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6. Epcoritamab
Drug: Epcoritamab
Companies: AbbVie and Genmab
Used for: Lymphoma
Est. 2028 sales: $1.7 billion
A bispecific battle over the CD20 bispecific lymphoma market has long been somewhat quietly raging. Come a
Prescription Drug User Fee Act date of May 21, the fight will crank up as the FDA decides on AbbVie and Genmab’s epcoritamab.
The CD3xCD20 bispecific antibody seems poised to compete with Roche’s glofitamab, which has an FDA decision date of July 1. The therapies work by binding to CD20 on malignant B cells and CD3 on T cells to kill cancer cells, bringing CAR-T-like efficacy without the complexity of cell therapies.
If approved, epcoritamab can stand apart as the first subcutaneous bispecific antibody approved in the large B-cell lymphoma market.
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AbbVie got a piece of the therapy in mid-2020 by handing Genmab $750 million upfront for a stake in epcoritamab and the rest of the company’s pipeline of anti-cancer bispecifics, starting an ongoing oncology collaboration. Under the deal,
AbbVie will share commercial responsibilities for the therapy with Genmab in the U.S. and Japan and fly solo for commercialization in the rest of the world, giving Genmab tiered royalties of between 22% and 26%.
Last June, the partners revealed promising results from a phase 2 trial in lymphoma. In 157 patients with relapsed or refractory large B-cell lymphoma, epcoritamab proved an objective response rate of 63% and a complete response rate of 39%.
The median duration of response stood at 12 months. Almost 90% of the complete responders had not relapsed by nine months, meaning that group had yet to reach the median duration of response.
As for safety, 2.5% of participants suffered grade 3 cytokine release syndrome with a median onset of 20 hours post subcutaneous injection and a median resolution time of 48 hours.
Now, the companies are testing subcutaneous epcoritamab across different types of lymphoma. At ASH 2022, the two announced initial results for a combination of epcoritamab plus Rituxan and Bristol Myers Squibb’s Revlimid in newly diagnosed follicular lymphoma, which proved a 90% response rate. Regeneron’s bispecific odronextamab is also going after that indication, having bagged an 82% objective response rate in a phase 2 trial. However, Regeneron’s studies have been marred by treatment-emergent adverse events, deaths and dropouts.
As for AbbVie and Genmab’s bids, the two submitted applications to the European Medicines Agency in October for the treatments use in relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy. Thanks to the FDA granting priority review, that agency will decide on epcoritamab’s approval in May.
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The Genmab and AbbVie partnership will extend beyond epcoritamab. It gave AbbVie similar commercialization rights to a CD3x5T4 antibody plus another bispecific that targets CD37. Together with epcoritamab, the three are worth up to $1.2 billion for Genmab in clinical and commercial milestones. Even past those three, the two companies will join up in a discovery-stage collaboration to create up to four additional candidates Genmab will take through phase 1.
By Zoey Becker
7. Zuranolone
Drug: Zuranolone
Companies: Biogen and Sage Therapeutics
Used for: Major depressive disorder, postpartum depression
Est. 2028 sales: $1.5 billion
The mental health market is historically filled with gaps in treatment options. Since selective serotonin reuptake inhibitors (SSRIs) hit the market in the 90s, approvals for innovative treatments have been few and far between, leaving a high unmet need for patients with depression disorders.
Enter Biogen and Sage Therapeutics. If approved, zuranolone would be a groundbreaking option for two underserved markets in major depressive disorder (MDD) and postpartum depression (PPD).
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The two-week, once-daily therapy would be a first-in-class approval. Targeting the GABA-A receptor, the drug would be a game changer, treating a depressive episode with an “as-needed” short course. While a phase 3 trial of zuranolone in
MDD met its main goal of improving depression symptoms over placebo, it missed some secondary endpoints and effects of the drug began to taper off around day 42. But the drug undoubtedly proved its worth in PPD in a phase 3 trial, outperforming placebo on a depression scale at four different time points.
MDD constitutes a huge patient population that’s only gotten larger since the COVID-19 pandemic, with an estimated 17 million Americans experiencing symptoms every year. PPD, while not as large of a market, is no small fish either—in the U.S., an estimated 1 in 8 mothers experience it each year, making up approximately 500,000 cases annually.
Sage claimed the first-ever FDA approval for a PPD treatment in 2019 with Zulresso. While the therapy was a big step in the PPD market, the one-time infusion isn’t as convenient or accessible as zuranolone due to a continuous IV transfusion period of 60 hours. It also carries a black box warning for sudden loss of consciousness and extreme sedation during administration, meaning it must be administered in a restricted distribution program at a certified healthcare facility with close monitoring.
Through Zulresso, Sage was able to “really understand the treatment or the referral patterns in the PPD marketplace itself and establish strong working relationships with patient advocacy groups,” said Chief Business Officer Chris Benecchi at this year's J.P. Morgan Healthcare Conference.
Zuranolone would fit the bill for an ideal timeline to treat PPD. Currently available treatments can take months to set in, which doesn’t help new mothers and their babies in the crucial bonding weeks.
“When mom's unwell and can't attach to the baby, that's bad for the mom, the baby and [has a] generational impact,” CEO Barry Greene said at the J.P. Morgan Healthcare Conference.
Biogen, for its part, doesn’t have as much of a direct tie to the proposed indications but believes that the treatment would be “highly complementary” to several of its areas of focus, the company said in a statement announcing the partnership. MDD is a common comorbidity in many neurological disorders, including multiple sclerosis, Alzheimer’s disease, spinal muscular atrophy, amyotrophic lateral sclerosis and Parkinson’s disease, all of which Biogen targets.
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The two companies partnered up in late 2020 to jointly develop and commercialize zuranolone and another Sage prospect, SAGE-324, which is currently in a phase 2 trial for essential tremor. Biogen coughed up $1.525 billion in total for the deal, including potential milestone payments.
Zuranolone will likely face approval near the end of the year unless the FDA grants a priority review, which could speed up the decision by four months.
By Zoey Becker
8. MirikizumabDrug: Mirikizumab
Company: Eli Lilly
Used for: Ulcerative colitis, Crohn's disease
Est. 2028 sales: $1.2 billion
In a phase 3 trial three years ago, mirikizumab established its bona fide by besting Novartis’ Cosentyx in plaque psoriasis.
But Eli Lilly wasn’t satisfied with potentially entering a crowded marketplace, which included two other blockbusters in its IL-23 class—AbbVie’s Skyrizi and Johnson & Johnson’s Tremfya. In addition, Lilly also had a blockbuster in psoriasis with Taltz.
So the company grounded mirikizumab in the indication, opting to investigate its potential in two other autoimmune diseases.
Two years later, Lilly has the monoclonal antibody on the verge of an approval in ulcerative colitis (UC) and is on track for the same in Crohn’s disease in 2025.
With its novel mechanism of action—targeting the p19 subunit of IL-23—mirikizumab has a chance to make a splash as a first-in-class treatment in UC and third in class in Crohn’s disease.
In both indications however, several novel agents are launching (PDF) within the next few of years, making “competition fierce and the market increasingly fragmented,” according to Clarivate’s 2023 Drugs to Watch report.
In UC, for example, Lilly is in a race with more than a dozen candidates now in phase 2b or phase 3 trials, many with promising novel mechanisms of action and new routes of administration, according to analytics company GlobalData.
While numerous agents are currently approved in the indication, GlobalData pharma analyst Garrett Towler believes that therapies in development will soon loom large.
In addition to mirikizumab—which Towler believes will be approved first—he cites the potential of Abivax’s obefazimod and InDex Pharmaceuticals’ cobitolimod. Also in the running are Takeda’s Entyvio along with Skyrizi and Tremfya.
“Becoming the first approved IL-23 inhibitor for this indication will help establish Eli Lilly as a key player in the UC market,” Towler wrote.
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Lilly has always had faith in mirikizumab. In 2020, the company was spending $300 million testing it in eight trials spanning the three disease types, according to an estimate from Evaluate Pharma.
Because many patients lose response to biologics, a treatment gap mirikizumab could potentially fill would be sustainable long-term remission. Another is that its alternative mechanism of action could be the answer for patients who are intolerant or resistant to TNF inhibitors such as AbbVie’s Humira or Amgen’s Enbrel.
Mirikizumab proved its efficacy in a trial of 1,281 patients with moderate to severe UC who had not experienced remission with any prior treatments. At Week 12 in the mirikizumab group, 24% of patients were in remission versus 13% in the placebo group.
In addition, while 7% of placebo patients withdrew from the trial because of an adverse event, only 2% of those on mirikizumab did the same.
In the second phase of the trial, involving 544 patients who had a clinical response to mirikizumab in the induction trial, 50% of those on the drug were in remission at Week 52 versus 25% of patients on placebo. Of the 143 patients who had already reached clinical remission at Week 12 in the induction study, 63% maintained it for the rest of the study period.
In its report, Clarivate warns that once on the market for both UC and Crohn’s, mirikizumab could have trouble differentiating itself from other IL-23 inhibitors. Additionally, the launch of biosimilar versions of Stelara, which is scheduled to begin this year, could encroach on the use of all IL-23 inhibitors.
“The data for mirikizumab are very good,” an unidentified gastroenterologist from Italy told Clarivate. “I do not have a preference among all interleukin inhibitors. However, there is preference for (Stelara) because it is already in the clinical practice system.”
By Kevin Dunleavy
9. Etrasimod
Drug: Etrasimod
Company: Pfizer
Used for: Ulcerative colitis
Est. 2028 sales: $1.2 billion
In March of last year, just three weeks after closing an acquisition of Arena Pharmaceuticals for $6.7 billion, Pfizer reported news that indicated it made a good buy.
The key piece of the deal, ulcerative colitis (UC) candidate etrasimod, aced a pair of phase 3 trials, suggesting that the selective sphingosine 1-phosphate (S1P-1) modulator has blockbuster potential.
Scooping up the 25-year-old San Diego biotech with one approved drug—weight loss pill Belviq, which was sidelined by the FDA in 2020 for safety concerns—was a gamble when the deal was struck. At the time, Pfizer didn’t have much to go on—just some blinded data and results from a phase 2 trial. But the company was buying what Arena’s etrasimod UC brain trust, led by Sheldon Sloan, M.D., was selling.
“We got to actually know the team at Arena and what we learned is we really trusted that they knew what they were doing,” Michael Corbo, Pfizer’s chief development officer for inflammation and immunology, told Fierce Pharma in May of last year. “They were a talented group of people not only in drug design, but their ability to design and conduct GI studies.”
In December of 2022, the FDA accepted Pfizer’s new drug application, putting it on track for approval in the second half of 2023. Regulators in Europe have done the same, with a decision expected in the first half of 2024.
The acceptances were based on data from the ELEVATE UC 12 and ELEVATE UC 52 studies, which showed rates of clinical remission at 25% and 32% at 12 and 52 weeks, respectively, in patients with moderate to severe UC, compared to rates of 15% at Week 12 and 6.7% at Week 52 in patients on placebo.
Additionally, in the ELEVATE UC 52 trial, at the 12-week mark, the clinical remission rate for etrasimod patients came in at 27% versus 7.4% for patients on placebo.
The trial utilized a treat-through design which closely mimics real-world clinical practice, Pfizer said. Statistically significant improvements were attained in secondary endpoints, including endoscopic improvement, symptomatic remission, and mucosal healing at weeks 12 and 52, and corticosteroid-free remission and sustained clinical remission at Week 52.
“We believe the treat-through design of the ELEVATE UC 52 study more accurately reflects a real-world treatment approach than the re-randomization design often used in UC clinical trials,” Corbo said.
It could be the start of something big for etrasimod. The once-daily immuno-inflammatory disease treatment also is under investigation for alopecia areata, atopic dermatitis, Crohn’s disease and eosinophilic esophagitis.
The primary competition for etrasimod in UC figures to be Bristol Myers Squibb’s S1P drug Zeposia, which was approved for UC in May of 2021 and is being investigated in the same indications as etrasimod.
While the market is crowded in UC—with treatments such as AbbVie’s Humira—Zeposia and etrasimod figure to have an edge as they are taken in pill form as opposed to being injected. Another oral therapy in the space, Pfizer’s Xeljanz, is under scrutiny as drugs in its JAK inhibitor class face safety concerns.
By Kevin Dunleavy
10. SotaterceptDrug: Sotatercept
Company: Merck
Used for: Pulmonary arterial hypertension
Est. 2028 sales: $1 billion
The pièce de resistance of Merck’s $11.5 billion deal to acquire Acceleron in 2021 was sotatercept, which could finally be the disease-modifying breakthrough needed in pulmonary arterial hypertension (PAH).
Sotatercept, a first-in-class fusion protein, was targeted by Merck in its effort to diversify from immuno-oncology and its superstar cancer treatment Keytruda. So far, so good, as positive top-line data released from a phase 3 trial in October 2022 have promoted analysts to peg sotatercept’s peak sales at $2 billion.
Sotatercept is an add-on therapy to standard of care treatment. With its novel mechanism of action, targeting BMPR-II signaling, sotatercept could potentially address the underlying cause of PAH as opposed to current therapies that simply target symptoms by dilating blood vessels. While current therapies offer relief, they are not curative.
Also adding to sotatercept’s value is that it is injected under the skin.
“All of those factors are unique to sotatercept,” CEO Rob Davis said upon inking the Acceleron deal. “There are no other drugs in development that’s that same profile either within Merck or outside.”
Merck’s heart disease offerings are relatively thin, though the company has a history of success in the area. Cholesterol-reducing drugs Vytorin and Zetia made a combined $3.7 billion in 2016 before they were overrun by generic competition.
In its current portfolio, Merck (along with partner Bayer) has Verquvo in a crowded heart-failure market. And in PAH specifically, Merck (also along with Bayer) boasts oral sGC stimulator Adempas, which generated $181 million in sales in the first three quarters of 2022.
In the registrational STELLAR trial of 324 patients, those on sotatercept showed improvement in a six-minute walk test over those on placebo at 24 weeks. Sotatercept patients also saw statistically significant improvements in eight of nine secondary measures.
“The results from the secondary efficacy outcomes, including a favorable benefit seen in patients’ time to a clinical-worsening event, are especially noteworthy,” Dean Li, M.D., Ph.D., Merck’s Research Laboratories head, said in a release. “The results observed in the Stellar study suggest that sotatercept has the potential to transform the treatment of patients with PAH.”
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The condition results when high blood pressure in the arteries of the lungs causes difficulty in breathing and walking. If left untreated it can lead to heart failure. In idiopathic PAH, the cause of the disease is unknown. Heritable PAH is acquired genetically, while associated PAH comes from other conditions such as sickle cell disease, HIV, lupus or congenital heart disease.
Merck expects to file for approval in early 2023 with a potential launch late in the year. Two other trials are underway for sotatercept, which has received fast-track and breakthrough designations.
A potential stumbling block for sotatercept is its arduous administration regimen, starting with five subcutaneous doses every 21 days.
The primary competition in the PAH market is United Therapeutics’ Tyvaso, which generated sales of $483 million in 2020, $607 million in 2021 and through three quarters of 2022 had racked up $631 million in revenue.
Originally approved in 2009, Tyvaso is gaining steam thanks to an April 2021 blessing from the FDA for pulmonary hypertension associated with lung disease. Then, last May, United won another nod for an inhaled dry powder version of Tyvaso.
