Snippets

Vantage Snippets are short summaries of breaking news stories.

Cholesterol “win” does Ionis and Pfizer a fat lot of good

Investors were unconvinced by yesterday’s apparent mid-stage success with Ionis and Pfizer’s cholesterol-lowering project vupanorsen. On the face of it the anti-ANGPTL3 antisense did what it needed to do in the dose-ranging Translate Timi 70 trial, statistically lowering non-HDL cholesterol at all doses tested versus placebo at week 24. However, Pfizer’s commitment to the asset is far from clear: the big pharma left Ionis to report the results, and also seemed lukewarm about further development, only saying it was reviewing the findings before determining next steps. In another potential red flag, the study found liver enzyme elevations, primarily at the highest doses tested, as well as increases in hepatic fat fraction at “certain doses”. Ionis said there were no Hy’s law cases. More information is needed, but there must now be fears that the group might not be able to find a therapeutic window for vupanorsen; Ionis’s stock sank 2% yesterday and another 2% after hours. The liver findings could also throw doubt on ANGPTL3 as a target. However, the pivotal trial of Regeneron’s Evkeeza in homozygous familial hypercholesterolaemia was not marked by liver enzyme worries, something that could provide solace to other developers of anti-ANGPTL3 projects, though of course Evkeeza is a MAb, unlike the other projects in this space. 

ANGPTL3 modulators in clinical development for cardiometabolic indications
Project Company Description Indication  Trial details
Approved
Evkeeza (evinacumab) Regeneron Anti-ANGPTL3 MAb HoFH Elipse, 49-point reduction in LDL-C vs SOC 
Phase 2
Vupanorsen (AKCEA-ANGPTL3-LRx/ PF-07285557) Ionis/Pfizer ANGPTL3 antisense oligonucleotide Dyslipidaemias Translate Timi 70, "statistically significant" reduction with all dose vs placebo at week 24
ARO-ANG3 Arrowhead Anti-ANGPTL3 RNAi therapeutic Dyslipidaemias Arches-2, completes Oct 2022
Phase 1
LY3561774 Lilly/Novo (Dicerna) Anti-ANGPTL3 small interfering RNA Dyslipidaemias NCT04644809, completes Apr 2022
HoFH=homozygous familial hypercholesterolaemia. Source: Evaluate Pharma & clinicaltrials.gov.

Kura death deals novel leukaemia mechanism a blow

Kura dealt the nascent menin inhibition space a blow today with news of a patient death in the phase 1b Komet-001 trial of KO-539. The study has now been paused. The cause of the death was probably differentiation syndrome, a potentially life-threatening complication seen with so-called differentiation agents used to treat various leukaemias. Differentiation syndrome is “absolutely a class effect” of menin inhibitors, Kura’s chief executive, Troy Wilson told analysts on a call today, describing it as “part and parcel of this mechanism of action”. Other cases of DS seen with menin inhibitors have been mild and manageable, he said, adding that the patient had very extensive disease, having failed four prior treatments. But the fact that mitigation strategies for DS were already in place, yet the death still happened, is concerning; that the patient was being treated at the lower of two doses is another worry. Kura remains committed to menin inhibition, executives insisted, but at the very least this means a delay for KO-539, and Kura's stock fell 17% this morning. Others working in this space will be looking on nervously, particularly Syndax, which has had its own problems with the menin contender SNDX-5613. 

Trials of the menin inhibitors: a nascent pipeline
Project Company Trial details 
Early clinical 
KO-539 Kura Oncology Ph1/2; 90 pts, AML, on clinical hold (NCT04067336)
SNDX-5613 Syndax  Ph1/2; 186 pts, AML, primary completion Jul 2022 (NCT04065399)
DS-1594 Daiichi Sankyo Ph1/2; 122 pts, AML & ALL, primary completion Nov 2022 (NCT04752163)
JNJ-75276617 Johnson & Johnson Ph1; 110 pts, AML & ALL, primary completion Dec 2023 (NCT04811560)
Preclinical
BMF-219 Biomea Fusion IND approved Sep 2021
Source: Evaluate Pharma & clinicaltrials.gov.

Arrowhead finds its target with Glaxo Nash deal

The RNAi specialist Arrowhead Pharmaceuticals is on a run in fatty liver disease, yesterday striking a $120m up-front licensing deal with Glaxosmithkline for the Nash candidate ARO-HSD. Interest in the molecule, which targets HSD17B13, has been growing since Arrowhead’s presentation at this year’s AASLD meeting, where ARO-HSD showed reductions in several biomarkers for Nash, including HSD17B13, ALT and AST proteins. The deal, however, highlights the wider interest in RNA therapies. Only last week Arrowhead revealed that an October 2018 deal with Johnson & Johnson had yielded JNJ-75220795, an siRNA in a phase 1 Nash study, and earlier this month Novo Nordisk shelled out $3.3bn for Dicerna, to get its hands on the group’s RNAi technology for diseases including Nash. For its money Glaxo will get the exclusive right to develop ARO-HSD globally, except in China. This is Glaxo’s first foray into Nash, marking a high-risk gamble for the company given the numerous failures in this space. And, while ARO-HD might be a relatively low-value investment, with activist investors circling any more failures in Glaxo’s lacklustre pipeline will only increase the pressure on management.

Recent Arrowhead RNA deals
Deal date Product Company Upfront payment ($m) Therapeutic focus Phase
Nov 2021 ARO-HSD Glaxosmithkline 120 RNAi therapy for non-alcoholic steatohepatitis 1/2
Jun 2021 ARO-XDH Horizon Therapeutics 40 RNAi therapy for uncontrolled gout Pre-clinical
Oct 2020 TAK-999 Takeda 300 RNAi therapy to treat alpha-1 antitrypsin-associated liver disease 2
Apr 2018 JNJ-75220795 Johnson & Johnson 175 siRNA therapy for non-alcoholic steatohepatitis 1
Source: company releases, Evaluate Pharma.

Ash 2021 late-breakers enable neat comparisons

The Ash late-breaker abstracts, just unveiled, mean that a direct cross-trial comparison of three approved Car-T therapies in second-line lymphoma will be possible after all. Breyanzi’s Transform study and Yescarta’s Zuma-7 had already featured in the meeting’s main programme, and now Kymriah’s failed Belinda study has been confirmed as a late-breaker; no doubt much of the focus will be on trial differences and baseline imbalances. A separate neat comparison will be possible for Sanofi/Alnylam’s delayed haemophilia A and B RNAi project fitusiran, which secured a plenary spot for its Atlas-INH trial in patients with inhibitors. Today it became apparent that Atlas-A/B, in those without, will feature at a late-breaker. While both studies comfortably hit statistical significance in terms of annualised bleeding rate the spotlight will be on adverse events, which had prompted Sanofi to investigate a lower dose of fitusiran. Finally, Roche’s attempt to move Polivy into front-line lymphoma will be scrutinised with full data from the Polarix trial, earlier touted as the first in two decades to show improved PFS in front-line disease. The abstract suggests that the effect is modest, and moreover there is no benefit in overall survival.

Selected Ash 2021 presentations
Project Mech Company Trial Abstract Detail
Car-T therapy in 2nd-line B-cell lymphoma
Yescarta CD19 Car-T Gilead Zuma-7 2 (plenary) Median EFS 8.3mth vs 2.0mth for SoC (HR=0.398; p<0.0001)
Breyanzi CD19 Car-T Bristol Myers Squibb Transform 91 Median EFS 10.1mth vs 2.3mth for SoC (HR=0.349; P<0.0001)
Kymriah CD19 Car-T Novartis Belinda LBA-6 Median EFS 3.0mth vs 3.0mth for SoC (HR=1.07; p=0.69)
Haemophilia A & B
Fitusiran Antithrombin RNAi Sanofi/Alnylam Atlas-INH 4 (plenary) Pts with inhibitors: ABR 1.67 vs 18.07 for on-demand BPA (p<0.0001); 17.1% rate of serious TEAEs (NB old dosing regimen)
Atlas-A/B LBA-3 Pts without inhibitors: ABR 3.1 vs 31.0 for on-demand factors (p<0.0001); 6.3% rate of serious TEAEs (NB old dosing regimen)
1st-line B-cell lymphoma
Polivy CD79B ADC Roche Polarix LBA-1 mPFS HR=0.73 for Polivy-R-CHP vs R-CHOP (p<0.02); no difference in OS (HR=0.94, p=0.75)
Note: ABR=annualised bleeding rate; BPA=bypassing agents. Source: Ash.

Vifor plumps for a double acquisition

Following the failure of two of Vifor’s partnered assets in just over a year, the group needed to plug the gaps in its pipeline. It has opted to do so via two buyouts of companies looking at chronic kidney disease, complimenting Vifor’s tight focus. The Spanish group Sanifit has been taken out for €205m ($231m), with potential milestones of up to €170m and tiered royalties. Vifor will get full global rights to Sanifit’s thrice-weekly intravenous project SNF472, which it calls a first-in-class inhibitor of vascular calcification. The asset is intended for the treatment of calcific uremic arteriolopathy (CUA) and peripheral artery disease (PAD) in patients with end-stage renal disease, and results from an ongoing phase 3 CUA study could come next year. Meanwhile, patients with earlier-stage kidney disease could benefit from INS-3001, a once-daily subcutaneous treatment for those with aortic valve stenosis and PAD that is the flagship asset of Inositec, the other company Vifor bought today. At SFr20m ($22m) plus potential clinical earn-out payments, the Inositec deal is much smaller than Sanifit – understandably, as INS-3001 is not yet in the clinic.

Vifor's pipeline
Product Status Vifor rights Partner
Vadadustat Filed for anaemia in CKD in dialysis and non-dialysis patients, but failed in the latter population in Sep 2020 US profit share Akebia
SNF472  274 pt ph2b Calipso trial hit 2019; ph3 CUA trial data expected mid-2022; ph2 in PAD in patients on dialysis planned for 2022 Global Acq via Sanifit
Sparsentan Data from 371pt Duplex trial Ph3 trial in focal segmental glomerulosclerosis expected 2022 and from 380pt Protect Ph3 trial in IgA nephropathy in 2023 Europe, Australia and New Zealand Travere Therapeutics
Vamifeport (VIT-2763) 80 pt ph2 in beta-thalassaemia ongoing; ph2 in sickle cell disease completed Global  
ANG-3777 Data from ph2 study in AKI associated with cardiac surgery expected this year; ph3 in kidney transplant patients at risk for delayed graft function failed Oct 2021 Global ex China, Hong Kong, Macau & Taiwan Angion Biomedica
INS-3001 Ph1 imminent; ph2 in non-dialysis CKD patients with PAD and separately in AVS planned for 2023 Global Acq via Inositec
CKD = chronic kidney disease; AKI = acute kidney injury; CUA = calcific uremic arteriolopathy; AVS = aortic valve stenosis. Note: excludes approved and marketed drugs. Source: Evaluate Pharma, clinicaltrials.gov & company websites.

Molecular Partners' Covid-19 therapy proves inactiv

Ensovibep has become the latest Covid-19 treatment candidate to crash out of the NIH-sponsored Activ-3 basket trial, wiping 34% off Molecular Partners’ share price. A planned futility analysis of the cohort evaluating ensovibep, a darpin Molecular Partners licensed to Novartis, concluded that enrolment should be stopped. Activ-3 is looking at potential therapies for hospitalised patients, but no agent in the trial has yet succeeded. The study's clinicaltrials.gov entry was also edited this month to state that Astrazeneca’s MAb combo AZD7442 was no longer being administered either, but no explanation has been offered for this. As a result, Pfizer’s IV antiviral PF-07304814 (lufotrelvir) is the only project still standing in Activ-3, at least until any new ones are added. There is some comfort for Molecular Partners in that Activ-3 backed ensovibep’s safety profile, which was consistent with the standard of care, Gilead’s Veklury, the company said. Ensovibep is in a separate phase 2/3 trial, Empathy, in Covid-19 outpatients, with interim data on the first 400 expected in early 2022. But in this niche Pfizer’s Paxlovid, an oral drug related to lufotrelvir, has set a standard that will be very hard to beat – as Molecular Partner’s shareholders clearly understand. 

Activ-3: NIH-funded phase 3 trial in hospitalised patients
Company Project  Description Outcome 
Lilly/Abcellera Bamlanivimab Infused MAb 326 pt arm closed for futility Oct 2020
Vir Biotechnology Sotrovimab Intramuscular or infused MAb 344 pt arm closed for futility Mar 2021
Brii Biosciences BRII-196 and BRII-198 Infused MAb combination  343 pt arm closed for futility Mar 2021
Molecular Partners  Ensovibep Infused antiviral 470 pt arm closed for futility Nov 2021
Astrazeneca AZD7442 (tixagevimab + cilgavimab) Infused MAb combination  Arm closed Nov 2021, reason unclear
Pfizer Lufotrelvir Infused antiviral Arm ongoing
All patients received a backbone of Gilead's Veklury as standard of care. Source: clinicaltrials.gov.

Fate buries bad data and moves on

It is just as well that the NK cell projects FT500 and FT516 were not a huge part of Fate’s investment case, because clinical trial results revealed quietly yesterday suggest them to be commercially unviable, at least in solid tumours. Perhaps this too explains Fate’s decision to sneak the data into an obscure investor presentation rather than announce them more broadly. The results for FT500, unmodified NK cells, show three remissions in eight patients, while FT516, an NK cell project with a high-affinity CD16 receptor, has yielded just one PR in nine. Not only is this efficacy poor, the fact that the cells were given with an anti-PD-1 MAb as well as IL-2 makes the data uninterpretable. The enrolment targets for the PD-1 combo studies of FT500 and FT516 have now been reduced, respectively, from 76 to 37 and from 27 to 12, according to clinicaltrials.gov. Fate called FT500 and FT516 “pilot programmes” that “started the journey”, and its focus is switching to FT538, an NK construct with additional CD38 knockout. Meanwhile, investors’ attention remains on a key clinical update for the Car-NK project FT596, due to be presented at Ash next month.

This is a corrected version of an earlier story.

Source: Fate presentation.

SITC 2021 – Iovance can’t catch a break

Already reeling from a double delay and the possible non-approvability of its TIL cell therapies, Iovance now has disappointing clinical data to contend with. Presentation at the SITC meeting of results from an NSCLC cohort of a multi-tumour basket study of the company’s lifileucel prompted a 10% selloff on Friday, as investors panicked about a surprising lack of durability. The six remissions previously reported in 24 evaluable patients are down to just two after one previously disclosed relapse was followed by two more disease progressions and one death. Stifel analysts said this suggested three to four months’ response duration – worse than in melanoma, where a US filing is now due next year. A separate cervical cancer filing looks doubtful after Keytruda’s accelerated label was formalised with a confirmatory study in October. A second SITC presentation on Sunday concerned lifilucel/Keytruda combos from two clinical trials in checkpoint inhibitor-naive patients, but this failed to stem the bleeding. ORRs of 60% were reported in melanoma, 57% in NSCLC and 39% in head and neck cancer, with 12 of 19 remissions ongoing at data cutoff. Though this looked better on a cross-trial basis than Keytruda monotherapy Iovance fell another 7% yesterday.

Six NSCLC responses to lifileucel become two. Source: SITC.

AHA 2021 – Merck’s oral cholesterol lowerer could heap more misery on Esperion

Merck & Co might have succeeded where others have failed and developed an oral PCSK9 inhibitor. Data presented at the American Heart Association meeting today, although early, put the cholesterol-lowering abilities of Merck’s project, MK-0616, on a par with injectable PCSK9 MAbs from Amgen and Sanofi/Regeneron and Novartis’s longer-lasting RNAi therapy Leqvio. The results could also represent another nail in the coffin for Esperion; that group has struggled to sell its oral therapy Nexletol, which it had positioned between statins and PCSK9s, arguing a convenience advantage over the latter. However, cholesterol lowering of 15-25% with Nexletol alone, or around 38% when combined with ezetimibe, pales against around 65% LDL-C lowering with Merck’s agent in phase 1. Merck’s Douglas Johns, presenting the MK-0616 results, admitted that larger studies would now be needed. But he added that availability of an oral agent could extend the reach of PCSK9 inhibitors, whose uptake has been limited. Still, one reason for lack of use has been the high cost of the MAbs – Mr Johns told a press briefing that it was too early to talk about MK-0616's price tag, but that this was something Merck was taking “very seriously”. 

LDL lowering with the PCSK9 inhibitors
Product/project Company Description LDL lowering
MK-0616 Merck & Co Oral PCSK9 ~65%
Repatha Amgen SC PCSK9 MAb 55%*
Praluent Sanofi/Regeneron SC PCSK9 MAb 58%**
Leqvio (inclisiran) Novartis SC PCSK9 RNAi therapy 50-52%^
All on top of background statins; Repatha, Praluent & Leqvio data placebo-adjusted; SC=subcutaneous; *Descartes; **Odyssey Long Term; ^Orion-10 & 11. Source: product labels, clinicaltrials.gov & NEJM article.

AHA 2021 – Amarin not prepared in Covid battle

Amarin is officially two for two in its failure to prove that its only product, Vascepa, has any impact on reducing infections, hospitalisation rates or death from Covid-19. Today it was the turn of the Prepare It-2 trial to disappoint. Results presented at the AHA conference showed that, among non-hospitalised Covid patients, there was no significant difference with Vascepa versus placebo on the primary endpoint, Covid hospitalisations or death. However, there was a numerical improvement with Vascepa. A generous interpretation might be that Prepare It-2 was underpowered. But confirmation of any signal would require Amarin to conduct a much larger trial, a difficult endeavour given rising vaccination rates and improved treatment options. Today’s data follow a flop in the Prepare It-1 trial, which showed that Vascepa did not prevent healthcare and public workers at high risk of Covid from catching the virus. Success in any of the trials would have been helpful for Amarin, which this year lost a battle to protect patents on Vascepa. With no seeming Covid boost on the horizon, and US competitors already on the market, Amarin will have to rely on increasing Europe sales, but a recent launch in Germany has disappointed.

Prepare-IT slide
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