Rick, here's what you missed at the stockholders meeting on Friday (again, I apologize that SI interprets each of my apostrophes and quotation marks as a "?"):
CEO John Monahan gave the following overview presentation of the company:
Getting DNA into the cell is only half the problem. The DNA may be present in the cell but turned off, ?repressed.? In such a mode, it may also behaving like a viral infection, causing the cell to attempt to get rid of it.
AAV is not recognized by a cell as a foreign infection. The cell begins, over a period of days, to accept the AAV-injected DNA and allows the protein coded by that DNA to be made produced continuously and long term.
The natural AAV virus contains single stranded DNA consisting of two genes: a replication (rep) gene and a cap gene. The cap gene codes for the protein coat. The rep gene replicates the DNA.
AAV is incredibly stable. It is unique among viruses in that it will get into any cell of your body or of any other animals. You can test with AAV in animals with the exact same material that you will use in humans. There is no need to ?humanize? the vector.
Avigen removes the AAV DNA (both the rep gene and the cap gene) and puts in a control element and the therapeutic gene. The resulting vector is no longer capable of replicating itself, but it can transfer the therapeutic gene payload into cells of the host animal into which it gets injected.
Preclinical studies showed one-year duration of AAV-Epo (Factor 9) production after inoculation.
There are two main forms of Hemophilia: Hemophilia A (Factor 8 deficiency) and Hemophilia B (Factor 9 deficiency).
One of the dogs treated with AAV for Factor 9 is now out 2-1/2 years with continued efficacy after a single injection of the vector.
The protocol for the Phase I human trials calls for a single intramuscular injection of the vector into the leg of the patient.
This Phase I trial is a FIRST in at least two respects. It is the first AAV gene therapy trial for Hemophilia in humans and it is the first gene therapy protocol ever (of any kind) for patients who are not life threatened. Ordinarily, gene therapy is considered so risky that the FDA only allows human trials in life threatened patients. The FDA recognizes, however, that the AAV vector looks to be incredibly safe, so the FDA has allowed it to be used in human trials for patients who are not life threatened.
The Phase I trials are being conducted at two centers: The Children?s Hospital of Philadelphia and The Stanford Medical Center.
Definitive endpoints: whole blood clotting time and Factor 9 levels in the blood. Whole blood clotting time is a very objective test. You agitate blood in the test tube and measure how long it takes to clot. For a normal person, it should start to gel in a few seconds. In a Hemophilia patient, it may take hours before it begins to gel. There is nothing ambiguous about this test.
This Phase I trial is really a Phase I/II trial. They aren?t just looking for safety. They are also looking for efficacy, at three different dosing levels.
9 patients are enrolled. They are treated approx. 4 weeks apart. 3 will be treated with a low dose injection, 3 with a medium dose, and 3 with a high dose.
The trial will be 12 to 18 months in duration.
They have completed treatment of all three of the low dose patients.
Avigen has committed to give an update on the data from these low dose patients at the ASH meeting on Dec. 3rd or 4th and will then issue a summary-type press release. They have promised ASH not to make any announcements before that meeting.
The total market for Hemophilia B is $300M.
Next goals: Hemophilia A Factor VIII ($1,200M market); Gouchers Disease ($500M market); Emphysema; and Thalassemia.
If the Phase I data are positive, they will explore licensing the AAV-vector technology off to other companies for other indications.
AAV Vectors are safe, efficient, stable; this is a huge advantage over competing viral vectors for gene therapy.
They have a large-scale manufacturing capability; this will require a modest build-out of additional space.
They will probably go into the liver with the Hemophilia A vector. There are technical reasons for this, which John did not elaborate upon.
As mentioned in the recent press release, the gene for Factor 8 is too large to fit comfortably into the AAV virus, but they have been successful (as explained in the press release) at splitting the gene and introducing each half of the gene into a separate vector, both of which vectors can be injected into the patient. The are also working on a technique for squeezing oversized genes to fit them into the vector.
Most genes fit quite comfortably into the AAV vector. Of the genes coding for the major commercial proteins used therapeutically, about 80% should fit into the AAV vector. The gene missing in muscular dystrophy patients is one notable exception.
With the currently marketed recombinant Factors 8 and 9 used by Hemophilia patients, many patients develop an immune response. However, that immune response is treated by tolerization; as the body is continuously exposed to the recombinant Factor 8 or 9 over time, the body eventually accepts it.
Less than 25 patients were required for the Phase III pivotal trial that resulted in FDA approval for the current recombinant factor 9. That the current Phase I/II trial only includes 9 patients is not unusual for a Hemophilia therapy trial. It is not inconceivable that the FDA could be persuaded to allow Avigen to proceed immediately to a pivotal Phase III trial if the results from the current trial are convincingly successful. But don?t count on it, of course.
The first patient they studied in the current Phase I/II trial is out 5 months now.
Avigen is not anxious to partner away it?s the AAV vector to Factor 8 or 9. They would prefer to keep those indications for themselves and partner away instead some of the indications that are not as far along in development. For any indication that they would partner away, they would retain the manufacturing rights. And rightly so: these vectors are not easy to create.
Avigen?s patent expert acknowledged that Avigen does not have the AAV market all locked up to itself. The strength of Avigen?s patent estate is twofold: the first prong of their patent estate is their proprietary methodology for creating a gene therapy vector from an AAV virus. But there are other companies that have patented other techniques for creating AAV vectors, and their techniques also appear viable. Avigen believes that its technology is superior and has safety advantages, but that is not a decisive advantage. The second prong of their patent estate is the growing number of genes for which they have developed AAV vectors. This is where the action is. They are trying as rapidly as possible to tie up the patent right to use AAV vectors for as many therapeutic genes as possible. In furtherance of this strategy, they have formed alliances with many Universities, allowing them to use the AAV vector technology to develop specific vectors to transmit specific therapeutic genes. Obviously, the development rights to the resulting new vectors will then be shared between Avigen and the University that created the specific vector. They already have patent rights to AAV vectors for many genes, and the number is growing.
After the meeting I asked John how tempting it might be to management to have a big pharma company offer to buy them out and provide vast sums of research money that would allow them to fulfill all their ambitions for expanding the number of diseases for which they could develop AAV vectors. I suggested that maybe a buy-out at $50 a share would be tempting to them. John scoffed at the suggestion. He clearly thinks the company is worth much more than that (assuming the Phase I/II trial is successful). Also, he said that after spending 7-1/2 years developing this platform technology, they really wanted to keep the glory and the success for themselves. The company has a 2-1/2 year supply of cash, so they will not be negotiating from a position of weakness in any proposed deal with a big pharma partner.
Marc |
