Vantage Snippets are short summaries of breaking news stories.

The FDA brushes off the pandemic with a pick-up in novel drug approvals

The US drugs regulator approved 58 novel drugs last year, the highest number for three years and well above the 10-year average of 48. With travel limitations blamed for decision delays in a number of cases, Novartis’s Leqvio and UCB’s Bimzelx included, this uptick could presumably have been steeper under more normal conditions. The only Covid product included in this count is Biontech and Pfizer’s Comirnaty; all the other pandemic-related projects are on the market under emergency use authorisations, rather than full approvals. The mRNA vaccine is almost certainly going to become last year’s biggest approval commercially speaking, though by 2026 sales are forecast to have dipped substantially. This time last year Biogen’s Aduhelm was looking like the class of 2021's biggest seller, according to fifth-year sales as predicted by sellside analysts. Should last week’s punitive US coverage decision hold consensus is likely to drop to close to zero. That still leaves plenty of potential future blockbusters that arrived on the market last year, according to Evaluate Pharma's consensus in the table below. That said, it is worth remembering that several of these projects need to win expanded labels, or carve out share in highly competitive therapy areas, to reach these lofty levels.

Predicting great things: 2021's arrivals with blockbuster potential
Product Company Description  2026e US sales 
Leqvio Novartis siRNA-based anti-PCSK9 for high cholesterol; approved in heterozygous familial hypercholesterolaemia and atherosclerotic cardiovascular disease.  $1.7bn
Abecma Bristol Myers Squibb/Bluebird Anti-BCMA Car-T cell therapy; approved for B-cell and follicular lymphomas  $1.4bn
Comirnaty Pfizer Covid-19 vaccine  $1.4bn
Tezspire Amgen Anti-TSLP MAb; approved in severe asthma $1.2bn
Vyvgart Argenx Anti-FcRn MAb for IgG-mediated autoimmune diseases; approved in myasthenia gravis $1.2bn
Lumakras Amgen Kras G12C inhibitor; approved in non-small cell lung cancer $1.2bn
Lupkynis Aurinia  Calcineurin inhibitor; approved in lupus nephritis $1.1bn
Source: Evaluate Pharma.

Valneva's Omicron splash masks a delay in Europe

Valneva’s announcement yesterday on the performance of its Covid vaccine candidate VLA2001 against the Omicron variant was light on details, but managed to send the group’s stock up 45%. Still, all is not completely rosy: the EMA is awaiting more data on VLA2001, its head of biological health threats and vaccines strategy, Dr Marco Cavaleri, disclosed during a press briefing on Tuesday. He added that the agency hoped to progress its rolling review, which began in December, “in the coming months”, but would not provide further timelines. Full data have yet to emerge from the phase 3 Cov-Compare study, which Valneva toplined as positive in October; however, these will not elucidate VLA2001’s effect on Covid outcomes, as the trial merely tested immunogenicity versus Astrazeneca’s Vaxzevria. Yesterday’s results, though far from comprehensive, make VLA2001 look less than stellar against Omicron: of 30 serum samples from people who had received three doses of VLA2001, 100% presented neutralising antibodies against the original virus and Delta variant, but this fell to 87% against Omicron. The mean reduction in neutralisation versus the original virus was 2.7-fold for Delta and 16.7-fold for Omicron. Valneva shares fell 19% this morning, but the group is still worth $2bn.

The ups and downs of Valneva's investigational Covid vaccine
Date Event
Jan 19, 2022 Company releases lab data on VLA2001 vs Omicron; shares rise 45%
Jan 18, 2022 EMA discloses that it is waiting for more data on VLA2001
Dec 16, 2021 Valneva releases "positive" homologous booster data from VLA2001's phase 1/2 trial
Dec 8, 2021 Valneva signs contract with Bahrain for 1m doses of VLA2001
Dec 2, 2021 UK Cov-Boost study, of 7 vaccines, shows disappointing results with VLA2001 
Dec 2, 2021 EMA begins rolling review of VLA2001
Nov 23, 2021 Valneva signs contract with EMA for up to 60m doses of VLA2001 over 2yrs
Oct 18, 2021 Valneva reports topline results from ph3 Cov-Compare trial, showing superior immunogenicity vs Astra's Vaxzevria
Sep 13, 2021 UK cancels contract for 100m doses of VLA2001
Aug 23, 2021 Valneva starts rolling submission with UK's MHRA
Aug 11, 2021 Valneva starts ph3 VLA2001-304 study in elderly 
May 6, 2021 Valneva prices US IPO
Apr 21, 2021 Valneva starts Cov-Compare study
Apr 20, 2021 Valneva deprioritises discussions with EMA over VLA2001 supply
Apr 6, 2021 Valneva reports ph1/2 data with VLA2001
Feb 1, 2021 UK government exercises option for a further 40m doses of VLA2001 in 2022
Sep 14, 2020 Valneva signs contract with UK for initial 60m doses of VLA2001
Source: company releases, The Lancet & EMA press briefing.

Asco-GI – narrow bile duct win sets Imfinzi on an approval course

Astrazeneca’s Imfinzi could soon add front-line bile duct cancer to its approved uses, though its supporting Topaz-1 study, being presented in full at Asco-GI, has revealed a benefit that might appear underwhelming. In the trial, toplined last October, Imfinzi plus chemo reduced risk of death by 20% versus chemo alone, but median overall survival was just 1.3 months longer than for chemo. However, Dave Fredrickson, Astrazeneca’s head of oncology, told Evaluate Vantage that the medians belied a strong tail in the survival curves, adding: “At two years one in four patients are alive on the Imfinzi/chemo regimen versus one in 10 on chemo alone.” As for biomarkers, he said patients’ PD-L1 status did not seem to be an obvious reason for the late survival benefit. Bile duct cancer patients have seen US approvals of Incyte’s Pemazyre and Bridgebio’s Truseltiq, both in FGFR2-mutant disease, and Agios’s Tibsovo, but these have all been second line. Whether follow-on use of any of these might have affected the Topaz-1 data has yet to be analysed. Either way, Topaz-1 marks the first win for IO here, and 2023 should see data from front-line studies of Merck & Co’s Keytruda (Keynote-966) and Roche’s Tecentriq (Imbrave-151).

Summary of Topaz-1 data
  Imfinzi + chemo Chemo
mOS (primary endpoint) 12.8mth 11.5mth
Stats HR=0.80 (p=0.021)
mPFS (secondary endpoint) 7.2mth 5.7mth
Stats HR=0.75 (p=0.001)
ORR (secondary endpoint) 26.7% 18.7%
Grade 3/4 AEs 75.7% 77.8%
Treatment-related deaths 2/341 1/344
Source: Astrazeneca & Asco-GI.

Asco-GI 2022 – Cardiff’s data weaken, but pivotal plans are afoot

Cardiff Oncology's attempt to hit all subtypes of Kras-mutated colorectal cancer with its PLK1 inhibitor onvansertib is being tested in an ongoing second-line study, but the latest data cut makes for disappointing reading. Responses waned on last year, in confirmed and unconfirmed analyses alike. The company's massaging of the numbers also failed to impress investors, with the stock plunging 23% in early trade. A patient who improved from stable disease to an unconfirmed partial response after data cutoff was included in results presented to analysts last night, a PR that will not feature in a poster due to be presented at Asco-GI this weekend. Cardiff execs stressed that the data remained stronger than the “proof-of-concept” criteria set for this trial. This called for ORR of 20% and median PFS of at least six months – mPFS currently sits at 9.4 months, though this is an interim finding. They also pointed to responses across several subtypes of Kras mutation. Cardiff plans to move into phase 3 later this year, and Pfizer has first pass at any data as part of an equity investment made last year, but jittery biotech investors have clearly seen enough to fret about for now.

Onvansertib in Kras-mutant colorectal cancer: the evolving data from a phase 1/2 dose finding study
Announced Data cutoff Responses (ORR) Confirmed responses (ORR)
28 Apr 2020 (AACR) 24 Jan 2020 3/8 PR (38%) Unclear
17 Sep 2020 (Esmo) 4 May 2020 5/11 PR (45%) 4/11 PR (36%)
15 Jan 2021 (Asco-GI) 1 Nov 2020 5/12 PR (42%) 4/12 PR (33%)
12 Apr 2021 Unclear 7/18 PR (39%) 4/18 PR (22%)
8 Sep 2021 2 Jul 2021 12/32 PR (38%) 10/32 PR (31%)
2 Jul 2021 at RP2D 8/19 PR (42%) 7/19 PR (37%)
18 Jan 2022 (Asco-GI) 3 Dec 2021* 17/48; 1 CR, others PR (35%)*  13/48; 1 CR, others PR (27%)
  3 Dec 2021 at RP2D* 12/35; 1 CR, others PR (34%)* 10/35; 1 CR, others PR (29%)
RP2D=recommended phase 2 dose. *Data as presented by the company, including a patient who achieved a PR (from SD) after cutoff; data on the poster due to be presented at Asco-GI will not include this PR, so ORR will be lower. Source: company statements.
Source: Cardiff Oncology company presentation.

Asco-GI 2022 – Seagen keeps the faith in souped-up CD40 agonism

Do not write off CD40. Stimulating this target for oncology use has proved difficult, but companies are not giving up, though many have accepted that something more than a simple agonist approach might be needed. Seagen’s SEA-CD40 is a nonfucosylated CD40 agonist MAb, and phase 1 data just unveiled at the Asco-GI meeting show 44% overall response across two doses in 61 evaluable patients in a first-line pancreatic ductal adenocarcinoma cohort; median PFS and OS are 7.4 and 15.0 months respectively. It is difficult to parse SEA-CD40’s contribution, as the project was combined with Keytruda, Abraxane and gemcitabine, but Abraxane’s label cites ORR, mPFS and mOS of 23%, 5.5 months and 8.5 months, respectively, in combination with gemcitabine. SEA-CD40 recently moved into phase 2, as did Celldex’s fully human agonist CDX-1140, while new clinical entrants since Evaluate Vantage last analysed the CD40 field include Abbvie’s ABBV-927, Biontech/Genmab's GEN1042, Lyvgen’s LVGN7409 and Shattuck’s SL-172154. Discontinuations include ABBV-428 and Astrazeneca’s MEDI5083, while Roche recently canned selicrelumab in favour of RG6189, a bispecific that induces CD40 stimulation solely in the presence of FAPα and is now in a phase 1 Tecentriq combo trial.

Selected clinical assets targeting CD40 in cancer
Project Company Mechanism Clinical trial
Phase 2
APX005M/ sotigalimab Apexigen CD40 agonist MAb Melanoma and oesophageal/GEJ
CDX-1140 Celldex Therapeutics Fully human CD40 agonist MAb Pancreatic cancer
SEA-CD40 Seagen Nonfucosylated CD40 agonist MAb Combo trial
ABBV-927 Abbvie CD40 agonist MAb Pancreatic cancer
YH003 Eucure (Biocytogen) Humanised CD40 agonist MAb Toripalimab combo
Phase 1/2
Mitazalimab/ ADC-1013 Alligator Bioscience CD40 agonist MAb; J&J terminated deal Jul 2019 Pancreatic cancer
GEN1042 Biontech/Genmab CD40 & 4-1BB Duobody Solid tumours
Phase 1
FAP-CD40/ RO7300490 Roche FAPα-dependent CD40 agonist bispecific  Tecentriq combo
LVGN7409 Lyvgen Biopharma CD40 agonist MAb MonoRx & combo
SL-172154 Shattuck Labs CD40L-SIRPα fusion protein Ovarian and head & neck cancers
Source: Evaluate Pharma. Note: excludes non-oncology applications and CD40-blocking approaches for autoimmune diseases.

Roche and Ionis bring tominersen back from the dead

Roche is not the first company to persevere with a neuroscience project that previously looked dead and buried, but at least it is going about resurrecting the Huntington’s antisense asset tominersen in the right way. The project, licensed from Ionis, flunked the pivotal Generation HD1 study last year, but Roche now says it has seen a signal in a post-hoc analysis in young adults with a low disease burden. Instead of running another phase 3, or indeed seeking approval, Roche is now going back to phase 2, although details are scant. If the asset is to progress further Roche will need to provide reassurance about worrying findings in Generation HD1: tominersen-treated patients did numerically worse than the placebo group on several clinical measures, with the highest dose performing the worst. And tominersen’s phase 1/2 trial found increases in neurofilament light chain, a marker of neuronal injury; together, these results raise the possibility of toxicity. There is also the theoretical risk that knocking down healthy as well as mutant huntingtin protein might be harmful. Still, with no approved therapies for Huntington’s, and a couple of more recent disappointments, Roche looks justified in trying again.

Selected novel approaches in Huntington's disease
Project Company Description Status/trial details
Phase 3
Pridopidine Prilenia Therapeutics Sigma-1 receptor agonist Proof-HD, topline results due Q1 2023
Phase 2
ANX005 Annexon Bioscience Complement factor C1q antibody NCT04514367, interim data disappointed, full data due Q2 2022
SAGE-718 Sage Therapeutics NMDA receptor regulator NCT05107128 completes Dec 2024
Branaplam Novartis Small-molecule RNA splicing modulator Vibrant-HD completes Feb 2025
PTC518 PTC Therapeutics Small-molecule RNA splicing modulator PIVOT-HD to start Q1 2022
Tominersen Roche/Ionis Huntingtin antisense oligonucleotide Generation HD1 study failed; ph2 to start in younger pts with lower disease burden
Pepinemab (VX15) Vaccinex Semaphorin 4D antibody Ph2 Signal study failed in Sep 2020; Vaccinex looking for partner for ph3
Phase 1/2
AMT-130 Uniqure Gene therapy silencing huntingtin gene NCT04120493, initial data disappointed; full data on cohorts 1 & 2 due H1 2023
WVE-003 Wave Life Sciences* Stereopure huntingtin SNP3 antisense oligonucleotide Select-HD completes Dec 2022
*Takeda has option to co-develop and co-commercialise. Source: Evaluate Pharma &

Reneuron crashes out of retinitis pigmentosa

Reneuron had hoped to reinvent itself as a retinitis pigmentosa player, backed by phase 2 data in a handful of patients. Now this chapter of the company’s history has come to a sorry end, after disappointing results in more subjects spurred the group to deprioritise its human retinal progenitor cells (hRPCs). Seven patients treated with a high dose of two million cells had “very limited efficacy”, while surgical complications also caused concern. Signs are not great for the low dose, one million cells, either: the group had previously disclosed a 9.9-letter improvement in visual acuity among seven evaluable patients at one year, but said today that the effect waned thereafter. Reneuron believes that a new phase 2 trial of the low dose could pinpoint subgroups of patients with a higher and more durable response, but is looking to license the asset out. Whether anyone will bite is another matter, although Jcyte signed a $50m ex-US deal with Santen in 2020 despite its stem cell project, jCell, flunking a phase 2b study. Jcyte says it has found a suitable population for its pivotal trial. Reneuron, meanwhile, will focus on its exosome technology, but unimpressed investors sent its stock down 38% this morning.

The rise and fall of Reneuron's hRPCs in retinitis pigmentosa
Date Event
Feb 2019 Promising data from first 3 pts receiving 1m cell dose in phase 1/2 trial (Reneuron eyes a partner with new stem cell data, February 20, 2019)
Oct 2019 Data in 8 pts receiving 1m cell dose disappointed; 2 pts had procedure-related vision loss (Reneuron’s reinvention falters, October 2, 2019)
Jun 2020 Regulatory approval to expand study to include higher 2m cell dose
Nov 2020 Data showing 9.9-letter improvement in 7 pts receiving 1m cell dose at 12 months (incl pts with successful surgical procedure only)
Jun 2021 Study put on hold to investigate presumed case of bacterial endophthalmitis in pt receiving 2m cell dose
Oct 2021 Regulatory approval to restart study
Jan 2022 "Limited efficacy" in 7 pts receiving 2m cell dose, plus waning effect after 12 months in 7 pts receiving 1m cell dose; Reneuron to seek licensing partners
Source: company releases.

Groups slam Philip Morris, but the Vectura deal has precedent

Six respiratory health societies have slammed the recent takeover by Philip Morris of the UK drug delivery biotech Vectura, but the move, seeking to prevent tobacco companies from benefiting from such acquisitions, comes somewhat late to the game. Friday’s joint statement bans employees of tobacco-owned companies from featuring data in journals or meetings run by the European Respiratory Society, American Thoracic Society, International Union Against Tuberculosis and Lung Diseases, Asian Pacific Society of Respirology, Asociación Latino Americana De Tórax, and Global Initiative for Asthma. No products of tobacco-owned companies will be promoted at the groups’ future scientific meetings or co-sponsored conferences. This mirrors a similar stance taken by the British Thoracic Society, which last month ran an editorial entitled “Vectura and Philip Morris: the leopard has not changed its spots”. This could discourage moves such as BAT setting up a biotech business, Kbio, to use a plants to develop treatments for rare and infectious diseases. However, tobacco companies like Japan Tobacco have a long history of investing in drug development. Philip Morris itself has held a stake in Medicago, a Canadian player seeking to enter Covid vaccine business, since 2008, and last year bought Fertin Pharma and Oti-Topic too.

A history of drug development: selected projects with tobacco company involvement
Project Indication Status Current owner Originator
Vitekta (elvitegravir) HIV Marketed Gilead Sciences Japan Tobacco
Mekinist Melanoma Marketed Novartis Japan Tobacco
Enaroy (enarodustat) Chronic kidney disease Marketed Torii Pharmaceutical Japan Tobacco
Flutiform Asthma Marketed Philip Morris Skyepharma
Enerzair Breezhaler Asthma Marketed Novartis/Philip Morris Vectura
AirFluSal Forspiro COPD/asthma Marketed Novartis/Philip Morris Vectura
Ultibron Neohaler COPD Marketed Novartis/Philip Morris Vectura
Hualan Influenza vaccine Marketed Hualan Biological Engineering Medicago (20% owned by Philip Morris)
MT-2271 Influenza vaccine Filed Mitsubishi Chemical Medicago (20% owned by Philip Morris)
MT-2766 Covid vaccine Filed Mitsubishi Chemical Medicago (20% owned by Philip Morris)
Dalcetrapib Hyperlipidaemia Phase 3 Dalcor Pharmaceuticals Japan Tobacco
MK-5442 Osteoporosis  Discontinued Merck & Co Japan Tobacco
MEDI-570 Cancer Discontinued Astrazeneca Japan Tobacco
Bradanicline Schizophrenia Discontinued Catalyst Biosciences Targacept (RJ Reynolds spin-out)
TC-6987 Asthma Discontinued Catalyst Biosciences Targacept (RJ Reynolds spin-out)
Source: Evaluate Pharma.

Glaxo is right to hold out for a better offer

As one of the largest consumer health businesses in the world, Glaxosmithkline’s over-the-counter unit was always likely to attract corporate rivals. Therefore the most surprising aspect of this weekend’s news – that Unilever had bid three times for the business – was that interested parties took so long to show their hands. With a value of at least £50bn ($68bn) not many could afford it, of course, and it is far from certain that Unilever will be able to offer sufficient cash to persuade the Glaxo board to veer from its long-stated strategy. The spin-off into a separately listed company, around mid-year, will proceed as planned, Glaxo insists. Many large institutional investors have expressed enthusiasm for holding the new business's shares, and several analysts have declared the offer lowball; the FT reported this weekend that offers in the region of £60bn would warrant more serious consideration. Such a sum would provide Glaxo with serious firepower to rebuild its drugs business, but a trade sale would take many more months to consummate than the spin-off, which has been years in the making and is now just around the corner. Glaxo is right to hold out for an offer it cannot refuse.

Jaks finally crack atopic dermatitis

It took a while, but the FDA has approved two Jak inhibitors, Pfizer’s Cibinqo and Abbvie’s Rinvoq, in atopic dermatitis. Given the toxicity concerns linked with this class, it is not surprising that Jaks are only recommended for patients who have failed on or cannot take other drugs. But, in a bonus for the developers, the FDA has waved through multiple doses of both products, scotching fears that only low doses would get the nod. The next question is whether the drugs can live up to their sales expectations. At the JP Morgan conference last week Abbvie forecast Rinvoq revenues of over $7.5bn across all indications in 2025, a downgrade from its previous prediction of over $8bn. That group has much more riding on its Jak than Pfizer, which recently dialled down its commitment to the class and focused its entire JP Morgan presentation on mRNA. Although the latest green lights are probably the best that the companies could have hoped for under the circumstances, neither drug looks set to challenge Dupixent’s dominance in atopic dermatitis. Meanwhile, Lilly’s Olumiant, which has had its own worries with side effects, is still awaiting an FDA decision in the disease.