Chasing BMS, J&J files BCMA CAR-T for multiple myeloma to FDA

Johnson & Johnson’s Janssen unit has filed a rolling submission for its multiple myeloma CAR-T ciltacabtagene autoleucel (cilta-cel) to the FDA, in hot pursuit of Bristol-Myers Squibb’s delayed rival therapy.

Cilta-cel – which targets B-cell maturation antigen (BCMA) – has been submitted as a treatment for patients with relapsed or refractory myeloma, an incurable form of blood cancer, specifically in heavily treated adults who currently have few therapeutic options.

BMS’ CAR-T idecabtagene vicleucel (ide-cel) is going after the same indication and is due for a verdict from the US regulator on 27 March 2021.

The rolling application allows portions of the dossier to be filed as they become available, shortening the review time, although BMS is still in pole position to bring a multiple myeloma cell therapy to the US market, despite a setback earlier this year when the FDA rejected the filing for the CAR-T, asking for more data.

Cilta-cel’s filing triggers a $75 million payment from J&J to its development partner Legend Biotech under the terms of a deal signed in December 2017. It is J&J’s first application for a cell therapy.

The submission is based on results from phase 1b/2 CARTITUDE-1 study, which showed an overall response rate of 97% with cilta-cel, with 67% of patients achieving a stringent complete response despite having received a median of five prior therapies.

The median duration of response and progression-free survival still have not been reached in the study, suggesting the effect is long-lasting, according to Janssen.

Like other CAR-Ts the therapy isn’t without risk however, and there were 14 deaths reported during the study, including six due to complications related to treatment itself.

With all the caveats about comparing different trials, cilta-cel’s results look a little better than those of ide-cel’s KarMMa study, which had an overall response rate of 73%, including 33% complete responses, among patients who had a median of six prior treatments.

BMS is also developing another BCMA directed CAR-T – orvacabtagene autoleucel (orva-cel) – which generated positive results in the EVOLVE trial this year.

Ide-cel and cilta-cel aren’t the first BCMA-targeted drugs for myeloma, however. GlaxoSmithKline’s antibody-drug conjugate (ADC) Blenrep (belantamab mafodotin) has already been approved in the US and Europe, making almost $11 million in third-quarter sales in its first few weeks on the market.

There are other BCMA drugs coming through the pipeline as well, including a string of bispecific antibody therapies from Regeneron, Amgen, J&J and others that could sidestep the cumbersome and risky treatment and manufacturing process for CAR-T therapies.

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Bluebird trumpets long-term data from beta-thalassaemia gene therapy

bluebird bio has presented long-term data from its Zinteglo one-time gene therapy for the blood disorder beta-thalassaemia, as the company continues talks with payers in Europe to bring the ultra-pricey treatment to market.

The European Medicines Agency (EMA) has granted a conditional marketing authorisation for the drug that will be marketed as Zinteglo (betibeglogene autotemcel), meaning its licence must be renewed each year until confirmatory data is available.

Results announced at the American Society of Hematology could help bluebird make the case for the long-term use of the therapy as the treatment approaches the market in Europe.

In the US, Zinteglo has hit a speed-bump with the FDA, which is asking for more information about production facilities before a review of clinical data can begin.

Of the 10 patients enrolled in the ongoing long-term study (LTF-303) from a phase 3 programme, 9/10 (90%) were transfusion independent (TI) and all these patients remain transfusion independent.

David Davidson, chief medical officer at bluebird, said: “All of the patients in our phase 3 studies who achieved transfusion independence have maintained it, with the durability of the treatment effect underscored by patients from our earlier studies reaching their five-year anniversaries of freedom from transfusions. “

In a group of patients aged under 18 from the Northstar-2 and Northstar-3 phase 3 studies, 87% (13 out of 15) achieved TI and remained so.

In a long-term follow-up 53% of patients who achieved TI and restarted iron chelation have since stopped and 30% who achieved TI now receive phlebotomy to reduce iron levels.

Davidson added: “Transfusion independence has been observed in paediatric, adolescent and adult patients and across genotypes – suggesting outcomes with this gene therapy may be consistent regardless of age or genotype.”

In Europe bluebird has set a price of up to $1.58 million euros for a single shot.

This is paid in instalments, with 315,000 euros paid up front and four additional payments due only if the treatment continues to be effective.

Zinteglo is already launched in Germany and is nearing the end of its year of free pricing.

But it’s fair to say that the therapy won’t come cheaply even though most member states will likely end up negotiating a lower price

In England, cost-effectiveness body NICE is reviewing Zinteglo and is due to publish draft document early in the new year.

Although it’s too early to say how the review will go, NICE will be looking for more certainty on the long-term effects of the therapy.

The latest data won’t be part of the submission to NICE, but the company hopes that an ongoing review of the cost-effectiveness body’s methodology will help novel gene therapies get to market.

Nicola Redfern, general manager of bluebird bio UK, is hopeful that NICE will refine its existing Quality Adjusted Life Year (QALY) and find better ways to deal with uncertainties in clinical data.

“How we deal with uncertainties is going to be fundamentally important,” she said.

Another issue to address is the discount rate NICE uses to calculate the value of medicines and their long-term impact on patients’ lives.

The 3.5% discount rate currently used means that these benefits reduce quickly over time in the view of NICE and Redfern agrees with NICE’s own proposals to adopt the 1.5% discount rate used by the Treasury.

“We agree with NICE that there is already evidence to bring it in line with the rate in the Treasury Green Book.”

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GSK moves further ahead in BCMA with EU okay for Blenrep

GlaxoSmithKline has approval on both sides of the Atlantic for its multiple myeloma drug Blenrep, after getting the nod from the European Commission.

Blenrep (belantamab mafodotin) becomes the first BCMA-targeted drug for myeloma to be approved in the EU, and according to its label can be used to treat the blood cancer in adult patients who have received at least four prior therapies.

Prior drugs have to include an immunomodulatory agent, a proteasome inhibitor and a CD-38 monoclonal antibody, and the patient must show progression of the disease since the last therapy.

Among a crowded field, GSK has now won the race to bring an anti-BCMA drug to market in both Europe and the US. The FDA backed Blenrep for the same indication three weeks ago, despite some reservations about eye toxicity, which set the drug on course for what some analysts think could be revenues of around $1.5 billion in 2026.

The EU and US approvals for Blenrep are based on two phase 2 trials – DREAMM-1 and DREAMM-2 – which showed that the antibody-drug conjugate (ADC) achieved responses in around a third of patients who had received an average of seven prior treatments for the cancer.

The conditional approvals mean that GSK may need survival data from a larger trial to keep the drug on the market in the longer term.

That data should come from an ongoing phase 3 study comparing Blenrep with BMS’ immunomodulatory drug Pomalyst (pomalidomide) plus low-dose dexamethasone, the standard treatment option for relapsed and refractory multiple myeloma.

It’s a key new launch for GSK as it tries to rebuild its oncology business under chief scientific officer Hal Barron, along with PD-1 inhibitor dostarlimab and PARP inhibitor Zejula (niraparib) – acquired as part of its $5.1 billion takeover of Tesaro.

Blenrep looks set to have a longer-than-expected period without direct BCMA competition after a BCMA-targeted cell therapy from Bristol-Myers Squibb and bluebird bio – ide-cel (bb2121) – was held up by an FDA request for more data.

Ide-cel was resubmitted to the FDA earlier this month, while other BCMA drugs coming through the pipeline include Amgen’s AMG-429 and Regeneron’s REGN5458 – both bispecific antibodies – as well as ADCs from AstraZeneca and BMS.

With approvals in hand for later-line therapy of myeloma, GSK’s attention will now switch to developing the drug for earlier use in the disease.

Its head-to-head trial with Pomalyst is recruiting patients with at least two prior lines of anti-myeloma treatments, and it also has a phase 3 trial running adding Blenrep to standard first-line treatment with Takeda’s proteasome inhibitor Velcade (bortezomib), BMS’ immunomodulator Revlimid (lenalidomide) and dexamethasone in newly-diagnosed patients ineligible for a bone marrow transplant.

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Novartis eyes filings for leukaemia drug asciminib after phase 3 win

A first-in-class STAMP inhibitor developed by Novartis – asciminib – has outperformed a current drug for chronic myeloid leukaemia (CML) in a head-to-head trial, setting up regulatory filings.

The ASCEMBL trial compared asciminib (ABL001) to Pfizer’s Bosulif (bosutinib) in Philadelphia chromosome-positive CML patients who had previously been treated with two or more tyrosine kinase inhibitors (TKIs), the go-to treatment for this form of CML.

Current treatment for these patients relies on first-generation TKI imatinib – sold by Novartis as Glivec but also available as a generic – as well as second-generation drugs such as Bosulif, Bristol-Myers Squibb’s Sprycel (dasatinib) and Novartis’ Tasigna (nilotinib).

These drugs have transformed the prospects of people with CML, but most patients eventually see their cancer progress despite TKI therapy, and resistance to these drugs can lead to treatment failures. They can also be hard to tolerate, as they can affect healthy as well as leukaemic cells.

Asciminib’s novel mechanism of blocking STAMP – the ABL myristoyl pocket of the BCR-ABL tyrosine kinase – could sidestep conventional TKI resistance and side effects and provide a new third-line treatment option for CML patients, says Novartis.

In ASCEMBL, asciminib was better than Bosulif at achieving a major molecular response (MMR) at 24 weeks than Bosulif in Ph+ CML patients in chronic phase, the stage of the disease when the blood and bone marrow contains less than 10% malignant cells.

Molecular response is measured using a genetic probe to detect BCR-ABL gene mutations in blood or bone marrow based on the number of leukaemic cells present, and is considered to be MMR when the mutations are found at a rate of 1/1000th or less than would be expected in an untreated patient.

“Our ability to treat patients with TKIs changed CML care forever. However, the risk of disease progression is a reality for many patients,” said Novartis’ chief medical officer John Tsai.

“These results with asciminib are a testament to our commitment to further transform CML care – this time through STAMP inhibition, by exploiting a natural regulatory mechanism of the ABL kinase,” he added.

The FDA has awarded the drug fast-track status, given to new therapies that treat a serious or life-threatening condition and fill an unmet medical need, which means it could be eligible for a speedy review after filing.

Novartis originally planned to go after approval as a second-line treatment option as well on the back of another trial called ASC4MORE, but is sticking with third-line for the time being.

Data from the ASCEMBL trial will be submitted for presentation at an upcoming medical meeting, and results will be shared with regulatory authorities, said the drugmaker.

If approved, asciminib would beef up Novartis’ CML portfolio, which is a big earner for the company. Tasigna made sales of $1.8 billion last year, and despite generics Glivec is still a blockbuster brand for the company, adding almost $1.3 billion to its 2019 revenues.

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How to increase haematologists’ and oncologists’ confidence with new treatments

A new whitepaper from Medscape highlights the difficulties haematologists and oncologists face in keeping up with rapid developments in treatment. We speak to the company’s Katie Lucero and Victoria Harvey-Jones to find out how independent medical education is changing to help HCPs increase their confidence in treating cancer patients.

It’s an exciting time to be a haematologist/oncologist, with new clinical data emerging and new drugs being approved at a stunning pace. But this comes at a price – physicians sometimes struggle to keep pace with the mountains of data, and the resulting implications for clinical practice and the patient sitting in front of them.

Decision making is becoming particularly difficult for haematologists/oncologists in the community setting – who treat more than 50% of all cancer patients in Europe. Community haematologists/oncologists can also see patients who present with every type of solid tumour, as well as haematological malignancies.

A Medscape confidence-based assessment of European Union haematologists/oncologists found that, when selecting from eight different treatment choices for a patient with relapsed/refractory multiple myeloma, only 43% of them were confident in their choice, at best (see figure 1).


• Read the full article in pharmaphorum’s Deep Dive digital magazine

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