When optimizing the efficacy of a new drug, a central challenge is the search for minimum effective dose (MED).
We see this playing out today in the world of gene therapy.
In general, if you want a gene therapy to work, you need to deliver sufficient levels of missing protein into the correct location of a sick person’s body. These proteins need to be functional and actually fix the cellular deficiency that is responsible for the genetic disorder.
As companies move through Phase 1 and 2 trials, they tinker with viral load (viral genomes/kg. of patient’s body weight) in order to optimize exogenous protein levels in patients. As you increase the intensity of the gene therapy (viral load), you should be inserting more genetic material for the deficient protein into the necessary cells. However, an excessively high viral load can cause toxicity issues (liver damage, hyper-activated immune system).
So, an ideal gene therapy protocol will administer the minimum effective dose of virus. This ideal viral dose will generate a protein level sufficient to eliminate all symptoms of the genetic disorder – and it will do so without triggering a toxic reaction to the virus.
We currently see the quest for minimum effective dose in the hemophilia space. Multiple companies (Spark, Sangamo, BioMarin, etc.) are vying to be first to market with a gene therapy for hemophilia.
Hemophilia is a genetic disorder caused by a missing or defective clotting protein. The disorder is passed down from parents to children, however about a third of all cases are caused by somatic mutations. About 1 in 5000 babies are born with hemophilia, resulting in about 20,000 hemophiliacs in the US. Hemophilia A is 4 times more common than hemophilia B.
Hemophilia A is caused by missing a clotting protein called factor VIII. If your factor VIII protein levels are below 50%, you begin to show symptoms of hemophilia (excessive bleeding). If your blood levels of factor VIII are below 1%, you have a severe form of hemophilia.
Spark is one of the front-runners in the quest to develop an approved gene therapy for hemophilia A. Spark has been releasing results from an ongoing Phase I/II study. Like most companies, Spark is monitoring a dose-dependent response. A dose-dependent experiment will test multiple dosages and examine results for efficacy and safety. Dose-dependent experiments allow a company to explore their MED (minimum effective dose).
Spark has been focusing their hemophilia A trial at the high end dose of 2 x 10¹² vg/kg.
In August, 2018. Spark reported mixed results for their viral load of 2 x 10¹² vg/kg. These results sent Spark’s stock price down 30%.
The good news: 5 of the 7 patients experienced FVIII activity levels between 16% and 49%. This is in Spark’s projected range of 12% to 100% factor VII blood levels for up to 30 weeks.
The bad news:
Of note, across the study, seven of the 12 participants received a tapering course of oral steroids in response to an alanine aminotransferase (ALT) elevation above patient baseline, declining FVIII levels and/or positive IFN enzyme-linked immunospots (ELISPOTs). For these seven participants, steroids led to normalization of ALT and ELISPOTs.
ALT is a readout for problems with the liver. Alanine aminotransferase is an enzyme released by the liver when the liver is in trouble. We already know that a high dose of gene therapy can cause serious toxicity issues. When physicians observe patients struggling with a toxic reaction to a therapy, they administer steroids to lessen the effect.
So, in this press release, Spark is letting investors know – they have found that their current dosage can, in some patients, cause liver trauma and also declining levels of factor VII (below 5%).
In the future, Spark will want to find the dosage that delivers the highest % of factor VIII in the blood while minimizing stress on the liver. While this report shook many investors, it is important to remember that Phase 1/2 trials exist so that experts can tinker with dosage and efficacy. The long term goal is a cure for hemophilia. To reach that goal, companies need to optimize many experimental variables, including MED.
When we look ahead to the future of gene therapy . . . the company that becomes first to market for one particular genetic disorder will need to determine the optimal MED for their viral treatment. In the case of hemophilia, a gene therapy must boost factor VII protein levels in the blood to the point where bleeding events are severely reduced, possibly eliminated. Furthermore, this outcome must occur in the absence of a toxic reaction, i.e. a spike in liver enzymes (ALT).
If you’re an investor in gene therapy stocks, prepare for a bumpy road whenever a company reports trial data that indicates they haven’t yet determined MED.