Roche's Oncology Subcutaneous Formulations Gain Dual FDA Approvals Within Two Days, Marking a Strategic Shift in Cancer and MS Therapy Delivery

1. Subcutaneous formulations of two key Roche oncology drugs arrive in quick succession

Roche's Multiple Sclerosis (MS) blockbuster drug Ocrevus (ocrelizumab and hyaluronidase) received FDA approval on September 13 for its subcutaneous injection formulation, Ocrevus Zunovo, further reinforcing the trend in the development of subcutaneous antibody formulations for oncology products.

This new subcutaneous formulation of Ocrevus can be administered in just 10 minutes.Compared to the original two-hour intravenous infusion, this undoubtedly provides patients with a more convenient treatment option, especially for those who have difficulties accessing infusion centers. The two formulations of Ocrevus are priced the same, but the subcutaneous injection version can save some infusion-related costs.Since the molecules in the two formulations are identical, Roche anticipates that the subcutaneous version will not be able to avoid the impact of Ocrevus' future patent expiration.Ocrevus' patent will expire in Europe in 2028 and in the United States in 2029.

Roche MS Chief Medical Officer David Jones said in an interview that Ocrevus is a highly impactful drug that has changed the lives of many multiple sclerosis patients, but some patients are still unable to access it due to non-economic factors. These limitations may include the absence of infusion centers nearby due to geographical location or resource constraints at infusion centers making it difficult to schedule appointments. Some patients may also find it challenging to receive Ocrevus treatment due to difficulty with venipuncture or the need to spend an entire day on infusion. Although this CD20 antibody only requires infusion twice a year, each infusion takes two hours. Jones also stated,Roche's launch of the subcutaneous injection formulation is not intended to replace intravenous infusion, but rather to allow patients who currently cannot access Ocrevus treatment to benefit.Many patients actually prefer to go to the infusion center, where they can not only see their doctors but also communicate with other patients sharing the same condition. However, the subcutaneous injection version still needs to be administered by professional medical staff, so patients cannot inject themselves at home.

This approval is based on the results of the Phase III OCARINA II trial, which showed that a 10-minute subcutaneous injection was non-inferior to the intravenous infusion version in maintaining blood drug concentration and had similar effects in controlling lesions. MRI scan data indicated that the subcutaneous injection version nearly completely suppressed relapse activity (97%) and MRI lesion formation (97.2%) over 48 weeks. Additionally, the safety profile of the subcutaneous injection was consistent with the intravenous infusion version, with the most common adverse event being injection-site reactions (51.5%), although no cases led to treatment discontinuation. This subcutaneous formulation was developed using Halozyme Therapeutics' Enhanze drug delivery technology.

New Subcutaneous Formulation Also Helps Ocrevus Face New Competitors in the Multiple Sclerosis Treatment Field. TG Therapeutics launched Briumvi (ublituximab), an anti-CD20 antibody for relapsing MS, in 2023, with an infusion time of only one hour. Novartis' anti-CD20 antibody Kesimpta (ofatumumab), which has been on the market since 2020, is administered once a month via subcutaneous injection. Despite new competitors, Ocrevus remains dominant in this drug category. Since its approval in 2017, Ocrevus quickly became a blockbuster drug. In 2023, Ocrevus generated revenue of 6.38 billion Swiss francs (approximately $7.48 billion), while Kesimpta's sales were $2.17 billion and Briumvi's were $89 million.

The attempt to switch monoclonal antibody administration from intravenous to subcutaneous routes is not limited to Ocrevus at Roche., Their Tecentriq Hybreza (atezolizumab with hyaluronidase-tqjs), co-developed with Halozyme Therapeutics, is known as the first and only subcutaneous anti-PD-(L)1 cancer immunotherapy, which received FDA approval on September 12, just one day before Ocrevus was approved. The brand name Tecentriq Hybreza distinguishes it from the intravenous version, Tecentriq.

Tecentriq Hybreza is the first and only PD-(L)1 inhibitor approved in the U.S. for subcutaneous injection. Its indications are the same as the intravenous infusion version, including various types of skin cancer, liver cancer, lung cancer, and soft tissue cancer. Roche stated that the approval of Tecentriq Hybreza is based on the safety and efficacy of the intravenous infusion version, Tecentriq. The subcutaneous injection formulation allows patients to receive treatment in a shorter amount of time and in a more convenient setting, while offering greater flexibility and treatment options for patients with various cancers and their doctors.

Tecentriq Hybreza Utilizes Halozyme Therapeutics' Enhanze Technology

FDA Approval of Tecentriq Subcutaneous Injection Opens New Avenues in Merck's Keytruda-Dominated PD-1 Market. In 2023, Tecentriq's sales reached approximately $4.45 billion, while Keytruda maintained its leading position in the PD-1 market with over $25 billion in revenue. The approval of Tecentriq Hybreza subcutaneous formulation is expected to impact the sales distribution in this market.

At the same time, Merck is also accelerating the development of a subcutaneous injection version of Keytruda, which is currently in Phase III clinical trials and is expected to be completed by the end of 2026. However, before that, the top-selling drug will still face a stern challenge from its most direct competitor—Bristol-Myers Squibb's PD-1 inhibitor Opdivo (nivolumab). The BLA application for the subcutaneous injection version of Opdivo has already been accepted by the FDA, with a PDUFA date set for February 28, 2025.

Bristol-Myers Squibb Seeks Approval for Indications Including All 22 Adult Solid Tumors Previously Granted to Opdivo

The subcutaneous injection version of Opdivo is based on the Phase 3 CheckMate-67T study, demonstrating non-inferiority to intravenous infusion according to two metrics: Cavgd28 (the time-averaged serum concentration of Opdivo over 28 days) and Cminss (steady-state serum trough concentration). The study enrolled patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who had previously received systemic therapy. In this study, 242 patients were treated with the subcutaneous formulation, while 245 patients received the intravenous formulation. Compared to intravenous Opdivo, subcutaneous Opdivo demonstrated non-inferiority in the key secondary endpoint of objective response rate (ORR). The ORR was 24.2% in the subcutaneous group and 18.2% in the intravenous group. The median progression-free survival for subcutaneous Opdivo was 7.23 months, compared to 5.65 months for the intravenous formulation. The safety profiles of both formulations were consistent.

2. Subcutaneous Injection Version of Heavyweight Monoclonal Antibody/Protein Drugs Approved by FDA

In addition to the above-mentioned latest FDA-approved SubQ monoclonal antibody blockbuster drugs, other similar heavyweights (including protein-based drugs) that have already received FDA approval include the following:

● DARZALEX (daratumumab)

Developer: Johnson & Johnson

Subcutaneous Formulation Name: Darzalex Faspro (Daratumumab/Hyaluronidase)

Indications: Multiple Myeloma, AL Amyloidosis

Approval date for intravenous injection version: November 16, 2015

SubQ Approval Date: May 1, 2020

● Kesimpta (Ofatumumab)

Developer: Novartis

Subcutaneous Formulation Name: Kesimpta

Indications: Relapsing Multiple Sclerosis (MS)

Approval date for intravenous injection version: October 26, 2009

Subcutaneous Formulation Approval Date: August 20, 2020

● ENBREL (Etanercept Fusion Protein)

Developer: Amgen/Pfizer

Subcutaneous Formulation Name: ENBREL

Indications: Rheumatoid arthritis, Psoriatic arthritis, Ankylosing spondylitis, Plaque psoriasis

Approval Date for Intravenous Injection Version: No IV Formulation

Subcutaneous Formulation Approval Date: November 2, 1998

● Humira (Adalimumab)

Developer: AbbVie

Subcutaneous Formulation Name: Humira

Indications: Rheumatoid arthritis, Psoriatic arthritis, Ankylosing spondylitis, Crohn's disease, Ulcerative colitis, etc.

Approval Date for Intravenous Injection Version: No IV Formulation

Subcutaneous Formulation Approval Date: November 2, 2002

● Herceptin (Trastuzumab and Hyaluronidase-oysk)

Developer: Genentech (Roche)

Subcutaneous Formulation Name: Herceptin Hylecta

Indications: HER2-positive breast cancer

Intravenous injection version approval date: September 25, 1998

Subcutaneous Formulation Approval Date: February 28, 2019

● Rituxan (Rituximab)

Developer: Genentech (Roche)

Subcutaneous Formulation Name: Rituxan Hycela

Indications: Non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia

Approval Date for Intravenous Injection Version: June 22, 2017

Subcutaneous Formulation Approval Date: November 26, 1997

3. Why the Development of Subcutaneous Injection Formulations for Monoclonal Antibodies Has Become a Hotspot

Subcutaneous Delivery of Therapeutic Proteins: A Rapidly Evolving Field

4. The Correlation Between Subcutaneous Formulation Development and Indications

From the perspective of indications, it is not difficult to see that immunology monoclonal antibody drugs like Humira were developed from the outset for SubQ administration, while many oncology monoclonal antibody drugs were initially launched as IV injectables. The development strategies for SubQ and IV formulations in immunology and oncology vary due to several factors, including the nature of the disease, patient needs, and treatment goals.

Immunological drugs are commonly used to treat chronic diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. These conditions often require long-term or even lifelong treatment. Subcutaneous injection formulations are more convenient for long-term medication, allowing patients to self-administer at home, which helps improve adherence and quality of life. Subcutaneous injections are generally less invasive and more convenient compared to intravenous injections. For patients with chronic illnesses who require frequent dosing, subcutaneous administration reduces the need to visit medical facilities for intravenous infusions. Additionally, subcutaneous formulations decrease reliance on medical facilities and professionals, reducing the demand for infusion centers and, consequently, associated healthcare resource consumption. For example, drugs like Humira (adalimumab) and ENBREL (etanercept) were initially developed as subcutaneous formulations to meet the needs of patients with chronic inflammatory diseases.

In contrast, in oncology, the focus during the initial development phase is usually on demonstrating the efficacy and safety of the drug. Intravenous injection allows for precise dosage control and immediate management in case of adverse reactions, which is crucial in early clinical trials. This development strategy has determined that many oncology drugs, particularly monoclonal antibodies, were initially developed for intravenous administration to ensure maximum bioavailability and rapid onset, which are critical for treating aggressive cancers. Moreover, cancer treatment often involves complex regimens, including the combination of multiple drugs, typically administered in a controlled clinical setting. Intravenous administration facilitates better management of these complex treatment protocols.

Once the efficacy and safety of a drug are established, developing subcutaneous formulations to enhance patient convenience and reduce the burden of frequent hospital visits becomes a developmental direction. Subcutaneous formulations in oncology aim to improve patients' quality of life, shorten treatment time, and reduce medical costs associated with intravenous infusions. Oncology drugs like Herceptin (trastuzumab) and Rituxan (rituximab) were initially developed as intravenous formulations to ensure precise dosing and manage adverse reactions in a controlled environment. Their subcutaneous versions were introduced 21 and 20 years later, respectively.

5. Pharmacokinetic Differences Between Intravenous Infusion and Subcutaneous Injection and Their Potential Impact on Safety and Efficacy

● General Differences in Pharmacokinetic Characteristics Between Intravenous Infusion and Subcutaneous Injection

Intravenous infusion of biomolecules directly injects into the bloodstream, typically resulting in an immediate maximum serum concentration (Cmax), whereas the pharmacokinetic profile of subcutaneous injection usually shows a slow absorption rate from the subcutaneous extracellular matrix, with Cmax levels lower than those achieved through intravenous infusion. This is primarily due to the relatively poor ability of large biomolecules to traverse vascular endothelial cells. Other factors reducing bioavailability include the formulation’s components, volume, pH, viscosity, interactions with glycosaminoglycans and proteins in the interstitial matrix, as well as enzymatic degradation.

● Subcutaneous Injection of Biologic Therapies for Hypersensitivity Reactions

The underlying mechanisms of monoclonal antibody infusion hypersensitivity reactions remain incompletely understood. Symptoms include flushing, rash, fever, chills, dyspnea, mild to severe hypotension, accompanied by bronchospasm, cardiac dysfunction, and anaphylaxis. Reactions caused by monoclonal antibodies are typically mild to moderate, primarily occurring during the first infusion, and can be mitigated by a slower infusion rate. From a pharmacokinetic perspective, reducing the intravenous infusion rate slows the increase of monoclonal antibody serum levels, similar to the effect achieved with subcutaneous administration. Therefore, it has been suggested that switching to subcutaneous administration may benefit patients when Cmax-related adverse effects are observed during intravenous infusion.

● The Impact of Subcutaneous Administration on Bioavailability

One drawback of subcutaneous administration of biologic therapeutic agents is the relatively lower bioavailability of the injected molecules compared to intravenous infusion; the bioavailability of monoclonal antibodies (mAbs) can range from 50% to 80%. For mAbs, subcutaneous bioavailability appears to be inversely related to the clearance rate after intravenous administration, meaning that mAbs with lower intravenous clearance may exhibit higher subcutaneous bioavailability. This correlation may be due to the involvement of hematopoietic cells (e.g., macrophages or dendritic cells) in the subcutaneous first-pass clearance and systemic clearance following intravenous administration.

6. Subcutaneous Injection of Monoclonal Antibody Development Strategy

The Preferred Design for Conventional Tumor Monoclonal Antibody Therapy is Intravenous Infusion, Determined by the Dose Required to Achieve Efficacy. For Subcutaneous Injection, Aggregation of Monoclonal Antibody Molecules Under High Concentration Conditions Leads to Increased Viscosity and Reduced Stability, Limiting Monoclonal Antibody Concentration to Below 150–200 mg/mL. Administering a Single Subcutaneous Injection of 2-2.5 mL Solution for an Effective Dose of 500 mg (7 mg/kg Required for a 70 kg Patient) Also Poses a Challenge. Currently, At Least Four FDA-Approved Products Enable Large-Volume Subcutaneous Injection of Monoclonal Antibodies. These Drugs Are Formulated as Fixed-Dose Combinations with Recombinant Human Hyaluronidase. Hyaluronidase Is an Enzyme That Catalyzes the Hydrolysis of Hyaluronic Acid, A Component of the Extracellular Matrix in Subcutaneous Tissue Spaces. This Action Temporarily Reduces the Viscosity of Hyaluronic Acid, Thereby Enhancing the Ability of Drugs to Penetrate Tissues, Allowing for Large-Volume Drug Delivery via Subcutaneous Injection Through Increased Tissue Permeability. Compared to Subcutaneous Administration Without Enzyme, Hyaluronidase-Facilitated Subcutaneous Administration Increases Bioavailability by Approximately 20%. In the Presence of Hyaluronidase, The Time to Reach Cmax (Tmax) for Monoclonal Antibody Molecules Is Shorter, Indicating Faster Absorption Into the Circulatory System When Hyaluronidase Is Present.

The development of subcutaneous injection formulations for monoclonal antibodies allows them to rapidly reach effective concentrations and achieve sustained release comparable to intravenous formulations. This revolutionary advancement has transformed patient care, particularly for individuals with chronic diseases. By reducing the time required for intravenous infusion and offering the convenience of self-administration, subcutaneous injections embody a patient-centered approach to development.

Immunogenicity risk is an important consideration in clinical pharmacology and needs to be assessed early in the development of subcutaneous administration programs. This assessment should take into account predictors of the occurrence and severity of immunogenic responses, such as whether the drug mimics endogenous substances or contains non-human protein sequences, dose levels, and frequency.

Ref.       

FDA Approves Genentech’s Tecentriq Hybreza, the First and Only Subcutaneous Anti-PD-(L)1 Cancer Immunotherapy. Genentech Press Release. 12. 09. 2024.

FDA Approves Ocrevus Zunovo? as the First and Only Twice-A-Year 10-Minute Subcutaneous Injection for People With Relapsing and Progressive Multiple Sclerosis. Genentech Press Release. 13. 09. 2024.

Myshko, D. FDA Assigns Action Date for Subcutaneous Opdivo. Formulary Watch. 06. 05. 2024.

Bittner, B. et al. Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities. BioDrugs 32, 425–440 (2018). https://doi.org/10.1007/s40259-018-0295-0

Davis, J. D. et al. Subcutaneous Administration of Monoclonal Antibodies: Pharmacology, Delivery, Immunogenicity, and Learnings From Applications to Clinical Development. Subcutaneous Biologics: Clinical Pharmacology and Drug Development, Clinical Pharmacology & TherapeuticsClinical Pharmacology & TherapeuticsClinical Pharmacology & Therapeutics, 10.1002/cpt.3179, 115, 3, (385-390), (2024).Bernardo Perez-Ramirez, B. et al. Approaches in subcutaneous delivery of monoclonal antibodies. European Pharmaceutical Review. 24. 08. 2016.

Merrill, J. Roche’s Subcutaneous Ocrevus Could Extend Access To Patients. Scrip. 13. 09. 2024.       

U.S. Food and Drug Administration Accepts Bristol Myers Squibb’s Application for Subcutaneous Nivolumab (nivolumab and hyaluronidase). BMS Press Release. 06. 05. 2024.