Vantage Snippets are short summaries of breaking news stories.

Merck circles back to RNA with big early-stage bet

Researchers are already working on improving the mRNA technology behind the hugely successful Covid vaccines, and circular RNA is a leading idea. That approach received a big endorsement from Merck & Co today in the form of an infectious disease and oncology discovery deal with Orna Therapeutics. The biotech will receive $150m up front, a hefty fee considering that its work is very much preclinical; its most advanced project is described as an in-situ anti-CD19 Car that it aims to get into the clinic by 2024, and does not seem to be covered by the Merck deal. The pharma giant is also contributing $100m towards a $221m series B that Orna announced today. Gilead, Bristol Myers Squibb, Astellas and Novartis all participated in Orna’s series A, so this is clearly a space that big developers have their eyes on. Few small start-ups are focused on the approach, although the bigger mRNA players are presumably already active. The idea behind circular RNA is to produce more stable, and therefore durable, therapeutics; linear mRNA is susceptible to degradation from its loose ends. More efficient delivery into cells, improved protein expression and cheaper manufacturing is being claimed.

Putting the O in RNA… companies working with circular RNA
Company Description Financings
Orna Therapeutics Technology described as oRNA; very early-stage pipeline includes a CD19 Car, DMD agent and vaccines Raised ~$321m to date (founded by MPM Capital), emerged from stealth in early 2021
Laronde Technology described as eRNA (endless RNA); claims broad therapeutic focus, building capacity to generate up to 100 candidates in the next 10 years Raised ~$490m to date (founded by Flagship), emerged from stealth in Oct 2021
Therorna China based; company focus unclear but founder has published on circular RNA vaccines for Covid Raised ~ $90m since early 2021
Circode China based; company focus unclear Raised ~$20m in seed funding since 2020
Circular Genomics Developing a diagnostic and therapeutic circular RNA-based genomic assay for depression Raised $4.5m in seed funding in Dec 2021
Chimerna Discovery-stage pipeline focused on kidney disease, Parkinson's and Alzheimer's Founded in 2020; no disclosed venture financing, <$1m in grant funding  
Source: Evaluate Pharma & company statements. 

Is Pfizer’s pneumococcal dominance under threat?

News of a stumble in a crucial paediatric trial of Pfizer’s latest pneumococcal vaccine, Prevnar 20, made for worrying reading last week. Six viral serotypes failed to meet non-inferiority on one of the co-primary endpoints of a US pivotal trial, two by a wide margin and four narrowly, the group said on Friday. Without knowing which serotypes were at fault it is hard to judge the significance; SVB wrote that if these strains were not already covered by Merck & Co’s rival 15-valent shot, Vaxneuvance, and/or were not associated with invasive disease, Prevnar 20 should still have a chance to compete. Vaxneuvance won its paediatric approval last month, and Pfizer needs to defend the dominance of earlier Prevnar iterations. A further observation by SVB gives further reason for pessimism, however. Last month Pfizer started a phase 1 trial testing six new pneumococcal vaccine candidates that look to have fewer strains than Prevnar 20. Being able to maintain ironclad protection while expanding a vaccine's coverage has always been the challenge in this space, and perhaps Pfizer is also preparing for more Prevnar 20 disappointment. Either way, all eyes now turn to the next pivotal readout, due before year end.   

Pfizer's pivotal Prevnar 20 efforts in infants
Trial Details Outcome 
Prevnar 20 vs Prevnar 13 (immunogenicity) US trial testing four-dose schedule Co-primary endpoint of NI on predefined serotype-specific IgG after dose 3 hit by 14 serotypes; co-primary endpoint of NI of IgG geometric mean concentrations after dose 4 hit by all serotypes
Prevnar 20 vs Prevnar 13 (immunogenicity) Japan trial testing four-dose schedule Completed
Prevnar 20 vs Prevnar 13 (immunogenicity) Europe and Australia trial testing three-dose schedule Results due before year end
Prevnar 20 vs Prevnar 13  Global trial looking at safety and tolerability Results due before year end
Prevnar 20  Trial testing four different single doses Results due before year end
NI=non-inferiority. Source: company statement &

Finally! A positive surprise for Gilead

If Enhertu has not already rendered Gilead’s Trodelvy irrelevant in Her2-negative breast cancer then today’s overall survival hit in the Tropics-02 trial represents a major surprise for the disaster-prone Gilead. This morning’s anaemic 2% share price increase suggests that the boat for Trodelvy has already sailed, but the result will nevertheless be pored over when presented at a scientific conference – not least because Gilead revealed that it had filed Trodelvy on the strength of it. Tropics-02’s relevance was in doubt since a Q&A for investors glossed over whether its positive PFS outcome was clinically meaningful, before a late-breaker at Asco revealed a modest median PFS benefit, late separation of the PFS curves, and an ultimately not unimpressive 34% reduction in risk of progression. OS at that first interim analysis, when just over half of Tropics-02’s 543 patients had died, was still negative, so the question will be what changed between then and today’s second interim analysis hit. Perhaps a similar late separation, driven by the Trop-2 biomarker, has occurred in the OS curves. Importantly, Gilead now says the result is “clinically meaningful”, though some will note that this is a subjective claim.

Source: Dr Hope Rugo & Asco.

The way clears for 2022's biggest acquisition (so far)

If Merck & Co buys Seagen – which, after Friday’s legal verdict, looks more likely than before – the move would rank as the biggest takeover of the year so far. And a Seagen takeover, widely rumoured in recent weeks, is thought likely by investors. That much is clear given that Seagen stock was virtually unmoved on Friday’s news that an arbitration had ruled against the company, and in favour of Daiichi Sankyo, in a dispute over rights to antibody-drug technology that lies behind Enhertu and related projects. Seagen had earlier prevailed in a jury trial over the key patent involved, and the sellside had generally been expecting a similar result in the more important arbitration process. As such, the markets are shrugging off Seagen’s loss of a potentially large royalty line, and instead seeing this as a clearing event that gives Merck more certainty over valuation. As the biotech bear market shows signs of bottoming out M&A is back on the agenda, with Pfizer and Amgen’s recent moves on Global Blood and Chemocentryx respectively, for instance. A Seagen takeover would maintain this momentum, even if the target’s valuation is not, after all, as high as once hoped for.

Seagen, and 2022's biggest acquisitions
Acquirer Target Status Value ($bn)
Merck & Co Seagen Not announced 30.0+
Pfizer Biohaven Open 11.6
Pfizer Global Blood Therapeutics Open 5.4
Bristol Myers Squibb Turning Point Therapeutics Open 4.1
Amgen Chemocentryx Open 4.0
GSK Affinivax Open 3.3
UCB Zogenix Closed 1.9
GSK Sierra Oncology Open 1.9
Astrazeneca Teneotwo Closed 1.3
Abbvie Syndesi Therapeutics Closed 1.0
Source: Evaluate Pharma. 

Sanofi slumps as stagnation and litigation collide

Sanofi’s terrible week started with news of a global recruitment pause on tolebrutinib, the group’s BTK inhibitor that is mired in liver injury concerns. The project is for now Sanofi’s most valuable pipeline asset, according to Evaluate Pharma, although forecasts are under threat. Analysts at UBS this week halved their tolebrutinib peak sales estimate to €1bn, citing the liver toxicity issue, and raised serious concerns about the company’s lack of growth. The note also flagged approaching Zantac litigation court cases – the drug was withdrawn in 2019 on a link with cancer – an issue to which the market seems to have just woken up. Zantac rights were passed around over the years, and the numerous companies involved are already fighting among themselves, seeking indemnification from losses. Morgan Stanley says damages could reach $45bn. Sanofi, Haleon and GSK are bearing the brunt of the concerns, but investors appear to be fearing the worst for all associated. All of which could not have come at a worse time for Sanofi, which looks like ending the week nursing a drastic valuation slump: its shares hit an 18-month low today and are down 16% since Monday.

Causing heartburn: tracing potential Zantac liability  
1981 Glaxo (legacy company) wins first approval for prescription Zantac, which goes on to become the world's biggest-selling drug ($3.7bn peak sales in 1994) 
1993 As Zantac patents start to expire, Glaxo and Warner Lambert form a joint venture to develop an OTC product
1995-1998 OTC Zantac is launched and marketed by the Glaxo-Warner Lambert joint venture
1998 JV terminated, Warner Lambert retains full rights
2000 Warner Lambert is acquired by Pfizer
2006 Johnson & Johnson buys Pfizer's OTC business; Zantac OTC rights sold to Boehringer Ingelheim to satisfy antitrust
2017 BI sells consumer health business to Sanofi, including OTC Zantac, as part of animal health asset swap
2018 Concerns emerge about NDMA levels in drugs containing ranitidine, Zantac's active ingredient
2019 Sanofi voluntarily withdraws ranitidine-containing Zantac from the market 
Source: company statements & Haleon F1 document.

Reva revives

Dissolving drug-eluting stents were one of those devices that sounded like a great idea, but which in practice didn’t really take off. Abbott withdrew the best-known one, Absorb, in 2017 after it failed to sell, and when Reva Medical went into bankruptcy protection in early 2020 the technology was largely regarded as defunct. But it takes more than that to keep Reva down, it seems: the company is back with a $45m series B round and a new bioresorbable device for a different indication. Where formerly it was trying to treat blocked coronary arteries with a scaffold called Fantom, it is now heading to pivotal trials in below-the-knee peripheral vascular disease with a scaffold called Motiv. Motiv is made of a polymer called Tyrocore that Motiv developed itself, and leaches the antiproliferative sirolimus. Reva believes that the new cash, from “a global strategic investor with deep experience in medical devices”, as well as Biostar Capital and existing investors, will allow it to take Motiv to the FDA. Data from an uncontrolled pilot trial were encouraging, but the pivotal, versus balloon angioplasty, will be a far harder test.

Status of selected bioresorbable scaffolds
Company Device Material Drug Status
Reva Medical Motiv* Tyrocore Sirolimus Pilot trial data encouraging; pivotal study to start soon
Reva Medical Fantom Desaminotyrosine polycarbonate Sirolimus CE marked Apr 2017; company filed for bankruptcy protection Jan 2020 
Biotronik Magmaris  Magnesium alloy Paclitaxel CE marked Jun 2016, device still on sale
Meril Life Science MeRes 100 Polylactic acid Sirolimus CE marked Aug 2019, device still on sale
Abbott Absorb Polylactic acid Everolimus CE marked Jan 2011; FDA approved Jul 2016; withdrawn from sale worldwide Sep 2017
Elixir Medical DESolve Polylactic acid Novolimus/ myolimus CE marked May 2013, device not mentioned on company website
Amaranth Medical Aptitude Polylactic acid Sirolimus CE mark had been expected Dec 2017; company website now defunct
Amaranth Medical Magnitude Polylactic acid Sirolimus CE mark had been expected in Mar 2018; company website now defunct
Arterial Remodeling Technologies Pure Polylactic acid No drug CE marked May 2015; company website now defunct
*For below-the-knee peripheral vascular disease; all others for coronary arteries. Source: Evaluate Medtech & company websites.

Valneva throws in the Covid towel

Valneva had always looked like a Covid vaccine also-ran, and now it is finally facing reality. During its second-quarter results today the group said it had suspended manufacturing of VLA2001, and is exploring strategic options. A look at Valneva’s rising costs since Covid hit explain why the group is walking away from the jab, which has proven more of a money pit than a money maker. Novavax is another Covid vaccine laggard that looks like it will struggle to make a return on its investment; earlier this month that company slashed its 2022 sales guidance from $4-5bn to $2-2.3bn – a number that could still be hard to hit given the lacklustre demand for its product, Nuvaxovid. Novavax’s outlay dwarfs Valneva’s, but it has received plenty of government funding, with the US administration ploughing in nearly $800m last year. At least Valneva has some other irons in the fire, like its Chikungunya vaccine VLA1553 and the Pfizer-partnered Lyme disease candidate VLA15. Pfizer’s recent investment and the start of a pivotal trial of the latter look like a vote of confidence; Valneva will have to hope it can do better in these diseases than it did in Covid.

Gemini's Disc(ontinuation)

Undeterred by clinical failure Gemini Therapeutics was set to continue flogging the dying horse of its complement inhibitor GEM103 in geographic atrophy. But a pivotal trial never started, and today the group did investors another favour: realising that its value lay as a shell, Gemini is being reversed into by Disc Medicine, a private US company founded by Atlas Venture in 2019. Disc’s focus lies in red blood cell biology, where mid-stage trials recently began for two lead assets, bitopertin for protoporphyria and DISC-0974 for myelofibrosis. Both are big pharma castoffs: bitopertin came from Roche, while DISC-0974 was part of Disc’s anaemia-focused licence from Abbvie. The latter has mechanistic backing, courtesy of early clinical data at this year’s EHA meeting, but bitopertin’s history is more bizarre: Roche had been developing the molecule, a GlyT1 inhibitor, for schizophrenia before it failed six phase 3 trials in 2015. Research published last year backs the repurposing of GlyT1 inhibitors for protoporphyria, but Boehringer Ingelheim continues to study the mechanism in schizophrenia, in a phase 3 trial of BI 425809 incorporating speech analytics and virtual reality. Disc’s reversal into Gemini includes a $53m financing, adding to $140m of VC cash raised earlier.

Disc's clinical focus as a public entity
Project Mechanism Source Clinical trial
Bitopertin GlyT1 Inhibitor Roche, May 2021 Ph2 in erythropoietic protoporphyria ends Jul 2023
DISC-0974 anti-HJV mAb Abbvie, Oct 2019 Ph1/2 in myelofibrosis with anaemia ends Oct 2024
GlyT1=glycine transporter-1; HJV=hemojuvelin. Source: company presentations.

After Astra’s exit Zentalis doubles down on Wee1

Things might be looking up in biotech but it is too early to declare the bear market over, and hard choices still have to be taken in prioritising R&D spending. So Zentalis should be congratulated for pulling the plug on ZN-c5 and ZN-e4, respectively an oral Serd and EGFR inhibitor. Radius/Menarini’s elacestrant could soon become the first approved oral Serd, and pivotal data are expected from Astrazeneca and Lilly’s contenders. And the EGFR space is fiercely competitive, featuring Astra’s blockbuster Tagrisso and numerous advanced players. The question for Zentalis, fresh from a $200m equity raise and $25m share purchase by Pfizer, is whether in focusing on ZN-c3 and ZN-d5 it is backing the right horses. ZN-d5, a BCL-2 inhibitor, has marketed competition, though not in its selected niche of AL amyloidosis. ZN-c3 could be the big one: after Astra pulled adavosertib ZN-c3 is the industry’s most advanced Wee1 inhibitor – a mechanism that has promised much but delivered little. Zentalis will argue that ZN-c3 has better tolerability, and might not hit adavosertib’s problematic lack of a therapeutic window. Perhaps Astra’s decision encouraged Zentalis; a phase 2 ZN-c3 trial ending in December could reveal all.

Zentalis makes some hard decisions
What's in…
Project Mechanism Clinical trial 2028e sales ($m) Commercial position
ZN-c3 Wee1 inhibitor Ph2 in uterine serous carcinoma 244 Astra discontinued adavosertib in Jul 2022; ph1 projects from Debiopharm, Impact Therapeutics & Shouayo
ZN-d5 Bcl-2 inhibitor Ph1/2 in AL amyloidosis NA* Roche/Abbvie's Venclexta is marketed for blood cancers; clinical lead is Abbvie's navitoclax, in ph3 for myelofibrosis
…and what's out
ZN-c5 Oral Serd Ph1/2 in ER+/Her2- breast cancer 686 Radius/Menarini's elacestrant filed; Sanofi's amcenestrant & Roche's giredestrant failed in ph3; pivotal data from Astra's camizestrant in H1 2023, and from Lilly's imlunestrant in mid-2023 
ZN-e4 EGFR inhibitor Ph1/2 in EGFR+ve NSCLC NA* Marketed drugs include Astra's Tagrisso, Pfizer's Vizimpro & J&J's Rybrevant, plus 1st-gen products Tarceva, Iressa etc; pipeline includes J&J's lazertinib & Dizal's sunvozertinib; Black Diamond recently discontinued BDTX-189
Source: Evaluate Pharma sellside consensus; *no analyst consensus available.

Cincor’s blood pressure win quickens investors’ pulses

Cincor has proved itself to be a rare beast in the current markets: a biotech trading significantly above its IPO price. The group’s almost 50% stock price jump yesterday came courtesy of positive results for baxdrostat from the Brightn trial in treatment-resistant hypertension. The aldosterone synthase inhibitor produced double-digit reductions in systolic blood pressure across all three trial doses, including a 20.3mmHg drop at the highest dose. On a cross-trial basis the project compares favourably with mid-stage results from Idorsia’s Johnson & Johnson-partnered aprocitentan; full pivotal data are keenly awaited on the dual endothelin antagonist. Another feather in Cincor’s cap was baxdrostat’s clean safety profile, with the asset avoiding hyperkalaemia and showing no impact on cortisol levels. Unsurprisingly, Cincor wasted no time in capitalising on its share price gain by announcing a fundraising. The company is also trying to maximise its market, and results from the phase 2 Halo trial for patients who have failed two standard of care BP drugs – a slightly less stubborn population – are expected later this year. Access to the wider primary market is unlikely given the numerous generic blood pressure products on offer, but for now the treatment resistant market is poorly served. 

Cross-trial comparison of phase 2 data on baxdrostat and aprocitentan
Project Baxdrostat (Brightn, NCT04519658) Aprocitentan (NCT02603809)
Dose  0.5mg 1mg 2mg  5mg  10mg 25mg 50mg Placebo
Decrease in systolic BP (mmHg) 12.1 17.5 20.3 10.3 15 18.5 15.1 7.7
Decrease in diastolic BP (mmHg) 8.6 11.8 14.3 6.3 9.9 12.0 10.0 4.9
Decreases in BP at 12wk for baxdrostat and 8wk for aprocitentan. Source: company releases.
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