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Msg  9405 of 10139  at  4/1/2022 5:09:47 PM  by


 In response to msg 9403 by  mymorningsong
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ROR1 is being pursued using a number of technologies. Since these are early days, coming to conclusions about the outcome of a trial is premature, as the construct or trial design in pioneering technologies can introduce delays. 
This is true across the industry, but listening to Rupert Vesey articulate this point may be helpful.
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No regrets as Lyell prepares for its first clinical trial

The preclinical company pulled off a giant flotation, and though its stock has since slumped it now has several years’ cash to play with.


With the IPO class of 2021 looking like one of the worst in years for post-float performance, how early a biotech should go public has come under the investor spotlight. A case in point is Lyell Immunopharma, which without ever conducting a clinical trial raised $425m in an IPO at a $4bn valuation, but which now trades at one third of that.

The company has taken a modality-agnostic approach to overcoming current cell therapies’ limitations, but arguably its biggest selling point was the presence of the Juno founder Hans Bishop as a director. So, in hindsight, was it a mistake for Lyell to list so early? “I don’t regret it for a moment,” Liz Homans, the group’s chief executive, tells Evaluate Vantage.

“Our peer group has lost 60-80% of its value, and we’re at the 70% range. We’re in good company, and we recognise that there’s a market dynamic going on that’s beyond Lyell,” she adds. “When I think about our funding and our bank balance right now I don’t think [floating] was a bad thing to do at all.”

No funding threat

The funding will allow Lyell to get on with development without stressing about its next cash call. The clinical focus is a pipeline comprising Car-T as well as TILs (tumour-infiltrating lymphocytes), and a separate engineered TCR project is the subject of a deal with Glaxosmithkline.

Though all three are cell therapies, the different modalities do not make comfortable bedfellows ideologically. But here, too, there are no regrets from Ms Homans, who had interestingly earlier been a senior exec at Roche, a company that steadfastly refused to go into cell therapy.

She says the most important point is “getting the cells right” and improving their functionality. Lyell’s technology has two pillars, to overcome two of the most important barriers for cell therapies – T-cell exhaustion and inability to self-renew. Since these are common problems it makes sense to apply the fixes to all three modalities.

The first signs of whether this has legs could come next year with data from a study of the Ror1-directed Car-T therapy LYL797 in Ror1-positive cancers, including triple-negative breast and NSCLC. Lyell is focused on generating “real data” from this first-in-human trial rather than dribbling findings out piecemeal.

LYL797 uses both of Lyell’s ex vivo technology approaches. The T cells are modified to make them overexpress the protein c-Jun and thus resist exhaustion, an approach Lyell calls Gen-R; and they are “reprogrammed”, possibly by triggering signalling pathways including WNT–β-catenin, SMAD, Stat3 and Foxo, to give them durable stemness, meaning the ability to self-renew and generate potent daughter cells (Epi-R).

It is these two technologies, plus an EGFR tag to track the cells, that make LYL797 unique, as the binding domain and construct are derived from work at Fred Hutch that separately lies behind Bristol Myers Squibb’s JCAR024. On the question of possible IP infringement, Ms Homans states: “We’re comfortable that we have all our inventions and constructs covered appropriately.”

Lyell's pipeline
ProjectDescriptionTech used & statusNote
LYL797Anti-Ror1 Car-TGen-R & Epi-R (ph1 starting patient screening in Q1 2022)Bristol Myers Squibb developing an anti-Ror1 Car-T therapy, JCAR024, apparently based on the same rabbit-derived binder
LYL845Polyclonal TILsEpi-R (IND filing H2 2022)Targeting solid tumour use
LYL132 Anti-NY-ESO-1 eTCREpi-R (IND cleared)New versions of Adaptimmune's letetresgene autoleucel, partnered with Glaxosmithkline
UnnamedAnti-NY-ESO-1 eTCRGen-R (preclinical)
Source: company information.

The still preclinical TIL asset LYL845 aims to address the struggles others have had to get TILs to work in settings beyond melanoma, and use of Epi-R gives LYL845 a proprietary step, something many competitors lack and something that could improve Lyell's commercial prospects.

Ms Homans says there is lots of room to improve on efficacy, which she reckons is hampered by many TIL clones being poorly functional. Epi-R could help overcome this, and the tech also preserves LYL845’s polyclonality, which she says is key for specificity; Gen-R might be “stacked on” to this asset in future, though this is a “bit more difficult from a process perspective”.

Meanwhile, Lyell’s TCR involvement centres on the deal with Glaxo, which has a separate alliance to develop Adaptimmune’s lete-cel, an NY-ESO-1-directed asset in a pivotal phase 2 trial. Glaxo is investigating the addition of Gen-R and/or Epi-R to lete-cel to improve efficacy, work that could be threatened by Hal Barron’s impending departure, though Ms Homans insists that the deal does not hinge on Mr Barron.


Lyell clearly has plenty to be getting on with, and the fact it was able to float when it did has given it a remarkable cash pile – $936.4m at the end of last September, to be precise. Even more remarkable is that it plans to burn through all of this in little over three years.

“I’d love the stock price to go up,” says Ms Homans. “But it’s not something that's going to cause consternation for us, because we’re not looking to fund any time soon.”

Merck inks $2.8B VelosBio to snag anti-ROR1 ADC
by Nick Paul Taylor  Nov. 5, 2020

Merck has struck a deal to buy VelosBio for $2.75 billion. The takeover will give Merck control of an antibody-drug conjugate (ADC) that caused objective responses in 80% of previously treated diffuse large B-cell lymphoma (DLBCL) patients in a small clinical trial.

VelosBio’s ADC, VLS-101, targets ROR1, a tyrosine-protein kinase transmembrane receptor thought to be overexpressed in multiple cancers. The target has attracted a small clutch of companies, including Bristol Myers Squibb’s Juno Therapeutics, but there are limited clinical data to show it works as hoped.

Merck has swooped in to buy VelosBio in the run up to the presentation of data that will start the process of validating the target. At the American Society of Hematology's annual meeting next month, VelosBio will share data from a phase 1 trial that gave VLS-101 to previously treated hematological cancer patients.
Boehringer inks $1.5B NBE buyout, joining Merck in new cancer race
Nick Paul Taylor  Dec. 10, 2020
Boehringer Ingelheim has struck a deal to buy NBE-Therapeutics for €1.2 billion ($1.5 billion) to add a ROR1-directed antibody-drug conjugate (ADC) to its pipeline. The deal comes one month after Merck agreed to pay $2.8 billion to acquire VelosBio for its anti-ROR1 ADC.

Basel-based NBE is advancing a pipeline of ADCs led by NBE-002, an ADC directed at tyrosine-protein kinase transmembrane receptor ROR1. Merck put the target on the map last month when it struck its deal to buy VelosBio. The back-to-back deals mean the only two clinical-phase anti-ROR1 ADCs listed on have been snapped up by large pharma companies in a matter of weeks.

CStone Pharmaceuticals and LegoChem recently partnered on a preclinical-stage anti-ROR1 ADC, and other players are applying different modalities to the target, including Bristol Myers Squibb through a CAR-T. But Boehringer and Merck’s biotechs are making the early running in the ADC space.

VelosBio is the more advanced of the two companies, having recently begun enrolling subjects in a phase 2 solid tumor trial. NBE began a phase 1/2 trial of its rival asset over the summer. The target is overexpressed in multiple cancers, giving Boehringer and Merck chances to use the acquired ADCs to tackle tumors such as triple-negative breast cancer and non-squamous non-small cell lung cancer.

The potential for NBE-002 to improve outcomes in patients with those hard-to-treat cancers is just part of the appeal of the NBE buyout. Boehringer framed the takeover as a way to gain a platform that can support a portfolio of ADCs suitable for use as monotherapies and in combination with its cancer immunology assets. NBE’s site in Basel will become part of Boehringer’s R&D network.

Having embarked on an oncology strategy focused on hard-to-treat solid tumors, Boehringer saw the need for drugs that induce tumor cell death. The recent progress of ADCs has shown the potential for the modality to cause cell death without exposing patients to intolerable toxicity.

Boehringer and Merck are part of a growing group of large biopharma companies to bet on ADCs. Gilead Sciences struck the landmark deal for the modality earlier this year when it bought Immunomedics for $21 billion to add anti-Trop-2 ADC Trodelvy to its portfolio.

The Gilead deal is the biggest of a series of ADC agreements struck in the second half of 2020. Merck paid $1.6 billion upfront, including a $1 billion equity investment, to partner with Seagen before going on to buy VelosBio. And AstraZeneca agreed to pay Daiichi Sankyo $1 billion, plus up to $5 billion in milestones, to secure rights to a rival to Trodelvy.

Boehringher said the total transaction value for the NBE acquisition is €1.18 billion and includes contingent clinical and regulatory milestones. The deal follows the May takeover of Northern Biologics and the July 2019 acquisition of AMAL Therapeutics, both of which expanded Boehringer’s immuno-oncology pipeline.


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