Capacity to meet demand is a challenge for the entire class of CAR-T treatments.
With the drugs now moving into earlier lines of therapy, the supply issue takes on added significance, namely whether their manufacturers can meet what’s sure to be increased demand for prescriptions.
Earlier this month, the Food and Drug Administration greenlit Johnson & Johnson and Legend Biotech’s Carvykti to climb from fifth- to second-line use in adults with relapsed refractory multiple myeloma (MM).
Bristol Myers Squibb and of 2seventy Bio’s Abecma was also cleared to move up to third-line therapy for people with the blood cancer.
Both approvals came after outside advisors to the FDA voted in favor of allowing the earlier use. Late-stage studies showed the therapies helped extend the time that patients lived without disease progression, to a greater extent than when subjects got non CAR-T, “standard of care” treatments. These include daratumumab, pomalidomide and dexamethasone or pomalidomide, bortezomib and daratumumab – cocktails known as DPd or PVd, respectively.
Thousands more people now become eligible for the therapies. However, their bespoke, “autologous” production process, with each drug custom made based on a patient’s own white blood cells modified to attack cancer, has limited production.
In addition, the CAR-T class has been under the regulatory microscope of late for fear of secondary cancer. Earlier this year, the FDA ordered that warnings be added to prescribing information for the therapies following an investigation into reports of lymphoma after T-cell treatment.
Both Abecma and Carvykti’s Phase 3 trials showed a higher risk of early death for those enrolled in the CAR-T arm.
In both cases, analysts said, it’s more likely the deaths were related to patients’ disease worsening or because they occurred at a time when the patients were taking so-called “bridge therapies.”
Nevertheless, the approvals prompted rosy forecasts. Leerink Partners analyst Daina Graybosch projected that uptake in earlier lines will lift Abecma revenues to $91.8 million in the second quarter and $138 million in Q3, with a total of $625 million in estimated 2031 sales.
By contrast, Carvykti could generate $7 billion in 2032 worldwide sales. This year, the drug could bring in $173 million in the first quarter on the way to $957 million in global sales, according to J.P. Morgan analysts.
Focus now shifts to management’s ability to unlock growth by ramping up manufacturing capacity.
To that end, MM+M spoke with Legend Biotech CEO Ying Huang about how the company and its partner, J&J, plan to meet expanding demand.
This interview has been lightly edited for clarity and brevity.
MM+M: What does the FDA’s approval mean for the Carvytki’s prospects within the broader MM treatment landscape?
Ying Huang: Right now, the indication is that any patient with MM who has been treated with one prior line of therapy, including an oral immunomodulator and then a protease inhibitor, if they are also refractory to Revlimid then they’re eligible to receive CAR-T.
First of all, if you look at the addressable patient population, we looked at the three major markets that are served by CAR-T therapy – including the U.S., Europe and Japan – with our own indication, which was fifth-line in the U.S. and fourth-line and beyond in Japan and Europe.
The addressable patient population was about 20,000 patients per year. Now, with this new approval in the U.S. as a second-line therapy – and we also expect European official approval later this month, again in second-line, and hopefully also a second-line label granted by the Japanese regulatory authorities. Then, that combined market will grow to about 80,000 patients per year.
Essentially, the addressable patient population will quadruple from where it was. More importantly, this gives the patients in the earlier spectrum of the disease progression the opportunity to receive CAR-T.
This is important, the reason being that CAR-T is a unique therapy. It’s different from the monoclonal antibody or small-molecule drugs in that we’re actually taking immune cells from the patient’s body and then we use genetic engineering technology to transduce an antibody fragment called a CAR onto the T-cells.
So as you can imagine, when the patients are earlier, younger and healthier compared to when they are much later in the disease spectrum, the immune cells are actually healthier. We can also collect more of those immune cells. So scientifically there’s a strong rationale here to give a therapy such as CAR-T early because we expect to get better results in those patients.
Indeed, if you look at CARTITUDE-4 results, compared to a control arm – which is composed of typically a three-drug cocktail such as DPD – we’re able to show that you can reduce the risk of cancer progression or death from cancer by a big number. The hazard ratio here on the label is 0.41, which means we can reduce that risk by 59%.
That is why we think it’s important to bring this potentially lifesaving therapy to earlier-line patients in myeloma.
MM+M: The label is straightforward, avoiding any kind of downside scenario like a box warning on earlier death risk. How big of a concern was that leading into the PDUFA date?
Huang: In fact, the main reason why FDA held the ODAC [Oncology Drugs Advisory Committee] meetings was because they would like to debate and also trying to see what this means for the label and also for our patients.
With our partner J&J, we provided a detailed analysis for those early deaths. In fact, what we found out is that only in the first three months we saw an imbalance in deaths between the CAR arm and the control arm.
If you look at the reason for the death, it’s due to, for example, pneumonia from COVID and other adverse events that happened before those patients even received Carvykti.
We don’t believe this phenomenon has to do with the treatment itself. It may have to do with the fact that these patients are so sick when they are enrolling into the trial that their disease quickly progressed even before we could deliver care to those patients.
That is why we are pleased with the outcome of the ODAC panel, where all 11 members voted “yes” to recommend the approval. And “yes,” there’s a significant clinical benefit that [supersedes] the risk associated with CAR-T treatment.
MM+M: You mentioned the ODAC panel, which unanimously voted for the approval of Carvykti and that affirmed the high unmet need for earlier use of this therapy. In November of last year, the FDA started an investigation into the risk of lymphoma with the approved BCMA-targeted, CAR-T drugs. In January, FDA’s Dr. Peter Marks said there probably is a link to lymphoma, but the benefit-risk profile of these products continues to favor use of the products. Can you comment on the findings from that investigation?
Huang: As you rightfully mentioned, in November of last year, FDA issued a public communication about the new lead identified safety signal, specifically T-cell lymphoma or T-cell-related malignancies. But if you look at the total number of the cases, I believe the FDA was analyzing a total of 23 cases. And the denominator, though, is about 27,000 patients who’ve been treated with CAR-T therapy.
In fact, just for Carvykti alone, we have treated more than 2,500 patients to date. So it is a risk, however, if you look at the number of the events, it’s a rare risk. We believe that there are no causal relationships. Maybe there’s an association between the CAR-T therapy and the T-cell lymphoma as a second primary malignancy (SPM).
So we do take patient safety as a top priority, and we take this seriously.
That is why we agree with the agency putting SPM or T-cell lymphoma into the warning so that patients and also physicians are much aware of this potential risk.
On the other hand, we also firmly believe that given the data to date, given all the clinical evidence we have seen so far, Carvykti clearly demonstrates a favorable benefit-risk for those patients who are diagnosed with MM.
Just like anything in the world of medicine, there’s not a perfect medicine out there. There are always adverse events for any therapy, but it’s always a balanced look into the risk versus benefit.
MM+M: We know that Carvykti has been expanding its manufacturing capacity and site expansion. I’ve also read that Carvykti is on the higher end in terms of the time to product release, which is six weeks, while Yescarta’s is two weeks. Can you comment on where you fall in that range and your efforts to speed up the production?
Huang: We and our partner, J&J, acutely understand the urgency for our patients in need of Carvykti and we’re committed to doing everything we can to accelerate our capability to deliver this important, one-time treatment in a reliable and also timely manner.
Since the drug was approved by the FDA in February 2022, Legend and J&J have made significant investments in our manufacturing facilities to rapidly scale up the production.
We have also increased the number of certified treatment centers from 10 hospitals at launch to now more than 70 activated, certified treatment centers in the U.S. If you look also at the manufacturing capacity itself, in 2023 we more than doubled manufacturing capacity for Carvykti.
We’re striving to double [again] in 2024. We continue to invest in capacity to provide this important therapy to our patients. In terms of what we call “van-to-van time,” or turnaround time, our goal this year is to deliver the large majority of the production within about one month, or 31 days. That is our goal and right now we’re making substantial progress toward that goal.
There are a lot of technical hurdles we would have to overcome in order to achieve that goal, because this is a complicated manufacturing protocol. It’s also a 100% personalized medicine, so we have to produce one individual batch for each patient and that, as you can imagine, is not a straightforward task.
MM+M: We see the next generation beyond the autologous therapies – the allogeneic ones – promising an off-the-shelf version, where it’s not one batch per patient. Do you have a comment on that? Are Legend and J&J looking to expand into that area, as well?
Huang: Allogeneic is a great scientific idea. If we can make a batch of multiple doses of cell therapy coming from donor cells, then it could become an off-the-shelf, ready-to-go medicine, just like small molecules or injectable antibodies today.
However, there are a lot of technical challenges here.
First, you would have to show that those allogeneic therapies are as effective as the autologous, which by the way the autologous cell therapies have set a high bar on efficacy in terms of durability, the progression-free survival and also the depth of the response.
So far, unfortunately, we have not been able to come up with an allogeneic therapy in the industry that can match the level of response and also the durability provided by any autologous cell therapy.
Secondly, if you take cells from another healthy donor, you might get into rejections. The first one is what we call graft versus host disease (GVHD). The second is host versus graft disease (HVGD). Rejection has been a big challenge for the field. If you look at what’s happening in the field, we’re not seeing that kind of durability or persistence for the allogeneic cell therapy in the patient’s body.
I don’t know when the scientific breakthrough will come, but it’s worth trying. Our research team has been working on different modalities of allogeneic therapies, including alpha/beta, gamma/delta and also NK [natural killer] cells.
We have a couple of programs already in the clinic in Phase 1, so we’re still trying to work out an allogeneic therapy. It’s probably not going to happen in the near future. It will take a while before an allogeneic cell therapy becomes reality.
MM+M: Will we see J&J and Legend make a bigger deal about manufacturing capacity in the way you communicate that to the market?
Huang: Given the current supply constraint and also given the demand, coming from second line and beyond indications for multiple myeloma patients, our top priority will be scaling up our manufacturing operation and providing more supply to the market. That’s our top priority now.
We have already clearly stated a goal of exiting 2025 with an annualized capacity of 10,000 doses or more. We also can go beyond that. That’s our first priority in the next couple years that we want to achieve.
Then, of course, we’re interested in investing in a new and updated manufacturing protocol that could shorten the cycle time.
For example, in the industry, there’s certain technology that can complete the manufacturing in one or two days – the so-called fast manufacturing. We’re working on that in our lab, as well. Hopefully, one day we can also bring this type of short manufacturing technology to Carvykti so that we can also shorten the cycle times significantly.
Obviously, this is still early in the research stage. Once we get to a point where we have the regulatory approval for a shorter manufacturing cycle, of course we’ll let everyone know. But recently we provided a shorter turnaround time in our system that will actually be available for hospitals and also physicians who use Carvykti. Every time we make an improvement in our supply chain operation, of course we’ll let our customers know so that they can also convey the message to the patients.
MM+M: When do you expect the FDA to approve that shorter turnaround time?
Huang: It’s a little premature to talk about that because it depends on whether we can achieve this goal by using analytical methodology rather than going to a clinical trial to show that. This is a comparable procedure, because cell therapy is not easy to characterize. You have certain [manufacturing] release specifications or release-back to make sure it actually conforms to the FDA-approved label.
One way to do that is through analytical methodology to demonstrate a so-called comparability between the two different manufacturing protocols. If you can just achieve that without doing a clinical study, then it may take a couple of years to get to that goal.
On the other hand, if this becomes a clinical trial task, then it may take quite a few years to demonstrate that among patients to the agencies that this is actually an equivalent or similar clinical result. It depends what route we take and also depends whether we can achieve the goal by using just analytical methods.
(Note, along with the second-line approval, regulators also reportedly OK’d expanded manufacturing release specifications for Carvykti, which could widen supply by minimizing manufacturing fail rate.)
MM+M: Considering the approval, do you have any big marketing initiatives coming up in the next six to 12 months?
Huang: Our message is clear to the community: Carvykti should be used as early as the second line whenever the patient has one relapse from existing therapies.
We would like to provide Carvykti to more patients in the earlier setting of MM so they can reap this longer-term treatment benefit in terms of complete response; durable, long-term, progression-free survival; and potentially – eventually – a survival benefit. We can demonstrate from the clinical setting.
It requires Legend and J&J to continue to execute the upscaling of our manufacturing operation, because really we have to broaden the access. We have to provide this therapy to more patients. That’s our key message.
MM+M: Anything else?
Huang: We’re pleased with the recent FDA approval, because Carvykti is the first and so far only BCMA-targeting CAR-T therapy that’s been indicated in the second-line setting of MM. So we think it’s an important milestone for the company. It’s also great news for patients who suffer from MM.
