Katherine E. Rebello, PharmD Clinical Project Manager
Nothing herein is or shall be construed as a promise or representation regarding past or future events and Magellan Rx Management expressly disclaims any and all liability relating to the use of or reliance on the information contained in this presentation. The information contained in this publication is intended for educational purposes only and should not be considered clinical, financial, or legal advice. By receipt of this publication, each recipient agrees that the information contained herein will be kept confidential and that the information will not be photocopied, reproduced, distributed to, or disclosed to others at any time without the prior written consent of Magellan Rx Management.
Editor-in-Chief's MESSAGE
Welcome to the MRx Pipeline. This quarterly publication offers clinical insights and competitive intelligence on anticipated drugs in development, so you are well-sourced on the drug pipeline.
MRx Pipeline, our universal forecast, addresses trends applicable across market segments. Traditional and specialty drugs as well as agents under the pharmacy and medical benefits are featured. Also profiled in the report are new molecular entities, pertinent new and expanded indications for existing medications, and biosimilars.
Clinical analyses, financial outlook, and pre-regulatory status are considered. The products housed in the MRx Pipeline have been researched in detail. They have been developed in consultation with our internal team of clinical and analytics experts.
METHODOLOGY
Emerging therapeutics continue to grow and influence the clinical and financial landscape. Therefore, Magellan Rx Management has developed a systematic approach to determine the products with significant clinical impact. For the in-depth clinical evaluations, the products’ potential to meet an underserved need in the market by becoming the new standard of care, and the ability to replace existing therapies were investigated. The extent to which the pipeline drugs could shift market share on a formulary and their impact on disease prevalence were also important considerations. In order to assist payers with assessing the potential impact of these pipeline drugs, where available, a financial forecast has been included for select products. Primarily complemented by data from EvaluateTM, this pipeline report looks ahead at the 5-year projected annual US sales through the year 2027. These figures are not specific to a particular commercial or government line of business; rather, they look at forecasted total US sales. Depending on a variety of factors, including the therapeutic categories, eventual FDA-approved indications, populations within the plan, and other indices, the financial impact could vary by different lines of business.
REFLECTION
Thus far in 2023, the agency has approved 29 novel drugs, roughly 45% more approvals compared to about the same time last year. Notably, most of the approvals so far in 2023 use at least one of the FDA’s expedited approval methods and the majority of drugs are designated as Orphan Drugs. Approvals included many firsts. Among them are first-time approvals for gene therapies for hemophilia A and Duchenne muscular dystrophy, first once-weekly topical gene therapy for a rare dermatologic condition, first vaccines for RSV prevention in older adults, first single-injection monoclonal antibody for RSV prevention in infants, first cell-based therapy for type 1 diabetes, and a full traditional approval for an Alzheimer’s anti-amyloid antibody. Several long-awaited biosimilars to adalimumab (Humira®), including citrate-free and high-concentration formulations plus an interchangeable product, have launched.
While numbers do not tell the entire story, they do represent significant innovation in patient care and advance public health for the American public.
ON THE HORIZON
As we look ahead, there is a continued trend towards the approval of specialty medications and drugs for rare conditions, with 74% and 36% of approvals expected, respectively, for agents with applications submitted to the FDA. There is 1 agent seeking FDA’s Accelerated Approval, which allows for earlier drug approval for serious conditions that fill an unmet need based on a surrogate endpoint reasonably likely to predict a clinical benefit. Approval of 2 new gene therapies for sickle cell anemia and thalassemia are on the horizon. FDA decision for a biosimilar to Neulasta® Onpro® is anticipated. Moreover, sprouting products for obesity, NASH, and Alzheimer's disease are being actively monitored through MRx Pipeline. Other noteworthy pipeline trends to watch include the development of complex therapies, cell and gene therapies “CGT,” oncology, immunology, and therapeutic options for ultra-rare hereditary diseases.
The drug pipeline ecosphere will continue to evolve as it faces challenges and successes. Innovative agents that show positive results without compromising patient safety and access offer true therapeutic advances and hold the promise to alter the treatment paradigm.
Objective evidence-based methodology was used to identify the Deep Dive drugs in the upcoming quarters. This section features a clinical overview and explores the potential place in therapy for these agents. Moreover, it addresses their FDA approval timeline and 5-year financial forecast.
Specialty drug names appear in magenta throughout the publication.
avacincaptad pegol intravitreal
Astellas
PROPOSED INDICATIONS
Geographic atrophy (GA) secondary to age-related macular degeneration (AMD)
CLINICAL OVERVIEW
Avacincaptad pegol is a pegylated RNA aptamer that inhibits complement C5.
The safety and efficacy of avacincaptad pegol were evaluated in the randomized, double-masked, shamcontrolled, phase 2/3 GATHER1 (NCT02686658; n=286) and GATHER2 (NCT04435366; n=448) trials in adults ≥ 50 years of age with GA secondary to AMD. Enrolled patients had no foveal involvement and a best-corrected visual acuity (BCVA) between 20/25 and 20/320 in the study eye. In both trials, at month 12, avacincaptad pegol 2 mg doses led to a significant reduction from baseline in the primary endpoint of mean change in the GA area compared to sham (GATHER1: 0.668 mm2 [35.4%]; p=0.005; GATHER2: 0.376 mm2 [17.7%]; p=0.0039). Avacincaptad pegol was generally well-tolerated. Notable ocular TEAEs were conjunctival hemorrhage and choroidal neovascularization (CNV). No cases of endophthalmitis or ischemic optic neuropathy were reported. Data also showed a 56% relative risk reduction in persistent vision loss (over 2 consecutive visits) with avacincaptad pegol 2 mg compared to sham.
Avacincaptad pegol was administered as monthly intravitreal injections in the affected eye(s). In GATHER2, at month 12, patients in the avacincaptad pegol arm were re-randomized to receive avacincaptad pegol 2 mg once monthly or once every other month through month 24. Results are pending.
PLACE IN THERAPY
GA is an advanced form of nonexudative (dry) AMD, which is the leading cause of blindness in the US. GA typically occurs in both eyes and is characterized by chronic, progressive atrophy of outer retinal tissue, retinal pigment epithelium, and choriocapillaris that lead to marked decline of visual acuity. As the condition advances, GA lesions can expand into the fovea, resulting in loss of central vision. The rate of progression of GA varies. The reported median lesion growth rate is 2.1 mm2/year, but may range up to 10.2 mm2/year. Some data suggest that over 31% of patients with GA will lose ≥ 3 lines of vision in 2 years. GA affects approximately 20% of individuals with AMD. It is estimated that 1 million people in the US have GA and the incidence will likely rise as the age-burden increases. Risk factors for GA include age ≥ 60 years, family history of AMD, and current or past smoking.
The complement cascade has been implicated in the development of GA. This system is important for tissue homeostasis and can lead to excessive cell death when unregulated. If approved, avacincaptad pegol will be the second agent in the US to treat GA secondary to AMD, following the February 2023 approval of pegcetacoplan (Syfovre™). Both agents are administered via intravitreal injection. While avacincaptad pegol inhibits complement C5, located distally in the complement cascade, pegcetacoplan inhibits complement C3, which is centrally located in the cascade. Pegcetacoplan has demonstrated a reduction in the mean GA lesion growth through 24 months (range, 17% to 22%) with doses administered every 25 to 60 days in patients with or without foveal involvement. In clinical trials, avacincaptad pegol demonstrated mean GA lesion reduction at 12 months (range, 17.7% to 35.4%) when given once monthly and has the potential for every-other-month dosing (pending study results). Post hoc analyses for each drug showed slowing of decline in visual acuity.
FDA APPROVAL TIMELINE
August 19, 2023 Breakthrough Therapy Fast Track Priority Review
FINANCIAL FORECAST (reported in millions)
Year
2023 2024 2025 2026 2027
Projected Total US Sales $8 $126 $297 $534 $765
Multiple myeloma
elranatamab SC
Pfizer
PROPOSED INDICATIONS
Relapsed or refractory multiple myeloma (RRMM)
CLINICAL OVERVIEW
Elranatamab is an off-the-shelf B cell maturation antigen (BCMA) CD3-targeted bispecific antibody. It binds to and bridges BCMA on the surface of myeloma cells and CD-3 receptors on T cells. This leads to T cell activation and myeloma cell death.
The ongoing, multicenter, open-label, single-arm, phase 2 MagnetisMM-3 study (NCT04649359) evaluated the efficacy and safety of elranatamab monotherapy in 123 patients with RRMM. Enrolled patients had received prior treatment with ≥ 1 proteasome inhibitor, ≥ 1 immunomodulatory agent, and ≥ 1 anti-CD38 antibody. After a median follow-up of 10.4 months, the ORR for elranatamab was 61%, with 55% of patients achieving at least a very good partial response (VGPR). It was estimated that 84% of patients would maintain the response at 9 months. In addition, an analysis of pooled data from 3 MagnetisMM studies (MM-1 [phase 1; NCT03269136], MM-3, MM-9 [phase 2; NCT05014412]) included data from 86 patients (64 from MM3) whose prior therapy included BCMA-directed therapy (ADC and/or CAR T). After a median follow-up of 10.3 months (range, 0.3 to 32.3), the ORR was 41.4% and 52.8% in patients with prior BCMA-directed ADC and CAR T therapies, respectively. Among the responders, the median time to achieving an objective response was 1.9 months. At 9 months, the DOR rate was 67.3% and 78.9% in patients with prior ADC and CAR T therapy, respectively.
In the MagnetisMM-3 study, elranatamab was administered as 76 mg SC once weekly on a 28-day cycle with a step-up priming dose regimen of 12 mg and 32 mg administered on day 1 and day 4, respectively, during cycle 1.
FDA APPROVAL TIMELINE
August to September 2023
Breakthrough Therapy
FINANCIAL FORECAST (reported in millions)
talquetamab SC
Janssen
PROPOSED INDICATIONS
Relapsed or refractory multiple myeloma (RRMM)
CLINICAL OVERVIEW
Talquetamab is an off-the-shelf bispecific T cell engager antibody. It binds to G protein-coupled receptor class C group 5-member D (GPRC5D) on the surface of myeloma cells and CD-3 receptors on T cells. This leads to T cell-mediated myeloma cell death.
Multiple myeloma (cont.)
talquetamab (cont.)
CLINICAL OVERVIEW
(cont.)
An ongoing, open-label, phase 2 study (NCT04634552) evaluated the efficacy and safety of talquetamab in patients with RRMM who received ≥ 3 prior lines of therapy, including ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 antibody. Data from 288 patients have been reported, of whom 51 received prior T cell-redirection therapy (CAR T cells, bispecific antibodies). The study demonstrated an ORR of 71.7% and 74.1% in patients who received talquetamab dosed once weekly (at median follow-up of 12.7 months) and every other week (at median follow-up of 18.8 months), respectively. In each dosing group, approximately 60% achieved a VGPR or better, approximately 9% achieved a complete response, and about 24% and 30%, respectively, had a stringent complete response. Among patients with prior T cell-redirection therapy, at a median follow-up of 14.8 months, the ORR was 64.7%, with a VGPR or better of 54.9%. The DOR was ≥ 9 months in all groups, with the longest among those who experienced a complete response. The median PFS was 7.5 and 11.9 months in the weekly and every-other-week dosing cohorts, respectively, and 5.1 months among the prior T cell-redirection cohort. Most adverse events were mild to moderate and manageable. CRS occurred in 75% to 79% of patients across the 2 study cohorts. The incidence of infections, a common comorbidity in patients with multiple myeloma, was 58% to 71% (grade 3/4, 16% to 26%) across the cohorts. No deaths occurred related to talquetamab therapy.
In the phase 2 study, talquetamab is given SC as 0.4 mg/kg once weekly or 0.8 mg/kg every other week with step-up doses. Treatment is continued until disease progression.
Talquetamab is also being studied in an ongoing phase 3 study (NCT05455320) in combination with daratumumab ± pomalidomide. Encouraging results were also seen with talquetamab plus teclistamab (ORR ≥ 85%) in a phase 1b/2 dose escalation study (NCT04586426).
FDA APPROVAL TIMELINE
December 11, 2023
Breakthrough Therapy Orphan Drug
FINANCIAL FORECAST (reported in millions)
PLACE IN THERAPY
MM is a malignancy of plasma cells that accumulate in bone marrow resulting in marrow failure. It accounts for about 18% of all hematologic malignancies in the US. Approximately 35,730 new cases of MM and 12,600 deaths due to the condition are predicted in the US in 2023. MM is usually diagnosed in adults ≥ 65 years of age and is twice as likely to occur in African Americans than Caucasians. Risk factors may include obesity/ overweight, other active plasma cell diseases, and a family history of MM. There is no cure for MM. While patients typically respond to initial therapy, eventual treatment-resistant relapse usually occurs, including after HSCT and radiation therapy.
Triplet therapy is the standard pharmacotherapy for previously treated MM. Preferred regimens consist of dexamethasone plus 2 of the following: a proteasome inhibitor, an immunomodulatory agent, or a monoclonal antibody. Newer alternatives for patients who have received ≥ 4 prior lines of therapies include agents that target BCMA, which is present in 60% to 70% of patients with MM. BCMA-directed treatments include monotherapy with the ADC teclistamab-cqyv (Tecvayli™) and the CAR T therapies idecabtagene vicleucel (ide-cel; Abecma®) and ciltacabtagene autoleucel (cilta-cel; Carvykti®). Notably, the ADC belantamab mafodotin-blmf (Blenrep®) was withdrawn from the US market based on poor confirmatory trial results in patients with RRMM.
Multiple myeloma (cont.)
talquetamab (cont.)
PLACE IN THERAPY (cont.)
If approved, elranatamab and talquetamab will be off-the-shelf (ready-to-use), SC-administered, T cellredirecting bispecific antibody options for RRMM, in addition to the currently available teclistamab-cqyv. Initial approvals for elranatamab and talquetamab are expected to be in heavily pretreated patients. In non-comparative monotherapy trials, the ORR for talquetamab, but not elranatamab, was higher compared to teclistamab-cqyv (ORR, >71% and 61%, versus 63%, respectively) and are lower than the ORR for CAR T cell therapies (ORR, 95% with Carvykti and 72% with Abecma). However, bispecific antibody therapies have an overall more favorable tolerability profile compared to CAR T therapies, including a lower incidence and severity of CRS. Elranatamab, talquetamab, and teclistamab have the potential for use in combination with other agents (e.g., daratumumab, pomalidomide, dexamethasone) in earlier lines of therapy.
exagamglogene autotemcel IV
Vertex/CRISPR
PROPOSED INDICATIONS
» Transfusion-dependent beta-thalassemia (TDT)
» Severe sickle cell disease (SCD)
CLINICAL OVERVIEW
Exagamglogene autotemcel (exa-cel) is an autologous, ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene-edited therapy. With exa-cel, a patient’s hematopoietic stem cells (HSCs) are engineered to produce RBCs with high levels of fetal hemoglobin (hemoglobin F; HbF). Increased levels of HbF may reduce vaso-occlusive episodes (VOEs) in patients with SCD and the need for blood transfusions in those with TDT.
The single-arm, open-label phase 1/2/3 trials CLIMB-THAL-111 (NCT03655678) and CLIMB-SCD-121 (NCT03745287) evaluated the efficacy and safety of exa-cel in patients 12 to 35 years of age with TDT and severe SCD, respectively. At the time of data cut-off in CLIMB-THAL-111, 27 patients with TDT had received exa-cel and had evaluable data. Among these patients, 88.9% achieved the primary endpoint of transfusionindependence for ≥ 12 months. The mean duration of transfusion independence was 20.5 months (maximum 40.7 months). Rapid and sustained increases in total Hb (≥ 11 g/dL) were seen as early as month 3. In CLIMBSCD-121, at data cut-off, 17 patients with SCD who received exa-cel had evaluable data. The primary endpoint of freedom from VOEs for ≥ 12 months was achieved by 94.1% of the patients. The mean duration of freedom from VOEs was 18.7 months (maximum 36.5 months). Early and sustained increases in total Hb and HbF were demonstrated within the first few months. In both studies, the mean proportion of edited BCL11A alleles in the bone marrow and peripheral blood was stable over time, demonstrating a successful permanent editing in the long-term hematopoietic stem cells. Two patients with TDT experienced serious TEAEs; 1 instance each of hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome, headache, and idiopathic pneumonia syndrome was reported. No serious TEAEs were reported in patients with SCD.
In both trials, after packed RBC transfusions and stem cell mobilization, CD34+ hematopoietic stem and progenitor cells (HSPCs) were collected from patients via apheresis. Collected cells were then edited with CRISPER-Cas9 technology. Patients received myeloablative therapy before receiving a single, 1-time IV infusion of the edited HSPCs (exa-cel).
FDA APPROVAL TIMELINE
SCD – December 8, 2023
Fast Track
Orphan Drug
TDT – March 30, 2024
Fast Track
Orphan Drug
Priority Review
RPD
FINANCIAL FORECAST (reported in millions)
RPD
RMAT
RMAT
Year 2023 2024 2025 2026 2027
Projected Total US Sales $0 $141 $360 $577 $780
Includes projected annual sales for TDT and SCD.
lovotibeglogene autotemcel IV
Bluebird Bio
PROPOSED INDICATIONS
Severe sickle cell disease (SCD) in patients with a history of vaso-occlusive events (VOEs)
CLINICAL OVERVIEW
Lovotibeglogene autotemcel (lovo-cel) is a gene therapy that modifies a patient’s hematopoietic stem cells with the addition of functional copies of a modified β-globin gene (βA-T87Q-globin gene). The resulting cells are designed to reduce RBC sickling and hemolysis.
The single-arm, phase 1/2 HGB-206 trial (NCT02140554) evaluated the efficacy and safety of lovo-cel in patients 12 to 50 years of age with severe SCD. The study included patients with ≥ 4 severe VOEs in the 24 months prior to enrollment (cohort C). After receiving 1 dose of lovo-cel, 31 patients (96%) had complete resolution of severe VOEs (VOE requiring ED or hospital visit or priapism requiring medical facility visit; primary endpoint) through 24 months of follow-up. The safety profile in the 24 months following lovo-cel was generally consistent with busulfan conditioning. The most common TEAEs were pain, anemia, opiate withdrawal, nausea, suicidality, and vomiting. Graft failure, insertional oncogenesis, and replication-competent lentivirus were not observed.
The treatment process for lovo-cel involved the following steps: pre-collection preparation, cell mobilization, and apheresis. This was followed by ex vivo transduction of autologous HSPCs with the BB305 lentiviral vector encoding the βA-T87Q transgene. Patients then received myeloablative conditioning followed by IV infusion of a single dose of lovo-cel.
FDA APPROVAL TIMELINE
December 20, 2023
Fast Track
Orphan Drug
Priority Review
FINANCIAL FORECAST (reported in millions)
PLACE IN THERAPY
Sickle Cell Disease
An estimated 100,000 people in the US are diagnosed with SCD, with the highest prevalence in African Americans. The hereditary condition is characterized by sticky, sickle-shaped RBCs. The abnormal RBCs cause chronic anemia, vaso-occlusion, and eventual multiorgan damage. VOEs (also called vaso-occlusive crises [VOC]) occur when the microcirculation is obstructed by sickled RBC, leading to ischemic injury and pain. VOEs are the most common manifestation of SCD and the most common reason for ED visits. The life expectancy of people with SCD is reduced by ≥ 20 years compared to the general population.
Pharmacologic agents approved for use in patients with SCD include the oral antimetabolite hydroxyurea, the oral amino acid L-glutamine (Endari®), and the IV selectin blocker crizanlizumab-tmca (Adakveo®). In clinical trials, these agents led to a reduction in VOEs. Hydroxyurea reduces the need for blood transfusion, but is associated with leukemogenic and carcinogenic toxicities. The oral hemoglobin S (HbS) inhibitor voxelotor (Oxbryta™) is also approved for SCD. In clinical trials, it increased Hb levels, but did not have a significant impact on VOEs. The only curative treatment for SCD is allogeneic bone marrow transplantation; however, its use is limited by associated risks and lack of matched donors.
The gene therapies, exa-cel and lovo-cel, treat the underlying cause of SCD using a patient’s own hematopoietic stem cells that have been genetically modified. Exa-cel achieves this through CRISPR-Cas-9 technology to produce RBCs with high levels of HbF, while lovo-cel’s process adds functional copies of a modified β-globin gene (βA-T87Q-globin gene). If approved, they will be the first gene therapies to treat SCD. Both have demonstrated safety and efficacy for SCD, based on VOE reduction, in patients ≥ 12 years of age. Ongoing clinical trials are also assessing exa-cel and lovo-cel in patients as young as 2 years of age with SCD.
lovotibeglogene autotemcel (cont.)
PLACE IN THERAPY (cont.)
β-thalassemia
β-thalassemia is a chronic, autosomal recessive disorder caused by a mutation in one or both hemoglobin beta (HBB) genes. Symptomatic cases are estimated to occur in approximately 1 in 100,000 individuals in the general population. β-thalassemia is reported most often in populations in the Mediterranean, Africa, India, and Asia, with prevalence reported as high as 10%. The condition is characterized by a reduction in Hb and RBC levels, resulting in anemia. Other complications include iron overload, skeletal changes, and functional changes in the heart, liver, gall bladder, and spleen.
TDT is a severe form of β-thalassemia that requires the use of RBC transfusions (every 2 to 4 weeks) and iron chelation therapy to manage anemia and associated complications. Splenectomy may decrease transfusion requirements in select patients. Allogeneic HSCT may be curative in some cases but requires a well-matched donor (~60% of TDT patients do not have a suitable sibling donor) and carries risks of graft rejection and GVHD. Two pharmacologic treatments are FDA-approved to treat anemia in patients with TDT. They include the erythroid maturation agent luspatercept-aamt (Reblozyl®), which is given by SC injection every 3 weeks by an HCP, and the single-dose IV gene therapy betibeglogene autotemcel (beti-cel; Zynteglo®). In clinical trials, both treatments significantly reduced the need for RBC transfusions in patients with TDT.
If approved, exa-cel will be the second gene therapy approved to treat TDT. Using the patient’s own genetically modified hematopoietic stem cells, beti-cel and exa-cel target the underlying cause of β-thalassemia and have demonstrated safety and efficacy in patients ≥ 12 years of age with a single IV dose. In clinical trials, exa-cel led to freedom from transfusions for ≥ 12 months in patients with TDT. An ongoing clinical trial is also assessing exa-cel in patients ages 2 to 11 years with TDT.
Takeda/Hutchmed
PROPOSED INDICATIONS
Refractory metastatic colorectal cancer (mCRC) as 2nd-line or later therapy
CLINICAL OVERVIEW
Fruquintinib inhibits vascular endothelial growth factor receptors (VEGFR) -1, -2 and -3, which impedes new blood vessel growth (angiogenesis) of malignant tumors.
The multicenter, double-blind, phase 3 FRESCO-2 (NCT04322539) study evaluated the efficacy and safety of fruquintinib in adults with refractory mCRC who had progressed on or were intolerant to trifluridine/ tipiracil and/or regorafenib. Patients also had prior treatment with standard therapies (e.g., chemotherapy [2 lines], biological VEGF inhibitor, EGFR inhibitor [if RAS wild-type], immune checkpoint inhibitor [if MSI-H/ dMMR], BRAF inhibitor [if V600E mutated]). A total of 691 patients were randomized 2:1 to fruquintinib or placebo in addition to best supportive care (BSC). After a median follow-up of 11 months, the primary endpoint of OS was significantly longer in patients treated with fruquintinib than placebo (median, 7.4 versus 4.8 months, respectively; HR, 0.66; p<0.001). The PFS was greater with fruquintinib compared to placebo (median, 3.7 versus 1.8 months, respectively; HR, 0.32; p<0.001) as was the DCR (median, 55.5% versus 16.1%, respectively). Results were consistent regardless of prior therapy. Grade 3 or 4 TEAEs were reported in 62.7% of patients in the fruquintinib arm and 50.4% in the placebo arm, with the most common being hypertension, asthenia, and hand-foot syndrome.
Fruquintinib 5 mg orally once daily was given on days 1 through 21 of each 28-day cycle.
PLACE IN THERAPY
CRC is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the US. It is predicted that in 2023, approximately 153,000 new cases of colorectal cancer and 52,550 associated deaths will occur in the US. Risk factors for CRC include inflammatory bowel disease, smoking, diabetes, obesity, low levels of physical activity, alcohol consumption, and diet.
In patients with mCRC, intensive chemotherapy with 5-FU/leucovorin or capecitabine, with oxaliplatin and/ or irinotecan, is the standard for 1st- and 2nd-lines of therapy. The addition of targeted therapies, such as injectable antibodies and oral kinase inhibitors is also typical. These agents target markers such as VEGF, EGFR, microsatellite instability (MSI), HER2 overexpression, and BRAF mutations. For mCRC that is refractory to chemotherapy, trifluridine/tipiracil (Lonsurf®) or regorafenib (Stivarga®) ± bevacizumab is recommended.
Fruquintinib is a selective kinase inhibitor that targets VEGFR-1, -2, and -3, thereby diminishing angiogenesis that may lead to tumor metastasis. If approved, it will likely compete with trifluridine/tipiracil or regorafenib in patients with refractory mCRC. In non-comparative clinical trials, the median OS of fruquintinib, trifluridine/ tipiracil, and regorafenib were 7.4 months, 7.1 months, and 6.4 months, respectively. Notably the fruquintinib clinical trial included patients previously treated with trifluridine/tipiracil or regorafenib. In addition, fruquintinib displays a more favorable safety profile than the other 2 agents. The TEAEs associated with fruquintinib are similar to regorafenib but occurred at a lower incidence, and trifluridine/tipiracil is associated with neutropenia, anemia, and thrombocytopenia, which have not been reported with fruquintinib.
FDA APPROVAL TIMELINE
November 30, 2023
Fast Track Priority Review
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $17 $44 $69 $101 $123
Iovance
PROPOSED INDICATIONS
Advanced unresectable or metastatic melanoma that has progressed after anti-PD-1/PD-L1 therapy and targeted therapy
CLINICAL OVERVIEW
Lifileucel is an autologous tumor infiltrating lymphocyte (TIL) therapy. It uses T cells extracted from a tumor and expanded ex vivo using a centralized manufacturing process. The T cells are engineered to recognize tumor antigens and are then infused back into the patient.
A multicenter, single-arm, open-label, phase 2 trial (NCT02360579) evaluated lifileucel in 66 patients with advanced unresectable or metastatic melanoma (stage IIIC or IV) that progressed after anti-PD-1/PD-L1 and BRAF ± MEK targeted agents (if BRAF V600 mutation-positive). Patients had received a mean of 3.3 (range, 1 to 9) prior lines of treatment. In the study, patients received a nonmyeloablative lymphodepletion regimen (cyclophosphamide, fludarabine), followed by a single infusion of lifileucel, and up to 6 doses of high-dose interleukin-2. The ORR (primary endpoint) was 36%, with a 3% complete response rate. The DCR was 80%, and after a median 18.7 months of follow-up, the median DOR was not reached; however, the 1-year DOR was 69%. In addition, the median OS was 17.4 months. The best response was reached in a median of 1.4 months after the lifileucel dose. No difference in response was seen based on age, prior anti-CTLA-4 use, BRAF mutation, or PD-1/PD-L1 status. The most common grade 3 or 4 TEAEs were thrombocytopenia (82%), anemia (56%), febrile neutropenia (55%), neutropenia (39%), hypophosphatemia (35%), leukopenia (35%), and lymphopenia (32%).
Lifileucel was administered as a single IV infusion of 1 x 109 to 150 x 109 cells.
PLACE IN THERAPY
While melanoma accounts for about 1% of all cases of skin cancers in the US, it causes the most deaths from skin cancer. It is estimated that nearly 8,000 deaths from melanoma will occur in the US in 2023. Regional disease (stage III) is present in approximately 9% of patients at diagnosis, which is associated with a 71% 5-year survival rate. Approximately 4% of patients have distant metastatic disease (stage IV) upon initial diagnosis, which has an estimated 5-year survival rate of 32%. Tumor thickness, ulceration, and mitotic rate are the most important characteristics to predict treatment outcome. Tumor-infiltrating lymphocytes (TIL) may also help predict clinical outcome.
For 1st-line and subsequent systemic therapies for metastatic or unresectable melanoma, the NCCN recommends an anti-PD-1/PD-L1 antibody; preferred agents include nivolumab (Opdivo®) ± ipilimumab (Yervoy®), nivolumab/relatlimab-rmbw (Opdualag™), or pembrolizumab (Keytruda®) monotherapy. In patients with BRAF V600 mutations, combination therapy with a BRAF inhibitor plus an MEK inhibitor is recommended; regimens include dabrafenib (Tafinlar®)/trametinib (Mekinist®), vemurafenib (Zelboraf®)/cobimetinib (Cotellic®), and encorafenib (Braftovi®)/binimetinib (Mektovi®). For 2nd-line or subsequent therapy, targeted agents may be considered based on mutation status (KIT mutations, ROS1 fusions, NTRK fusions, NRAS mutations).
Lifileucel is a first-in-class TIL therapy. If approved, it will be the only autologous tumor-specific treatment for patients with advanced or metastatic melanoma who have progressed on or after SOC therapies.
FDA APPROVAL TIMELINE
November 25, 2023
Biolinerx
PROPOSED INDICATIONS
Stem cell mobilization for autologous transplantation in patients with multiple myeloma (MM)
CLINICAL OVERVIEW
Motixafortide is a selective cyclic-peptide inhibitor of the C-X-C motif chemokine receptor 4 (CXCR4) with high affinity (Ki, 0.32 nM), long receptor occupancy, and extended clinical activity (> 48 hours).
The international, double-blind, phase 3 GENESIS (NCT03246529) trial evaluated the safety and efficacy of adding motixafortide to G-CSF therapy in patients with MM undergoing HSPC mobilization prior to autologous HSCT. The median age was 63 years and 70% of patients received lenalidomide-containing induction therapy. Following initiation of G-CSF, randomized patients received either motixafortide (n=80) or placebo (n=42) added to G-CSF. The study demonstrated that significantly more patients in the motixafortide group met the primary endpoint of collecting ≥ 6 x 106 CD34+ cells/kg within 2 apheresis days compared to the placebo group (92.5% versus 26.2%, respectively; OR, 53.3; p<0.0001). Similarly, more patients in the motixafortide group achieved ≥ 6 x 106 CD34+ cells/kg within 1 apheresis day (88.8% versus 9.5%, respectively; OR, 118; p<0.0001). As a comparison, in a prospectively enrolled, demographically similar, contemporaneous cohort that included patients (n=14) who were mobilized with plerixafor plus G-CSF, 50% of patients achieved this amount with 1 apheresis day. The median number of CD34+ cells/kg HSPCs mobilized in 1 apheresis day was 10.8 x 106 with motixafortide, 2.25 x 106 with placebo, and 5.47 x 106 with plerixafor. The mean number of apheresis procedures was 1.23 in the motixafortide group and 3.24 in the placebo group (p<0.0001). In addition, patients in the motixafortide group received 5.26 G-CSF injections compared to 8.12 G-CSF injections in the placebo group (p<0.0001). The median time to neutrophil engraftment, platelet engraftment, graft durability, PFS, and OS were similar between the motixafortide and placebo groups. Compared with plerixafor, motixafortide significantly increased the number of multipotent progenitors (MPPs), common myeloid progenitors (CMPs), common lymphoid progenitors (CLPs), and basophil precursors (BPs) when added to G-CSF. The most common TEAEs reported with motixafortide were mild to moderate local injection site reactions, flushing, pruritis, urticaria, and erythema. Bone pain was reported less often with motixafortide than placebo (18% versus 31%, respectively).
All patients received G-CSF 10 mcg/kg on days 1 through 5 (and 6 through 8, as needed). Motixafortide 1.25 mg/kg was administered SC on day 4 (and day 6, if needed). In the contemporaneous cohort, plerixafor was administered SC at a dose of 0.24 mg/kg on day 4 (and 5 through 7, if needed). Apheresis was performed on day 5 (and 6 through 8, if needed).
PLACE IN THERAPY
MM is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to destruction and failure of the bone marrow. It is estimated that 35,730 new cases of MM and 12,590 deaths due to MM will occur in the US in 2023. Patients are typically diagnosed with MM between 65 and 74 years of age. The 5-year relative survival rate is 79% for localized disease and 57% for distant disease.
High-dose chemotherapy (e.g., cyclophosphamide, etoposide, doxorubicin, bendamustine), often combined with corticosteroids and immunomodulating agents, followed by autologous HSCT is used to treat MM. In preparing for HSCT, G-CSF therapy is administered to increase (mobilize) peripheral blood progenitor cells (PBPCs) to a minimum of 2 to 5 x 106 CD34 cells/kg for autologous donors; however, in up to 35% of patients, G-CSF alone does not lead to an adequate PBPC level, particularly in those with advanced age, extensive prior therapy, prior bone marrow radiation, and WBC count < 4,000. The addition of the CXCR4 inhibitor plerixafor has been shown to improve PBPC collection yield.
If approved, motixafortide will be the second CXCR4 inhibitor in the US, competing with plerixafor (Mozobil®) for PBPC mobilization in patients with MM. In clinical trials, motixafortide was well tolerated and demonstrated a higher success rate in PBPC collection of ≥ 6 x 106 CD34+ cells/kg compared to placebo and plerixafor (contemporaneous cohort). Motixafortide produced rapid and durable engraftment and led to significantly fewer doses of G-CSF and number of apheresis days required compared to placebo. Notably, several generics for plerixafor were approved in July 2023 and could launch at any time.
motixafortide (cont.)
FDA APPROVAL TIMELINE
September 9, 2023
Orphan Drug
FINANCIAL FORECAST (reported in millions)
pozelimab IV, SC
Regeneron
PROPOSED INDICATIONS
CD55 deficiency with hyper-activation of complement, angiopathic thrombosis, and severe protein-losing enteropathy (CHAPLE) syndrome
CLINICAL OVERVIEW
Pozelimab is an IgG4 antibody that inhibits complement factor C5.
A multicenter, open-label, single-arm, phase 2/3 trial (NCT04209634) evaluated the safety and efficacy of pozelimab in 10 patients with CD55-mutation confirmed CHAPLE syndrome. Enrolled patients were ≥ 1 year of age. At 24 weeks, all 10 patients achieved the co-primary endpoints of normalization of serum albumin, a marker of disease improvement, and improvement or stabilization of clinical symptoms (e.g., abdominal pain, number of daily bowel movements, and edema). The trial also revealed marked reductions in hospitalization days and albumin transfusions, as well as meaningful increases in body weight and growth. Seven patients experienced mild to moderate adverse events, including iron deficiency, pyrexia, rhinitis, urticaria, and vomiting (n=2 for each).
Pozelimab was administered as a single 30 mg/kg IV loading dose on day 1, followed by weekly SC weightbased doses.
PLACE IN THERAPY
CHAPLE syndrome is a form of primary intestinal lymphangiectasia (also known as Waldmann’s disease). The ultra-rare disease (< 100 known cases worldwide) is caused by a defect in the CD55 gene, leading to a deficiency of the CD55 protein in the immune regulating complement pathway. A lack of CD55 results in overactivity of the complement pathway that in turn leads to blood and lymph vessel damage in the GI tract and loss of immune proteins and blood cells. CHAPLE syndrome is associated with severe protein-losing enteropathy, abdominal pain, bloody diarrhea, vomiting, malabsorption, hypoproteinemia, delayed growth, edema, and recurrent infections. Life-threatening infections and thrombosis may also occur.
There is currently no treatment approved for CHAPLE syndrome. Off-label use of the complement inhibitor eculizumab (Soliris®) corrects GI protein loss in patients with CHAPLE syndrome; however, it appears that there are no studies evaluating eculizumab for CHAPLE syndrome in the US. If approved, pozelimab will be the only agent indicated for the treatment of CHAPLE syndrome. In the clinical trial, it demonstrated rapid and sustained clinical improvement (up to 24 weeks) and few side effects with weekly SC maintenance dosing. Pozelimab is also in phase 3 development for paroxysmal nocturnal hemoglobinuria (PNH).
FDA APPROVAL TIMELINE
August 20, 2023
Fast Track Orphan Drug Priority Review RPD
FINANCIAL FORECAST (reported in millions)
The financial forecast for pozelimab is not currently available.
PROPOSED INDICATIONS
Duchenne muscular dystrophy (DMD)
CLINICAL OVERVIEW
Vamorolone is a dissociative steroid that binds to the glucocorticosteroid receptor.
The double-blind, placebo-controlled, phase 2b VISION-DMD trial (NCT03439670) evaluated the safety and efficacy of vamorolone in boys 4 to < 7 years of age with DMD who were not previously treated with corticosteroids. A total of 121 patients were randomized 1:1:1:1 to vamorolone 2 or 6 mg/kg/day, prednisone 0.75 mg/kg/day, or placebo. A total of 114 patients completed the initial 24-week treatment period of this 2-part study. At 24 weeks, the study met the time to stand (TTSTAND) velocity endpoints with vamorolone 6 mg compared to placebo (LS mean, 0.05 versus -0.01 m/s, respectively; p=0.002), a primary endpoint, and with vamorolone 2 mg (LS mean difference compared to placebo, 0.05 m/s; p=0.02), a secondary endpoint. The vamorolone 6 mg dose displayed a shorter time to onset of activity than vamorolone 2 mg (approximately < 1 week versus 6 weeks, respectively). At 24 weeks, both doses also met the 6MWT endpoint and the vamorolone 6 mg dose met the time to run/walk 10 meters (TTRW) endpoint. Height percentile increased in patients treated with vamorolone 6 mg and 2 mg, but decreased among those treated with prednisone (3.86 and 0.26 versus -1.88, respectively); the difference was significant between the vamorolone 6 mg dose but not the 2 mg dose when each were compared to prednisone (p=0.02 and p>0.05, respectively). The vamorolone and prednisone treatment groups showed similar overall increase in BMI.
Interim data from an 18-month, non-randomized, open-label phase 2a trial (NCT02760277) reported fewer adverse effects (e.g., cushingoid appearance, hirsutism, weight gain, behavior change) with vamorolone than have been reported for treatment with prednisone and deflazacort. In addition, vamorolone did not lead to stunting of growth that is seen with deflazacort or prednisone.
PLACE IN THERAPY
DMD is a rare, X-linked neuromuscular disorder characterized by progressive muscle degeneration and weakness. An estimated 400 to 600 boys are born with DMD each year in the US. In DMD, gene mutations lead to a lack of functional dystrophin protein involved in maintaining muscle fiber integrity. Onset of signs and symptoms of DMD occurs between 3 to 5 years of age. Most boys affected lose the ability to walk by age 12. Moreover, death due to respiratory or cardiac failure typically occurs by the early 30s. Select corticosteroids (prednisone) have been used historically to treat DMD and deflazacort (Emflaza®) is the only steroid FDA-approved for DMD. Corticosteroids may be used in combination with other agents for DMD, including casimersen (Amondys 45), eteplirsen (Exondys 51), golodirsen (Vyondys 53), and viltolarsen (Viltepso®). While corticosteroids have been a SOC in DMD to delay progression of muscle weakness and improve respiratory function, their use is associated with side effects such as weight gain, slowed growth trajectories, bone fractures, and cataracts. Recently, Sarepta’s delandistrogene moxeparvovec-rokl (Elevydis) became the first gene therapy approved, via Accelerated Approval, to treat DMD.
If approved, oral vamorolone will provide an additional steroid option for the treatment of DMD. In clinical trials, it led to improvement over placebo in key mobility endpoints and had an improved safety profile (including growth trajectory) compared to prednisone. Vamorolone has the potential to replace other steroids, including deflazacort, as SOC for DMD based on an improved safety profile and potential for dosing flexibility.
FDA APPROVAL TIMELINE
October 26, 2023
Fast Track Orphan Drug RPD
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $7 $70 $117 $237 $308
zilucoplan SC
PROPOSED INDICATIONS
Myasthenia gravis (MG) that is acetylcholine receptor antibody positive (AChR-Ab+)
CLINICAL OVERVIEW
Zilucoplan is a complement C5 inhibitor.
The double-blind, phase 3 RAISE trial (NCT04115293) evaluated zilucoplan in 174 adults with AChR+ generalized myasthenia gravis (gMG). Enrollees had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score ≥ 6. Participants were randomized 1:1 to zilucoplan or placebo. At week 12, a greater reduction in the primary endpoint of MG-ADL score from baseline was reported in patients who received zilucoplan compared with those who received placebo (LS mean change, -4.39 versus -2.3, respectively; LS mean difference, -2.09; p=0.0004). In addition, more patients in the zilucoplan arm achieved a clinically meaningful (≥ 3-point) reduction in the MG-ADL score without the need for rescue therapy, compared with those in the placebo arm (73% versus 46%, respectively; p=0.0005). Greater improvement from baseline in the Myasthenia Gravis Quality of Life (MG-QOL) score was also reported with zilucoplan compared to placebo (-5.65 versus -3.16; p=0.013). The most common TEAE reported with zilucoplan was injection site bruising. Interim data from the ongoing RAISE-XT open-label extension study (NCT04225871) reported continued long-term safety and response through extension week 12 that were maintained through extension week 48.
Zilucoplan was administered as 0.3 mg/kg SC once daily by self-injection.
PLACE IN THERAPY
MG is an autoimmune neuromuscular disorder that affects an estimated 37 per 100,000 people in the US. The mean age at onset is 28 years in females and 42 years in males. This chronic condition is characterized by muscle weakness and fatigue and affects muscles of the arms, legs, neck, face, and eyes. A reported 15% to 20% of patients will experience an MG crisis that may result in respiratory failure requiring emergency care. Anti-AChR antibodies are identified in approximately 85% of patients with gMG and lead to disruption in neuromuscular signaling, primarily through activation of the classic complement pathway.
There is no cure for MG. Plasmapheresis and IV immunoglobulins have provided benefit in severe cases. Thymectomy may also significantly improve MG symptoms. Pharmacotherapy includes 1st-line use of anticholinesterase inhibitors (e.g., pyridostigmine) followed by immunosuppressants (e.g., corticosteroids, azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus). In recent years, IV-administered biologics have been approved to treat gMG in AChR-Ab+ adults. They include the IV and SC formulations of the neonatal FcRn blocker efgartigimod alfa (Vyvgart®; Vyvgart® Hytrulo), the SC neonatal FcRn blocker rozanolixizumabnoli (Rystiggo®), and the IV complement C5 inhibitors eculizumab (Soliris) and ravulizumab-cwvz (Ultomiris ®).
If approved, zilucoplan will likely compete directly with the complement C5 inhibitors. In non-comparative trials, zilucoplan resulted in a greater reduction in the MG-ADL score compared to eculizumab and ravulizumabcwvz (-2.09 versus -1.9 and -1.6, respectively). Zilucoplan may provide a more preferable self-administered SC once-daily regimen, compared to the other complement inhibitors which require IV administration by an HCP at every 2-, 4-, or 8-week maintenance intervals, depending on the product. Eculizumab and ravulizumabcwvz carry boxed warnings for serious meningococcal infections and are available only through a REMS program. No cases of meningococcal infections were reported with zilucoplan in the RAISE trial, which required meningococcal vaccination for all participants. It remains to be seen if zilucoplan will also carry this warning and limited access via REMS.
FDA APPROVAL TIMELINE
October to December 2023
Orphan Drug
FINANCIAL FORECAST (reported in millions)
Biosimilar Overview
CLINICAL OVERVIEW
Biosimilars are very different from generic drugs in that they are not exact duplicates of their reference biologic product. The FDA approval process for biosimilars is designed to ensure that the biosimilar product is highly similar to the reference product without having any meaningful clinical differences. Moreover, an interchangeable biological product is a biosimilar that is expected to produce the same clinical result as the reference product in any given patient. Switching or alternating between the reference and interchangeable products should have been evaluated and should not negatively impact the safety and efficacy of therapy.
Many controversies have surrounded biosimilars, and regulatory and litigation hurdles remain. The FDA has issued final and draft guidances. Select FDA biosimilar guidances are noted here. In January 2017, the agency issued final guidance on the nonproprietary naming of biologic products, which also applies to biosimilars. The biological products must bear a core name followed by a distinguishing 4-letter, lowercase, hyphenated suffix that is devoid of meaning. The international nonproprietary name (INN) impacts interchangeability as it affects pharmacists’ ability to substitute an interchangeable biosimilar for the reference product.
The FDA withdrew the September 2017 draft industry guidance on determining similarity of a proposed biosimilar product to its reference product to allow for further consideration of the most current and relevant scientific methods in evaluating analytical data. The agency focuses on providing flexibility for the efficient development of biosimilars while maintaining high scientific standards. In July 2018, the FDA finalized its guidance on labeling biosimilars. The guidance pertains to prescribing information (PI) but does not contain specific recommendations on interchangeability in the labeling. The labeling guidance provides recommendations on how to include, identify, and differentiate the biosimilar and the reference product in various sections of the PI. The basic premise remains that the originator product’s safety and effectiveness can be relied upon for HCPs to make prescribing decisions; therefore, a biosimilar should include relevant data from the originator in its PI. In May 2019, the agency released its final guidance on interchangeability. Most states have enacted biosimilar substitution laws. An interchangeable product may be substituted for the originator at the pharmacy without the involvement of the prescriber. In December 2022, the FDA announced a pilot regulatory science program that focuses on advancing the development of interchangeable products and improving the efficiency of biosimilar product development. The Purple Book is an FDA database of licensed biological products that lists biosimilar and interchangeable products. The FDA has approved 4 biosimilars for interchangeability to their reference product: insulin glargine-yfgn (Semglee®), insulin glargineaglr (Rezvoglar™), adalimumab-adbm (Cyltezo®), and ranibizumab-eqrn (Cimerli™).
Biosimilars can receive extrapolation to gain an indication without direct trials of the biosimilar for the eligible indication(s) of the reference products without requiring additional trials. Nevertheless, as each biosimilar comes to market, it will need to be considered individually. The FDA historically regulated insulins as small molecules. However, effective March 23, 2020, drugs such as insulin and growth hormone were deemed biologics and transitioned from the drug pathway to the biologic pathway. Their licensure as biologics allows these agents to be considered in the biosimilar space and promotes competition and access.
PLACE IN THERAPY
The patents of several biologic drugs are set to expire in the next few years, opening the US market for biosimilar entry; however, patent litigation has resulted in significant launch delays of FDA-approved biosimilars. In June 2017, the US Supreme Court issued 2 landmark rulings: (1) allowing a biosimilar manufacturer to provide launch notice of commercial marketing to the originator manufacturer before or after FDA approval of the biosimilar product and (2) eliminating any federal requirement for disclosure, also known as the “patent dance.” Some states, however, mandate disclosure. These decisions may bring biosimilars to the market sooner and potentially create price competition in the marketplace.
In July 2018, the FDA unveiled its Biosimilar Action Plan (BAP), a series of 11 steps to encourage biosimilar market competition, some of which were previously announced or underway. The BAP contains 4 key strategies: (1) improve the biosimilar development and approval process; (2) maximize scientific and regulatory clarity for sponsors; (3) provide effective communications for patients, clinicians, and payers; and (4) reduce unfair tactics that may delay market approval and entry. The BAP strives to promote access to biosimilar products and reduce healthcare costs.
To date, a total of 41 biosimilars have received FDA approval. Of these, 37 have entered the market.
APPROVED BIOSIMILARS
Brand Name (Nonproprietary name)
Zaxio® (filgrastim-sndz)
Inflectra® (infliximab-dyyb)
Erelzi® (etanercept-szzs)
Amjevita™* (adalimumab-atto)
Renflexis® (infliximab-abda)
Cyltezo* (adalimumab-adbm)
Mvasi® (bevacizumab-awwb)
Ixifi™ (infliximab-qbtx)‡
Ogivri® (trastuzumab-dkst)
Retacrit® (epoetin alfa-epbx)
Fulphila® (pegfilgrastim-jmdb)
Nivestym® (filgrastim-aafi)
Hyrimoz®* (adalimumab-adaz)
Udenyca® (pegfilgrastim-cbqv)
Truxima® (rituximab-abbs)
Herzuma® (trastuzumab-pkrb)
Ontruzant® (trastuzumab-dttb)
Trazimera® (trastuzumab-qyyp)
Eticovo™ (etanercept-ykro)
Kanjinti® (trastuzumab-anns)
Zirabev® (bevacizumab-bvzr)
Hadlima™* (adalimumab-bwwd)
Ruxience® (rituximab-pvvr)
Abrilada™* (adalimumab-afzb)
Sandoz March 2015
Pfizer April 2016
Sandoz August 2016
(Manufacturer)
Neupogen® (Amgen)
Remicade (Janssen)
Enbrel® (Amgen)
Amgen September 2016 - Humira (Abbvie)
Merck/Organon May 2017
Boehringer Ingelheim August 2017
Amgen September 2017
Pfizer December 2017
Mylan/Biocon December 2017
Pfizer/Vifor/ Hospira May 2018
Mylan/Biocon June 2018
Pfizer July 2018
Sandoz October 2018
Coherus November 2018
Cephalon/Teva November 2018
Teva December 2018
Merck January 2019
Pfizer March 2019
Samsung Bioepis April 2019
Amgen June 2019
Pfizer June 2019
Organon July 2019
Pfizer July 2019
Pfizer November 2019
Remicade (Janssen)
Humira (Abbvie)
Avastin® (Genentech)
Remicade (Janssen)
Herceptin® (Genentech)
Epogen® (Amgen) Procrit® (Janssen)
Neulasta (Amgen)
Neupogen (Amgen)
(only HCF) Humira (Abbvie)
Neulasta (Amgen)
Rituxan® (Genentech)
Herceptin (Genentech)
Herceptin (Genentech)
Herceptin (Genentech)
Enbrel (Amgen)
Herceptin (Genentech)
Avastin (Genentech)
Humira (Abbvie)
Rituxan (Genentech)
Humira (Abbvie)
Brand Name (Nonproprietary name)
Ziextenzo® (pegfilgrastim-bmez)
Avsola® (infliximab-axxq)
Nyvepria™ (pegfiltrastim-apgf)
Semglee (insulin glargine-yfgn)
Hulio®* (adalimumab-fkjp)
Riabni™ (rituximab-arrx)
Byooviz™ (ranibizumab-nuna)
Rezvoglar™ (insulin glargine-aglr)
Yusimry™* (adalimumab-aqvh)
Releuko® (filgrastim-ayow)
Alymsys® (bevacizumab-maly)
Fylnetra® (pegfilgrastim-pbbk)
Cimerli (ranibizumab-eqrn)
Stimufend® (pegfilgrastim-fpgk)
Vegzelma® (bevacizumab-adcd)
Idacio® (adalimumab-aacf)
Yuflyma®* (adalimumab-aaty)
APPROVED BIOSIMILARS
Sandoz November 2019
Amgen December 2019
Pfizer June 2020
Mylan/Biocon June 2020
Mylan/Biocon July 2020
Amgen December 2020
Biogen September 2021
Eli Lilly December 2021
Coherus December 2021
Amneal March 2022
Amneal April 2022
Amneal May 2022
Coherus August 2022
Fresenius Kabi September 2022
Celltrion September 2022
Fresenius Kabi December 2022
Celltrion May 2023
Originator (Manufacturer)
Neulasta (Amgen)
Remicade (Janssen)
Neulasta (Amgen)
Lantus® (Sanofi-Aventis)
Humira (Abbvie)
Rituxan (Genentech)
Lucentis® (Genentech)
Lantus (Sanofi)
Humira (Abbvie)
Neupogen (Amgen)
Avastin (Genentech)
Neulasta (Amgen)
Lucentis (Genentech)
Neulasta (Amgen)
Avastin (Genentech)
Humira (Abbvie)
Humira (Abbvie)
* Abbvie’s adalimumab (Humira), adalimumab-adaz (Hyrimoz), and adalimumab-bwwd (Hadlima) are approved in 50 mg/mL (with citric acid/ citrate) and 100 mg/mL (citrate-free) concentrations. Adalimumab-aaty (Yuflyma) is only approved as a 100 mg/mL high concentration citratefree formulation. All other biosimilars for Humira are approved as 50 mg/mL concentrations only.
† Pfizer’s Inflectra is marketed in the US; Pfizer has not announced plans to launch Ixifi.
Also available are Eli Lilly’s Basaglar® insulin glargine, a follow-on to Sanofi’s Lantus, and Sanofi’s Admelog® insulin lispro approved as a follow-on to Eli Lilly’s Humalog®
Specialty medications, which include biologics, continue to grow and constitute a large part of drug spend. In the US, it is estimated that biosimilars will cost approximately 15% to 35% less than the originator product, although price dynamics vary. Further, the potential cost savings can vary based on the market segment where brand contracts can play a role. A host of factors will contribute to market acceptability and the potential success of biosimilars. Payers, pharmacies, prescribers, and patients each play an important role in market adoption of biosimilars.
The first biosimilar version of Abbvie’s adalimumab (Humira), adalimumab-atto (Amjevita) became available in the US in January 2023. Several Humira biosimilars, including citrate-free and high-concentration formulations as well as an interchangeable product, launched in July 2023.
BIOSIMILAR OVERVIEW continued
IMMUNOLOGY
adalimumab SC
Pfizer is seeking interchangeability of FDA-approved adalimumab-afzb (Abrilada) 50 mg/mL biosimilar to Abbvie’s 50 mg/mL Humira. Celltrion is also seeking interchangeability for their FDA-approved adalimumab-aaty (Yuflyma) 100 mg/mL, a biosimilar to Abbvie’s citrate-free, high-concentration (100 mg/mL) Humira. Abbvie’s Humira is a tumor necrosis factor alpha (TNF-α) blocker indicated for the treatment of autoimmune disorders, including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), plaque psoriasis (PSO), psoriatic arthritis (PsA), Crohn’s disease (CD) in adults and children, ulcerative colitis (UC), hidradenitis suppurativa (HS), and noninfectious uveitis.
FDA APPROVAL TIMELINE
50 mg/mL
• Pfizer (Abrilada) – Pending for interchangeability
100 mg/mL
• Celltrion (Yuflyma) – TBD for interchangeability
FINANCIAL FORECAST (reported in millions) Year 2023 2024 2025 2026 2027
Projected Total US Sales $11,900 $7,164 $5,480 $4,435 $3,744
The forecast is a projection of total US sales per year for the branded originator product
OPHTHALMOLOGY
aflibercept intravitreal
Biocon/Janssen, Celltrion, and Coherus are seeking approval of their investigational biosimilars to Regeneron’s Eylea® , a vascular endothelial growth factor (VEGF) inhibitor indicated for the treatment of neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME), and diabetic retinopathy (DR).
FDA APPROVAL TIMELINE
• Biocon/Janssen (MYL-1701) – Pending
• Celltrion (CT-P42) – June 28, 2024
• Coherus (FYB-203) – June 28, 2024
FINANCIAL FORECAST (reported in millions)
The forecast is a projection of total US sales per year for the branded originator product
BIOSIMILAR OVERVIEW continued
ONCOLOGY bevacizumab IV
Bio-Thera Solutions/Sandoz, Centus, and Samsung Bioepis/Organon are seeking approval for their investigational biosimilars to Genentech’s Avastin, a vascular endothelial growth factor (VEGF)-specific angiogenesis inhibitor indicated for the treatment of metastatic colorectal cancer, nonsquamous non-small cell lung cancer, glioblastoma, metastatic renal cell carcinoma (RCC), and recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.
FDA APPROVAL TIMELINE
• Bio-Thera Solutions/Sandoz (BAT1706) – Pending
• Centus (FKB238) – Pending
• Samsung Bioepis/Organon (Aybintio) – Pending
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $505 $431 $388 $350 $316
The forecast is a projection of total US sales per year for the branded originator product
ENDOCRINE denosumab SC
Sandoz
Sandoz is seeking approval for their investigational biosimilar (GP2411) to Amgen’s receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor denosumab (Prolia®, Xgeva®). Prolia is indicated for the treatment of osteoporosis in men and postmenopausal women, treatment of glucocorticoid-induced osteoporosis in men and women, and to increase bone mass in women receiving adjuvant aromatase inhibitor therapy or men receiving androgen deprivation therapy; all indicated populations are high risk for fracture. Xgeva is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors, treatment of select patients with giant cell tumor of bone, and treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.
FDA APPROVAL TIMELINE
December 6, 2023
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $4,253 $4,486 $4,578 $3,973 $3,181
The forecast is a projection of total US sales per year for the branded originator product
BIOSIMILAR OVERVIEW continued
IMMUNOLOGY
eculizumab IV
Amgen
Amgen is seeking approval for their investigational biosimilar (Bekemv) to Alexion’s complement inhibitor eculizumab (Soliris) that is indicated for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).
FDA APPROVAL TIMELINE
February 2024
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $1,779 $1,402 $1,113 $745 $548
The forecast is a projection of total US sales per year for the branded originator product
BLOOD MODIFIER
filgrastim IV, SC
Apotex
Apotex is seeking approval of their investigational biosimilar (Grastofil) to Amgen’s Neupogen, a leukocyte growth factor indicated for use in patients with nonmyeloid malignancies who are receiving myelosuppressive anti-cancer drugs; following induction or consolidation chemotherapy for acute myeloid leukemia (AML); with nonmyeloid malignancies in patients who are undergoing myeloablative chemotherapy followed by bone marrow transplantation; to mobilize autologous hematopoietic progenitor cells for collection by leukapheresis; with symptomatic congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia; and who are acutely exposed to myelosuppressive doses of radiation (hematopoietic syndrome of acute radiation syndrome [HSARS]).
FDA APPROVAL TIMELINE
Pending
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $50 $41 $34 $28 $24
The forecast is a projection of total US sales per year for the branded originator product
BIOSIMILAR OVERVIEW continued
ENDOCRINOLOGY
insulin aspart SC
Gan & Lee/Sandoz
Gan & Lee/Sandoz are seeking approval for their investigational biosimilar (GL-ASP) to Novo Nordisk’s rapid-acting human insulin analog insulin aspart (Novolog®) that is indicated to improve glycemic control in patients with diabetes mellitus.
FDA APPROVAL TIMELINE
April 14, 2023
FINANCIAL FORECAST (reported in millions)
The forecast is a projection of total US sales per year for the branded originator product
ENDOCRINOLOGY
insulin glargine SC
Gan & Lee/Sandoz
Gan & Lee/Sandoz are seeking approval for their investigational biosimilar (Basalin) to Sanofi-Aventis’ long-acting human insulin analog insulin glargine (Lantus) that is indicated to improve glycemic control in patients with diabetes mellitus.
FDA APPROVAL TIMELINE
December 23, 2023
FINANCIAL FORECAST (reported in millions)
The forecast is a projection of total US sales per year for the branded originator product
BIOSIMILAR OVERVIEW continued
ENDOCRINOLOGY
insulin lispro SC
Gan & Lee/Sandoz
Gan & Lee/Sandoz are seeking approval for their investigational biosimilar (Prandilin) to Eli Lilly’s rapid-acting human insulin analog insulin lispro (Humalog) that is indicated to improve glycemic control in patients with diabetes mellitus.
FDA APPROVAL TIMELINE
April 1, 2024
FINANCIAL FORECAST (reported in millions) Year 2023 2024 2025 2026 2027 Projected Total US Sales $1,032 $850 $781 $723 $672
The forecast is a projection of total US sales per year for the branded originator product
NEUROLOGY/IMMUNOLOGY natalizumab IV
Polypharma/Sandoz
Polypharma/Sandoz are seeking approval for their investigational biosimilar (PB006) to Biogen’s Tysabri®, an integrin receptor antagonist indicated for treatment of multiple sclerosis (MS) and Crohn’s disease (CD).
FDA APPROVAL TIMELINE
Pending
FINANCIAL FORECAST (reported in millions)
The forecast is a projection of total US sales per year for the branded originator product
BIOSIMILAR OVERVIEW continued
BLOOD MODIFIER
pegfilgrastim SC
Apotex and Lupin are seeking approval for their investigational biosimilars to Amgen’s Neulasta and Coherus is seeking approval for their investigational biosimilar to Amgen’s Neulasta Onpro. Neulasta and Neulasta Onpro contain pegfilgrastim, a leukocyte growth factor indicated for use in patients with nonmyeloid malignancies who are receiving myelosuppressive anti-cancer drugs and in patients acutely exposed to myelosuppressive doses of radiation (HSARS).
FDA APPROVAL TIMELINE
• Apotex (Lapelga) – Pending
• Coherus (Udenyca OBI®) – October 2023
• Lupin (Lupifil-P) – Pending
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales Neulasta $622 $420 $347 $283 $234
Projected Total US Sales Neulasta Onpro $2,972 $2,576 $2,390 $2,084 $1,833
The forecast is a projection of total US sales per year for the branded originator product
OPHTHALMOLOGY
Stada Arzneimittel/Xbrane
Stada Arzneimittel/Xbrane are seeking approval for their investigational biosimilar (Ximluci) to Genentech’s Lucentis, a vascular endothelial growth factor (VEGF) inhibitor indicated to treat wet age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy, and myopic choroidal neovascularization (mCNV).
FDA APPROVAL TIMELINE
April 21, 2024
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $718 $533 $408 $335 $303
The forecast is a projection of total US sales per year for the branded originator product
BIOSIMILAR OVERVIEW continued
IMMUNOLOGY/ONCOLOGY rituximab IV
Dr. Reddy’s
Dr. Reddy’s is seeking approval for their investigational biosimilar to Genentech’s Rituxan, a CD20-directed cytolytic antibody indicated for the treatment of select patients with non-Hodgkin’s lymphoma (NHL), mature B-cell NHL/ mature B-cell acute leukemia, chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA), and pemphigus vulgaris.
FDA APPROVAL TIMELINE
July 12, 2024
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $1,133 $919 $766 $685 $611
The forecast is a projection of total US sales per year for the branded originator product
IMMUNOLOGY tocilizumab IV, SC
Biogen/Bio-Thera Solutions and Fresenius Kabi are seeking approval for their investigational biosimilars to Genentech’s Actemra®, an interleukin-6 (IL-6) receptor antagonist indicated for the treatment of rheumatoid arthritis (RA), giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular and systemic juvenile idiopathic arthritis (JIA), and cytokine release syndrome.
FDA APPROVAL TIMELINE
• Biogen/Bio-Thera Solutions (BIIB800) – October 9, 2023
• Fresenius Kabi (MSB11456) – Pending
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $1,088 $861 $709 $603 $528
The forecast is a projection of total US sales per year for the branded originator product
BIOSIMILAR OVERVIEW continued
ONCOLOGY trastuzumab IV
Henlius/Accord
Henlius/Accord are seeking approval of their investigational biosimilar (HLX02) to Genentech’s Herceptin, a HER2/ neu receptor antagonist indicated for the treatment of HER2-overexpressing breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.
FDA APPROVAL TIMELINE
December 15, 2023
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $388 $335 $300 $269 $236
The forecast is a projection of total US sales per year for the branded originator product.
IMMUNOLOGY
ustekinumab SC
Alvotech
Alvotech is seeking approval for their investigational biosimilar (AVT04) to Janssen’s Stelara®, an interleukin 12/23 (IL-12/23) antagonist indicated for the treatment of plaque psoriasis (PSO), psoriatic arthritis (PsA), Crohn’s disease (CD), and ulcerative colitis (UC).
FDA APPROVAL TIMELINE
July to December 2023
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $6,036 $4,149 $2,954 $2,243 $1,779
The forecast is a projection of total US sales per year for the branded originator product.
Keep on Your RADAR
Notable agents that are further from approval have been identified in this unique watch list. These are products with the potential for significant clinical and financial impact. Their development status is being tracked on the MRx Pipeline radar. These pipeline products, their respective class or proposed indication, as well as an estimated financial forecast for the year 2027, are displayed. The financials are projected total annual US sales, reported in millions.
Specialty drug names appear in magenta throughout the publication.
Pipeline DRUG LIST
The pipeline drug list is an aerial outline of drugs with anticipated FDA approval through 2024. It is not intended to be a comprehensive inventory of all drugs in the pipeline; emphasis is placed on drugs in high-impact categories. Investigational drugs with a Complete Response Letter (CRL).
APPLICATION SUBMITTED TO THE FDA IN PHASE 3 TRIALS
3
Specialty drug names appear in magenta throughout the publication.
PIPELINE DRUG LIST
Specialty drug names appear in magenta throughout the publication.
capivasertib AstraZeneca Breast cancer (R/R, HR+/HER2-, locally advanced or metastatic, in combination with fulvestrant, prior endocrine-based therapy)
Multiple myeloma (R/R, prior immunomodulatory, proteasome inhibitor, and anti-CD38 therapy)
Gastric and gastroesophageal junction adenocarcinoma (locally advanced unresectable or metastatic, 1st-line, in combination with fluoropyrimidine & platinum chemotherapy)
COVID-19 prevention (bivalent primary series and booster doses)
Octapharma von Willebrand disease (routine prophylaxis)
