Snippets

Vantage Snippets are short summaries of breaking news stories.

Diabetes approval fires the gun on Lilly blockbuster

Tirzepatide was always going to be 2022’s big approval, and a green light late Friday in the US fires the starting gun on a franchise that comes with huge expectations. Six doses of Mounjaro, as the drug has been trademarked, were approved to treat type 2 diabetes; Lilly is keeping the price under wraps for now. The lack of this crucial piece of information has not held the sellside back, with sales forecasts jumping higher in the wake of impressive obesity data. Analysts at Berenberg are among the most bullish, with a peak sales estimate in obesity alone of $13bn; the more cautious sit at around $4bn at peak. Diabetes is seen as the larger opportunity, and here the numbers get very big indeed – Mizuho for example has pencilled in $10bn in this setting by 2030. The optimists have peak sales across all settings sitting up towards the $20bn mark which, if they turn out to be accurate, will make Mounjaro one of the most commercially successful diabetes drugs. It’s now down to Lilly to deliver, although the group’s fierce competitors in this space, Novo Nordisk for one, will not be sitting still in the meantime.

Mounjaro's challenge: selected top-selling type 2 diabetes drugs
Drug Sales ($bn) Detail 
Ozempic (GLP-1, Novo) 10.3 Peak predicted in 2031
Trulicity (GLP-1, Lilly) 7.4 Peak predicted in 2023 
Lantus (insulin, Sanofi) 6.7 Peaked in 2014
Rybelsus (oral GLP-1, Novo) 6.5 Peak predicted in 2031
Januvia/Janumet (DPP4, Merck) 6.1 Peaked in 2016
Jardiance (SGLT2, Boehringer) 6.0 Peak predicted in 2027
Actos (PPAr, Takeda) 4.5 Peaked in 2010
Victoza (GLP-1, Novo) 3.9 Peaked in 2018
Farxiga (SGLT2, Astrazeneca) 3.4 Consensus predicts 2024 peak
Note: type 2 diabetes sales only. Source: Evaluate Pharma. 

Valneva and Synairgen remain Covid laggards

While some biotechs made hay during Covid, others demonstrably failed to cash in on the pandemic. This morning two laggards, Valneva and Synairgen, reminded investors of their failings. The former’s vaccine VLA2001 did secure regulatory approval in the UK last month, but only after the country cancelled a 100 million-dose contract, citing an alleged breach of obligations. Now another contract has been terminated, this time with the EU for up to 60 million doses. Apparently the European commission could cancel this order if VLA2001 had not received marketing authorisation by April 30; such approval is still awaited after EMA requests for additional data. Meanwhile, Synairgen’s interferon beta-1a project SNG001 failed in the Sprinter study in treating hospitalised Covid patients. Now the company has carried out post hoc analyses, in one of which, in patients with compromised respiratory function (oxygen saturation ≤92% or respiratory rate ≥21 breaths/min), SNG001 “significantly reduced risk of progression to severe disease and death” versus placebo. Even so, this was on a per-protocol rather than intent-to-treat basis, and the nominal p value claimed is an underwhelming 0.046. Synairgen rose 35% this morning, still some 80% off where it was trading before Sprinter blew up.

UCB feels the pain of rejection

UCB was always going to be late to the highly competitive US psoriasis market with bimekizumab, and yet another setback raises serious doubts about the drug’s potential. A complete response letter from the FDA, requiring the resolution of certain “pre-approval inspection observations”, could push back its arrival to the second half of next year, Berenberg analysts believe; the decision had already been delayed from last October. The company needs a boost to its top line, with sales of its two blockbusters peaking last year. Cimzia is under pressure from growing use of biosimilars in the anti-TNF class and Vimpat, an epilepsy drug, is about to lose exclusivity. UCB shares slumped 15% today, shaving around €3bn from the company’s market cap, on disappointment at this missed opportunity. Bimekizumab, which is already approved in Europe and other countries as Bimzelx, looks very competitive to other psoriasis agents, at least according to cross-trial comparisons. Its problem has always been timing, causing sellside analysts to predict a relatively modest future versus other novel psoriasis agents. Those sales forecasts are about to get a lot smaller.

The Kras Shp has not yet sailed for Bristol

Bristol Myers Squibb might be a bit late to the party, but it has signalled that it could be getting into Kras, via a deal today for Bridgebio’s Shp2 inhibitor BBP-398. The agreement raises eyebrows for a couple of reasons: Shp2 inhibition has disappointed as monotherapy, and it is now thought that it will need to be combined with direct Kras inhibition. But Bristol does not have a Kras inhibitor of its own – cue rumours about which of the many Kras players Bristol might want to acquire. This includes Bridgebio itself; however, given the group’s undemanding $770m valuation, surely Bristol would have taken out the whole company if it had been interested in Bridgebio's BBP-454. In the event, Bristol is paying $90m up front to license BBP-398, building on a clinical collaboration last year to test its combination with Opdivo. This represents an inexpensive bet for Bristol and handy cash for Bridgebio, which crashed after the failure of its lead asset, acoramidis, in amyloidosis last year. The group has around $630m in the bank, enough to last into 2024, but it might need to sell off more of the family silver before too long.

UCB needs a stronger rare disease hand

Data from two generalised myasthenia gravis projects that UCB hopes will compete against Astrazeneca’s blockbuster Soliris/Ultomiris franchise and Argenx’s Vyvgart suggest that these incumbents have little to worry about. UCB has taken two shots at this rare disease with zilucoplan and rozanolixizumab, the former a C5 inhibitor and the latter an FcRn MAb, with efficacy looking comparable. Argenx used a different endpoint in its myasthenia gravis programme, so a side-by-side comparison against it is harder than against Astra. But the fact that Vyvgart is off to a strong start speaks to that drug’s potential: first-quarter sales, announced last week, came in well ahead of expectations. Should UCB's contenders make it to market safety and convenience will also matter, and here the subcutaneously delivered zilucoplan appears to have an edge, with treatment-emergent adverse events occurring at a similar rate to placebo (76.7% vs 70.5%). Roza has long been considered more problematic, requiring a lengthy transfusion, while toxicity could prove a problem, with cases of severe headache emerging. Coming late to this space could ultimately be UCB’s biggest challenge, however. The company is unlikely to reach the market until late in 2023.

Asco 2022 – Affimed suffers withdrawal symptoms

After becoming the first company to see an NK cell engager, AFM13, score clinical validation, courtesy of an MD Anderson trial splashed at AACR in April, Affimed was priming investors for more at next month’s Asco conference. Not any more, it seems: MD Anderson’s abstract 7505, which yesterday was still listed for oral presentation on June 3, no longer appears in the meeting programme. At the time of going to press neither Asco nor Affimed had responded to questions seeking to clarify the situation. And Affimed has not issued a public statement about it – something that presumably will need to be rectified soon, given that the planned presentation was press released on April 27. Assuming that this is not a technical glitch, one reason for the presentation’s removal might be that the results have been deemed old, with nothing new versus the AACR dataset. There is precedent: at the 2016 Asco meeting, for instance, the organisers removed from a press briefing a late-breaking presentation by Dr James Kochenderfer that had already been disclosed in an EHA abstract, and kicked Immunomedics out entirely for revealing embargoed data at investor meetings. Affimed is off 10% today, still with no explanation.

Update: after market close Affimed issued a statement confirming the abstract's withdrawal, citing non-compliance with Asco's embargo policies given that the data had been presented at AACR.

Source: Affimed & Asco.

Bausch & Lomb takes a haircut

If investors had hoped that the biggest medtech IPO for over a year could defy market sentiment, they were in for a disappointment. Bausch & Lomb, spun off from its parent Bausch Health, raised just $630m today – missing its target figure by more than $200m. Despite being profitable Bausch & Lomb was forced to price its shares $20% lower than its preannounced range. This is the latest chapter in the eye care company’s turbulent history: it is in fact returning to the New York exchange, having been listed there for half a century before being taken private by Warburg Pincus for $4.5bn in 2007. Warburg sold it to Valeant Pharmaceuticals six years later for $8.7bn. Valeant changed its name to Bausch Health in 2018 in an effort to shake off accusations of price-gouging and sharp accounting practices, and today owns 90% of Bausch & Lomb. Perhaps Bausch & Lomb is lucky to get away at all in such a volatile market – it is notable that the deal is only the third listing of a medtech company this year. Still, its current valuation of around $6.3bn means that the parent group has lost out in a major way. 

2022's medtech IPOs so far
Date Company Focus Amount raised ($m) Premium/
discount
Exchange
Feb 16 Meihua International Medical Technologies General & plastic surgery 36 0% Nasdaq
Apr 27 Tenon Medical Orthopaedics 16 0% Nasdaq
May 6 Bausch & Lomb  Ophthalmology 630 -20% NYSE
Source: Evaluate Medtech.

Anthos goes pivotal as Novartis and Pfizer look on

In about 18 months' time Novartis will find out whether it made a mistake to give up on the blood-thinning project abelacimab. The MAb, spun out into the Blackstone-backed Anthos Therapeutics in 2019, yesterday became the first factor XI inhibitor to begin phase 3 patient enrolment. Two pivotal studies, Aster and Magnolia, are now under way, both with primary completion dates of September 2023. The mechanism (abelacimab also hits factor XIa) is an unusual area of research, featuring a small handful of big players, with Bayer and Bristol Myers Squibb working on several distinct assets. Both have franchises to defend: the former’s Xarelto loses US patent protection in 2024, while the latter’s Eliquis will likely go two years later. Unusually, Bristol’s Eliquis partner Pfizer is not active in factor XI, and was asked about this on its first-quarter call. It said: "We really want to see a similar step-up in breakthrough potential as we saw with Eliquis. And we haven't yet been convinced about that step-up, but we are carefully monitoring." The Aster study compares abelacimab head to head against Eliquis, so the answer – for Novartis and Pfizer alike – will come soon enough.

Selected inhibitors of factor XI or XIa
Project Company Mechanism Study design/status
Phase 3
Abelacimab (MAA868) Anthos (ex Novartis) Anti-factor XI & XIa MAb Aster vs Eliquis
Magnolia vs LMW heparin
Phase 2
Osocimab (BAY1831865) Bayer Anti-factor XIa MAb Convert, in dialysis, ended Dec 2021
Fesomersen (IONIS-FXI-LRx/ ISIS 416858/ BAY2306001) Bayer/ Ionis Factor XI ligand conjugated antisense Emerald, in dialysis, ended Dec 2019
Asundexian (BAY 2433334) Bayer Oral factor XIa inhibitor Pacific-AMI ended Feb 2022
Pacific-Stroke ended Feb 2022
Milvexian (JNJ-70033093/ BMS-986177) Bristol Myers Squibb/J&J Oral factor XIa inhibitor Axiomatic-SSP ended Apr 2022
AB023 Aronora Anti-factor XI MAb NCT03612856, in dialysis, ended 2019
Phase 1
ONO-7684 Ono Pharmaceutical Oral factor XIa inhibitor NCT03919890 ended 2019
BMS-986209 Bristol Myers Squibb Oral factor XIa inhibitor NCT04154800 ended Aug 2021
BMS-262084 Oral Bristol Myers Squibb Non-peptide factor XIa inhibitor Unclear
Source: Evaluate Pharma & clinicaltrials.gov.

Jazz overture rekindles hopes for orexin agonism

After Takeda stopped trials of TAK-994 last year the future for treating narcolepsy with orexin-2 agonists looked bleak. But hopes were rekindled yesterday when Jazz endorsed the approach with a $50m up-front payment to Sumitomo Pharma to license the latter’s DSP-0187. The companies describe DSP-0187, which recently entered phase 1 in Japan, as a highly selective oral agent, and perhaps the hope is that selectivity will circumvent the toxicity signal that appeared to trip up TAK-994 in phase 2. While antagonising orexin receptors to develop sedative drugs is the subject of much clinical work the pipeline for agonists, which cause the opposite effect, is barren. The most advanced asset is NLS Pharmaceutics’ Quilience, an extended-release formulation of mazindol, a drug that had been sold for decades for weight loss under the brand name Sanorex, but which is no longer marketed. Despite Takeda’s termination of TAK-994 studies the Japanese group has two other orexin-2 receptor agonists in clinical trials. And perhaps the most heavily invested company is the Centessa subsidiary Orexia, set up specifically to develop oral and intranasal orexin receptor agonists, which last October struck a discovery deal with Schrödinger.

Orexin agonists in development
Project Company Mechanism Status
Quilience (mazindol) NLS Pharmaceutics Pan-monoamine reuptake inhibitor & orexin 2 receptor agonist Ph2
TAK-994 Takeda Orexin 2 receptor agonist Ph2 terminated
TAK-925 Takeda Orexin 2 receptor agonist Ph1 completed
TAK-861 Takeda Orexin 2 receptor agonist Ph1
DSP-0187/ JZP441 Jazz/ Sumitomo Orexin 2 receptor agonist Ph1
Centessa-Schrödinger Research Project Orexia (Centessa)/ Schrödinger Orexin 2 receptor agonist Preclinical
Source: Evaluate Pharma, clinicaltrials.gov & Japan Registry of Clinical Trials.

With crucial readouts looming, Intercept reaches for a lifeline

Considering Ocaliva's tarnished history it is pretty remarkable that Intercept has managed to drum up commercial interest in the drug. Sales in its globally approved indication of primary biliary cholangitis are flatlining thanks to tightened label warnings, while Intercept is clinging to hope that regulators’ minds can be changed in Nash, after an FDA rejection two years ago. The company is also heavily indebted, so the sale of overseas rights, announced today, offers some breathing space before some important readouts. The buyer is Advanz, a private European speciality pharma group, which as part of a fairly complex deal is paying $405m for Intercept’s various foreign operations and ex-US commercialisation rights to Ocaliva. Intercept will continue to supply the drug in bulk tablet form but will only receive royalties if Ocaliva is approved in Nash. The chances of that happening should soon become clear, with Intercept due in the coming months to unveil a re-analysis of the controversial Regenerate trial, as well as topline data from Reverse, a new study in more advanced patients. Ahead of these results it is hard to tell whether this sale represents a lifeline or a last gasp. 

Crunch time for Intercept: the crucial read outs
Timing Event Details
H1 2022 Reanalysis of ph3 Regenerate trial Trial in advanced fibrotic Nash; company hopes to resubmit application this year based on new analyses
Q3 2022 Ph3 Reverse trial readout Ocaliva in compensated cirrhotic Nash, delayed from YE 2021 owing to complexities gathering data
Source: company communications.
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