Comparison of LVV to AAV and Abs
LVV and AAV are in their infancy - Don’t doubt their ability to take market share like antibody Abs have!!!
No one can deny that Abs therapies have matured….. But it took a while.
First Abs hit the market in 1992 and it took about 20 years for them to mature towards an explosive growth in medical application use. See image below for how indication expansion and new products for Abs started to accelerate in antibody space starting in about 2012.
If we make a comparison to lenti viral vector (LVV) and adeno-associated virus (AAV), we see that they are tracking similarly to Abs.
For LVV as ex vivo where it is used to make a Cell-based Gene Therapy (CbGT), we have 11 products on the market
For AAV as in vivo, where it is used to make a Vector-based Gene Therapy (VbGT). we have 7 products released
Both AAV and LVV have only recently obtained their market approvals starting 2017. So we are not even 10 years into their run.
Will it take another 10 years before they explode in growth?
Probably not, if the all the reports of what is in the preclinical and clinical pipeline are to be believed.
The plots used in this article are extraction of purple book data from the FDA:
https://purplebooksearch.fda.gov/downloads/files/2024/purplebook-search-may-data-download.csv
The purple book lists the 2,126 biologics that have been released by FDA for product + indication + dose. Of these, 526 entries are either Cell-based Gene Therapy (CbGT), Vector-based Gene Therapy (Vb-GT), or Antibody Therapy (AbT).
The CbGTs are the following:
Yescarta axicabtagene ciloleucel gRV (cart-CD19)
Kymriah tisagenlecleucel LVV (cart-CD19)
Tecartus Brexucabtagene Autoleucel gRV (cart-CD19)
Abecma idecabtagene vicleucel LVV (cart-BCMA)
Breyanzi lisocabtagene maraleucel LVV (cart-CD19)
Zynteglo betibeglogene autotemcel LVV (mod-HBB)
Skysona elivaldogene autotemcel LVV (ABCD1)
Carvykti ciltacabtagene autoleucel LVV (cart-BCMA)
Casgevy Exagamglogene autotemcel Cas9 (mod-BCL11A)
LYFGENIA lovotibeglogene autotemcel LVV (mod-HBB)
Lenmeldy atidarsagene autotemcel LVV (ARSA)
Tecelra afamitresgene autoleucel LVV (cart-TCR)
Aucatzyl Obecabtagene autoleucel LVV (cart-CD19)
Encelto revakinagene taroretcel-lwey transfected (CNTF)
zevaskyn Prademagene zamikeracel RRV (COL7A1)
Abecma, idecabtagene vicleucel, LVV (cart-BCMA)
11 of 16 (69%) are LVV based.
The VbGTs are the following:
Imlygic, Talimogene laherparepvec, HSV (GM-CSF)
Imlygic, Talimogene laherparepvec, HSV (GM-CSF)
Luxturna, Voretigene Neparvovec, AAV (RPE65)
Zolgensma, onasemnogene abeparvovec-xioi, AAV (SMN1)
Adstiladrin, nadofaragene firadenovec-vncg, AV (IFNA2)
Hemgenix, etranacogene dezaparvovec-drlb, AAV (F9)
Roctavian, valoctocogene roxaparvovec-rvox, AAV (F8)
VYJUVEK, beremagene geperpavec-svdt, HSV (COL7A1)
ELEVIDYS, delandistrogene moxeparvovec-rokl, AAV (DMD)
KEBILIDI, eladocagene exuparvovec-tneq, AAV (DDC)
BEQVEZ, fidanacogene elaparvovec-dzkt, AAV (F9)
7 of 11 (64%) are AAV based
The antibodies have 497 approvals
We can distill that down to 208 proper names with 19 of them as drug combinations. This gives an average of 2.5x indication expansions per drug type
Next, I used Gemini AI to ask of each drug:
“How many people have been treated in the three categories?"
We get:
CbGTs at 46,852 treatments performed. Most of this is for cancer applications. The biggest risk in these thereapies is the possible oncogenic activation from random gene insertion. When the transgene in an LLV is driven by EF1a promoter for the non-cancer CbGTs, so far, NO genotoxicity has been seen in 258 patients treated (PMID: 35288539). However when a very promiscuous promoter with enhancer sequences is used, genotoxicity can occur at nearly 10% (PMID 40200078). So vector design is critical to making these cell based integrations more safe to use.
VbGTs is at 8760 treatments performed. The most striking and experienced of these is Zolgenzma. Estimated at over 4000 doses done, there have been two death that has been reported as possibly attributable to the therapy (PMID 36389770) Thats 0.5 deaths per 1000. For reference, elective hip replacement surgery is 3 deaths per 1000.
AbTs appears to be approaching 100 M treated. Much of this is in the the “blockbusters” entities that hit the market more than 10 years ago. The two most common adverse events with Abs are infusion reactions and cytokine release syndrome.
So as we look at Abs as a predictor of the evolution of cell and gene therapies (CGTs), it appears that contrary to many current investors sentiments, there is not much to fear here, and there is much to be gained by jumping in!
Yep they are expensive. So was Abs back in the day.
They have patient risk. Sure, but this is occurring at a background rate that is nearly the same as what occurs for many other procedures, which the system currently tolerates.
Biggest dramatic challenge that does not have predicate: The duration of therapeutic effect from one dose is on the spectrum of years to decades. That is something the system does not know how to tolerate. With the average payee lifespan on a plan at 2.9 years on any given health insurance plan, there is very little incentive for payors and integrated health plans to eat the full cost of highly expensive, super-duration therapies. Some countries are taking the rather heartless tact of saying NO to near lifetime cures for the small segments of their patient populations. But with more am more common cures splintering into rare genetic disease, as their genetic drivers get recognized for their role in phenotypic presentation, there is a need to accommodate these amazing CGTs and get their reimbursement figured out. Part of that will occur with costing efficiencies as time and AI get more integrated into the pipeline, but the right values-based pricing and how it gets reimbursed is ripe for new invention.
