Prior to attending last week’s J.P. Morgan Healthcare Conference in San Francisco, I posted a piece listing five launches to track this year. 

After drinking from the firehose that is JPM week, I realized that those five were hardly the last word on launches. Of course, there are other, potentially game-changing drugs set to be approved by the Food and Drug Administration over the next 11 months. 

My earlier analysis employed the term “practice-changers” to describe the spotlighted agents, which ranged from Bristol Myers Squibb’s/Karuna Therapeutics’ KarXT in schizophrenia to Janssen’s/Legend Biotech’s Carvykti in second-line-plus multiple myeloma, and Casgevy from CRISPR Therapeutics/Vertex in sickle cell disease (SCD).

As for this most recent batch, all are expected to create volatility in one way or another. Some may do so by dint of their first-in-class status or differentiated profile, others via a major marketing push designed to shake up entrenched competition or expand a therapeutic category. 

In other words, although they may not all be consensus blue-ribbon picks, ignore these “volatile debutants” at your peril. The usual caveats apply here, as well: FDA approval times are subject to change and are approximate, as are revenue forecasts.

To that end, here are five more worthy candidates poised for a significant market debut. 

1. Merck’s sotatercept (PAH) 

During their JPM investor presentation, Merck CEO Rob Davis and R&D chief Dean Li touted two forthcoming launches with “multibillion-dollar” revenue peaks, sotatercept for treating pulmonary arterial hypertension (PAH) and V116 in pneumococcal disease. 

While opinions are mixed on V116’s potential, sotatercept has earned consensus for having a substantial upside. The activin receptor 2a regulator’s FDA decision date is set for March 26, and Merck envisions sotatercept cementing itself in the PAH treatment paradigm rather quickly.

Indeed, analysts expect an unusually fast sales ramp. The street is modeling $330 million in sales by this year, with UBS analyst Trung Huynh pegging 2024 sales closer to $600 million – notable for a drug’s initial year on market. Revenues for 2028 are forecast to reach $2 billion, according to Evaluate Pharma. 

That’s thanks to a bolus of patients who, according to multiple analysts, have been “warehoused” in anticipation of approval; impressive efficacy data, with more on the way from its ZENITH, HYPERION and CADENCE trials as well as high clinician awareness.

The company estimated the market size to be about 90,000 patients globally, about half of whom are located in the U.S. With half of the domestic group primarily treated at 150 specialist centers, marketing should be efficient, observed Huynh in an investor note. 

Sotatercept’s outlook strengthened over the course of 2023, which may be why the asset has flown somewhat under the radar. Still, post-JPM, it seems to be on everyone’s hit list.

The company raised the target for its cardiometabolic portfolio to more than $15 billion (versus more than $10 billion prior) by the mid-2030s, based partly on sotatercept’s potential.

Adding to the hype, KOLs have praised sotatercept’s disease-modifying mechanism, specifically its ability to “remodel mangled vasculature and fundamentally reverse the course of disease,” per a UBS analysis. 

Management said the agent remains Merck’s most significant near-term opportunity, going so far as to say it could smooth out mega blockbuster Keytruda’s anticipated U.S. loss of exclusivity in 2028 into a “hill rather than a cliff.”

Longer term, Merck may aim to transition the drug into an easier-to-use injector, which could allow more at-home administration and drive further uptake. 

2. Madrigal’s resmetirom (NASH/MASH)

There are no FDA-approved treatments for nonalcoholic steatohepatitis (NASH), a type of fatty liver disease which was recently renamed metabolic dysfunction-associated steatohepatitis (MASH). So resmetirom, being developed by Madrigal Pharma, could be big as the first-to-market therapeutic this year. 

An FDA decision for the drug in NASH patients with advanced fibrosis is due March 14, under a previously granted priority review. If greenlit, the THR beta-agonist could ring up 2028 sales of $2.1 billion, according to an estimate by Evaluate Pharma.

Resmetirom’s pivotal Phase 3 MAESTRO-NASH data yielded a “best-case dataset,” according to a note from SVB Securities analyst Thomas Smith. The study, which read out in late 2022, showed dose-dependent success on both dual primary endpoints along with no safety surprises.

Anticipation for its approval and launch has been building for more than a year. Given the lack of forebears, resmetirom would need to build the NASH/MASH market. That could be challenging given there is no established guideline on diagnosis or treatment. Nor does Madrigal have any experience marketing any approved therapeutics.

In November, the company took a step forward by naming a former Sanofi exec, Carole Huntsman, as its chief commercial officer, and the company raised another $500 million for its warchest. 

Other pre-commercial efforts have included tackling access and reimbursement, patient and prescriber education, and early launch commercialization plans. 

Management’s comments suggest “a very targeted launch with resmetirom positioned as a specialty therapeutic,” Smith wrote in another investor note, suggesting the firm could price the drug “aggressively.” 

Supporting that notion, a recent ICER report found that resmetirom’s favorable clinical profile could achieve cost effectiveness at prices up to $50,000 a year. Nonetheless, KOLs believe resmetirom should be widely prescribed upon approval.

Meanwhile, the NASH/MASH pipeline is a crowded one. Other THR-beta agonists have shown promise, not to mention FXR agonists, PPAR agonists (see below), FGF analogs and other therapeutics chasing this opportunity.

3. BridgeBio’s acoramidas (ATTR-CM)

Last month, BridgeBio filed an NDA for acoramidas (AG10) for transthyretin amyloidosis, a potentially fatal, genetic heart condition. A U.S. launch, along with additional ex-U.S. filings, are expected in the second half of this year

The Phase 3 ATTRibute-CM results, read out in mid-2023, met the company’s pre-defined “bar for best-in-class,” per a note by Leerink Partners’ Mani Foroohar. The progress represented a stunning turnaround for the company, which some had written off two years ago. 

At the time, subjects in ATTRibute-CM who had taken a walk test closely correlated with heart health performed better on placebo, a baffling finding. However, the most recent data showed the metric flipping from that negative outcome.

In addition to the difficulty BridgeBio has experienced trying to bring its first drug to market, the asset is somewhat undifferentiated from standard of care, Pfizer’s Vyndamax (tafamidis), so analysts are somewhat skeptical.

That said, the transthyretin (TTR) stabilizer is expected to reach $1 billion in sales, as per Evaluate Pharma’s 2028 estimate. If it’s approved, all eyes will be on seeing how twice-daily acoramidas performs versus once-a-day tafamidis. 

BridgeBio noted some potential headwinds to efficacy, although a comparative post-hoc analysis suggested its agent may possess better preclinical potency than its rival. The firm has also signaled an openness to signing a co-commercialization agreement with another company to maximize the launch.

4. Verona’s ensifentrine (COPD) 

Verona Pharma‘s inhaled drug ensifentrine (RPL554) could be practice-changing in the U.S., although its status as a nebulized, add-on therapy may curb uptake in other markets. 

The PDE3/4 inhibitor combines bronchodilator and nonsteroidal anti-inflammatory treatments in one compound. 

Two Phase 3 trials, dubbed ENHANCE-1 and ENHANCE-2, demonstrated an ability to lower exacerbations in moderate-to-severe COPD, as monotherapy or as an add-on to traditional LABA/LAMA drugs, minus the unpleasant systemic side effects of current PDE inhibitors that are delivered orally.

The FDA accepted the drug’s NDA in September and is expected to render a decision by June 26. Clarivate forecasts a 2029 sales range of $500 million to $750 million.

As a novel agent that can be added onto today’s classic LAMA/LABAs, ensifentrine should get a warm welcome from U.S. clinicians. 

In the E.U., where the product is likely to be available in nebulized form versus the more preferred dry powder or metered dose inhaler, the outlook is less clear, however.

“The need to learn how to use, clean and maintain a nebulizer plus the twice-daily administration at home could be a major hurdle,” Clarivate cautioned in its 2024 Drugs to Watch report. “Therefore, in its nebulized form, ensifentrine might be limited to hospital-bound or the most elderly patients.”

5. Ipsen’s/Genfit’s elafibranor and Cymabay’s seladelpar (PBC)

These two assets should certainly change things in second-line primary biliary cholangitis (PBC), an autoimmune disease in which the bile ducts in the liver are inflamed and slowly destroyed, causing cirrhosis. 

Both regulatory reviews are highly anticipated. The drugs belong to the selective peroxisome proliferator-activated receptor (PPAR) class of medicines, which exert an anti-inflammatory effect in the liver. 

Cymabay’s management has said they’re confident in landing a differentiated label through the addition of an explicit pruritus benefit. That could confer an edge over elafibranor, which demonstrated a non-statistically significant trend toward improvement on pruritus during trials.

Elafibranor, though, has at least a two-month lead on its rival. The FDA accepted Ipsen’s/Genfit’s priority review NDA last month and set a deadline of June 10. Cymabay Therapeutics submitted seladelpar to the agency last month, setting up a possible decision day in August.

While the PBC population is a small one, with just one in 1,000 people affected, the market could be worth $1.5 billion in 2035, according to a Genfit forecast. As a second-line treatment, elafibranor could take around a third of that total, or $515 million, per the company’s estimate.

Cymabay, for its part, said there are about 100,000 U.S. patients diagnosed with PBC, including 75,000 on first-line treatment, Around 25,000 to 30,000 of these are uncontrolled, and about 9,000 are currently being treated with second-line therapy. 

The firm has begun preparing medical teams for a potential seladelpar launch and intimated that field teams could be in place as early as two months prior. Although, the company disclosed in December the departure of its chief commercial officer.

Nonetheless, SVB’s Smith wrote that several factors could make seladelpar the “treatment of choice” in second-line PBC. These include its unique pruritus improvement benefit, along with a potential edge on safety and tolerability.