Pfizer banks on ultra‑long‑acting GLP‑1 as post‑COVID portfolio takes shape

Obesity moonshot moves from theory to trial design

Pfizer used its fourth‑quarter stage to shift the investor narrative decisively toward obesity, unveiling data that, in the company’s telling, finally validate its long‑trailed ultra‑long‑acting peptide platform.

At the centre is PF‑393944, a GLP‑1 receptor agonist engineered to bind its receptor while still hitched to albumin—a tweak in lipidation at the terminus of the peptide chain that, management argues, translates into a markedly longer half‑life without sacrificing receptor engagement. That structural nuance underpins the company’s bid to move from weekly to monthly injections, and to do so at efficacy levels that can credibly sit alongside today’s market leaders.

The Phase 2b VSPR‑3 study was designed as a stress test: patients titrated over up to 12 weeks, then switched to a four‑fold equivalent monthly maintenance dose without the safety valve of down‑titration, which is usually permitted in obesity trials. At 28 weeks, the low and medium monthly regimens delivered placebo‑adjusted weight loss of 10% and 12.3%, respectively—“robust” and statistically significant, in Chris Boshoff’s phrase, and in line with Pfizer’s modelling.

Those models matter. The same meta‑analysis, built on 3944’s own data plus published trials of other agents, forecasts nearly 16% placebo‑adjusted weight loss at week 28 for the high 9.6 mg monthly dose—the equivalent of the 2.4 mg weekly regimen already being tested in the ongoing Phase 3 VESPA‑4 trial. Perhaps more tellingly, no plateau was seen at week 28 in VSPR‑3, leaving management to hint at further loss out to week 64.

The other half of the equation is tolerability. Here, Boshoff promised that full details would be saved for an oral presentation at the American Diabetes Association in June, but sketched in the key contours: gastrointestinal adverse events were “predominantly mild or moderate”, with at most one case of severe nausea or vomiting in any dose group and no severe diarrhoea. Discontinuations due to adverse events were five patients in the weekly phase and five in the monthly phase across doses intended for Phase 3, with none in placebo. Crucially, switching to the four‑fold monthly dose did not produce a cluster of drop‑outs, despite the rigid titration.

For management, that is enough to green‑light an ambitious 2026 development calendar. Around 20 key pivotal studies are slated to start across the portfolio, 10 of them in the Metsera obesity franchise alone, spanning chronic weight management, obesity‑related comorbidities, and switching strategies for patients already on weekly GLP‑1s. Pfizer is targeting the first in a series of potential regulatory approvals in 2028.

The company is also drafting a second act. An ultra‑long‑acting amylin analogue, PF‑393945 (MET‑233), has already shown 8.4% placebo‑adjusted weight loss at day 36 as monotherapy and additive effects in early combination with 3944. A Phase 2 programme for the monthly GLP‑1/amylin injectable combo is due to begin this year, with an eye to Phase 3 in 2027. Alongside that sit an internally discovered oral GIPR antagonist in Phase 2, an ultra‑long‑acting injectable GiPA agonist, and a potential quarterly GLP‑1 analogue in Phase 1, plus an in‑licensed oral GLP‑1 from Yaopharm now being moved into US‑based development.

If that sounds like a bid to match or outflank incumbents on breadth as much as on depth, the commercial rhetoric is similar. Aamir Malik, head of commercial, described a strategy built on “optionality”: a monthly injectable backbone that can compete on efficacy with current weekly standards, combined with tailored offerings for patients who need higher weight loss, better tolerability, or more convenient maintenance. Outside the US, Alexandre de Germay pointed to a surprisingly robust self‑pay market, with consumers in Europe, Canada, Australia and parts of the emerging world accepting monthly price points of $250–$350—higher than Pfizer had anticipated, and importantly bypassing often‑protracted reimbursement negotiations.

Oncology and beyond: Seagen integration and pipeline pruning

Obesity may be the headline grabber, but oncology remains Pfizer’s other declared growth pillar. The integration of Seagen, closed in late 2023, is now far enough along for management to present it as largely complete. Most of the Seagen scientific workforce has stayed, the Seattle site has effectively become a major Pfizer research hub, and key programmes have been pushed into later stages at a brisk pace.

PADCEV (enfortumab vedotin) is the standout beneficiary. The drug has already secured a US approval in combination with pembrolizumab for muscle‑invasive bladder cancer patients ineligible for cisplatin‑based chemotherapy, and management is now banking on a further label expansion into cisplatin‑eligible muscle‑invasive disease. That would swell the US addressable population from roughly 19,000 metastatic urothelial cancer patients to around 41,500 across earlier‑stage, cis‑eligible and ineligible muscle‑invasive disease.

The success of PADCEV has had portfolio consequences. Chief financial officer Dave Denton disclosed that one of the assets written down in the quarter—part of the $4.4bn in non‑cash intangible impairments—was dicitamab vedotin in bladder cancer, whose value proposition is now diminished relative to PADCEV’s expanding franchise. It is an illustration of the sharpened internal prioritisation that Bourla and Boshoff say has characterised the last 18 months: pruning back to four core therapeutic areas, reallocating capital to assets with clearer paths to market, and using AI to squeeze more work from a roughly flat R&D budget.

A second antibody‑drug conjugate, targeting integrin beta‑6, is slated to deliver a key readout this year in second‑line and later non‑squamous metastatic non‑small cell lung cancer—a setting affecting some 50,000 US patients and over 200,000 worldwide. Pre‑Phase 3 data, including response rates above 30% and median overall survival of 16.3 months in phase 2, have emboldened Pfizer to launch two pivotal trials, one against docetaxel in second line and another in first‑line combination with pembrolizumab in PD‑L1‑high disease.

Parallel to the ADC push, the company is moving quickly with 4404, a PD‑1/VEGF bispecific antibody licensed from 3S Bio. Preclinical work suggests a hundred‑fold increase in PD‑1 affinity in the presence of VEGF and binding across VEGFA isoforms. Seven near‑term or ongoing trials, including large global Phase 3 studies in colorectal and first‑line lung cancer, are intended to establish the molecule as a backbone therapy across multiple solid tumours and to dovetail with the ADC portfolio.

In haemophilia, the FDA has granted breakthrough designation to hemgenix successor kimbanzi (Hembabsi) for children aged six to 11 with haemophilia B, with or without inhibitors—another niche where Pfizer believes it can extend the reach of a newer asset into earlier lines of care.

Beyond oncology and obesity, management flagged a near‑term catalyst in vaccines. A Phase 3 readout from the VALOR trial of Pfizer’s multivalent Lyme disease vaccine candidate is expected in the first half of 2026. With roughly 400,000 US cases and 132,000 European cases of Lyme disease each year, and no vaccine currently on the market, successful data could open up a high‑profile, first‑in‑class opportunity in an area of growing public health concern.

Financials: COVID fades, cost discipline hardens

Behind the science narrative, Pfizer’s 2025 financials paint the picture of a company still digesting the COVID windfall while trying to prove that its core business can grow without it.

Reported full‑year revenue slipped 2% operationally to $62.6bn, as an approximate 40% operational decline in COVID‑related products in the fourth quarter underscored how far that once‑dominant franchise has shrunk. Vaccines were hit by a narrower US recommendation, and Paxlovid by lower infection rates. Stripping out COVID, however, revenue grew 6% operationally for the year and 9% in the fourth quarter, with solid contributions from Abrisvo, Eliquis, the Prevnar family and Vyndaqel.

Gross margins improved. On an adjusted basis, 2025’s 76% was at the upper end of management’s mid‑to‑high‑seventies aspiration, supported by lower‑margin COVID product mix rolling off and ongoing “manufacturing optimisation”. In the quarter, adjusted gross margin was around 71%, lower than the full‑year average but consistent, Denton said, with the product mix in the period and the 50/50 profit split with BioNTech on remaining COVID vaccine sales.

Bottom‑line performance was mixed by design. GAAP diluted EPS for the year came in at $1.36 (down from $1.41), weighed by the $4.4bn in impairment charges across both development‑stage and in‑line assets. Adjusted diluted EPS, the metric investors tend to track, rose to $3.22 from $3.11, ahead of consensus. In the fourth quarter, Pfizer posted a GAAP loss per share of $0.29, but adjusted diluted EPS of $0.66.

Cost control has done more than its share of the work. Pfizer claims to be on track to deliver $7.2bn in net cost savings from its productivity programmes by 2026, including $5.7bn from a broad cost realignment effort and $1.5bn from manufacturing optimisation. About $600m of the manufacturing savings hit in 2025, with a further $700m expected in 2026 and $200m in 2027. Notably, R&D savings from the cost realignment are being recycled into late‑stage programmes rather than dropping to the bottom line, leaving 2026 R&D guidance at around $11bn even as the company prepares to launch roughly 20 pivotal studies.

Capital allocation remains orthodox. Pfizer returned $9.8bn to shareholders via dividends in 2025, kept the payout intact despite signalling a pause in dividend growth, invested $10.4bn in internal R&D and about $8.8bn in business development, dominated by the Metsera (obesity) acquisition and the 3S Bio PD‑1/VEGF deal. Net leverage is expected to end 2025 around 2.7 times EBITDA, in line with the company’s target, though Denton cautioned that LOE headwinds between 2026 and 2028 mean leverage may sit at or slightly above that level for several years.

The planned sale of Pfizer’s stake in the ViiV Healthcare HIV joint venture, meanwhile, will both simplify the portfolio and free up cash. Including the anticipated ViiV proceeds, Denton estimated around $7bn in current business development capacity. The signal is that bolt‑on deals of the Metsera or 3S Bio variety remain very much on the table, but within an envelope that preserves the dividend and does not stretch the balance sheet.

Guidance: managing the LOE valley

Management reaffirmed 2026 guidance, effectively daring investors to look through another year of COVID erosion and loss‑of‑exclusivity pain to a more expansive back half of the decade.

For the year ahead, Pfizer expects revenue of $59.5bn to $62.5bn and adjusted diluted EPS of $2.80–$3.00. COVID products are guided to around $5bn in combined sales, trending lower again as the pandemic recedes from public consciousness and health systems adjust to endemic management. Non‑COVID revenues are expected to be “stable”, but that includes about $1.5bn in revenue compression from products facing generic entry in 2026.

Excluding both COVID and LOE‑impacted products, Pfizer’s guidance implies approximately 4% operational revenue growth at the midpoint—a modest but respectable rate in a period when several key franchises are losing patent protection and the obesity engine is still in the shop. Gross margins are expected to remain in the mid‑seventies on an adjusted basis, supported by cost programmes and manufacturing rationalisation. The company will continue to monitor currency swings, but did not flag foreign exchange as a major headwind at this stage.

The question for investors is whether the forward curve—a burst of late‑stage obesity and oncology trials, a broader migraine portfolio from Biohaven, a potentially first‑in‑class Lyme vaccine, and the long‑promised fruits of AI‑enabled R&D—will be enough to bridge the trough between 2026 and 2028. Bourla’s answer is that the hard work of pruning and re‑plumbing the portfolio is now largely done, and that Pfizer can “invest strategically, balancing cost savings with funding high‑value products,” while still maintaining and, over time, growing its dividend.

The earnings call underscored how much of that argument now rests on a once‑monthly GLP‑1 injection and a cluster of related peptides that, for now, are lines on a Gantt chart. In a sector where obesity has become both the biggest opportunity and the most crowded trade, Pfizer has chosen differentiation by time rather than molecule alone. The coming two years will show whether a monthly cadence can reset the rhythm of weight loss investing—or whether the company has simply tuned into the market a beat too late.