Novartis dumps 2nd bispecific from $2.6B Xencor pact

 Novartis has hacked off another piece of its $2.6 billion deal with Xencor, terminating its rights to a CD123xCD3 blood cancer bispecific that had a troubled time in early clinical development.

Xencor granted Novartis ex-U.S. rights to CD123xCD3 candidate vibecotamab and a second bispecific antibody back in 2016. Novartis dumped the other drug candidate, XmAb13676, in 2019, but it stuck by vibecotamab as Xencor battled through a partial clinical hold triggered by two patient deaths that were considered at least possibly related to the bispecific and went on to post phase 1 data.

Now, Novartis is cutting its ties to vibecotamab. The Swiss Big Pharma communicated its decision to Xencor in August and will complete the termination of its rights in February, when a phase 1 study of vibecotamab is scheduled to wrap up. Novartis will cover its share of the costs until August 2022.

The action marks the end of active development of vibecotamab, with Xencor opting against taking the candidate forward itself. The termination of work on vibecotamab marks another blow to hopes that CD123 offers a way to improve outcomes in patients with acute myeloid leukemia (AML).

CD123 is upregulated in AML, leading drug developers to deploy a range of modalities against the target. Companies including CSL and Johnson & Johnson trialed anti-CD123 monoclonal antibodies only to stop work in response to lackluster efficacy. Seagen dropped a CD123 antibody-drug conjugate in response to safety concerns, but ImmunoGen is still applying the modality to the target.

Multiple groups including Novartis, Sanofi and J&J identified bispecifics as a better way to go after CD123, but the programs have been beset by problems. J&J’s Genmab-partnered candidate suffered clinical holds in phase 1. The study wrapped up earlier this year. Genmab still lists the drug in its pipeline, but further clinical development is yet to start. Sanofi terminated a trial of its drug this year.

Aptevo Therapeutics and MacroGenics have active clinical trials of CD123 bispecifics, but the field has thinned considerably, denting hopes that the modality is the key to unlocking the therapeutic power of the target.   

For Xencor, Novartis’ decision to ditch vibecotamab ends collaboration on the two headline assets in the 2016 agreement. However, the agreement could yet spawn a success, with Novartis selecting a candidate developed under another part of the deal in June. Novartis is fully responsible for taking the candidate forward.

https://www.fiercebiotech.com/biotech/novartis-dumps-second-bispecific-from-2-6b-xencor-pact-dealing-further-blow-to-hopes-for

Mirati gets a combo coup

 Amgen has sewn up the later-line non-small cell lung cancer Kras inhibitor segment. But Mirati investors saw reasons to be cheerful after first-line data from a combination of its contender adagrasib plus Keytruda beat expectations. 

It is not yet time to call a winner in first-line NSCLC: Amgen will report its first combo data in the same setting in the first half of next year. Analysts are already talking up adagrasib’s potential differentiation, but even if they turn out to be right Mirati will have to improve its execution if it is to compete. 

At least the group now has a decent chance. The data, released after hours yesterday during Mirati’s third-quarter call, come from one cohort of the phase 1/2 Krystal-1 trial. One reason to be cautious is the small number of patients involved – just seven evaluable subjects receiving adagrasib 400mg plus Keytruda. 

But among this group Mirati reported four confirmed partial responses. A fifth patient had 49% tumour regression that allowed surgery, and a response was later confirmed.

This 57% overall response rate – 71% if the final patient is counted – is above the 50% analysts had hoped for. It also exceeds the 48% ORR seen with Keytruda plus chemo in the Keynote-189 trial, in non-squamous disease, cited by Mirati. However, Stifel analysts noted that Keynote-407, a Keytruda chemo combo trial in squamous NSCLC, showed a 58% ORR. 

PD-L1 status and toxicity 

There are a couple of other caveats about the latest findings. For one, analysts had hoped to see data on how the adagrasib/Keytruda combo performed according to patients’ PD-L1 status, but Mirati did not give such details, saying this was not measured when patients joined Krystal-1. 

Secondly, Mirati only reported data with the 400mg twice-daily dose of adagrasib, and did not give any results with 600mg twice daily, the combo dose originally tested. According to Leerink, the full intent-to-treat population for the combo numbered 18 patients.  

Mirati switched to the 400mg dose because of toxicity seen with 600mg, execs said during a conference call yesterday. They added that adverse events were similar to those seen with adagrasib monotherapy, and cited gastrointestinal events as being of particular concern, as these side effects can also occur with Keytruda. 

In addition, Mirati’s project has been linked with liver enzyme elevations and QT prolongation, which carries a risk of sudden cardiac death. 

These issues did not appear to faze investors, who sent Mirati’s stock up 6% this morning.  

And, with the 400mg dose, the group said there were no grade 4 or 5 adverse events and no treatment-related discontinuations.  

Mirati’s chances in first-line disease should become clearer with data from the ongoing phase 2 Krystal-7 Keytruda combo trial, which will now focus on the 400mg dose and is stratifying patients by PD-L1 status. 

But Amgen also has a combo readout looming, with data from Codebreak-101 due in the first half of next year (Amgen strikes while its rival is down, November 3, 2021). 

Somewhat counterintuitively, Stifel analysts wondered whether Amgen would be able to find a therapeutic window for Lumakras plus Keytruda, given that drug’s shorter half-life versus adagrasib; they reckon more consistent exposure to drug could help adagrasib “thread the needle” between efficacy and toxicity. Still, Lumakras, at least as monotherapy, appears to have a better side-effect profile than adagrasib so far. 

For now, Mirati has a slight head start in first-line NSCLC. But it has dropped the ball in second-line disease, and the jury is out on whether, and how, it can make any advantage count. 

https://www.evaluate.com/vantage/articles/news/trial-results/mirati-gets-combo-coup

GE Healthcare heads back to an independent future

 Having looked like it was undergoing death by a thousand cuts, General Electric has instead plumped for death by two big ones. The conglomerate is to split into three public companies, separately focused on healthcare, aviation and energy. GE Healthcare will be the first to go, with a spin out planned for early 2023; the parent company will retain a 19.9% stake. An independent GE Healthcare has been mooted for years, and it almost happened in 2019 before the group decided to sell off its biopharma unit-within-a-unit instead (GE Healthcare float sunk in favour of Danaher deal, February 25, 2019). In 2020, GE Healthcare’s revenue just topped $18bn, down 10% on 2019 largely due to the coronavirus pandemic. GE said that today’s dramatic move builds on its relatively strong financial position: it has cut its gross debt by more that $75bn since 2018. Shareholders appeared happy with the notion of new companies both more focused and more flexible than a single conglomerate, with GE’s stock climbing 6% in early trade. 

https://www.evaluate.com/vantage/articles/news/snippets/ge-healthcare-heads-back-independent-future

SITC 2021 – Immatics’ T-cell receptor success was no fluke

 After a long gestation T-cell receptor-based cell therapies were shown, courtesy of Adaptimmune and Immatics, to have a future after all. Today the latter company followed up an arguable early success with the project IMA203 by revealing improved signs of efficacy in more patients. A just unveiled late-breaker at the SITC conference includes 16 evaluable subjects with highly refractory solid tumours, eight of whom went into remission on treatment with IMA203, though four quickly relapsed. The data concerned the first three doses, the first of which elicited no responses; even so, a resulting 50% ORR for a TCR project in solid tumours looks impressive. In March a partial remission among the first four subjects given IMA203, an engineered TCR targeting the PRAME antigen, helped send Immatics up 30%. On an investor call Immatics said it would expand cohorts in five undisclosed cancers, and while initial efficacy was promising the next update, at dose level 4 and with six-month follow-up, would focus on durability. While initially Immatics stock shot up 25% it was off 9% in early trade. Developers of other PRAME-directed projects will be taking note.

Selected engineered projects targeting PRAME
Company	Project	Modality	Clinical trial	Note
Immatics	IMA203	eTCR (HLA-A*02-specific)	NCT03686124	50% ORR (62% at highest doses); also has IMA203CD8
Medigene	MDG1011	eTCR (HLA-A*02:01-specific)	NCT03503968	Topline data by end 2021; also has MDG1014
Immunocore	IMC-F106C	Immtac (HLA-A*02:01-specific)	NCT04262466	Initial data mid-2022
Bellicum	BPX-701	eTCR (HLA-A*02:01-specific; rimiducid-activated suicide switch)	NCT02743611	Deprioritised
Glaxosmithkline/ Adaptimmune	PRAME TCR	eTCR	NA	No clinical trial; status unclear
Source: company filings & clinicaltrials.gov.

Source: Immatics.

https://www.evaluate.com/vantage/articles/news/snippets/sitc-2021-immatics-t-cell-receptor-success-was-no-fluke

White House Won't Rule Out Mandating Vaccine For Domestic Air Travel

 by Paul Joseph Watson via Summit News,

The Biden White House has refused to rule out extending its vaccine mandate to cover domestic air travel.

On the day that U.S. airports re-opened to fully vaccinated international travelers for the first time in 20 months, the possibility that Americans using them would also have to be fully jabbed remains open.

After she was asked about vaccine mandates for domestic travel, White House Deputy Press Secretary Karine Jean-Pierre responded, “We say this all the time – everything is on the table.”

“We just don’t have an announcement to preview right now on this,” she added.

“So I don’t have anything more to share on the domestic travel.”

The option is being kept on the table despite a vaccine mandate imposed on businesses with over 100 employees being temporarily suspended by the 5th Circuit Court of Appeals over the weekend.

The administration has also previously suggested that it could try to extend the mandate to businesses with under 100 employees, impacting millions more companies.

Any attempt to ban unvaccinated Americans from domestic travel will further exacerbate a $300billion hit on the economy caused by the suspension of international travel.

Around 20 per cent of Americans remain unvaccinated while 70 per cent have received both doses of the jab.

https://www.zerohedge.com/political/white-house-wont-rule-out-mandating-vaccine-domestic-air-travel

Regeneron Gains on Claims its Antibody Cocktail Prevents Covid

 Regeneron Pharmaceuticals stock (NASDAQ:REGN) rose after the company said a single dose of its antibody cocktail significantly reduces the risk of contracting Covid-19.

Results of a late-stage trial showed that antibody therapy, Regen-Cov, has the potential to provide long-lasting immunity against the infection, said Myron Cohen, who heads monoclonal antibody efforts for the U.S. National Institutes of Health-sponsored Covid Prevention Network.

The trial, which was fully enrolled in early 2021, allowed participants to become vaccinated if they wished once the primary efficacy treatment period (month 1) was complete.

Regen-Cov is currently authorized in the U.S. to treat people who are at high risk of serious consequences from Covid-19 who are either already infected (but not hospitalized) or in certain post-exposure settings as a precaution. It is not authorized as a substitute for vaccination against Covid in the U.S.

Regeneron is collaborating with Roche to increase global supply of the antibody cocktail, with the Swiss company responsible for development and distribution outside the U.S.

https://finance.yahoo.com/news/regeneron-gains-claims-antibody-cocktail-095220104.html

LifeStance cut to Neutral from Overweight by JPMorgan

 Target to $12 from $24

https://finviz.com/quote.ashx?t=lfst&ty=c&ta=1&p=d