed, efficiency, and technology to advance quality medicines faster for patients,” said John V. Oyler, co-founder, chairman, and CEO of BeiGene, in the press release. “We are proud to be a part of New Jersey’s biopharmaceutical community that is rich in research and development and manufacturing talent. We look forward to deepening our relationships with key regional research institutions as we advance our robust pipeline of next-generation hematology and solid tumor medicines and continue to emerge as a leading global oncology innovator.”

The company expects to create hundreds of skilled high-tech jobs at the site by the end of 2025. BeiGene initially announced its 

 on the Hopewell site in November 2021 (1).

“I am thrilled by BeiGene’s contribution to our state’s thriving biopharmaceutical sector,” said Governor Phil Murphy, in the release. “The opening of BeiGene’s flagship campus underscores our commitment to fostering innovation and creating high-tech jobs in the Garden State. We look forward to the positive impact BeiGene will have on our economy and the advancements they will bring to cancer treatment. This significant investment highlights New Jersey’s role as a global leader in pharmaceutical manufacturing, research, and development. We are proud to support BeiGene’s mission to develop affordable and accessible treatments for cancer patients worldwide.”

As part of BeiGene’s sustainability efforts, the company has invested in sustainability measures both in the buildings and surrounding the 42 acres of the site. These measures include a heating and cooling system that employs recycled wastewater from the onsite wastewater treatment plant for the cooling towers and solar-ready capability.

1. BeiGene. BeiGene Closes on Property for New U.S. Manufacturing and Clinical R&D Center. Press Release, Nov. 23, 2021.

BeiGene has opened its new $800 million Hopewell, NJ-based biologics manufacturing facility, which also houses the company's clinical R&D capabilities.

BeiGene Opens New Jersey-Based Biologics Manufacturing and Clinical R&D Site

FDA has issued a Federal Register notice, dated July 24, 2024, entitled “Biosimilar Product Development Guidance; Establishment of a Public Docket; Request for Information and Comments,” seeking input from interested parties as to whether biosimilar product development would be better served in either of two ways: a focus on guidance documents that are product class-specific, addressing development issues that are common and apply broadly to products such as monoclonal antibodies, or an emphasis on developing product-specific documents—for example, for adalimumab (1).

This choice is one of two main questions FDA would like answered by the input it hopes to receive from industry on this notice, the other being whether FDA should focus on development of guidance documents, whether product-specific or product class-specific, in cases of biological products for which there are no approved biosimilars. Or alternatively, FDA asks, would it be of use to the biosimilar product development community to continue to develop guidance on biosimilar development programs even after one, or more, biosimilar products have been approved for a biological product or class of products (1)?

Following enactment of the Biosimilar User Fee Amendments of 2022 (BsUFA III), FDA updated its Biosimilars Action Plan and said these questions are now arising as the administration reexamines the best possible path to advancing development of new biosimilar products (1,2). Concentrating on product-specific guidance documents, FDA said, would be a development approach similar to the Generic Drug User Fee Amendments (GDUFA) program (3). According to FDA, under the conditions set forth by GDUFA, there are currently more than 2000 product-specific guidance documents from which to model biosimilars guidance (2).

The Biosimilars Action Plan (BAP), first released in 2018, has four overarching goals, each with its own subset of aims. FDA said in the five-plus years since the initial BAP report, it has accomplished most of the goals set forth and is now “modernizing the Agency’s strategic priorities” (2).

The originally stated goals are: to improve efficiency of the development and approval processes for biosimilars and interchangeable products; maximize both scientific and regulatory clarity for the community; develop effective communications to increase understanding among stakeholders; and support a robust, competitive marketplace (2).

Both electronic and written comments, data, or information are being accepted and, to be considered, must be received by FDA or the 

 portal on or before Oct. 23, 2024 (3). All submissions must include the docket number FDA-2024-N-3228. Although the notice and docket are publicly available, comments and other information can be volunteered confidentially; instructions on how to do this appear in the Federal Register notice.

1. FDA CDER Small Business and Industry Assistance. FDA Seeking Comments on Product Class-Specific vs. Product-Specific Guidances for Biosimilars. Press Release, July 24, 2024.
2. FDA. Biosimilars Action Plan. 

fda.gov/drugs/biosimilars/biosimilars-action-plan

, Apr. 26, 2024 (accessed July 25, 2024).
3. FDA. 

Biosimilar Product Development Guidance; Establishment of a Public Docket; Request for Information and Comments

The questions come as FDA is revisiting best practices for advancing the development of new biosimilar products under the terms of its updated Biosimilars Action Plan.

FDA Asks for Input on Guidance Documents for Biosimilar Product Development

Univercells Technologies, a Donaldson company, has expanded its evaluation agreement with the University of Pennsylvania's Gene Therapy Program (GTP). The collaborators will determine the scalability of GTP’s gene therapy product manufacturing with bioreactors provided by Univercells Technologies.

Under the expanded agreement, GTP will evaluate Univercells Technologies’ commercial- series bioreactor (scale-X nitro 600 m2 bioreactor). The evaluation is aimed at significantly increasing production per batch and potentially reducing cost of goods sold, according to a July 16, 2024 company press release.

“We are honored to extend our collaborative work with GTP in evaluating the scalability of gene therapy production,” said Mathias Garny, general manager, Univercells Technologies, in the press release. “Our mission aligns closely with GTP’s vision of making gene therapies more accessible globally, and we are committed to supporting their efforts with our innovative bioprocessing technologies.”

Under the Bill and Melinda Gates Foundation’s Global Grand Challenge initiative, Univercells Technologies developed the scale-X bioreactor, which was originally designed to lower the cost of viral vaccine production for critical public health vaccines. Through the GTP collaboration, this bioreactor will now be applied to viral vector manufacturing to enable accessibility of gene therapies.

“Our hope is that Univercells Technologies will improve the efficiency of AAV vector manufacturing and help play a role in decreasing costs and enabling access through more affordable prices in the future,” said James M. Wilson, MD, PhD, the Rose H. Weiss professor and director of the Orphan Disease Center, and a professor of Medicine and Pediatrics at the Perelman School of Medicine, in the press release.

GTP is an academic program focused on genetic medicines. It is led by Wilson and is well known for its pioneering work in gene therapy. The program specializes in increasing the accessibility of gene therapies for rare diseases to patients worldwide.

Univercells Technologies became a part of Donaldson through an 

 in June 2023. Through a €136 million (US$148 million at the time of acquisition) transaction, Donaldson gained Univercells Technologies, including that company’s product line, which includes the scale-X single-use structured fixed-bed bioreactor as well as NevoLine, Univercells Technologies’ automated upstream platform.

In the June 29, 2023 press release, Tod Carpenter, chairman, president, and CEO, Donaldson said, “The acquisition of Univercells Technologies represents an important next step in Donaldson’s life sciences strategy, as we continue to expand our product portfolio aimed at providing customers with a comprehensive, differentiated offering. Univercells Technologies’ engineered systems provide close adjacencies with our previous life sciences acquisitions as well as with our growing organic product suite.”

Donaldson provides filtration products and solutions for complex filtration challenges. It comprises three primary segments: Mobile Solutions, Industrial Solutions, and Life Sciences.

1. Univercells Technologies. Donaldson Acquires Univercells Technologies, Broadens Life Sciences Reach. Press Release, June 29, 2023.

Univercells and the University of Pennsylvania are expanding their collaboration to evaluate certain bioreactors with the aim to scale up gene therapy manufacturing.

Univercells and University of Pennsylvania Expand Agreement for Gene Therapy Program

GSK’s marketing authorization application (MAA) for Blenrep (belantamab mafodotin) combination therapies has been accepted by the European Medicines Agency (EMA). In the MAA, GSK is seeking approval of Blenrep in combination with bortezomib plus dexamethasone (BorDex) or pomalidomide plus dexamethasone (PomDex) for treating relapsed or refractory multiple myeloma (RRMM). Following EMA’s acceptance, the Committee for Medicinal Products for Human Use will begin formal review of the MAA and will make a recommendation to the European Commission, GSK announced in a July 19, 2024 company press release.

The MAA is based on interim results from two Phase III trials (DREAMM-7 and DREAMM-8), which both met their respective primary endpoints. The trials showed statistically significant and clinically meaningful improvements in progression-free survival for the belantamab mafodotin combinations compared to standard-of-care combinations in RRMM. The DREAMM-7 trial is evaluating the combination of belantamab mafodotin with BorDex versus daratumumab plus BorDex. The DREAMM-8 trial is evaluating the combination of belantamab mafodotin with PomDex versus bortezomib plus PomDex.

“[This] milestone reinforces the potential for Blenrep to redefine outcomes for patients with multiple myeloma at or after first relapse. We are working to bring Blenrep to patients as quickly as possible given the high unmet need and the clinically robust effects of the Blenrep combinations in the DREAMM-7 and DREAMM-8 [P]hase III head-to-head trials,” said Hesham Abdullah, senior vice-president, global head Oncology, R&D, GSK, in the press release.

Both Phase III trials also showed a positive overall survival (OS) trend, but the trend was not statistically significant at the time the interim analysis was conducted, according to the press release. Follow-up for OS is ongoing. Results did show clinically meaningful improvements across all other secondary efficacy endpoints, however, including deeper and more durable responses compared to respective standard-of-care therapy combinations. “The safety and tolerability profiles of the belantamab mafodotin combinations in DREAMM-7 and DREAMM-8 trials were broadly consistent with the known profiles of the individual agents,” GSK stated in the press release.

Multiple myeloma, the third most common blood cancer globally, is considered treatable but not curable (1,2). Approximately more than 180,000 new cases are diagnosed annually on a global basis. The diagnosis includes approximately 50,000 new cases in Europe (3).

Blenrep is an antibody-drug conjugate. The drug consists of a humanized B-cell maturation antigen monoclonal antibody (mAb) that is conjugated to auristatin F (cytotoxic agent) by a non-cleavable linker. According to GSK, the drug linker technology was licensed from Seagen. The mAb is produced using POTELLIGENT Technology, which was licensed from BioWa, a member of the Kyowa Kirin Group.

1. Sung, H.; Ferlay, J.; Siegel, R.; et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. 

 (3), 209–249. DOI:10.3322/caac.21660
2. Kazandjian, D. Multiple Myeloma Epidemiology and Survival: A Unique Malignancy. 

 (6), 676–681. DOI:10.1053/j.seminoncol.2016.11.004
3. Ferlay, J.; Ervik, M.; Lam, F.; et al. Multiple Myeloma. In 

; International Agency for Research on Cancer, 2024 [accessed July 23, 2024].

GSK's MAA is supported by an interim analyis of Phase III trials, which demonstrated significant progression-free survival benefit and positive overall survival trends from Blenrep combination therapies.

GSK’s Application Seeking Blenrep Combinations for Treating Multiple Myeloma Accepted by EMA

A Phase III study (AFFINE) has achieved its primary objective of not only non-inferiority but also superiority of total annualized bleeding rate (ABR) using giroctocogene fitelparvovec, an investigational gene therapy for adults with moderately severe to severe hemophilia A, from week 12 up to at least 15 months of follow-up post-infusion, when compared to routine Factor VIII (FVIII) replacement prophylaxis, Pfizer announced on July 24, 2024 (1,2).

A single dose of giroctocogene fitelparvovec, according to a Pfizer press release that summarized the findings of the study, yielded a statistically significant reduction in mean total ABR when measured against the pre-infusion period.

Giroctocogene fitelparvovec contains a bioengineered adeno-associated virus type 6 (AAV6) capsid and modified B-domain deleted human coagulation FVIII gene (1). The goal of treating hemophilia A patients with this therapy is to allow them to produce FVIII on their own for a certain period of time following a single infusion—which, in turn. offers bleed protection as well as a reduced need for routine prophylaxis with intravenous (IV) injections or infusions.

Hemophilia A, which occurs in approximately 25 of every 100,000 male births worldwide, is an inherited disorder causing those who are affected to bleed for longer than the normal amount of time because of a deficiency in the protein required for blood clotting (1). Anywhere from 55% to 75% of cases in males can be classified as moderate to severe, carrying with them increased risk of spontaneous bleeding or bleeding after injuries or surgery, and lifelong monitoring and therapy, among other potential health problems.

“For people living with hemophilia A, the physical and emotional impact of needing to prevent and treat bleeding episodes through frequent IV infusions or injections cannot be underestimated,” Andrew Leavitt, MD, AFFINE lead investigator and director of the departments of laboratory medicine and medicine division of hematology/oncology at the Adult Hemophilia Treatment Center, University of California, said in the press release. “I’m excited by the strength of these positive results from the AFFINE trial that show giroctocogene fitelparvovec was generally well tolerated, and demonstrate the transformative potential of this gene therapy candidate to provide superior bleed protection compared with routine FVIII prophylaxis, while helping relieve the treatment burden for people living with hemophilia A.”

“We are very pleased with these positive results from the Phase [III] AFFINE study demonstrating the safety and efficacy of our one-time gene therapy candidate for people with hemophilia A,” said James Rusnak, MD, PhD, senior vice-president and chief development officer, Internal Medicine and Infectious Diseases, Research and Development, Pfizer, in the press release. “We look forward to advancing this latest innovation to help address the medical and treatment burden associated with frequent and time-consuming IV infusions or injections.”

Analyses of the full dataset from the Phase III study are still ongoing, with additional data to be presented at future medical meetings.

1. Pfizer Inc. Pfizer Announces Positive Topline Results from Phase 3 Study of Hemophilia A Gene Therapy Candidate. Press Release, July 24, 2024.
2. National Library of Medicine. Study to Evaluate the Efficacy and Safety of PF-07055480 /​ Giroctocogene Fitelparvovec Gene Therapy in Moderately Severe to Severe Hemophilia A Adults (AFFINE). 

, July 24, 2024 (accessed July 24, 2024).

Giroctocogene fitelparvovec is designed to allow patients to produce FVIII on their own for a time after a single infusion, an alternative to routine IV injections.

Pfizer Gene Therapy for Hemophilia A Patients Shows Promising Results in Study

FDA published a guidance document on July 16, 2024 instructing staff members as well as the drug industry at large about the applicable user fees for applications for combination products, as defined under the 

), Title 21, Part 3.2(e) (1,2). Specifically, the guidance dictates that if a single application is submitted for a combination product, the user fee associated with that type of application should be assessed. It also outlines the process by which combination products are assigned for review.

, is characterized by any of four criteria:

Two or more regulated components (customarily a drug, biologic, and/or device) that are mixed or combined physically, chemically, or otherwise, and produced as one entity

Two or more products which are separate, but packaged together as a singular unit, comprised of drug, device, and or biological products

A drug, device, or biological product packaged separately and intended for use only with another individually specified drug, device, or biological product, required to achieve a desired effect, and for which labeling of the product would have to be changed upon approval, for example to reflect a change in intended use, strength, or dosage form

An investigational drug, device, or biological product, packaged separately, combined for usage with another individual, investigational entity as described above (2).

Drug–drug, device–device, and products containing only multiple biologics do not meet the definition of a combination product under these terms (1).

FDA precedent states that combination products may be reviewed in a single application or in separate applications for each constituent part, both of which are scenarios reviewed in the new guidance (1). If an applicant decides to submit two applications for a cross-labeled product, each application would be assessed its own particular user fee.

FDA may determine that a single application is not appropriate for a certain combination product, and that separate applications are warranted. In that case, which FDA said in the guidance document is rare, the total amount of the application fee could be reduced if the applicant qualifies for waiver provisions under the Prescription Drug User Fee Act (PDUFA) of the Federal Food, Drug, and Cosmetic Act (1). Provisions of this guidance do not apply to PDUFA prescription drug program fees.

The guidance document contains information on how to request a fee reduction or waiver under the PDUFA provisions and also how to do the same as a small business, pursuant to medical device user fee amendment guidelines.

The guidance was jointly issued by FDA’s Office of the Commissioner, Office of Clinical Policy and Programs, and Office of Combination Products and replaces a previous final guidance for industry from April 2005.

Application User Fees for Combination Products

 Title 21, Part 3.2(e) (Government Printing Office, Washington, DC) 173. 

ecfr.gov/current/title-21/chapter-I/subchapter-A/part-3/subpart-A/section-3.2

Combination products may be reviewed in a single application or in separate applications for each constituent part, and in rare cases, FDA may decide which type of application process is appropriate.

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