Carvykti: Solving Capacity Issues?

HealthTree for Multiple Myeloma has posted several articles over the past year  about the treatment successes from both anti-BCMA CAR-T products currently available in the US market [Abecma from Bristol Myers and Carvykti from Janssen/Johnson & Johnson/Legend Biotech].

Both organizations are also conducting additional clinical studies in an effort to secure approval for earlier line of treatment (the Holy Grail to expand the market, market share and long-term revenue potential). HealthTree has also mentioned the issue of patients having to wait a long time before they can be “slotted” before their T-cells can be harvested and processed into the CAR-T cells needed to treat their relapsed disease.

It is reasonable to wonder why a leading company in the myeloma space has been caught with the problem of not being able to supply the budding market for a key product. It is an even more reasonable question to ask considering that Bristol Myers ran into the same problem(s) following the launch of their anti-BCMA CAR-T product, Abecma, launched about a year earlier than Carvykti. In other words, what lessons did Janssen/Johnson & Johnson/Legend Biotech learn from the Abecma supply issues ? I will not speculate on an answer here.

Legend Biotech’s CEO, Ying Huang, Ph.D., has recently shed some light on what is behind the tight supply for Carvykti during an investor conference. There are three principle areas that the development and commercialization partnership of J&J/Legend has discussed with respect to supply issues:

• The industry-wide shortage of lentiviral vectors. [A very simple explanation of lentiviral vectors is a method of gene therapy involves modifying a virus to act as a vector to insert beneficial genes into cells.] This is nothing new in the CAR-T field and this has been an issue for a number of companies with approved CAR-T products. Pharma has been outsourcing the manufacture of lentiviral vectors for the past some years and with the substantial number of CAR-T clinical trials going on worldwide there has been a gap between supply and demand.
• The currently available capacity, or slots, to engineer and culture therapeutic T cells. In other words, tight current production capacity, in the face of the large pool of possible myeloma patients who may stand to gain from Carvykti. Bristol Myers has the same issue.

“During early launch days, J&J and Legend experienced a higher rate of manufacturing failure than they did in the CARTITUDE-1 trial used to support Carvykti’s existing FDA approval. The product release specification for commercial Carvykti that the FDA requires is more stringent than what was used in the clinical study. Besides, investigators screened patients to decide eligibility for the clinical trial, but patient baseline characteristics are more diverse in the real world. And a patient’s baseline health status affects the viability and the number of T cells collected, Huang said.”

• Tighter “commercial product release specifications” (compared to those used during product/clinical development) that are part of the final FDA approval of a company’s regulatory dossier is a plain fact of life in the pharmaceutical industry and should not come as a surprise to management. J&J/Legend’s admission of this issue is also nothing new in the CAR-T field, going back to similar issues seen after Novartis’ approval of Kymriah (August 2017). And, in fairness to J&J/Legend, has also been experienced at Bristol Myers in the production of Abecma.

What are J&J/Legend doing to solve the current shortage? The companies have clearly stated that major investments are being made:

• J&J and Legend “will double investment in their Raritan, New Jersey, manufacturing facility, bringing the total to $500 million.” This site is currently manufacturing the product for the US market. In addition, “Together with another factory under construction in Ghent, Belgium, J&J and Legend in the next few years will be in a position to have a capacity that accommodates the $5 billion-plus peak sales projected by J&J,” Huang said. [Emphasis added] Unfortunately, we do not have a more specific timeline for either the Raritan or the Ghent expansions.
• “… the two companies have decided to bring viral vector production in-house, currently managed by J&J’s Janssen vaccines department. And they expect to come out of the shortage “in the near future,” Huang said.” 
• “In the last few months, J&J and Legend have seen an ‘encouraging trend’ in terms of the out-of-specification rate in its manufacturing processing, and the two firms are working hard to fine-tune manufacturing protocol to improve the success rate,” Huang added. “I think at this point, we feel very confident that we will be able to overcome this.”

Taken together, it seems as if there is “light at the end of the tunnel” and all we, myeloma patients, can do is keep our fingers crossed that these three capacity expansion programs will progress rapidly to make this exciting product available to all of us in need.