Annex D
Attached memos about licensing deals
2 June 1997
MATCHBOXForeward
I would just say that I know Chuck Blitzer eight
years ago and while he is an excellent dinner companion and a
good man to have on your side like the hooker Brian Moore I certainly
wouldn't anticipate an easy game for the referee with him in the
opposition!
I have reviewed the three projects as requested.
Oral pilocarpine
Pilocarpine is one of the oldest known drugs;
as a muscarinic cholinergic agonist, its pharmacology is entirely
predictable, although it does cause anomalous CVS effects. As
a medical student I was taught to tell patients not to rub their
eyes after administration of drops because it increased systematic
absorption with unpredictable CVS effects. I am, therefore very
surprised to see it being administered systemically. Judging by
the publications, the sweating side effects, while very common,
are acceptable in the majority and this is presumably confirmed
to the extent that sales are rising, albeit from a small base.
At first sight it seems reasonable to conclude that doctors are
finding the compound to be clinically useful. However I feel suspicious
and I think it would be good to do our own market research to
confirm that the perceptions of non-triallist users are positive.
It seems quite possible that after an initial burst, enthusiasm
for the product might wane. I particularly predict that at some
stage, elderly patients will have hypotensive/tachydysrhythmic
events that will result in CVA or injury and this will cause a
decline in widespread use.
From two non-medical points of view, the patent
situation is presumably non-existent and anyway you look at it,
pilocarpine doesn't exactly fit BB core values.
Despite the NEJM publication I find it hard
to muster enthusiasm.
114
The compound is clearly potent with widespread
activity in models. However, it is not possible to judge how preclinical
data will translate into clinical utility. None of us need reminding
that most cytotoxics taken into clinical research have outstanding
features pre-clinically, not matched in the clinic. While the
mode of action may be novel (although, generically, chemical damage
to DNA is rather old hat) I would rate the possibility that it
will be more effective than other cytotoxics as low (<5 per
cent).
While tumour sensitivity, of course, is a sine
quo non, in the absence of a compelling steer from data, the
positioning of cytotoxics may be largely driven by market considerations.
In this case, since tumour sensitivity may be wide, selection
of target tumours should be based on where we can compete. To
be steered by tumour responses in small numbers in the current
phase I could be misleading, on the other hand, we should get
an indication of the magnitude of response rates from this study.
If the results are not particularly startling
(complete and partial responses <30 per cent at MTD), we will
compete head to head with established therapies without particular
advantage, unless there are any identified opportunities in this
crowded market. My own view is that there are not. In this "not
particularly startling" case, I would recommend that we discontinue
research.
If complete and partial responses are >30
per cent then further phase Is should be done in whichever cancer
type appear most appealing. These studies would optimise dosage
regimen and estimate true response rates from a larger number
of patients (~30-60). Combinations should be studied as these
are probably required in registration studies, although this depends
on target indication. These extended phase I studies could be
performed in one or two cancer types. Each study might take 18
months to complete with a budget of $150-300k. Phase II studies
may be started before the end of this period, but could need to
be repeated in the light of all information, which produces redundancy
and uncertainty.
For registration, my current assessment is that
we will need to prove clinical benefits and not just demonstrate
responses, unless these are absolutely outstanding or the cancer
type is untreatable or rare (eg refractory ovarian cancer, glioblastoma
or metastatic malignant melanoma). However, we will first have
to study response rates in order to persuade the oncological community
of the merits of a survival/disease free interval/clinical benefit
study.
Phase II studies measuring response rates would
require 50-100 patients each and take around 24-30 months, although
if they need to be comparative, they will be larger. Phase III
studies will measure survival/disease free interval/clinical benefit
and require 300+ patients over 36+ months, depending on design.
While it is possible that registration could be achieved with
the phase II results as indicated in the MGI pharma plan, I doubt
it. Phase III studies may be started before the end of phase II
if clinical data at that time justify them.
In summary then I anticipate the following:
Complete current phase I—another 9-12 months
(finish mid 98)
Start phase Ibs in one or two cancer types and
include extended dosing schedules and combination pilots (finish
end 99; total cost $500k per cancer type)
Conduct two short phase IIs (2 x $800k per cancer
type, finish 1Q2002)
Start phase III in 2001-2002 to finish 2004-5
(best case) costs $2M per cancer type
While this provides a skeleton, there would
almost certainly be further studies to cover different territories
and different cancer study groups as well. The clinical plan from
MGI pharma is extremely rudimentary. A much more in depth assessment
is required identifying a specific cancer type with appropriately
definitive registration target. This will require considerable
consultation and thought to develop. The target date for NDA of
March 2000 in the University of California, San Diego contract
takes little account of probable reality and should be regarded
as unattainable.
Additionally, I would say that we would be competing
head to head with the big boys in the clinical trial arena without
the unique selling points that we have enjoyed so far with marimastat.
In this regard I suspect we would find ourselves having to pay
for all sorts of things other than simple clinical trial grants.
We would also be in a position where it is much easier for established
players to block us with various tactics, so I do not think that
these programmes would be easy for us to conduct. Timescales are
therefore likely to be long.
Finally, as you know, the marimastat programme
is of extraordinary magnitude compared to usual oncological clinical
research and causes us daily logistical problems. Further programmes
in oncology will require the recruitment of new teams of people.
With regard to D-HAC, I am unclear as to whether
this is targetted at solid tumours or leukaemias. In the case
of solid tumours the comments for 114 apply equally to D-HAC.
With regard to leukaemias, requirements for registration of new
agents will take a great deal of consideration. Because leukaemia
can be effectively treated with high intensity regimens, entry
to this field may require showing that a new agent in combination
improves clinical response/outcome. In turn, in this field, all
clinical trials are co-ordinated by collaborative groups. We would
have to ask their advice on how to proceed with testing. I do
not anticipate that this will be rapid or cheap, but I cannot
be specific without consulting externally.
I am copying Paul Littlewood on this memo as
he wanted some of my estimates for contractual work.
26 June 1997
UMBRIA
Foreword:
I knew PS when I was Medical Director in Japan
eight years ago. He was trying to sell us his products including
hexalen, ethyol and PALA. I discovered that ethyol had been investigated
in phases I, II and III in Japan in the late 70s-80s and found
to be ineffective. P did not disclose this to us. While he has
since stood the test of time, I find it hard to advise anyone
to trust him. The other pertinent observation is that despite
his CV and previous chair of ODAC, the FDA has been unimpressed
by his submissions to date. The reasons are either scientific
which casts doubt on P's claims or personal, which begs other
questions.
Hexalen:
Hexalen was in clinical use in 1986. P said
it had unrecognised efficacy and that the indications would certainly
broaden. This has not happened. This is an old product which will
not grow.
Ethyol:
This compound, too, is old and well known. I
think that the mode of action is real and that there is some protection,
the key questions are "how much?" and "how is it
perceived?" While I do not have sufficient data to answer
the first with certainty, but am not over impressed, the second
can be answered as "luke warm" with some confidence
based on FDA reactions and sales. There is no doubt that clinicians
would like a drug which protected against toxicity, would pay
quite a bit for it and prescribe it a lot. They do not. This lack
of enthusiasm would make further clinical studies difficult and
it would take very convincing results indeed in order to overcome
the preconceptions of little real clinical benefit.
Ethyol has already been launched with rather
modest success and it is difficult to turn things around from
this position. It may require one clinical trial of about 600
patients taking three to five years per additional indication
and then acceptance would be open to question. In any case, in
view of the license and patent situation, any fruits of clinical
work would be for the benefit not only of the various licensees;
but also for the generic manufacturers rather than us.
Neutrexin:
Methotrexate has stood the test of time despite
the attempted development of a large number of other anti-folate
drugs, all of which have been billed as more effective and less
toxic. I would see little joy there.
Corporate:
I have managed one acquisition and lived through
one merger. Both are painful and individually demotivating and
both would be detrimental to our main operations namely to market
marimastat and lexipafant.
Conclusions:
While this deal would be good for the executives
of Umbria, there seem few merits for us.
| 
