During the National Organization of Rare Disorders (NORD) Annual
Awards Banquet in the Spring of 1995, Mr. Ken Mehrling, Chief Operating Officer
of Sigma-Tau Pharmaceuticals, Inc., learned of Nord's search through Ms. Abbey
Meyers, President of NORD, for a commercial developer of cysteamine
hydrochloride ophthalmic drops for the treatment of corneal cystine crystal
accumulation currently provided under an Investigational New drug Exemption
(IND) by the NIH. Cysteamine ophthalmic drops is the only available treatment
for approximately 300 nephrotic cystinosis patients who suffer with painful
corneal erosions, This investigational product was created by the Eye Institute
(NEI) & National Institute of Child Health Development (NICHD) of the NIH.
Mr. Mehrling agreed to work with NORD and the NIH in bringing this
product to the US market place. The National Organization for Rare Disorders is
a unique federation of voluntary health organizations dedicated to helping
people with rare "orphan" diseases and assisting the organizations that serve
them. NORD is committed to the identification, treatment, and cure of rare
disorders through programs of education, advocacy, research, and service.
Through NORD, Sigma-Tau Pharmaceuticals, Inc. has established the
NORD/Sigma-Tau Drug Assistance program to assist eligible financially needy
patients to obtain the drug Carnitor, a metabolic drug for use in Carnitine
deficiency.
Sigma-Tau Pharmaceuticals, Inc. recognized that the
following steps would be necessary to bring cysteamine eye drops to market:
1. Obtaining orphan drug designation.
2. Commercial formulation development to
obtain a room temp/refined storage product supported by stability studies,
preclinical safety and clinical safety and efficacy studies in the to be
developed commercial formulation to be incorporated via amendments to the NIH
IND held by Dr. William Gahl of the NICHD on the current NIH formulation.
3. Submission of a New Drug Application
(NDA) for approval to market a commercial cysteamine eye drop formulation
meeting FDA requirements for safety and efficacy.
For those who are
unfamiliar with the term orphan drug designation, on January 4, 1983 the
president signed the Orphan Drug Act which established for the first time a
federal government policy to cooperate and assist in a program to facilitate
the development of drugs for rare diseases. The act provided important new
incentives designated to encourage sponsors to develop drugs without commercial
value.
In order to qualify for orphan drug status in the development of
a drug, the rare disease must affect less than 200,000 people in the United
States. A drug for such a disease or condition will be recovered from sale in
the U.S. Upon FDA approval of a NDA, an orphan drug receives seven years of
exclusive marketing rights for the specific disease indication.
In
working with the NIH we learned that cysteamine hydrochloride active ingredient
was no longer available to the NIH from their current source. In light of this,
in the summer of 1995, we began a worldwide search for cysteamine active
ingredient suitable for pharmaceutical use.
Over a dozen firms were
identified as possible sources. However, with the exception of one, the
companies were not interested because of the low commercial value of producting
small quantities of raw material.
Fortunately, in early 1996 Farchemia
located in Treviglio, Italy and a division of Tessenderlo Chemie Brussels,
Belgium, a major European chemicals group, agreed as a humanitarian effort to
develop pharmaceutical grade cysteamine hydrochloride in the quantities
necessary to meet investigational and commercial needs for cystinosis patients
being treated for corneal crystal accumulation.
With Farchemia's
commitment to provide active ingredient to both Sigma-Tau and the NIH, we
contracted with Hi-Tech Pharmaceutical, Amityville, NY, an ophthalmic solution
manufacturer, to develop a stable commercial formulation of cysteamine eye
drops.
According to the NIH, their formulation, cysteamine
hydrochloride 0.55%, is stable one week at room temperature, two weeks under
refrigeration, and for eighteen months frozen. The current NIH formulation is
composed of a sterile solution of cysteamine HCI 0.55% w/v with benzalkonium
chloride and sodium chloride.
Hi tech developed a new formulation which
retains cysteamine as the free thiol in stable form for seven (7) months at
room temperature and up to twenty four (24) months under refrigeration. The
formulation consists of Cysteamine HCI, Monosodium Phosphate, Anhydrous,
Disodium EDTA, Benzalkonium Chloride, and Carbon Dioxide Free Purified Water
(pH 4.10-4.50).
Sigma-Tau Pharmaceuticals, Inc. met with FDA's Office
of Orphan Drug Products in the summer of 1996 on our progress with the active
ingredient search and the search for a firm to develop a commercial
formulation. During the meeting and also at the 1997 cystinosis conference in
San Diego we were made aware of the opportunity to apply for an orphan grant
for the upcoming clinical studies on the new formulation.
In May of
1997 we submitted an application for Orphan Drug Designation for cysteamine
hydrochloride in the treatment of corneal cystine crystal accumulation in
cystinosis patients. Orphan Drug Status was granted August 1997.
Our
next step was for the manufacture of scaled up batches of the Hi-tech
formulation for the purpose of testing the product for eye irritation in
rabbits and eventually, for evaluation in clinical trials in humans.
A
30 day ocular safety study in rabbits was completed by Toxikon contracted by
Sigma-Tau. The test article was evaluated for its potential to produce ocular
irritation after sustained use (2 drops per hour for 8 consecutive hours/day)
over a 30 day period. No lesions were noted in any of the treated or control
eyes of any of the animals at any of the observation points Based on the
evaluation criteria of the protocol, the test article, Cysteamine Hydrochloride
Eye Drops, was considered to be a non-irritant to the ocular tissue of albino
rabbits, under the experimental conditions employed.
On the basis of
these results, the way was cleared for testing of the new formulation from
Hi-Tech in patients to show equivalence in terms of clinical efficacy and
safety between the NIH and the new formulation.
Sigma-Tau sponsored a
study to evaluate the safety and efficacy of this new preparation in humans in
a multicenter clinical trial based on Protocol 98-EI-0109 developed by NEI
Clinical Center of the NIH. This protocol was established in two components;
one to access safety and one to access efficacy. As part of the clinical
program development, the new formulation prepared by Hi-Tech was evaluated for
safety in 20 current NIH patients and for efficacy in 16 new patients.
The primary objective of the safety study was to estimate the
proportion of patients experiencing a serious adverse effect (AE) in the new
formulation treated eye. The primary objective of the efficacy study was to
estimate the proportion of the patients with a reduction in crystal density of
1,000 unit to the eye treated with the new formulation in comparison to the old
formulation. The safety and efficacy studies were conducted concurrently.
In the safety study, 20 compliant cystinosis patients already receiving
the current preparation of eye drops and under follow-up at the NEI Clinical
Center were randomized to the current preparation in one eye and the new
preparation in the other at the time of their semi-annual ophthalmologic
examination. Patients were questioned periodically by phone regarding
complications, and a daily log of side effects in each individual eye was kept.
The study duration was 6 months.
Results: Upon completion of the study
no statistical difference was found between the two preparations in terms of
safety. The most common AE's were stinging and burning.
For the
efficacy study, 16 patients were randomized to the current formulation in one
eye and the new preparation in the other eye. Ophthalmic evaluations, complete
with corneal slit lamp examinations and standardized photographs, were
performed every 3 months at the NEI Clinical Center, Ann Arbor, Michigan, and
La Jolla, California. The photos were evaluated using a scale of standard
crystal densities in a masked fashion at the NEI Clinical Center. The study was
to be completed in one year, and the outcome was assessed by determining if the
new formulation was therapeutically equivalent to the old formulation.
Randomizing the different drops to the two eyes has been successfully
accomplished in previous studies of 115 patients. No episodes of systemic
non-adherence to the placement of the assigned drops to the assigned eye were
documented.
Results: Ten of fifteen eyes receiving the current
formulation experienced a 1 unit or more improvement at least once during the
follow-up, whereas 3 eyes receiving the new formulation experienced an
improvement of 1 unit or more during follow-up. Seven of the eyes receiving the
current formulation showed an improvement of 1 unit, or more at one year,
compared to 1 of the eyes receiving the new formulation (=0.04 by Fisher's
Exact Test). The new formulation was not therapeutically equivalent to the old
formulation in reducing corneal cystine crystal score (CCCS). The rates of
ocular adverse events were similar between the two treatments.
The
above clinical program was monitored and the data collected and analyzed by the
EMMES Corporation. EMMES was founded in 1977 and has a 20 year history of
providing monitoring, data management and statistical analysis for clinical
trials sponsored by the government, industry, or universities.
Concurrent with clinical safety and efficacy studies to determine the
equivalence of the Hi-Tech formulation to the NIH product, EMMES Corporation
was assigned the task of data abstraction and analyzes of five clinical studies
performed by NEI on the current and earlier NIH cysteamine eye drop
formulations. Such documentation is to be included in the clinical section of
the to be submitted NDA. These retrospective clinical studies may be summarized
as follows:
1. Study 86-EI-0062A in which
2 patients were treated with 0.1% cysteamine. There was a positive effect of
cysteamine eye drops, which was very well tolerated.
2. Study 86-EI-0006213-1 in which Nineteen
(19) patients in a double masked controlled trial were treated with
0.1%cysteamine. In terms of efficacy there was a 1;0 unit decrease in Corneal
Cystine Crystal Score (CCS) or failure to have a 1.0 unit increase of the
baseline score was less than 1.0 CCCS. This resulted in no statistical
difference (P=0.13) between treated and placebo eye. As to safety, three
patients reported itching and irritation in both placebo and treated eye.
3. Study 86-EI-00662B-2: In this double
blind study 8 patients were treated with the current 0.5% strength Cysteamine.
From an efficacy standpoint there was a 1.0 unit decrease in CCCS which
resulted in a statistical difference (P=0.013) between treated and placebo eye.
Seventeen (17) patients reported AE's with the two groups (pain and redness
were the most common AE's). The rate of AE's was equal between the two groups.
There was no report of photophobia or corneal erosions.
4. Study 92-EI-0230: In this double
masked study 20 patients received either 0.5% cysteamine or 0.5% cysteamine
with Benzoalkonium (preservative). Both regimes were equally effective in
preventing crystal formation in the one year follow-up period (patients had
little crystal formation CCCS <1.0) One AE was reported occurring in both
eyes (stinging and burning).
5. Study
94-EI-0016: In this double masked study 14 patients received either 0.5%
cysteamine or 0.5% cystamine. The study was stopped by the DDATA Safety review
board based on the planned preliminary analysis indicating no efficacy with
cystamine. Three patients reported AE's and the most common were burning
redness occurring in both treatments.
In terms of pre-clinical safety
studies the safety and tolerability of the NIH Cysteamine and/or Cystamine
(Cysteamine disulfide) eye drops at concentrations from 0.11% up to 10% were
evaluated in four different rabbit studies. The results were as follows: No
sign of toxicity at the 0.5% strength. There was an initial sign of toxicity at
the 1.0% strength and infiltrations and conjunctivitis were seen at the 2.0%
strength.
As shown above the six month safety study (Protocol
98-EI-0109) in patients who previously received cysteamine eye drops from the
NIH demonstrated no statistical difference between the NIH and Hi-Tech
formulations in terms of safety. While the results of the one year efficacy
study (Protocol 98-EI0109) in patients never receiving cysteamine eye drops
indicated that the new (Hi Tech) formulation was effective, it was not as
effective at reducing corneal cystine crystal score (CCCS) as the current NIH
formulation.
In light of the results of the studies under Protocol
98-E10109, and in consideration of time and the medical necessity for a
commercial form of cysteamine eye drops, our efforts are now being concentrated
on commercial form of cysteamine eye drops, our efforts are now being
concentrated on commercializing the current NIH formulation whose safety and
efficacy are further supported by the clinical studies.
Hi-Tech
Corporation has manufactured batches of the product via the NIH formula which
are on stability under freezer and refrigeration conditions. Data is being
generated on the chemistry manufacturing controls aspects of NIH formula by
Hi-Tech to prepare for the New Drug Application (NDA) submission to the Food
and Drug Administration (FDA) for approval to market the Hi-Tech prepared NIH
formula eye drop. Hi-Tech currently has twelve month data to support the
product under frozen storage. We await additional data from Hi-Tech to
determine the appropriate expiry date for storage of product under frozen and
refrigerated conditions.
Our plan for the NDA is to assemble and review
available pre-clinical and clinical safety and efficacy data generated on the
current NIH formulation eye drops supported by the safety and efficacy data
obtained from the clinical trials (in humans) comparing the NIH formulation and
the new (Hi-Tech) formulation. The chemistry manufacturing and controls (CMC)
section to be included in the application will include, in addition, to the
Hi-Tech CMC data on the to be marketed product (NIH formula eye drop), CMC
information on the drug substance (active ingredient) from our supplier,
Farchemia.
Once all of the above is collected, summarized and reviewed,
we will prepare the "package insert" labeling for the product which is based on
the chemistry, pre-clinical safety, clinical safety and efficacy information
from development of the drug. The package insert or direction circular is the
processing mechanism through which FDA and drug manufacturers communicate
essential science based prescribing information to health care professionals.
Our target for submission of the NDA is 2003 and if all goes well,
approval may be forthcoming in 12 months following submission. During review of
the application, FDA will consider the Good Manufacturing Practices (GMP)
profiles of Farchemia and Hi-Tech to determine if each meet requirements for
the manufacturing/packaging of the drug substance and drug product
respectively. In addition, there may be an evaluation/audit by FDA of the in
house records supporting the clinical trials of the NDA.
Due to the
need to store the NIH formula product under freezer conditions because of its
limited stability, we are evaluating various means of distribution to assure
that patients receive properly stored commercial product.
View the History in WSWord format - EyeDropDev.doc - You can save and print it.