D&MD:
Since Metris Therapeutics is a relatively new company, it would be helpful
if you could give me a general idea of its progress from inception to the
present day.
AH: Metris Therapeutics actually started in 1996. It was the
concept of a Prof. Stephen Smith, a highly respected gynecologist at the
University of Cambridge in England. He and his colleagues, in the course
of their clinical work, had observed that a particular condition, called
endometriosis, was not well treated. It was just a passing observation of
Prof. Smith that women who had had endometriosis and who then became
pregnant found that they had remission of the chronic pain of
endometriosis. Therefore, he hypothesized that there must be something
that was naturally occurring which could be used to treat
endometriosis—if he could identify what was causing that remission
during pregnancy.
That was the concept. He obtained venture-capital seed finance in 1996
and went forward to test the "proof of principle" using a
natural protein that pregnant women produce. Since those days, we have
come a long way, because we are still working on the original concept that
was developed by Prof. Smith, but we are no longer working with the
natural protein. We have made the decision, for a number of reasons, to
move that forward into a small-molecule program, which will have the same
effect as the natural protein—and we have demonstrated that—but it
will be more cost-effective as a therapeutic.
That's the background to the company. Based on the early success of the
proof-of-principle work, the company raised a full round of equity
financing in 1998. This enabled us to develop our existing program further
and, more importantly, to expand our portfolio. We took the decision—and
it was about that time that I became involved in the company—to focus
Metris in the women's healthcare area. That's where our roots were, where
our expertise is, and that today remains our priority—to treat
gynecological problems. We've now expanded into an alternative approach to
the treatment of endometriosis, we have a product in development for the
treatment of menstrual pain and menorrhagia, and we do have a product for
the treatment of the menopause.
That's the history of where we are. We had another round of private
equity funding in 2000, which allowed us to continue with our work in
those areas.
D&MD: Can you be more specific about the amounts of money;
in particular, about the venture-capital seed funding, the two rounds of
equity funding, and what your plans are for fund-raising.
AH: The seed capital in 1996 was just under £400,000
($625,000). The 1998 fund-raising was effectively £5 million ($8
million). In the 2000 fund-raising we raised £11 million ($17 million),
so the funding to date in the company has been about £16 million ($25
million).
D&MD: It seems that raising future funding is becoming quite
difficult. What is the current situation in terms of the forward funding
position?
AH: Well, we are doing a fund-raising at the moment. And we are
looking at a third round of finance before the end of this year. We have
tested the temperature.
D&MD: And, if that didn't work, how would you be placed in
terms of funding for a forward period?
AH: Currently, we've got funding into the early half of 2003. We
also have outstanding support from our existing institutional
shareholders—Schroder Ventures, Johnson & Johnson Development
Corporation, 3i, Sofinnova Partners, and Northern Venture Managers—and
they've committed to funding the company, one way or the other. It's more
attractive to us to extend the shareholder base so as to attract more
shareholders into the company. But the existing shareholders are very
pleased with the progress that we've made.
D&MD: I know that the original concept was that of Prof.
Smith, so what actually motivated you yourselves to come into the company?
AH: Let me answer first, just because that's in line with the
chronology. In fact, I should point out that I was, first of all,
Non-Executive Chairman of Metris for about 18 months before I became Chief
Executive. It's a slightly strange way to do it, as you normally go the
other way, but I went from non-executive to executive. My principal
motivation was that, having been a senior female executive in the
pharmaceutical industry for 25 years, I had the opportunity to get
involved in a company that was exclusively looking at women's health,
which I don't think the pharmaceutical industry has served that well in
the past. It just seemed like a fantastic opportunity, so I was very
pleased to be approached. I think also that Prof. Smith, in my experience,
is one of the most forward-thinking and exciting founders, and that was an
attraction, and the shareholder base was strong. Those were my principal
reasons.
PK: Many of the reasons were exactly the same as Ann's. I'd
moved around big pharma for quite a few years before I came to Metris, and
there is clearly now very significant development in gynecology. To that
extent, big pharma has paid little attention to some of the areas. In some
areas, they have actually moved up very, very significantly. But areas
like endometriosis, menorrhagia, and the menopause have had very little
attention, if at all. And these are very big markets, causing great
distress, certainly socio-economically. Most of the conditions that we're
interested in cause most women to be off work quite a few days every year
(AH: certainly not feeling great!). So you have severe, unmet
clinical need, a very large group, and not too much competition. To me,
that is very interesting. Certainly many other therapeutic arenas are
very, very crowded, in my opinion.
D&MD: Another category of women's gynecological disorders is
associated with reproduction. Do you intend to develop products for that
area?
AH: It wouldn't be the area that we would target next, I think.
Of all the areas, it is one of the better served by the pharma companies,
but I think that there are some other indications. I still think that
there's still a lot of work to be done in the women's cancer area, and I
think that we could be looking at female sexual dysfunction as well. I
think that they would probably come earlier in my list of areas to be
examined.
PK: We spend a lot of time just looking to see how satisfied
both patients and doctors are.
D&MD: How do you prioritize the treatments that you have in
development?
PK: I don't think that it's so much to do with prioritization,
but of looking at all of the factors: Is there an unmet clinical need? Can
we think of a way of addressing that? Is there something that could
enlighten us? It's like a checkerboard, rather than saying: "Let's
get out there and tackle x." It's knowing all the factors involved.
AH: It's looking at the risk associated with a clinical
development program, looking at how a product could be marketed and by
whom, bringing in finance—lots of factors like that. To date, we haven't
really had to prioritize a long list of product opportunities. We haven't
quite got to that position yet. That's how we would do it if we were doing
it in the future.
D&MD: So far, you've mentioned the three products that you
have in development. Do you have any other research in the pipeline beyond
these three product areas?
AH: Yes, we do.
D&MD: At what stage do you go public on that, in terms of
saying what these areas are?
PK: In some cases, we want to keep it very secret as long as
possible. Obviously, until we've filed patents and we know that we've got
the position covered, we'd like to keep it as quiet as possible. When
we're doing something quite novel, we want to keep quiet about that.
AH: But, if a product moves into preclinical or certainly into
the clinical phase of development, then, generally speaking, it's in a
company's interests to make that transparent, because that's what going to
persuade shareholders to continue to invest in the company—but generally
not before that.
D&MD: On your Web site, although you mention the three
product areas that you have in development, you don't give any details
about what stage of development they're at.
AH: Generally that's because, Web sites, unless you're very
careful, become out of date very quickly, so I tend to make sure it's
fairly bland and generic.
PK: We all have a slightly different approach. As a small
company, we don't want to put hype into the public domain. We actually
like to have some facts and I don't want to put something onto a Web site
when it's not even in the clinic yet. Our credibility is maintained if we
don't start advertising until we're sure about progress.
D&MD: Can you say what stage you are at with your three
products?
AH: We've got two products that are at preclinical for
endometriosis, one of which is being in-licensed and has already a track
record of clinical data and manufacturing data, and we're bringing it into
the gynecological area.
We then have a new, very exciting and novel vaginal drug-delivery
system, which we're using with our generic compound for the treatment of
menstrual pain, and that's in Phase I clinical trials.
And we have a treatment for menopause symptoms, which actually does
have a name now. It's called Continuelle. I can tell you that. This is in
Phase III clinical studies. That's the spectrum—right from preclinical
through to Phase III.
D&MD: I would have expected that the endometriosis product
would have been further forward, but, from what you've just said, I gather
that it's not.
PK: (The naming of a product is) another reason for not putting
something on the Web site too early. It can take sometimes more than a
year, perhaps even a year-and-a-half, to get a trade name validated. A lot
of people start using trade names before they've gone through the system.
We thought of the name a long time ago, but it wasn't until we were
actually granted it that we're ready to talk about it.
D&MD: What is the principle behind Continuelle?
AH: It's actually a combination of estrogen and progesterone, so
you may be aware that there was quite a lot of controversy (recently)
about HRT (referring to the findings of the Women's Health Initiative
study sponsored by the US National Institutes of Health regarding the
adverse effects of HRT treatment Prempro).
We are assessing data from the program that we've got ongoing. But, at
the moment, all I can say is that we're looking at very low doses of the
two constituents in a small tablet. The preliminary, or I should say the
interim, data from our Phase III study is encouraging. But I think that
it's only fair to say that the company needs to assess how that might
affect our position in the future in the light of our data...This is just
one pill a day. There's definitely a change in the market place, but we
need to reflect on that for the future.
D&MD: You mentioned your novel vaginal drug-delivery device.
How does that work?
AH: Let me back up a moment and explain our approach. Having
identified the unmet clinical need in the gynecological area, we could
have approached a new treatment from different angles. One is to design a
new therapeutic; that is, a drug that we can either develop from scratch
or find an existing drug, which, based on our expertise and experience, we
think would have an acuity in the gynecological area. An example of that
is the compound that we've recently in-licensed that we've got in
development. A third approach is to say, "Is there a targeted way
that we can deliver this drug for the treatment of patients?" And
that's really how the new drug-delivery system was evolved. In other
words, it's a dual approach. On the hand, we have a novel therapeutic in
the gynecological area and, on the other hand, we have a practical method
of taking the drug directly through the vagina into the uterus. Peter,
perhaps you could outline the benefits of vaginal delivery.
PK: One of the things that's been emerging over the past five to
ten years or so is that drugs will pass the vaginal mucosa and go into the
vascular and lymphatic system, which has connections directly to the
uterus and the womb. And remember that at the moment most of our patients
are looking at problems of the myometrium or the endometrium.
We've been quite surprised at how much drug, when it gets across the
vaginal mucosa will end up in the endometrium—about half. Classically,
you would expect that when a drug comes across the vaginal mucosa it would
go into the general circulation and travel around the body to get back to
the endometrium. That is not what happens. We know that we can get active
levels of drugs into the uterus and virtually have no increase in
circulating blood levels—which is perfect. So we are very interested in
this, and our Phase I trial is to deliver the drug vagina mucosally. But,
let's adopt the logic that a large number of women in the developed world
are using tampons once a month, so wouldn't it be nice if, as well as
carrying out that normal tampon function, you could have a nice
drug-delivery system in the same device. The woman would then not have to
do anything different from what she normally does, but she would get good,
rapid treatment for the pain. That's the concept, and we've managed to get
round the issue that tampons are very highly absorbent and, unless you do
something about it once the drug has become free it would get sucked back
in. So we have developed the system, where, by building up quite a complex
structure, the tampon will have the absolutely normal tampon function, but
the drug will be free to be delivered to the uterus. We call the added
layers "coupons" that build up the structure.
D&MD: I was intrigued as to how, once you'd designed this
system for treating pain, it could be used for other functions as well,
and you are offering it for use with in-licensed products.
PK: This is because it's a platform technology and we've put one
particular drug on as a start, but we already know lots of others as well,
and we've had remarkable interest in it.
AH: I think a number of companies have recognized the potential
value of vaginal drug delivery, and there are other systems out there.
Some of them are creams and gels, which women don't like very much because
they are a bit messy. There's also been recently introduced something
called a vaginal ring; but the ring is quite firm, though, and it does
need to be kept in position. It's being used initially for treatment of
fibroids, but it's not universally acceptable to women and it's not that
comfortable. We now see our vaginal delivery system as very easy to use.
D&MD: Do you have a name for it yet?
AH: No, not yet.
D&MD: "Vaginal drug-delivery system" seems a bit
cumbersome?
AH: Well, to the industry, it probably won't. But we want to
preserve a little bit of the intellectual property around it for the
moment.
D&MD: Do you have any results from that product yet?
AH: It's still in Phase I study, so the answer to your question
is "No, we haven't any data yet." Anecdotally, I'm very pleased
with the way it's going. The human volunteers have been complimentary
about it. It's a real credit to the company. It was an idea that Peter
came up with initially, got intellectual property, and I'm very passionate
about it. I think that it's a great concept. Some of the major
pharmaceutical companies are starting to take an interest.
D&MD: Of the products that are preclinical, what is the
small molecule?
PK: Endometriosis is the occurrence of lesions inside the
peritoneal cavity. The way that most people now believe that it occurs is
that the endometrium becomes much, much thicker during the menstrual
cycle. So, most importantly, you get a phenomenal amount of blood vessels
coming into the uterus—massive numbers of rather unusual blood vessels,
so the endometrium becomes very thick. These vessels break up at the end
of the month and the vast majority reflux through the vagina; but, for
some reason that we don't understand, a clump work their way through the
fallopian tubes in the wrong direction. They will then stick onto a whole
variety of organs near to the peritoneum—the bowel (very unpleasant),
the ovaries, the fallopian tubes. In the majority of cases, it is assumed
that, in some way, they hook onto the organs, which then become intensely
vascularized, then they grow and cause all sorts of very nasty
problems—not life threatening—but really very, very unpleasant.
One of the ways of tackling this is to try and stop that
vascularization process, because, if you don't get the blood vessels,
they're not going to grow. And we know that one of the factors involved is
called vascular endothelial growth factor (VEGF), and we are developing a
small molecule that will knock that out of the system. If you don't
prevent these blood vessels growing, they will grow and grow and cause
horrible pain and discomfort.
D&MD: Does it have any implications for a woman getting
pregnant if she's taking this treatment?
PK: The honest answer is that we don't know. We'd have to check
that out. We hope not. As in any treatments, it may be a case of getting
the endometriosis under control and then having a drugs holiday if you're
trying to get pregnant. So time will tell on that one.
The other thing that's happening is that, as the lesions become more
advanced, they become unusually aggressive, because they switch on their
own estrogen production. In the early stages, they're dependant on
estrogen coming from the ovaries, so, once they've switched on their own
enzyme, they have a little local factory and they're totally out of
control. So the other approach is to get into the lesions and block this
local production.
D&MD: Will that be using your vaginal drug-delivery system?
AH: We haven't made the decision. At the moment we expect,
certainly with the inhibition of the local estrogen, that is likely to be
vaginal delivery. With respect to the small molecule for the prevention of
vascularization, (it's) a little early to say. It could be vaginal. It
could actually be oral, if we can get the dose titrations right.
D&MD: All these products that you're developing, are they
meeting their milestones?
AH: By and large, yes. I mean I'd be lying if I said that we'd
met every single one of our milestones over the past few years. But we've
made excellent progress, and in a number of areas, including the vaginal
delivery system, we've exceeded our expectations and passed the
milestones. That product has come from concept through design, evolved
into preclinical testing and gone on to pre-INDA (Investigational New Drug
Application) with the FDA (US Food and Drug Administration), Phase I.
That's outstanding progress within the industry.
One of our endometrium products—the original protein—that has
slipped a little bit from the original timetable because, in my view, we
took the right commercial decision to take the small-molecule rather than
the biological approach—on commercial grounds, really. That one is
somewhat behind the original marketing plan, but the board acknowledges
that the timetable changed for good reasons. That will give us a more
robust product as that goes forward.
I think that, if you were to speak with our shareholders, one of the
marks of this management team is that we do get results when we say we're
going to—even though this is a very risky area of development.
D&MD: Are there any particular problems or setbacks that
you've been able to overcome?
AH: Just thinking about the endometriosis product for the
moment, the challenge that we had to try and produce and manufacture the
protein probably had not been appreciated, and, in the end, we felt that
it was something that was going to be almost impossible to overcome—and
that caused us to switch to the small molecule. In retrospect, that is
probably the most significant hurdle that we've had, but we've addressed
it in the manner we have.
D&MD: How interested are the research institutes and
pharmaceutical companies taking in your vaginal drug-delivery system?
AH: We haven't actually gone out to talk to pharmaceutical
companies about it yet. A few minutes ago, I referred to the fact that
some large pharmaceutical companies, particularly those with existing
interests in women's health, are now starting to be aware of this through
intellectual property searches and the like, so they are actually
spontaneously approaching us. But we haven't gone out and neither have we
met with any of them, as of today.
D&MD: When might the product that is in Phase III clinical
trials be released?
AH: Our intention is to file for marketing approval in one major
European market by the end of this year, or early next year, and therefore
to be marketing it in 2004, realistically.
D&MD: Isn't that a tight timetable in terms of getting
marketing approval, which tends to be quite slow?
AH: We've allowed in our timetable a year for that process, give
or take three months. For all of us, that's a bit of an unknown, as it's
out of our control.
D&MD: Why did you decide to focus on benign gynecological
conditions?
PK: In the fullness of time, we may go outside that. But, I
personally think that it's very important that the company keeps its
focus, not just in terms of clinical nature of the disease, knowledge
base, and specialty that we have in our group here (and) with our
advisers. We have become very, very expert in understanding
endometriosis—its biology, its chemistry and its pathology. It's is very
important that that core skill is concentrated.
AH: I think that there are a number of market drivers as well.
There is the predicted increase in the number of women in the
world—quite a substantial increase, compared with men. That certainly
justifies for me the women's-health focus. The benign gynecological
indications within that are going to increase, because women are reaching
puberty earlier, having fewer children, having children later, (and)
breast-feeding less than previous generations. What that actually means is
that women of my generation, or younger, compared with our mothers and
grandmothers, are actually having more menstrual cycles in their
productive years. And we believe that is driving an increase in some of
these benign gynecological and menstrual conditions. So not only is the
number of women increasing, but the incidence of some of these conditions
is being driven up by the number of menstrual cycles.
Also, in the last five years, certainly, there has been greater
awareness amongst women about the courses of treatment, and we start to
question: Why should women be in the position where they have to have
several days every month where they have to be below par? We're starting
to recognize some of the clinical effects of having these conditions month
after month after month, so there's a more demanding culture amongst women
with respect to treatment (and) pressure on the clinical area. And the
last point that I'd like to make is that, historically, women (for
example, with endometriosis or other conditions) have been faced with
major surgery, in the form of hysterectomy. Now . . . work
that was done in the US not so long ago . . . showed
that, of 560,000 hysterectomy operations carried out in the US alone in a
given year, only 10% of those were deemed to be really necessary for
clinical causes. And the other 90% were (carried out) because there were
not satisfactory medical treatments for some of these gynecological
conditions. You will appreciate that a hysterectomy operation is not one
that a woman wants to undertake willingly or lightly, as it has quite a
high morbidity. So I think that is also driving the need for medical
treatments—and rightly so, in my opinion. Some of these conditions are
affecting girls as young as 20 and hysterectomy is not just the way to
address that.
PK: We should not underestimate that there is now a complete
mismatch between social policy and natural evolutionary biology. The human
system was not designed to go through so many menstrual cycles, so the
biological consequences of that end up being quite phenomenal. In
Victorian times, women had a number of children, so they didn't have that
many menstrual cycles.
AH: The fact that child morbidity is down means that more
children are surviving and there are fewer pregnancies for a given number
of births.
