Hi wgg2,
Galafold is not a replacement therapy for Fabryzyme or Replagal. The latter two are iso-forms (alpha and beta) of the same enzyme of interest (agalsidase). So when these two are administered they are replacing the enzyme the deficient or lacking enzyme activity in the body. Hence why these are ERT (Enzyme Replacement Therapy).
Galafold is not the agalsidase enzyme. It is what is known as a chaperone protein for a sub-population of Fabry Patients that have certain mutations to the enzyme which means that while the patients are producing something close to a functional enzyme, it still can't carry out its job.
As the name suggests, a chaperone protein helps these specific mutated/mis-shapen enzyme by binding to it and causing it to take on its proper configuration, thereby allowing the enzyme to once again take on its action.
Technically yes, you could give Galafold and ERT together, but that would need to be proven more beneficial with less side-effects in clinical trials and such trials I don't believe have occurred or are planned.
PRX-102 ERT is essentially the exact same enzyme as Replagal (alpha iso-form), and essentially should be the same in activity as Replagal and Fabyzyme. The key difference is that PRX-102 has been engineered to be less attractive to natural degradation by the body, and to have an intrinsically longer half-life, so that it is available in the body for longer and can carry out its action over longer periods of time, leading to the greater efficacy seen to date.
Because ERT is replacing deficient enzyme or deficient enzyme activity, and not like Galafold being dependent on certain specific situations, it can be given theoretically to all Fabry patients.
Yes, as ERT is the current gold standard, PRX-102 could be come the gold standard for all Fabry patients (minus any unique patient issues), and yes dependent on the Phase III data, could therefore be used to replace all current Fabry products in all patients. It is currently being investigated in Balance and Bridge to be used in more severe situation patients at the 1mg/kg/2 weeks dosage (same dosing regimen as Fabryzme), and in less severe patients in the 2mg/kg/4 week dosage which would be far more convenient dosing, thanks to the significantly longer half-life of PRX-102.
Galafold's key selling point is that it is an oral product. However Galafold was approved (as Fabryzyme was) on Accelerated Approval based on surrogate endpoints without eGFR efficacy data. Fabryzyme followed with a clinical trial to prove benefit on eGFR, but Galafold has not yet done that.
Therefore while accounts of the proportion of amenable mutations and thus Fabry population size differ from between a theoretical population of 30-40%, thus far it would seem Galafold uptake has been improving over time but generally hampered by not having this eGFR efficacy data. Regarding mechanism, Galafold binds reversibly to amenable mutation agalsidase enzyme and therefore I would understand this to mean that due to the fact it is not maintaining the mutated enzyme in the correct conformation for 100% of the time, this will by default result in hampered enzyme activity compared to having actual normal enzyme available in the system as with Fabryzyme/Replagal and even more so PRX-102. Thus efficacy very much does need to be proved on eGFR at least, not just on the AA surrogate endpoints.
PRX-102 is currently also seeking this Accelerated Approval pathway, but a key difference is that PRX-102 has eGFR data on all patients it has ever tested the product on as well as all the usual surrogate endpoints employed by Fabryzyme and Galafold, giving years of data, which thus far are very positive. Thus while true PRX-102 will not be able to compete against the Oral characteristic of Galafold, it seems quite possible that it could out-do it on efficacy which is usually considered far more important.
Now if you were a physician choosing potentially less efficacious and oral, or definitively more efficacious and injectable, but with also same to less side effects as the current gold-standard ERT and potential less frequent dosing than current ERT, then I would believe the physician will opt for the product that could significantly extend the patient's life over current products.
Also just looking at Amicus, last year they had about 90 millon in Galafold global sales. In 1Q 2019 they had 34 million sales, which would translate to about 136 million for 2019 (but management thinks 160-180 million in 2019). Given that Galafold was approved in Europe in 2016 and then approved in USA Feb 2018, in Japan March 2018, we could expect this growth in revenue as they start accessing the relevant USA/Japan physicians and patient population, but from my perspective this isn't particularly mind-blowing. And I believe that is again a result of threefold, ERT being the gold-standard, an approx 20-30% of actual relevant Fabry population, and the lack of eGFR efficacy data.
Their earnings came out on May 8th, and as you can see by any chart, the market was not impressed with how things are going, seeing a 7.5% drop on the day of the earnings release, and seeing a 14.8% drop since the earnings to now.
Personally apart for low severity, amenable mutation patients that specifically request oral administration despite likely lower efficacy, I don't consider Galafold an important threat to PRX-102 Rx share.
