Robert Greer, RPh, BCOP Vice President, Clinical Strategy and Programs
Andrea Henry, PharmD, MBA, BCPS Specialty Drug Information Pharmacist
Katie Lockhart Manager, Forecasting and Pharmacoeconomics
Simone Ndujiuba, PharmD, BCOP Director, Clinical Strategy and Innovation, Oncology
Olivia Pane, PharmD, CDCES Drug Information Pharmacist
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
In 2022, the US FDA approved 37 novel drugs. This is lower compared to the recent past, with the last 5 years averaging 51 novel approvals per year. Notably, over half (54%) of novel approvals in 2022 were for rare or Orphan diseases. Moreover, 65% of novel approvals underwent at least one of the Agency’s expedited programs to speed approval for serious conditions, with 16% as Accelerated Approval.
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 66% and 36% of approvals expected, respectively, for agents with applications submitted to the FDA. There are 4 agents 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. The first Humira® biosimilar is anticipated to launch on January 31, 2023. Approval of 2 new vaccines and a biologic for RSV prophylaxis plus a gene therapy for hemophilia A are expected. Other noteworthy pipeline trends to watch include the development of complex therapies, cell and gene therapies, oncology, immunology, immunotherapy, and therapeutic options for ultrarare hereditary diseases. Moreover, sprouting products for obesity and menopause vasomotor symptoms are being actively monitored through MRx Pipeline.
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.
delandistrogene moxeparvovec IV
Sarepta/Genentech
PROPOSED INDICATIONS
Duchenne muscular dystrophy (DMD) in ambulant patients
CLINICAL OVERVIEW
Delandistrogene moxeparvovec is a gene transfer therapy intended to deliver the micro-dystrophin-encoding gene to muscle tissue for the targeted production of shortened, functional dystrophin protein.
An analysis from three phase 1 and 2 trials (ENDEAVOR, SRP-9001-101, and SRP-9001-102) included data from > 80 boys with DMD who were 3 to 7 years of age. Patients received a single IV infusion of delandistrogene moxeparvovec. The analysis reported positive results across multiple time points, including 1-, 2-, and 4-years after treatment, with a consistent safety profile.
The ongoing, multinational, double-blind, phase 3 EMBARK trial is evaluating the safety and efficacy of delandistrogene moxeparvovec in 125 ambulatory boys 4 to 7 years old with DMD. Patients are randomized 1:1 to receive a single IV infusion of delandistrogene moxeparvovec 1.33x1014 vg/kg or matching placebo. At week 52, patients who were previously treated with placebo will receive delandistrogene moxeparvovec, and patients who were previously treated with delandistrogene moxeparvovec will receive placebo. The primary endpoint is the change in NorthStar Ambulatory Assessment (NSAA) total score from baseline to week 52. Top-line results are expected in late 2023.
PLACE IN THERAPY
DMD is a rare X-linked neuromuscular disorder characterized by progressive muscle degeneration and weakness. An estimated 400 to 600 males 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 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 before age 30.
Historically, select corticosteroids (prednisone) have been used to treat DMD; deflazacort (Emflaza®) is the only steroid FDA-approved for this use. While corticosteroids have been the 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. Corticosteroids may be used in combination with the disease-modifying antisense oligonucleotides casimersen (Amondys 45), eteplirsen (Exondys 51), golodirsen (Vyondys 53), and viltolarsen (Viltepso®), which target exon skipping gene alterations to produce functional dystrophin protein.
If approved, delandistrogene moxeparvovec will be the first gene transfer therapy indicated to treat boys affected by DMD. Positive responses for up to 4 years have been reported after a single IV infusion. Pfizer’s single-dose fordadistrogene movaparvovec adeno-associated virus (AAV) gene therapy is also in a phase 3 trial in ambulatory patients 4 to 7 years old with DMD; primary completion is expected in January 2024. The oral agent ataluren, which enables production of full-length, functional dystrophin, is also in phase 3 trials. After multiple attempts for FDA approval, new data for ataluren released in mid-2022 reported a 21% slowing of DMD progression and significant improvement in 6MWT.
FDA APPROVAL TIMELINE
May 29, 2023
mirikizumab IV, SC
Eli Lilly
PROPOSED INDICATIONS
Moderate to severe active ulcerative colitis (UC)
CLINICAL OVERVIEW
Mirikizumab is an immunoglobulin G4 (IgG4) monoclonal antibody directed against the p19 subunit of interleukin-23 (IL-23).
The 12-week, double-blind, parallel-arm, phase 3 LUCENT-1 trial evaluated induction therapy with mirikizumab in 1,281 adults with moderately to severely active UC who failed or had intolerance to corticosteroids, immunosuppressants, biologics, or tofacitinib. Patients were randomized 3:1 to mirikizumab or placebo. At 12 weeks, among 1,162 patients included in the efficacy analysis, mirikizumab led to a significantly greater rate of clinical remission (primary endpoint) compared to placebo (24.2% versus 13.3%, respectively; p=0.00006). Mirikizumab also led to statistically significant improvement compared to placebo in all secondary endpoints, including modified Mayo score, endoscopic remission, symptomatic response, symptomatic remission, histologic remission, endoscopic response, bowel urgency, and fecal calprotectin, an indicator of intestinal inflammation. Among patients who responded to treatment in the LUCENT-1 trial, 716 enrolled in the doubleblind LUCENT-2 maintenance therapy trial. In this trial, patients were re-randomized to mirikizumab or placebo (withdrawal group). At week 40, clinical remission was maintained in 49.9% of those who continued mirikizumab and 25.1% of patients who were switched to placebo (p<0.001). Mirikizumab was well-tolerated during both trials.
In LUCENT-1, mirikizumab 300 mg IV every 4 weeks for 12 weeks was administered as induction therapy. In LUCENT-2, mirikizumab 200 mg SC every 4 weeks was administered as maintenance therapy.
PLACE IN THERAPY
UC is a chronic autoimmune disorder characterized by inflammation and ulceration of the large intestine mucosa. Disease onset typically peaks in early adulthood. If left untreated, UC follows a relapsing and remitting disease course. Approximately 15% of patients experience aggressive disease and may require colectomy within 5 to 10 years after diagnosis.
There are several DMTs from various drug classes available for long-term management of moderate to severe UC. These include injectable TNF-α inhibitors, adalimumab (Humira; SC), golimumab (Simponi®; SC), infliximab (Remicade®, biosimilars; IV), the anti-integrin agent vedolizumab (Entyvio®; IV), and the IL-12/23 antagonist ustekinumab (Stelara®; IV). Oral agents for UC include the Janus kinase (JAK) inhibitors tofacitinib (Xeljanz®/ Xeljanz XR®) and upadacitinib (Rinvoq®), and the sphingosine 1-phosphate receptor modulator ozanimod (Zeposia®). In general, most drugs that are successful for induction of remission are continued as maintenance therapy.
If approved, mirikizumab will be the first anti-IL23p19 treatment for UC. It could compete with the IL12/23 inhibitor ustekinumab (Stelara) which is the only other agent that blocks IL-23 approved for UC. While ustekinumab is administered IV for both induction and maintenance dosing, mirikizumab offers the convenience of SC maintenance dosing. Guselkumab (Tremfya®) also targets IL-23p19 and is currently in phase 3 trials for UC via IV and SC administration. The IV- or SC-administered IL-23 inhibitor risankizumabrzaa (Skyrizi®) is also in phase 3 trials for UC.
FDA APPROVAL TIMELINE
February to March, 2023
FINANCIAL FORECAST (reported in millions)
nogapendekin alfa inbakicept intravesical
Immunitybio
PROPOSED INDICATIONS
Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) with or without Ta or T1 disease
CLINICAL OVERVIEW
Nogapendekin alfa inbakicept (NAI) is an interleukin-15 (IL-15) superagonist complex comprised of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein.
The safety and efficacy of NAI was evaluated in the open-label, phase 3 QUILT-3.032 study in 171 adults with BCG-unresponsive NMIBC. Cohorts A (n=84) and C (n=10) included patients with CIS disease with or without Ta/T1 papillary disease. Cohort B enrolled patients (n=77) with high-grade Ta/T1 papillary disease. Patients in cohorts A and B were treated with NAI plus BCG. Those in cohort C received NAI alone. In cohort A, after a median follow-up of 23.9 months, 71% of patients achieved a complete response (primary endpoint); the probability of avoiding a cystectomy was 89.2% and probability of disease-specific survival was 100%. In cohort B, the estimated rate of disease-free survival (DFS) at 12 months was 55.4% (primary endpoint) and the median DFS was 19.3 months. In cohort C, at a median follow-up of 7.9 months, NAI monotherapy led to a complete response (primary endpoint) in 2 patients (20%); one patient maintained complete response at 6 months. The most common TEAEs reported with NAI were dysuria, pollakiuria, and hematuria, which are adverse events commonly reported with BCG.
NAI 400 µg was administered intravesically (bladder instillation) once weekly for 6 consecutive weeks during the induction treatment period. In cohorts A and B, patients also received BCG 50 mg intravesically weekly for 6 weeks.
PLACE IN THERAPY
Bladder cancer is the sixth most common cancer in the US. It is estimated that 81,180 new cases of bladder cancer and 17,100 deaths due to the condition occurred in 2022. The average age at diagnosis is 73 years. NMIBC accounts for approximately 75% of all new cases.
The standard initial treatment for NMIBC is transurethral tumor resection. This is followed by intravesical BCG (preferred) or intravesical chemotherapy (e.g., gemcitabine, mitomycin) in patients at intermediate or high risk of recurrence or progression. Up to 75% of cases will develop tumor recurrence after BCG therapy, and 20% have disease progression within 5 years. Notably, Merck is the sole supplier of the TICE attenuated, live BCG strain in the US and a number of other countries, and supply constraints have impacted the availability of BCG live. Priority for BCG induction is given to patients with high-risk NMIBC (cT1 high grade or CIS). Radical cystectomy is recommended in patients who do not respond to intravesical BCG therapy. In patients who wish to preserve their bladder or who are ineligible for cystectomy, nonsurgical options are limited to IV pembrolizumab (Keytruda®) and intravesical valrubicin (Valstar®). Both options are indicated in patients with BCG-unresponsive CIS bladder cancer. In December 2022, the FDA approved the gene therapy nadofaragene firadenovec-vncg (Adstiladrin®) for the treatment of high-risk BCG-unresponsive NMIBC with CIS, with or without papillary tumors. In clinical trials, it demonstrated a 51% complete response rate with a median duration of 9.7 months.
Nogapendekin alfa inbakicept is a first-in-class IL-15 superagonist. It acts as an activation and proliferation factor for natural killer (NK) cells as well as effector and memory T cells, which may overcome BCG therapy failure. NAI works locally in the bladder with no systemic IL-15 levels detected. In the clinical trial, it led to complete responses ranging from 71% to 89.2% when administered in combination with BCG in patients who previously failed BCG. If approved, NAI will provide an important option for patients with BCG-unresponsive NMIBC.
FDA APPROVAL TIMELINE
May 23, 2023
Breakthrough Therapy Fast Track
FINANCIAL FORECAST
(reported in millions)
The financial forecast for nogapendekin alfa inbakicept is not currently available.
palopegteriparatide SC
Ascendis
PROPOSED INDICATIONS
Hypoparathyroidism in adults
CLINICAL OVERVIEW
Palopegteriparatide is a long-acting prodrug of parathyroid hormone (PTH 1-34). It is designed to restore physiological levels of PTH 1-34 over 24 hours.
The 26-week, double-blind, phase 3 PaTHway trial evaluated palopegteriparatide in 82 patients with chronic hypoparathyroidism. Patients were randomized 3:1 to palopegteriparatide or placebo. The primary endpoint of serum calcium levels in the normal range (8.3 to 10.6 mg/dL) and independence from conventional therapy (active vitamin D and > 600 mg/day of calcium supplements) was achieved by significantly more patients in the palopegteriparatide group (78.7%) compared to placebo (4.8%) (p<0.0001). Statistically significant reductions in secondary endpoints of disease-specific physical and cognitive symptoms were also reported with palopegteriparatide compared to placebo. Notably, at week 26, the majority of patients (95%) treated with palopegteriparatide discontinued conventional treatment. Palopegteriparatide was well-tolerated, with injection site reaction and headache as the most common TEAEs reported. A 3-year, open-label extension period of the PaTHway trial, in which all patients enrolled (n=79) receive palopegteriparatide, is ongoing. The phase 2, PaTH Forward trial demonstrated a durable response through week 110. A normalized serum calcium level was maintained and 93% of palopegteriparatide-treated patients were independent of conventional therapy at this time point. The study also demonstrated that palopegteriparatide restored skeletal bone mineral density (BMD) toward sex- and age-expected values.
In the phase 3 PaTHway trial, palopegteriparatide was initiated at a self-administered fixed dose of 18 mcg/day SC using a prefilled pen. It was individually titrated to an optimal dose over 10 weeks, followed by individualized dosing up to 16 weeks.
PLACE IN THERAPY
Hypoparathyroidism is characterized by a decrease in function of the parathyroid glands, leading to reduced levels of PTH. This results in low serum calcium and elevated phosphorous levels. Hypoparathyroidism is typically caused by injury (surgical, autoimmune) to the parathyroid glands. It also manifests in the condition known as DiGeorge syndrome in which parathyroid glands are absent at birth. Hypoparathyroidism leads to an increased risk of bone loss, cataracts, kidney stones, Parkinson’s disease, and in the instance of autoimmune hypoparathyroidism, to Addison disease and pernicious anemia. The estimated prevalence of hypoparathyroidism in the US is 37 per 100,000 person-years.
Treatment focuses on restoring normal calcium and mineral levels in the body and includes lifelong calcium and vitamin D (e.g., calcitriol, alfacalcidol) supplementation. Recombinant human PTH 1-84 (Natpara®) via daily SC injection is approved for select patients, but carries a boxed warning for risk of osteosarcoma and has only been available through a Special Use program since September of 2019, when it was recalled due to reports of rubber particulates in the cartridge. If approved, palopegteriparatide will be the only hormonal replacement therapy indicated to treat hypoparathyroidism. Notably, palopegteriparatide is now available through an Expanded Access Program outside of clinical trials to select adults with hypoparathyroidism without other adequate treatment alternatives.
FDA APPROVAL TIMELINE
April 30, 2023 Orphan Drug
Priority Review
FINANCIAL FORECAST (reported in millions)
quizartinib oral
Daiichi Sankyo
PROPOSED INDICATIONS
Acute myeloid leukemia (AML) in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and as continuation monotherapy following consolidation
CLINICAL OVERVIEW
Quizartinib is a highly potent and selective inhibitor of type II FMS-like tyrosine kinase 3 (FLT3), a protein expressed by hematopoietic stem cells that plays a key role in the life cycle of the cell.
The ongoing, double-blind, phase 3 QuANTUM-First trial evaluated quizartinib in 539 adults ages 18 to 75 years with newly diagnosed FLT3-ITD positive AML, including those who underwent prior HSCT. Patients were randomized 1:1 to quizartinib or placebo given in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and as continuation monotherapy following consolidation for up to 36 cycles. After a median follow-up of 39.2 months, the addition of quizartinib to chemotherapy led to a 22.4% reduction in the risk of death (primary endpoint) compared to standard chemotherapy alone (OS, 31.9 versus 15.1 months, respectively; HR=0.776; p=0.0324). The rates for complete response and complete response without hematologic recovery were 71.6% and 64.9%, respectively, and relapse-free survival was longer with the addition of quizartinib than with chemotherapy alone (HR=0.733). The TEAEs with quizartinib were generally manageable and consistent with chemotherapy alone.
Quizartinib 40 mg/day was administered orally on days 8 through 21 of induction/consolidation and 30 to 60 mg/day was administered during continuation therapy for up to 3 years.
PLACE IN THERAPY
AML is a cancer involving the blood and bone marrow. It is the most common type of acute leukemia in adults, with an average age at diagnosis of 68 years. It is estimated that 20,050 new cases of AML and 11,540 deaths from the condition occurred in the US in 2022.
The FLT3 gene is involved in hematopoiesis. FLT3 mutations with internal tandem duplications (ITD) occur in approximately 30% of cases and are associated with shorter remissions and poorer survival outcomes (median OS, 6 to 12 months). Chemotherapy induction regimens in patients ages < 60 years with FLT3 mutation include standard dose cytarabine with daunorubicin and oral midostaurin. This regimen is followed by consolidation therapy with high-dose intermittent cytarabine with oral midostaurin. In those ≥ 60 years of age, venetoclax-based therapy (with azacitidine or decitabine) is preferred for induction followed by cytarabine with daunorubicin and or midostaurin. Post-induction therapy includes azacitidine or decitabine plus sorafenib. Recommended maintenance therapy in those with FLT3 mutation, regardless of age, is sorafenib.
If approved, quizartinib could compete with oral midostaurin (Rydapt®) for the treatment of newly diagnosed, FLT3 mutation-positive AML in combination with standard cytarabine and daunorubicin induction and consolidation therapy. In the phase 3 RATIFY trial (NCT00651261), midostaurin plus standard chemotherapy resulted in a similar improvement in OS compared with chemotherapy alone (HR, 0.77). In 2019, Daiichi Sankyo received a complete response letter (CRL) from the FDA for quizartinib for the treatment of R/R AML after the FDA’s Advisory Panel voted 8 to 3 against approval; the panel stated that quizartinib did not definitively demonstrate benefit that outweighed its potential risks.
FDA APPROVAL TIMELINE
April 24, 2023
Breakthrough Therapy
Fast Track
Orphan Drug
FINANCIAL FORECAST (reported in millions)
The financial forecast for quizartinib is not currently available.
Priority Review
INFECTIOUS DISEASE
respiratory syncytial virus (RSV) vaccines
GSK3844766A IM
GlaxoSmithKline
PROPOSED INDICATIONS
RSV prevention in older adults (ages ≥ 60 years)
CLINICAL OVERVIEW
GSK3844766A (also known as RSVpreF3 OA) is a recombinant vaccine that contains a proprietary adjuvant system, which has been approved for use in other vaccines, including against shingles (Shingrix®) and malaria (Mosquirix®).
The safety and efficacy of GSK3844766A was evaluated in the ongoing multinational, randomized, observerblind, placebo-controlled, phase 3 AReSVi-006 trial in 26,665 adults ≥ 60 years of age. In part 1 of the study, GSK3844766A was administered as a single IM injection into the deltoid muscle prior to the RSV season. The study demonstrated the vaccine produced an overall vaccine efficacy (VE), the primary endpoint, of 82.6% against RSV lower respiratory tract disease (RSV-LRTD). In addition, the VE against severe RSV-LRTD, defined as presence of ≥ 2 lower respiratory signs or assessed as severe by the investigator, was 94.1%. Among select populations, the VE against RSV-LRTD was 94.6% in those with pre-existing comorbidities and 93.8% in those ages 70 to 79 years. Efficacy was similar and robust against both the RSV A and RSV B strains. GSK3844766A was well tolerated. In part 2 of the ongoing study, individuals will receive annual revaccination prior to each subsequent RSV season.
FDA APPROVAL TIMELINE
May 3, 2023
Fast Track Priority Review
FINANCIAL FORECAST (reported in millions)
PF-06928316 injectable
Pfizer
PROPOSED INDICATIONS
RSV prevention in older adults (ages ≥ 60 years)
CLINICAL OVERVIEW
PF-06928316 (also known as RSVpreF) is a recombinant bivalent prefusion F-based vaccine that contains equal parts RSV types A and B.
The safety and efficacy of PF-06928316 was evaluated in the multinational, randomized, double-blind, placebo-controlled, phase 3 RENOIR trial in 37,630 adults ≥ 60 years of age. Interim data demonstrated an overall VE of 66.7% against RSV-lower respiratory tract infection (RSV-LRTI) (defined by ≥ 2 symptoms) and a VE of 85.7% against severe RSV-LRTI (defined by ≥ 3 symptoms). The vaccine was well tolerated. No safety concerns were observed.
PF-06928316 was administered as a single 120 µg injection.
Breakthrough Therapy Fast Track Priority Review
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $8 $163 $208 $312 $438
PLACE IN THERAPY
RSV is a common contagious respiratory virus that usually causes mild, cold-like symptoms lasting 1 to 2 weeks. However, RSV can cause serious illness, particularly in infants and older adults in whom bronchiolitis and pneumonia can occur and may require hospitalization. Older adults are at higher risk of serious illness due to weakened immunity and underlying cardiac or pulmonary conditions. In the US, RSV causes 60,000 to 120,000 hospitalizations and 6,000 to 10,000 deaths each year among adults ages ≥ 65 years. Typically, the RSV season in the US occurs during approximately November through April but may vary by region. However, since the start of the COVID-19 pandemic the regular RSV circulation pattern has been disrupted and began to rise during the Spring of 2021.
There is no agent FDA-approved to treat RSV infection. Treatment consists of symptom management, including antipyretics and analgesics. Palivizumab (Synagis®), an RSV F protein inhibitor monoclonal antibody, is the only agent FDA-approved for the prevention of RSV. It is indicated for use only in infants and young children. No vaccine has been FDA-approved for the prevention of RSV.
If approved, GlaxoSmithKline’s RSV vaccine GSK3844766A could be the first vaccine in the US available to prevent lower respiratory tract disease due to RSV infection in adults ≥ 60 years of age, closely followed by Pfizer’s PF-06928316 vaccine. Both are recombinant vaccines containing a subunit prefusion RSV F glycoprotein (RSVpref) antigen and target the viral fusion protein that the virus uses to enter the host cell; GlaxoSmithKline’s product also contains an adjuvant to boost its activity. Both vaccines are expected to require repeat dosing prior to each RSV season. RSV vaccines by Bavarian, Janssen, Novavax, and Moderna (mRNA) for use in older adults are also in phase 3 trials.
Notably, on the pediatric RSV pipeline front, PF-06928316 is in phase 3 investigation (MATISSE trial) for maternal administration during pregnancy to protect the infant from RSV after birth. An interim analysis reports favorable safety and efficacy (VE, 81.8% and 69.4% through first 3 and 6 months of life, respectively).
PF-06928316 has the potential to be the first RSV vaccine approved to protect infants from RSV-LRTI. Novavax’s RSV vaccine is also in phase 3 research for maternal administration. In addition, AstraZeneca submitted a BLA for the single-dose monoclonal antibody nirsevimab for prevention of RSV-LRTI in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. The FDA decision is expected in Q3, 2023. Merck’s monoclonal antibody clesrovimab is also in a phase 3 trial for use in patients < 1 year of age who are at increased risk for severe RSV.
PROPOSED INDICATIONS
Alopecia areata in patients ages ≥ 12 years
CLINICAL OVERVIEW
Ritlecitinib is a dual inhibitor of Janus kinase (JAK) 3 and the tyrosine kinase expressed in hepatocelluar carcinoma (TEC) family of tyrosine kinases. TEC proteins play a key role in T-cell-receptor signaling.
The double-blind, phase 2b/3, dose-finding ALLEGRO trial evaluated the safety and efficacy of ritlecitinib in 718 patients ≥ 12 years of age with alopecia areata, including alopecia totalis and alopecia universalis. Patients had ≥ 50% scalp hair loss, based on the Severity of Alopecia Tool (SALT) score (≥ 50%). Patients were excluded if they had other types of alopecia or other diseases that can cause hair loss. Patients were randomized to oral once daily ritlecitinib 50 mg or 30 mg (with or without 4 weeks of initial treatment with ritlecitinib 200 mg once daily), ritlecitinib 10 mg once daily, or placebo, across 7 study arms. After 24 weeks, significantly more patients treated with ritlecitinib 30 mg or 50 mg (with or without the loading dose) compared to those given placebo experienced the primary endpoint of hair regrowth, as indicated by a SALT score of ≤ 20%. The response was dose-dependent, ranging from 14.3% with ritlecitinib 30 mg with no loading dose to 30.7% with ritlecitinib 50 mg with a loading dose, compared to 1.54% with placebo (p<0.000001 for each compared to placebo). The ritlecitinib 10 mg dose was included for dose ranging purposes only and did not provide meaningful benefit. At week 48, durable dose-dependent responses (SALT ≤ 20%) were seen in 31.2% to 39.5% of patients who received 30 mg or 50 mg (with or without loading doses), respectively. The most common TEAEs were nasopharyngitis, headache, and upper respiratory tract infection. Among patients treated with ritlecitinib, 8 patients developed shingles, 1 patient developed pulmonary embolism, and 2 patients developed breast cancer. No deaths, MACE, or opportunistic infections were reported.
PLACE IN THERAPY
Alopecia areata is an autoimmune condition that attacks hair follicles causing hair loss. Patchy baldness can develop anywhere on the scalp, face, and body. Onset typically occurs during childhood, adolescence, or during the patient's 20s or 30s. Approximately half of individuals experience hair regrowth within a few months without treatment. Alopecia may reoccur with unpredictable cycles. Pharmacotherapies for alopecia areata include corticosteroids, immunosuppressants, and agents that stimulate hair regrowth. In June 2022, the JAK inhibitor baricitinib (Olumiant®) received FDA approval as the first medication to treat alopecia areata in adults. Baricitinib carries a boxed warning for serious infections, mortality, malignancy, MACE, and thrombosis. If approved, ritlecitinib will be the first-in-class of agents that inhibit both JAK3 and TEC tyrosine kinases. It could compete with baricitinib to treat alopecia areata in adults; however, ritlecitinib will be the only agent approved for use in adolescents in this setting. While ritlecitinib has high selectivity for JAK3, baricitinib has greater inhibitory potency for JAK1 and JAK2. Both agents are administered orally once daily. In noncomparison trials, ritlecitinib and baricitinib produced similar dose-dependent hair regrowth; for baricitinib, SALT score ≤ 20% at week 36 occurred in 17% to 35% of patients. Unlike baricitinib, serious events such as death, MACE, and serious infections were not reported with ritlecitinib. Ritlecitinib is also in phase 2 trials for vitiligo, RA, CD, and UC.
FDA APPROVAL TIMELINE
April to June 2023
Breakthrough Therapy
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $25 $73 $87 $133 $155
* Forecasted sales reported for all investigational indications
PROPOSED INDICATIONS
Prevention of recurrent Clostridioides difficile-associated diarrhea/infection (CDI)
CLINICAL OVERVIEW
SER-109 is an oral live microbiome therapeutic product that consists of purified Firmicutes spores, which are typically found in a healthy microbiome. Stool donations are from healthy, screened individuals.
The double-blind, placebo-controlled, phase 3 ECOSPOR-III study evaluated SER-109 in adults with recurrent CDI (≥ 3 CDI episodes within 12 months). The 182 enrolled patients had ≥ 3 unformed bowel movements over 2 consecutive days, a positive C. difficile stool toxin test, and had responded to SOC antibiotic treatment (vancomycin and/or fidaxomicin). Patients were randomized 1:1 to SER-109 or placebo and were monitored for 8 weeks for recurrence. SER-109 demonstrated superiority over placebo, as it reduced the risk of CDI recurrence (primary endpoint) by 68% (12% versus 40%, respectively; p<0.001). In addition, response was sustained through week 8 in 88% of patients treated with SER-109 compared with 60% who received placebo. No serious adverse events were reported. The most common adverse events were GI in nature and of mild to moderate severity, and occurred at similar rates in both groups. The open-label extension ECOSPOR-IV study (n=263) included patients from ECOSPOR-III and additional patients with only 1 prior CDI recurrence. The study also included patients with multiple comorbidities (e.g., CVD, tumors, diabetes, COPD, CKD). It reported similar findings, with a 91% sustained clinical response at 8 weeks and 86% at 24 weeks.
SER-109, at an approximate dose of 3 x 107 spore colony-forming units, was administered orally as 4 capsules once daily for 3 consecutive days.
PLACE IN THERAPY
C. difficile is a bacterium that causes diarrhea and colitis. Nearly 500,000 cases of CDI are reported in the US each year. CDI typically occurs during or shortly after a course of antibiotic therapy. Risk factors include age ≥ 65 years, recent hospital or nursing home stay, immunocompromise, and previous CDI. Recurrence of CDI is reported in approximately 15% to 30% of patients who initially respond to therapy; the rates of second and subsequent recurrences are 40% and 45% to 65%, respectively. It is estimated that 15,000 to 30,000 deaths each years in the US are attributed to CDI.
The IDSA recommends proper antibiotic stewardship to control CDI rates based on the local epidemiology and the C. difficile strains present. Appropriate restriction of fluoroquinolones, clindamycin, and cephalosporins should be considered, and use of the inciting antibiotic agent(s) should be discontinued as soon as possible. Data are insufficient to recommend use of probiotics for primary prevention of CDI. Oral vancomycin (Firvanq®, Vancocin®, generics) or fidaxomicin (Dificid®) is strongly recommended for the treatment of initial and recurrent CDI episodes in adults. Fecal microbiota transplantation is strongly recommended in patients who experience multiple recurrences and fail appropriate antibiotic treatments. The monoclonal antibody bezlotoxumab (Zinplava™) is indicated to reduce recurrence of CDI in adults on antibiotic CDI therapy who are at high risk for recurrence.
SER-109 alters the disrupted microbiome of the GI tract to resist growth of C. difficile. If approved, it will be the first oral live microbiome therapy approved in the US to prevent recurrent CDI; this follows the November 2022 approval of Ferring's rectally-administered live microbiota preparation (Rebyota®).
FDA APPROVAL TIMELINE
April 26, 2023
Breakthrough Therapy Orphan Drug Priority Review
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027 Projected Total US Sales $15 $38 $72 $110 $150
PROPOSED INDICATIONS
Heart failure (HF)
» To reduce the risk of CV death, hospitalization for HF, and urgent HF visit in adults with HF, including those with acute or worsening HF
» To reduce the risk of CV death, hospitalization for HF, urgent HF visit, nonfatal MI, and nonfatal stroke in adults with T2DM, CKD, and other CV risk factors, including a history of HF
CLINICAL OVERVIEW
Sotagliflozin is a dual inhibitor of sodium-glucose co-transporter (SGLT) types 1 and 2. SGLT1 is responsible for glucose absorption in the GI tract and SGLT2 mediates glucose reabsorption by the kidneys.
The double-blind, phase 3 SCORED trial enrolled 10,584 adult patients with T2DM, CKD, and other CV risk factors. Patients were randomized 1:1 to sotagliflozin or placebo, both added to SOC. After a median of 16 months, the rate of the composite primary endpoint of the total number of deaths from CV causes, hospitalizations for HF, and urgent visits for HF was significantly less with sotagliflozin (5.6 events/100 patient-years) compared to placebo (7.5 events/100 patients-years) (HR, 0.74; p<0.001). This was primarily driven by a reduction in hospitalizations and urgent visits for HF (HR 0.67; p<0.001); there was no significant difference in the rate of CV death (p=0.35).
The double-blind, phase 3 SOLOIST-WHF trial enrolled 1,222 adults with T2DM who had recently been hospitalized for worsening HF. Patients were randomized 1:1 to sotagliflozin or placebo; both were added to SOC. After a median of 9 months, the primary endpoint of total number of deaths from CV causes, hospitalizations for HF, and urgent visits for HF was significantly lower with sotagliflozin than placebo (51 versus 76.3 events/100 patient-years; HR, 0.67; p<0.001). The rate of hospitalizations and urgent visits for HF was significantly lower with sotagliflozin (HR, 64; p<0.001). The rate of CV death was numerically lower with sotagliflozin compared to placebo, but not to a significant level (10.6 versus 12.5 total events; HR, 0.84; p=0.36). Adverse events reported more often with sotagliflozin than placebo were diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis.
In both trials, sotagliflozin was initiated at a dosage of 200 mg orally once daily and, if tolerated, increased to 400 mg orally once daily.
PLACE IN THERAPY
An estimated 6.2 million adults in the US suffer from HF. It occurs when the heart fails to pump blood at an adequate rate to support the organs of the body. A wide range of pharmacotherapies are used for the management of HF. While several mechanisms have been proposed, the HF benefit that SGLT2 inhibitors provide appears to be independent of glucose lowering. The AHA, ACC, and HFSA recommend the use of SGLT2 inhibitors in patients with T2DM and either established CVD or at high CV risk to prevent hospitalization for HF. SGLT2 inhibitors are also recommended in patients with HF, with or without T2DM, to reduce hospitalization and CV mortality. SGLT2 inhibitors already approved to reduce the risk of CV death and hospitalization due to HF include canagliflozin (Invokana® and Invokamet®/XR-in patients with T2DM only), dapagliflozin (Farxiga® , Xigduo® XR), and empagliflozin (Jardiance®). If approved, sotagliflozin will be the first agent to target both SGLT1 and SGLT2 for use in this setting. Whether additional CV benefit is provided from SGLT1 inhibition beyond that provided by SGLT2 inhibition has not been established.
FDA APPROVAL TIMELINE
May 31, 2023
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales* $134 $267 $460 $626 $748
*Financial data reflected for all investigational indications combined.
Biogen
PROPOSED INDICATIONS
Amyotrophic lateral sclerosis (ALS) with superoxide dismutase 1 (SOD1) mutations
CLINICAL OVERVIEW
Tofersen is an antisense oligonucleotide designed to inhibit the production of the SOD1 protein.
The efficacy and safety of tofersen were evaluated in the 28-week, double-blind, placebo-controlled, phase 3 VALOR trial (n=108) that randomly assigned patients 2:1 to tofersen or placebo, and in the ongoing, open-label extension (OLE) study (n=95). In the OLE trial, all patients received tofersen, and the study compared earlystart with delayed-start of tofersen. All patients enrolled in the studies had ALS with a SOD1 mutation. Among patients in VALOR, 60 were predicted to have ALS with faster progression. At 28 weeks, treatment with tofersen resulted in greater reductions in SOD1 concentrations in the cerebrospinal fluid (CSF) and neurofilament light chains levels in plasma (both secondary endpoints) compared to placebo; this was maintained through week 52 of the OLE trial. Approximately, 33% and 51% of reductions in SOD1 and neurofilament light chains, respectively, were measured after 52 weeks of tofersen treatment. While improvements in these 2 biomarkers were observed, it did not correspond to a significant difference between the tofersen and placebo groups in the primary endpoint of total ALS Functional Rating Scale–Revised score (ALSFRS-R; range, 0 to 48). At 28 weeks, among patients predicted to have faster progression, the primary analysis subgroup, the change from baseline in ALSFRS-R for tofersen and placebo was -6.98 and -8.14 points, respectively (p=0.97). At 52 weeks, the change from the VALOR baseline in the ALSFRS-R total score was -6 points in patients originally randomized to tofersen (early-start cohort) and -9.5 points among those originally randomized to placebo (delayed-start cohort). The median time to death or permanent ventilation could not be estimated due to the small number of events. During the 52 weeks, serious adverse events were reported in 37% of tofersentreated patients. These included (≥ 5%) neurologic adverse events (e.g., myelitis, meningitis, radiculopathy, increased intracranial pressure, papilledema), respiratory failure, and pneumonia aspiration. Tofersen 100 mg was administered intrathecally over 24 weeks, as 3 doses once every 2 weeks, followed by 5 doses once every 4 weeks.
PLACE IN THERAPY
ALS is a rare, progressive motor neuron disease characterized by voluntary muscle weakness, atrophy, and paralysis. Eventually respiratory failure and premature death occur. The age at diagnosis is typically between 55 to 75 years. Once symptoms develop, life expectancy is 2 to 5 years. It is estimated that 31,000 people in the US have ALS, with approximately 5,000 new cases occurring each year. ALS occurs at similar rates in men and women. The exact cause of ALS is unknown. About 5% to 10% of cases appear to be inherited, and 12% to 20% of familial cases are due to SOD1 gene mutations.
There is no cure for ALS. FDA-approved DMTs include oral riluzole (generic, Exservan™, Rilutek®, Tiglutik®) and sodium phenylbutyrate/taurursodiol (Relyvrio™), and IV-administered edaravone (Radicava®). If approved, tofersen will be the first SOD1-directed DMT for ALS. In clinical trials, it reduced SOD1 concentrations in the CSF, an indirect marker of target engagement. It also reduced neurofilament light chains in the plasma, an indicator of axonal injury and neurodegeneration. While tofersen was associated with a smaller numeric decline in the ALSFRS-R score compared to placebo, the difference was not significant. The benefit of earlier versus delayed treatment continues to be assessed in the OLE trial. Evaluation of tofersen in presymptomatic SOD1 ALS is also underway.
FDA APPROVAL TIMELINE
April 25, 2023 Orphan Drug Priority Review seeking Accelerated Approval FINANCIAL FORECAST (reported in millions)
NEUROLOGY
Acadia
PROPOSED INDICATIONS
Rett syndrome
CLINICAL OVERVIEW
Trofinetide is a synthetic analog of the amino‐terminal tripeptide of insulin-like growth factor 1 (IGF-1) that has the potential to stimulate synaptic maturation and overcome the synaptic and neuronal immaturities that are observed with Rett syndrome. This may lead to reduced neuroinflammation and support of synaptic function.
The randomized, double-blind, placebo-controlled, phase 3 LAVENDER trial enrolled 187 females ages 5 to 20 years diagnosed with classic Rett syndrome. After 12 weeks, trofinetide significancy decreased the coprimary endpoint of the caregiver-rated Rett Syndrome Behavior Questionnaire (RSBQ) score compared to placebo (−5.1 versus −1.7, respectively; p=0.0175). The other primary endpoint of Clinical Global Impression of Improvement (CGI-I) was also significantly improved with trofinetide (mean, 3.5 versus 3.8, respectively; p=0.003). Trofinetide also resulted in less decline compared to placebo in the key secondary endpoint of Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist–Social composite score (−0.1 versus −1.1, respectively; p=0.0064). Diarrhea was reported in 80.6% of patients treated with trofinetide and led to treatment discontinuation in 17.2% of patients in this group. The majority of patients (95%) continued treatment in the 40-week open-label LILAC extension study; results are pending.
Trofinetide oral solution was administered as a weight-based dose twice daily by mouth or gastrostomy tube (G-tube).
PLACE IN THERAPY
Rett syndrome is a rare progressive neurodevelopmental disorder that is seen almost exclusively in females. In ≥ 90% of cases, a sporadic (non-inherited) mutation of the MECP2 gene, located on the X chromosome and is integral for brain development, is detected. Boys with this gene mutation typically die shortly after birth. Classic Rett syndrome is characterized by normal early growth and development, but after 6 to 18 months of age affected children experience a slowing of development, loss of purposeful use of the hands, distinctive hand movements (e.g., wringing, clapping, rubbing), slowed brain and head growth, difficulty walking, seizures, and intellectual disability. The estimated incidence of Rett syndrome in the US is 1 in 10,000 girls by age 12. The average life expectancy is 24 years; however, patients can live into their 40s or 50s with proper care, but suffer severe disability.
There is no cure for Rett syndrome. Therapy focuses on symptom management and support of physical functioning. If approved, trofinetide will be the first DMT available to treat the condition. In short-term (12week) clinical trials, it demonstrated significant benefit based on behavioral and clinical measures. Longterm data is pending. Avavex’s sigma-1 receptor agonist, blarcamesine, is also in phase 3 development for neurodegenerative and neurodevelopmental disorders, including Rett syndrome in adults. Topline data reported significant improvement in behavioral and clinical measures.
FDA APPROVAL TIMELINE
March 12, 2023
valoctocogene roxaparvovec IV
Biomarin
PROPOSED INDICATIONS
Severe hemophilia A
CLINICAL OVERVIEW
Valoctocogene roxaparvovec (val-rox) is an adeno-associated virus (AAV) vector gene therapy for the treatment of severe hemophilia A in adults.
The open-label, single-group, phase 3 GENEr8-1 study evaluated val-rox in adult males with severe hemophilia A (factor VIII level ≤ 1 IU/dL). Patients were receiving prophylactic factor VIII therapy for ≥ 1 year and were negative for factor VIII inhibitors. A total of 132 patients received a dose of val-rox 6×1013 vector genomes/kg of body weight and were HIV-negative. At weeks 49 to 52 after the val-rox infusion, significant changes from baseline were reported in factor VIII activity, the primary efficacy endpoint; mean and median increases from baseline were 41.9 IU/dL (p<0.001) and 22.9 IU/dL, respectively. At weeks 49 through 52, a median factor VIII activity level ≥ 40 IU/dL (equivalent to nonhemophilic) was reported in 37.9% of patients, levels between 5 and 40 IU/dL (equivalent to mild hemophilia) were reported in 50% of patients, and levels < 5 IU/dL were reported in 12.1% of patients. Among 112 patients enrolled from a prospective noninterventional study, the mean annualized factor VIII concentrate use decreased by 98.6% and treated bleeding decreased by 83.8% (p<0.001 for both). The most common adverse events were ALT elevations (85.8%), headache (38.1%), nausea (37.3%), and AST elevations (35.1%).
In addition, an ongoing open-label, phase 1/2 study demonstrated sustained hemostatic efficacy for 5 and 6 years after administration of val-rox at doses of 4×1013 and 6×1013 vector genomes/kg, respectively. Until the time of data cutoff, all but 1 patient remained off factor VIII treatment (the 1 patient resumed factor VIII for 1 month).
PLACE IN THERAPY
Hemophilia A is a congenital X-linked bleeding disorder that affects 1 in 5,000 male births. It is characterized by coagulation factor VIII deficiency leading to chronic spontaneous bleeding into muscles and joints that can progress to debilitating arthropathy.
The SOC for hemophilia A is routine infusion of factor VIII replacement, including extended half-life products. A major advancement in the hemophilia space is the SC monoclonal antibody emicizumab-kxwh (Hemlibra®), which provides routine prophylaxis in hemophilia A patients with or without inhibitors using a once every 1-, 2-, or 4-week dosing regimen.
If approved, val-rox will be the first gene therapy in the US for the treatment of severe hemophilia A. In clinical trials, it resulted in near elimination of bleeds with a single dose, with efficacy demonstrated for up to 6 years. Other products in phase 3 development for hemophilia A include the AAV gene therapies giroctocogene fitelparvovec (Pfizer) and SPK-8011 (Spark), and the bispecific monoclonal antibody Mim8 (Novo Nordisk/Genmab).
FDA APPROVAL TIMELINE
March 31, 2023
Breakthrough Therapy Orphan Drug RMAT
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $139 $292 $449 $614 $751
METABOLIC velmanase alfa IV
Chiesi
PROPOSED INDICATIONS
Alpha-mannosidosis
CLINICAL OVERVIEW
Velmanase alfa (VA) is a recombinant human alpha-mannosidase intended as an enzyme replacement therapy (ERT).
The 52-week, double-blind, phase 3 rhLAMAN-05 trial evaluated VA in 25 patients ages 5 to 35 years old, with a confirmed diagnosis of alpha-mannosidase as defined by alpha-mannosidase activity < 10% of normal activity in blood leukocytes. Eligible patients were able to walk without support. The study was conducted in 5 countries across Europe. Patients were randomized 3:2 to VA or placebo. After 52 weeks, patients either continued receiving VA or switched from placebo to VA. The coprimary endpoints were change from baseline to week 52 in serum oligosaccharides and the 3-minute stair climb test (3MSCT). At week 52, the mean relative change in serum oligosaccharide concentration was significantly greater with VA than with placebo (-77.6% versus -24.1%, respectively; adjusted mean difference, -70.5%; p<0.001). At the last observation (long-term outcome), the mean relative change from baseline was -62.9% with the VA group and -55.7% in the placebo-VA switch group. At week 52, there was no significant change in the 3MSCT from baseline with VA compared to placebo (mean change, -1.1% versus -0.0%, respectively; adjusted mean difference, +3; p=0.648). At the last observation timepoint, the mean relative change was +3.9% in the VA group and +9% in the placebo-VA switch group. In addition, a small increase in the secondary endpoint of change from baseline in 6MWT at week 52 was seen in the VA group compared with a small decline in the placebo group; the difference was not significant. Five serious TEAEs were reported, one of which was considered related to VA in a patient who received long-term ibuprofen who experienced acute renal failure; the patient recovered after VA interruption and was able to restart therapy without incident.
The single-center, open-label, long-term (up to 4 years) phase 3 rhLAMAN-10 trial assessed VA in 33 patients (14 adults, 19 pediatrics) with confirmed alpha-mannosidosis who had previously participated in phase 1/2 and phase 3 trials. The coprimary endpoint of serum oligosaccharide level was significantly reduced in the overall population at 12 months (mean change, -72.7%; p<0.001) which was reported through the last observation timepoint (mean change, -62.8%; p<0.001). An improvement in the other coprimary endpoint of change from baseline in 3MSCT was also observed at 12 months (mean change, +9.3%; p=0.013) and continued through the last observation (mean change, +13.8%; p= 0.004).
VA was administered via IV infusion once weekly at a dose of 1 mg/kg of body weight.
PLACE IN THERAPY
Alpha-mannosidosis is a rare genetic disorder caused by a mutation in the MAN2B1 gene that is responsible for the production of lysosomal alpha-mannosidase. Lysosomal enzymes, such as alpha-mannosidase, breakdown complex carbohydrates (oligosaccharides) in cell membranes. A deficiency in functional alphamannosidase results in mannose accumulation leading to tissue and organ damage. The global prevalence of alpha-mannosidosis is estimated to be 1 in every 500,000 individuals. Those affected by alpha-mannosidosis may experience hydrocephalus, intellectual disability, ataxia, myopathy, distinctive facial features, and skeletal abnormalities, as well as other complications. Manifestations of the condition can range from mild to severe. Three types of alpha-mannosidosis are identified. Type 1, the mildest form, progresses slowly and may appear during the teenage years. Type 2 is moderate in severity, may appear prior to 10 years of age, and progresses slowly. Type 3 is severe, may occur during infancy, with rapid progression and death during childhood. With milder forms of the disease, patients may survive through middle age (50s).
There are no FDA-approved medications to treat alpha-mannosidosis. Current therapy is supportive in nature and focuses on symptom management and prevention of complications. If approved, VA will be the first and only DMT available to treat alpha-mannosidosis. In clinical trials, it demonstrated a marked reduction in serum oligosaccharide level and mixed results regarding the effect on 3MSCT. Positive changes in endurance and pulmonary function with VA, particularly in pediatric patients, might suggest that greater clinical benefits could be achieved with initiation of therapy early in the disease course.
velmanase alfa (cont.)
FDA APPROVAL TIMELINE
January to June 2023
Orphan Drug Priority Review
FINANCIAL FORECAST (reported in millions)
The financial forecast for velmanase alfa is not currently available.
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 3 biosimilars for interchangeability to their reference product: insulin glargine-yfgn (Semglee®), adalimumabadbm (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 40 biosimilars have received FDA approval. Of these, only 27 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)
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
Merck April 2019
Amgen June 2019
Pfizer June 2019
Organon July 2019
Pfizer July 2019
Remicade (Janssen)
Humira (Abbvie)
Avastin® (Genentech)
Remicade (Janssen)
Herceptin® (Genentech)
Epogen® (Amgen) Procrit® (Janssen)
Neulasta® (Amgen)
Neupogen (Amgen)
Humira (Abbvie)
Neulasta (Amgen)
Rituxan® (Genentech)
Herceptin (Genentech)
Herceptin (Genentech)
Herceptin (Genentech)
Enbrel (Amgen)
Herceptin (Genentech)
Avastin (Genentech)
Humira (Abbvie)
Rituxan (Genentech)
Brand Name (Nonproprietary name) Manufacturer
Abrilada™* (adalimumab-afzb)
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)
APPROVED BIOSIMILARS continued
APPROVED BIOSIMILARS
Pfizer November 2019
Sandoz November 2019
Amgen December 2019
Pfizer June 2020
Mylan/Biocon July 2021
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
Originator (Manufacturer)
Humira (Abbvie)
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)
* Abbvie’s adalimumab (Humira) is available in 50 mg/mL (with citric acid/citrate) and 100 mg/mL (citrate-free) concentrations. All biosimilars for the product are approved as 50 mg/mL concentrations.
† Adalimumab-bwwd (Hadlima) by Organon is also approved as a 100 mg/mL high concentration citrate-free formulation (approved in August 2022).
‡ Pfizer already has Inflectra on the market and 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) is anticipated to be available in the US in January 2023. It is anticipated that multiple Humira biosimilars (including citrate-free and high-concentration formulations) will enter the market in July 2023.
BIOSIMILAR OVERVIEW continued
IMMUNOLOGY
adalimumab SC
Alvotech, Celltrion, and Sandoz are seeking approval for their investigational biosimilars 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 non-infectious uveitis.
Pfizer is seeking interchangeability of FDA-approved adalimumab-afzb (Abrilada) 50 mg/mL.
FDA APPROVAL TIMELINE
50 mg/mL
• Pfizer (Abrilada) – Pending for interchangeability
100 mg/mL
• Alvotech (AVT02) – April 13, 2023 for interchangeability
• Celltrion (Yuflyma) – Pending
• Sandoz (Hyrimoz) – March to April 2023
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $11,242 $6,894 $5,203 $4,199 $3,508
The forecast is a projection of total US sales per year for the branded originator product.
OPHTHALMOLOGY
intravitreal
Biocon/Janssen
Biocon/Janssen are seeking approval of their investigational biosimilar 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 Pending
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $6,401 $5,992 $5,147 $4,441 $3,933
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, Samsung Bioepis/Organon, and Biocon/Janssen 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
• Biocon/Janssen (Bmab-100) – Pending
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $505 $428 $379 $341 $308
The forecast is a projection of total US sales per year for the branded originator product
BLOOD MODIFIER
filgrastim IV, SC
Apotex and Tanvex are seeking approval of their investigational biosimilars 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 in patients who are acutely exposed to myelosuppressive doses of radiation (hematopoietic syndrome of acute radiation syndrome [HSARS]).
FDA APPROVAL TIMELINE
• Apotex (Grastofil) – Pending
• Tanvex (TX01) – February 2023
FINANCIAL FORECAST (reported in millions) Year 2023
The forecast is a projection of total US sales per year for the branded originator product
BIOSIMILAR OVERVIEW continued
NEUROLOGY
natalizumab IV
Polypharma/Sandoz
Polypharma/Sandoz are seeking approval for their investigational biosimilar to Biogen’s Tysabri®, an integrin receptor antagonist indicated for treatment of multiple sclerosis (MS) and Crohn’s disease (CD).
FDA APPROVAL TIMELINE
May to June 2023
FINANCIAL FORECAST (reported in millions) Year
The forecast is a projection of total US sales per year for the branded originator product
BLOOD MODIFIER
pegfilgrastim SC
Apotex and Lupin are seeking approval for their investigational biosimilars to Amgen’s Neulasta, 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).
Coherus is seeking approval of Udenyca OBI®, an investigational biosimilar to Amgen’s Neulasta Onpro®
FDA APPROVAL TIMELINE
• Apotex (Lapelga) – Pending
• Lupin (Lupifil-P) – Pending
• Coherus (Udenyca OBI) – October 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
IMMUNOLOGY
tocilizumab IV, SC
Fresenius Kabi and Biogen/Bio-Thera Solutions 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
• Fresenius Kabi (MSB11456) – April to June 2023
• Biogen/Bio-Thera Solutions (BIIB800 or BAT1806) – October 9, 2023
FINANCIAL FORECAST (reported in millions)
Year 2023 2024 2025 2026 2027
Projected Total US Sales $1,009 $822 $660 $542 $440
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 $6,389 $4,768 $3,606 $2,362 $2,351
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.
zuranolone
Behavioral health
$943
vamorolone
Musculoskeletal
$299
tabelecleucel Oncology
$410
talquetamab Oncology
$604
resmetirom
Endocrine
$686
nirsevimab
Infectious disease
$855
lenadogene nolparvovec
Ophthalmology/Gene therapy
$51
lebrikizumab Immunology
$944
avacincaptad pegol
Ophthalmology
$765
bimekizumab Immunology
$1,037
datopotamab deruxtecan Oncology
$1,036
epcoritamab Oncology
$625
etrasimod Immunology
$618
exagamglogene autotemcel
Hematology/Gene therapy
$495
fidanacogene elaparvovec
Hematology/Gene therapy
$263
giroctocogene fitelparvovec
Hematology/Gene therapy
$132
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.
Submitted (New Drugs)
pirtobrutinib Eli Lilly Mantle cell lymphoma
naloxone
zavegepant
tislelizumab
Beigene/Novartis
velmanase alfa
filgrastim (biosimilar to Amgen’s Neupogen) Tanvex
mirikizumab
Esophageal squamous cell carcinoma (unresectable or metastatic, 2nd-line)
(moderate to severe)
daprodustat GlaxoSmithKline Anemia due to CKD (dialysis-dependent, dialysis-independent)
elacestrant Menarini Breast cancer (ER+/HER2advanced or metastatic)
Bladder cancer (BCG-unresponsive, non-muscle invasive carcinoma in situ, in combination with BCG) Intravesical Submitted − BLA; Breakthrough Therapy; Fast Track 05/23/2023
Submitted − sBLA; Fast Track; Orphan Drug; RTOR February 2023
Breast cancer (unresectable, locally advanced or metastatic, HR+/HER2-, post endocrine therapy and ≥ 2 additional lines of systemic metastatic therapy)
