Actelion Ltd announced today a poster presentation at the annual conference of the American Society of Human Genetics (ASH-G) of one-year results from a randomized controlled study evaluating safety and efficacy of miglustat (Zavesca®) in patients suffering from Niemann Pick Type C (NP-C), a rare genetic disease associated with multiple neurological
manifestations.
Although not statistically significant, the 29-patient-study showed trends toward improvement or stabilization in terms of saccadic eye movements (by electrophysiological assessment) and swallowing and audition (by clinical assessment) in patients receiving miglustat compared to standard of care. The study will continue as planned for another 12 months, during which time all patients will receive miglustat. A complete discussion of currently available study findings are contained in: Patterson M., Vecchio D., Prady H., Ait-Aissa
N., Abel L., Wraith E. - Poster 2505/T, ASH-G 2005 (Salt Lake City).
Marc Patterson, M.D., FRACP, Professor and Head, Division of Pediatric Neurology at Columbia University New York/USA, commented: "We know already that miglustat crosses the blood-brain barrier and accesses the brain. For the first time, we have been able to observe some potentially beneficial effects in patients with NP-C. I am also encouraged with these observations as they could
suggest some restoration of function in neurons that have been altered by the disease process. As such, this study is another step forward in our quest to understand and potentially treat this complex disease."
Twenty-five patients have completed the first 12-month study period and four have discontinued treatment (three in the miglustat group, one in the standard care group). Results from the 12-month data showed improvement in horizontal saccadic eye movements (by blinded centralized assessment) and improvement in swallowing, none reaching formal statistical significance. The analysis also
showed stabilization in auditory acuity in treated patients compared with deterioration in the untreated group.
The safety profile of miglustat observed in this study was consistent with the results obtained in patients with GD1 treated with miglustat 100 mg three times daily, particularly regarding weight loss and gastro-intestinal disturbances.
Based on these results, the study will continue as planned for a further 12 months during which time all patients will receive miglustat and will be followed with the same set of assessments.
From Nikki Harrison, OGT-918 Clinical Trial Manager, April 14, 2005
The data collection for first 12 months of the study will be closed and the interim data analysis will begin in the summer of 2005.
At the point of closure of the data collection, a process will begin to validate the data, identify missing information, compare data and check for consistency between centers, the data also will be analyzed by external assessors. This process is likely to take several months due to the complexity of the disease however we hope that the initial results from the first 12 months of the trial will be available at the end of the year.
All patients currently taking part in the trial who have reached either Month 12 (Paediatrics) or Month 24 (Adults) will be given the option to continue the provision of treatment on an extended use study. This additional therapy will be provided to patients until such time as results are available from the Interim analysis.
It is difficult to know at this stage if we can expect positive results from 12 months of therapy in patients with Niemann-Pick type C disease but we very much hope that the signs will be positive and we remain committed to the study.
From Nikki Harrison, OGT-918 Clinical Trial Manager, October 21, 2004
The recruitment for the OGT 918-007 study is now officially closed for both the pediatric patients as well as the adults. The recruitment was completed
for the pediatric arm of the trial ahead of schedule in September and we now have 4 pediatric patients in the UK and 8 in the USA. Thank you very much
to you all for your continued interest in the trial.
From Nikki Harrison, OGT-918 Clinical Trial Manager, July 02, 2004
We are very pleased to announce that the recruitment for the Adult (over 12 year old) arm of the trial has been closed at both centres on 30th June 2004, just one patient short of our target number of 30 patients, which is fantastic.
Recruitment for the paediatric arm of the study will remain open until the end of September. Should you require further information regarding the trial please do not hesitate to contact either Darleen Vecchio on + 1 212 305 4136 or Helena Prady on + 44 (0) 161 727 2967.
From Actelion, June 16, 2004
Actelion and CellTech announced today that Actelion has been awarded an extended licensing agreement for Zavesca® (OGT-918). The agreement means that Actelion will take full responsibility for the management of ongoing or planned clinical trials in the approved indication as well as those exploring the use of Zavesca^® in other glycolipid storage disorders. Phase III trials in ... Late Onset Tay-Sachs, Type 3 Gaucher disease and Niemann-Pick Type C disease are being conducted.
Actelion will be responsible for all clinical, regulatory and marketing activities. Celltech is responsible for manufacturing. Zavesca® is currently commercially available in the UK, Germany, the Netherlands, France, Spain, Sweden and Austria. It will be marketed in other European countries in the coming months. In the United States, Zavesca^® became commercially available in January 2004 following FDA approval. In Canada, Zavesca® has been approved in March 2004.
[Webmaster Note: Any additional information that would be specific to the Niemann-Pick Type C clinical trial would be provided to participants by Actelion or CellTech.]
From CellTech, March 22, 2004
CellTech announced today that the NPC pediatric trial for OGT-918 has been approved in the United States. Applications for the trial are now being taken. A mailing has been sent to NPC families about this trial. To apply or to obtain further information about the pediatric trial, contact Darlene Vecchio at Columbia University. A total of 12 pediatric patients will be included in the trial (six from the U.S. and six from the U.K.). All pediatric patients in the trial will receive OGT-918 (no control group is planned).
Please note that the adult clinical trial has not filled all available placements. If you are interested in participating in the adult trial, you should also contact Darlene.
From Actelion, January 5, 2004
Actelion Ltd today announced the availability of Zavesca® (miglustat) capsules in the United States. Zavesca® is the first oral treatment option for type I Gaucher disease and is also already approved and available in the European Union. The FDA approved Zavesca® mid 2003 for the treatment of adult patients with mild to moderate type I Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity, or poor venous access).
Through a global steering committee, Actelion and Celltech are currently conducting clinical studies with Zavesca® for the treatment of other lipid storage disorders, such as type 3 Gaucher disease, Niemann-Pick type C, and Late Onset Tay-Sachs.
[ For more information about Zavesca®, visit www.zavesca.com. ]
Notice from the Webmaster, October 19, 2003
With the completion of the sale of Oxford GlycoSciences to Celltech, corporate email addresses and websites identified in earlier items are out of date.
From Celltech (Oxford GlycoSciences), August 13, 2003
"OGS was recently acquired by Celltech Group, a leading European biotechnology company, with a substantial long term commitment to innovative drug discovery and development. OGS/Celltech continue to be committed sponsors of the Niemann-Pick Type C disease area and the clinical trial with OGT 918 (Zavesca).
The adult/juvenile clinical trial is now running and we are pleased to say that at this moment in time we have 9 patients randomised to the trial in the US. The recruitment for the trial is still open and ongoing and Dr. Patterson and Lori Seidman are continuing to assess new patients for eligibility to participate. It is hoped to achieve the target number of 15 adult/juvenile patients as soon as possible.
Lori is busy preparing to start the paediatric part of the study (patients aged less than 12 years). This arm of the study will now use the capsule formulation of OGT 918 despite previous plans to use an Orodispersible formulation. Therefore all paediatric patients will need to complete the swallowing assessments in order to be eligible for the study.
Depending on when we receive IRB approval for the study in under 12s, we hope to commence screening of paediatric patients in October 2003. We will keep you updated as we progress through the clinical study review and approval process.
OGS appreciates that there is a huge amount of anticipation of these trials and that organising a trial, including the different stages of decision making, is complex and time intensive. However, please be assured of our commitment to performing the best clinical study we can to assess this drug in NPC disease. We would very much like to extend a big thank you to everyone for their support of this clinical programme.
If you have any questions please contact Medinfo@ogs.co.uk"
From Celltech (Oxford GlycoSciences), August 1, 2003
"The FDA has approved Zavesca(R) for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity, or poor venous access). Woman who are or may become pregnant should not take Zavesca(R). Zavesca(R) will be available to patients in the United States later this year."
From Douglas Pease (NNPDF), June 9, 2003
I spoke with representatives from OGS and Actelion at the 2nd International Symposium on Niemann-Pick Type C. Celltech, the new owner of OGS, has said it intends to continue with the pediatric clinical trials of Zavesca for patients under the age of 12. Regulatory approval to begin the pediatric trial in the United Kingdom is expected shortly. The pediatric trial in the United States is expected to be approved in the late summer or early fall.
From the OGS and Actelion websites, April 18, 2003
Oxford GlycoSciences Board of Directors is recommending sale of the company to Celltech. The OGS Board had previously recommended an offer by the Cambridge Antibody Technology Group but changing market conditions have made that offer unsuitable. Celltech has announced that it has purchased over 60% of the OGS stock, an action that effectively gives it control of Oxford GlycoSciences.
In late March, OGS filed an amendment to its application with the FDA seeking approval of Zavesca for Type 1 Gaucher Disease. The amendment includes additional safety data requested by the FDA. The FDA is reviewing the amendment.
Actelion is the company that will market Zavesca as it is approved in different countries. At present, Zavesca is only appoved in Europe. Actelion launched sales of Zavesca in the United Kingdom in early March. They expect it to be available in other European markets by the end of 2003.
From Lori Siedman, OGT-918 Clinical Trial Coordinator, issued on Feb. 6, 2003
"OGS gave me this information as I have been inquiring daily on behalf of the NPD foundation. While it is not official in terms of that it is definite, it is the best information they can give me at this time based on what they know at this time. As you heard they are merging with another drug company and things can always change because of this. In any case, the plan is the one I previously described. (Please see statement below). I'm hoping that all approvals will be ready sometime in April so that we can begin bringing in the younger children at the beginning of the summer.
OGS Tentative Timeline: The plan is to submit the IND (Investigational New Drug Application) for the pediatric formulation to the FDA in March. The FDA is obligated to give an approval or request more information within 4 weeks. OGS is hoping to have approval in April so that we can submit an amendment to our IRB (ethics committee) that would include pediatric subjects in our current protocol. I'm guessing it will take at least one month for our IRB to approve the change. The number of pediatric patients has still not been determined.
At this time, I think we are looking at May or June before we will begin bringing in children less than 12 years of age. We would have to move through our current list of patients before we could begin seeing the younger participants. As of today, I have scheduled the first five subjects and they are aware of when they will be seen for screening. I have scheduled this group up to the end of March. The first subject will be randomized this coming week."
From Lori Siedman, OGT-918 Clinical Trial Coordinator, issued on Jan. 22, 2003
"Dr. Patterson and I are pleased to announce that we have begun scheduling patients for the OGT-918 for Niemann Pick, Type C screening. As many of you
know, the screening involves two visits to Columbia University over the period of one month. The two visits must be at least eight days apart and must be completed within thirty days. Each visit will last approximately 3 days. During each screening visit, the family and subject will meet with Dr. Patterson to complete the informed consent and then have a physical and neurological exam. I will then assist the subject with doing a swallowing exam, peg board exam, quality of life questionnaire, and spiral drawings. Each subject will see the dietician for a nutritional evaluation and have their blood drawn at both screening visits. The following exams will be
scheduled one time over the course of the screening visits: tremor assessment, psychometric testing, CAT Scan of the abdomen, and nerve conduction testing. These tests will be repeated twelve months after each subject is randomized into the study.
During the last day of the second screening visit each subject will be randomized to the drug or non-drug group. Ten subjects will receive OGT-918 and five will not. Each family will know if their child will receive the drug or not prior to their departure from Columbia. There is no placebo. If the subject does receive the drug they will take home three months worth of OGT-918. All subjects will be followed up by phone one week after they leave Columbia and the again one month later and two months later. During month three they will return to Columbia to be re-assessed.
Depending on the availability of the staff at NIH, the subjects will travel to Bethesda for their eye exam either during screening visit one or two. The eye assessment involves two tests. Each test is one hour in duration. Each test will be done in the morning and than repeated in the afternoon.
I will be scheduling approximately two patients per month to be screened for a total of four visits per month. I would ask each family to be patient with the scheduling process as it takes many hours and sometimes days to coordinate the eight departments involved in the study. I can be contacted preferably by e-mail at Lseidman@neuro.columbia.edu or by phone at 212-305-4136 for any further questions.
I look forward to getting started and meeting all of the families who I have spoken to over the course of many months!"
Information from Oxford GlycoSciences on Jan. 23, 2003
Oxford GlycoSciences announced that it will merge with Cambridge Antibody Technology Group Plc (CAT). The new company will be called Cambridge Antibody Technology Group. The company will have a stronger financial position as well as a broader portfolio of products. The senior executives at Oxford GlycoSciences will continue with the new company as members of the Board or on the Executive Committee. Senior executives at Cambridge Antibody will continue in their present positions.
The Zavesca clinical trial underway in the United Kingdom and the United States will continue as planned. Marketing and distribution of Zavesca in Europe for Type 1 Gaucher's Disease will also continue.
The new company intends to review its drug development portfolio to focus on the highest quality projects. The results of the review will be announced in November 2003. It appears that OGT-923 would be included in the review.
Information from Oxford GlycoSciences on Nov. 5, 2002
Oxford GlycoSciences announced that a Phase I study with OGT 923 has commenced in healthy volunteers.
OGT 923 (N-butylgalactonorjirimycin) is an iminosugar and an analogue of Zavesca ™ (OGT 918, INN: miglustat). OGT 923 has demonstrated efficacy in in vivo studies, as well as a favourable pre-clinical tolerability profile. This initial study is double-blind to allow comparison to placebo for tolerability and an escalating dose design is being used to evaluate once and twice daily dose pharmacokinetics.
Chris Moyses, Chief Medical Officer and Development Director of OGS, said:"'The start of this OGT 923 study marks the achievement of a major OGS objective to bring a second iminosugar into clinical development for glycosphingolipid storage disorders. OGT 923 may be particularly suitable for studies in diseases with nervous system involvement, such as Sandhoff and Tay Sachs disease."
Information from Oxford GlycoSciences on Nov. 26, 2002
Oxford GlycoSciences announced that Zavesca (OGT-918) was approved in Europe for Type 1 Gaucher's Disease. The drug is expected to be available for sale in 2003. Regulators did limit the approval to Gaucher's patients who are not candidates for enzyme replacement therapy and did request follow up safety data. This is the first regulatory approval for Zavesca.
Information from Oxford GlycoSciences on Nov. 21, 2002
Oxford GlycoSciences has issued a statement about the FDA review of the Zavesca (OGT-918) clinical trial for Type I Gaucher's Disease. The full statement can be found on the OGS website under "Press Releases" or you can read the PDF version here (Adobe Reader is required).
The FDA had earlier indicated that Zavesca was "not approvable" based on data submitted, but this was not a formal and final disapproval. Representatives from the FDA and OGS met to clarify concerns and identify a way to proceed. The statement explains the results of that meeting.
Several OGT-918 clinical trials have been conducted or are underway, including the one for Niemann-Pick Type C. The Type I Gaucher's Disease trial has advanced the farthest in terms of U.S. regulatory approval. As noted below, Zavesca is awaiting final approval in Europe.
Information from Oxford GlycoSciences
[ Webmaster Note ] - OGT-918 has been renamed again. The new brand name is Zavesca. Previously it was known as Vevesca.
July 2002 OGT-923, an analogue of OGT-918, has shown efficacy in pre-clinical trials for Niemann-Pick Type C and may reduce side effects. A Phase I clinical trial of OGT-923 is targeted for the end of 2002. (Analogues are two similar chemicals that act the same)
July 2002 The Committee for Propietary Medicinal Products (CPMP) has recommended approval of Zavesca (OGT-918) in Europe for treatment of Type 1 Gaucher's Disease. The CPMP included several restrictions on its approved use, including that it only be used for individuals who cannot tolerate the existing enzyme replacement therapy. Final approval by the European Commission is expected in three to four months.
July 2002 The suspension of clinical trials of Zavesca in Isreal was lifted following a review of clinical data.
June 2002 The U.S. Food and Drug Administration (FDA) sent a "complete response" letter to OGS concerning Zavesca for Type 1 Gaucher's Disease. The letter stated the clinical trial data was insufficient to prove safety and efficacy. OGS has met with the FDA to identify the specific issues behind the letter and plans to address the concerns so the application can move forward.
From Dr. Marc Patterson and Barb Vorpahl issued on June 3, 2002
We have some good news for NP-C Families.
The clinical trial of OGT918 is now ready to get underway in the US. We are pleased to announce the IRB (Institutional Review Board) has finally given approval.
We are including a notice from Dr. Marc Patterson (below) with information on the Clinical Trial. If you are interested in taking part in the clinical study or wish additional information, please contact Lori Seidman, CPNP, Clinical Trial Coordinator at:
Phone: 212-305-4136
Lori will supply more detailed information on the clinical trial as well as information for applying to all interested NP-C families.
Information on OGS Clinical Trial in Niemann-Pick Type C Disease: May 29, 2002
The study will be conducted at 2 clinics specializing in the care of patients with NPC at Royal Manchester Children's Hospital in the UK and Columbia University in the US. Fifteen patients will be enrolled at each center.
The study will assess the safety and effectiveness of the glucosylceramide synthase inhibitor OGT 918 for the treatment of NPC. In order to do this, the study employs a no treatment control arm, whereby one-third of patients enrolled i.e. 10 patients (or 5 from each study center) will NOT receive the trial therapy for one year.
Patients with a proven diagnosis of NPC who are twelve years of age or older, able to cooperate with eye movement recording studies, and able to travel to the US study sites in New York, NY and Bethesda, MD may apply to participate (other exclusion and inclusion criteria will be reviewed in detail with potential participants)
The trial is now open for patient screening in the United States.
Interested families should contact the study coordinator, Lori Seidman, CPNP, at 212 305 4136 or by e-mail at ChildNeuro@neuro.columbia.edu. We anticipate a large number of calls, and trust that families will understand that Ms Seidman will reply to inquiries in the order on which they received, in as timely a fashion as possible.
From Oxford GlycoSciences (OGS) issued on April 24, 2002
For immediate release
OGS temporarily halts Vevesca (OGT 918) treatment in Israel as a precaution pending investigation of an unexplained adverse event
Oxford, UK, 24 April 2002 - Oxford GlycoSciences has been informed that a 66 year-old patient, formerly in the OGT 918-001 trial, who continued in the extended use capture protocol but stopped treatment with OGT 918 in October 2001, developed cognitive dysfunction of unknown cause. The patient is still under investigation and a diagnosis has not yet been established. There are other potential causative factors relevant to this event, and according to WHO criteria, a relationship to drug treatment appears unlikely at this time.
The Ethics Committee in Israel has abstained from expressing any opinion about a possible relationship until the results of the ongoing tests are obtained, and recommended that OGT 918 administration be temporarily stopped as a precaution, pending the outcome of the clinical investigations. All Investigators and relevant Regulatory Authorities are being informed.
Dr. Chris Moyses, Chief Medical Officer of OGS, said, "We are working with the investigator to clarify this issue and, whilst a relationship to drug treatment appears unlikely, treatment has been withdrawn purely as a precautionary measure."
[ Webmaster Note: The OGT 918-001 mentioned in the release appears to be the first Gaucher's trial. ]
From Oxford GlycoSciences (OGS) issued on March 11, 2002 On 7 Mar 02, Oxford GlycoSciences (OGS) announced that they will be conducting a clinical trial of their glucosylceramide synthase inhibitor OGT 918 in Niemann-Pick Type C disease (NPC).
The study will be conducted at 2 clinics specializing in the care of patients with NPC at Royal Manchester Children’s Hospital in the UK and Columbia University in the US. Fifteen patients will be enrolled at each center.
The study will asses the safety and effectiveness of OGT 918 for the treatment of NPC. In order to do this, the study employs a no treatment control arm, whereby one-third of patients enrolled i.e. 10 patients will NOT receive the trial therapy for one year.
The study has been initiated and patient screening has commenced at Manchester. Study start at Columbia University is imminent.
From Oxford GlycoSciences (OGS) issued on March 7, 2002
Webmaster Note: This is part of an R & D Update press release issued by OGS via PR Newswire. The compound OGT 923 noted in the second paragraph was not further identified.
"Lysosomal Storage Diseases:
-- The Company's lead compound Vevesca (OGT 918) is under regulatory review in Europe and the
United States for Type I Gaucher disease. Publication of the enzyme replacement switch/combination
data is progressing and is currently under peer review. The Company will today announce that it is
initiating new clinical studies to investigate the safety and efficacy of OGT 918 in Niemann-Pick Type C disease, Neuronopathic Gaucher disease and Late Onset GM2 Gangliosidosis.
-- The Company will also announce a new programme based on OGT 923, a new chemical entity which has shown efficacy in pre-clinical models of Sandhoff and Niemann Pick Type C disease. OGT 923 is now in development at OGS with a target date of first dose to man (Phase I) in Q4 2002.
Dr Chris Moyses, OGS' Chief Medical Officer said: "Evaluating potential new indications for OGT 918 and commencing a second development programme underscores our commitment to the therapeutic area. We continue to lead the evaluation of novel oral agents for substrate reduction therapy for patients with Gaucher disease and related glycolipid storage disorders."
From Susan Green, NPDG (UK) received on February 21, 2002
A Clinical Trial Nurse has been appointed for the OGT-918 trial and the first patient is scheduled for initial tests on Monday, February 25th. The trial is underway in the United Kingdom!
From the Willink Biochemical Genetics Unit protocol description received on January 25, 2002
Webmaster Note: This is a summary of the protocol description and is not the complete document. The summary was not written or approved by Willink.
The initial phase will last 12 months with a second 12 month extension possible. The study aims are to assess safety, tolerability, and efficacy (effectiveness).
A maximum of 30 patients will participate in the U.K. and the U.S., with approximately 15 being tested in each country.
Patients must be over 12 years of age
The patient must be able to swallow and participate in clinical assessments
During the initial phase, approximately one third of the participants will not receive OGT-918. This control group will be chosen at random and will undertake clinical assessments only. During any extension, all participants will receive OGT-918.
Up to seven clinic visits will be required during the initial phase with up to five additional visits during the extension. Some or all visits may require two days to complete the required tests. All visits will be done on an outpatient basis.
Assessment tests include blood samples, full body MRI, nerve conduction velocity, eye movement, hand movement, nuitrional review, and a general physical exam.
Oxford GlycoSciences will pay reasonable costs related to the clinical trial, including travel, accomodations, and meals.
From Susan Green (NPDG (UK) received on January 21, 2002
The United Kingdom has approved the OGT-918 clinical trial for children 12 and older. Patient Information Letters have been mailed to all known NPC families in the U.K. The letter describes the inclusion criteria and the procedure for applying for the trial. A research nurse has been appointed and the trial is scheduled to begin February 4th.
The United States is still reviewing the application for the trial. We will update this page as soon as possible with news about the U.S. trial.
From Barb Vorphal (NNPDF) received on November 26, 2001
Dr. Patterson has informed me that review of the OGT-918 protocol by U.S. and European regulatory bodies is nearing completion. It is hoped that approval of this clinical trial for juvenile and adult NPC patients (age 12 and older) will be issued soon. Oxford GlycoSciences continues to work on a formulation of OGT-918 for younger patients.
From Oxford GlycoSciences (OGS) issued on September 5, 2001
While Oxford GlycoSciences continue to develop a paediatric formulation of OGT-918, plans for a clinical trial in juvenile and adult patients with Niemann-Pick Type C are in progress. A meeting with the study investigators, Dr. Ed Wraith and Dr. Marc Patterson, was held at the Niemann-Pick Disease Group Conference in Telford this year to review potential study designs and response measurements for patients aged 12 and older.
As a result of the meeting, a study was agreed which would recruit up to 30 patients aged 12 and over with NPC and look at both the tolerability of OGT-918 and the response to treatment. An assessment of ey movement has been chosen as the primary measurement of response. At the time of writing, both investigators are reviewing the final protocoal and work has begun at OGS to apply to the national authorities for persmission to conduct the trial.
Alison Welsby
5th September 2001
A Note to the Families (March 24, 2001)
In posting the March 19th and March 22nd updates on the Vevesca (OGT-918) clinical trial, we have been asked to remind everyone that this project is a research study. As such, there will be delays as unforeseen problems are encountered and sudden progress as obstacles are overcome.
The ups and downs of this study are certainly frustrating for everyone. Dr. Patterson and OGS are working closely together to review all of the alternatives to the formulation, the protocol, and the timing of the study to ensure that the trial proceeds as quickly as possible.
Doug and Janet Pease
NNPDF Webmasters
From Oxford GlycoSciences (OGS) received on March 22, 2001
Good news ! It looks likely now that the delay will not be as bad as we feared. We are changing a few things around with regards the formulation and I have to amend the protocol and re-submit it for approval both in the US and the UK. Certainly the 6 months delay we were talking about should be considerably reduced. [Webmaster Note: See the March 19th update below for a discussion of possible delays]
I am hopeful of a Spring start to the study but how certain things will work out is still unclear. However I wanted to keep you informed of the progress.
Alison Welsby
Clinical Project Manager
From Oxford GlycoSciences (OGS) received on March 19, 2001
Development of a Pediatric Formulation by OGS
OGS began to develop a pediatric formulation of OGT 918 in March 2000 as a prelude to starting clinical trials following requests from a number of clinicians treating children suffering from a number of glycolipid storage diseases such as Niemann-Pick C.
The challenge to the formulation team was that any formulation developed would have to be easy for infants with swallowing difficulties to take. It also had to be sugar free (some sugars are known to interfere with OGT 918 action) and comply with all relevant Federal regulations regarding safety and quality.
It is generally assumed that children under the age of 12 have difficulties in swallowing tablets or capsules, so the existing formulation of OGT 918 in capsules was inappropriate for the children concerned. Children under the age of 12 also need to have the dose of medicine adjusted for their body weights. This is most easily achieved using a liquid formulation of OGT 918.
Initial studies of OGT 918 in water showed that OGT 918 has a very bitter taste, with an unpleasant aftertaste. Even high concentrations of sweeteners such as mannitol and sorbitol were unable to mask the bitterness.
In June 2000 OGS started work on formulations that contained additional artificial sweeteners such as aspartame (Nutrasweet(). Initial taste trials were encouraging as were the short term quality control checks on acidity (pH), appearance, smell and colour.
At this stage we also investigated the use of additional flavouring agents such as chocolate, strawberry, aniseed and cocoa powder to further hide the taste of OGT 918. Chocolate and cocoa were not progressed as they emphasised the bitterness of the OGT 918 and solutions containing aniseed were unpleasant in appearance (grey looking). Solutions containing strawberry flavourings were reasonably palatable and were taken into the next phase.
In August 2000, volunteers at OGS taste tested 3 formulations containing OGT 918, including the strawberry formulation above and two others, one with more strawberry flavouring and another containing a mixture of fruit flavourings. These trials showed that the most palatable formulation contained the variety of fruit flavouring agents. This formulation was optimised further by removing the preservative, adding an approved food colouring agent and natural gums to make the solution look and taste better still. The final formulation was a dried powder designed to be filled into foil sachets. The powder is then dissolved in water and the child given different amounts based on their body weight.
Before clinical trials could begin, it was necessary to prove that the sachet formulation was of the correct quality and was stable and suitable for clinical trials. To do this, OGS made 10kgs of the formulation and filled it into sachets for storage at high temperatures and humidities to see if the formulation would meet the Quality Control limits.
The testing followed strict guidelines set down by FDA and included looking at how much OGT 918 was in the powder; whether the OGT 918 was breaking down; how much water was in the powder and the change in acidity of the solution. OGS tested the sachets and the powder every month for 3 months.
The results became available in February 2001 and have been discussed with clinicians so that the information can be passed on to families and patient groups.
The results of the testing have shown that at high temperatures and humidities the amount of water in the powder increases and the amount of OGT 918 breakdown products are above specification. The results have also shown that the formulation is getting more acidic, that water is getting into the sachet and that the powder is sticking together. The results unfortunately mean that the formulation does not meet the requirements for clinical trials.
OGS have re-evaluated how to give the drug safely to children and have tried various juices/fruit sauces to disguise the taste of OGT 918. Unfortunately these have also been unsuccessful. Consequently OGS are evaluating other possible types of formulation and will endeavour to re-formulate as quickly as possible. However based on the challenges faced this is likely to take at least 6 months and perhaps longer.
From the Niemann-Pick Disease Group (UK) Newsletter on March 8, 2001
There has been considerable progress towards a clinical trial with OGT918 (now named Vevesca) involving NPC patients. Discussions/liaison on the topic have been ongoing between Dr Marc Patterson, Dr Ed Wraith and Oxford GlycoSciences. The trial protocol has now been finalised and approved and preliminary studies will go ahead once the drug has been produced in a formulation suitable for use in young children. Several issues need to be addressed in order to do this. At the moment OGT918 is only available in capsule form and it will need to be administered to children in a liquid form that is easy to drink or to administer to children who are tube fed. Certain ingredients will have to be changed in order to develop the paediatric formulation and stability will need to be assured. As with all new drugs in the development stage there are clearly defined regulatory guidelines on the conduct of such trials to be followed. In the case of paediatric studies, there is a considerable amount of additional work to be undertaken. We are confident that things are progressing as fast as is possible.
From Susan Green on December 21, 2000
Oxford GlycoSciences have decided to produce a bi-monthly newsletter which
will give updates on all the OGT 918 studies. The first issue will be produced in
the New Year and go to all the patient groups including Niemann-Pick, Gauchers, Fabry
etc. and be posted on the OGS Internet site. www.ogs.com
This will provide a consistent supply of information to the patient groups and is a
really positive development which will be of benefit to both OGS and the patient
communities."
Excerpts from December 6, 2000 Email of Susan Green to the NNPDF Electronic Mailing List
(Susan Green is Family Support Co-ordinator for the Niemann-Pick Disease Group of the United Kingdom (NPDG-UK) and a Director-at-Large of the NNPDF as well as a member of the NNPDF's Research Subcommittee. Her husband, Jim, is Chairman of the NPDG-UK. Jim and Susan are the parents of Roy Green (NPC) and Murray Green (NPC). Murray passed away from complications of NPC in October of 1996.):
Dear Friends,
I have however been reading all of the messages [on the NNPDF listserv] and felt that I should respond ... to those regarding the clinical trial for OGT 918 (now called Vevesca). I can understand how anxious everyone is, I look at Roy and see every day how he struggles to live with this disease. It is not easy to have patience! We have waited so many years with so little hope and seen so many
children die including our son Murray. It is easy to believe that there must be a miracle cure just around the corner. Perhaps there is - but it is not OGT 918! The most that this drug is expected to do is to slow down the progression of this disease, it will not cure our children.
At best, if it works, it might buy us a little more precious time with them. Time in which the scientists and clinicians who work so hard on our behalf, might possibly find something that will indeed cure our children. The thing is nobody knows for sure what exactly OGT 918 will do. That is why we need a good clinical trial, we need to find out exactly how it will affect children with NPC. We need to know that it will not make them worse!
The people at Oxford Glycosciences who are responsible for the conduct of the trial are, with the
help of Dr Patterson in the USA and Dr Wraith in the UK, working hard to ensure that the protocol
will be acceptable to the Institutional Revue Board in the USA and the Ethics Committee in the
UK. These are the people who must approve the trial before it can begin and monitor it at regular
intervals along the way. They must satisfy themselves that all the necessary arrangement are in
place to make sure that the risks are as low as possible and are worth any potential benefits.
Having an acceptable protocol for NPC, with measurable outcomes in such a variable
disease, can take a great deal of time and effort to devise before even the patients can be
recruited! Everything would now seem to be in place and approval is being sought. For various
reasons this looks as if it might be quicker to obtain this in the UK than in the USA so that is why it is planned that the first part of the trial will take place in late January in Manchester, England. I understand that only 6 patients will be required for this and that they are likely to be between the ages of 12 and 18 so Roy will not be taking part! The second stage will involve patients in both the USA and the UK and will likely start in April.
I have no further details but, together with Barb Vorpahl and Glen Shepherd will be contacting
OGS to let them know how anxious families are for news and we are sure that they will want to
give us some further details, which will be posted on the Website and circulated to all of those
families on our mailing list. ...if you get any of our newsletters
posted to you then you can be sure that you are on the Mailing List! Also any family who has
contacted us recently to express an interest will have been added to the mailing list. Because of
data-protection rules of confidentiality our groups do not share our mailing lists so you may end up receiving more than one set of information!
...the people who will be producing OGT 918 will be Oxford
GlycoSciences... I know that
things seem to be taking forever ... but believe me they are moving much faster than is usual
in these cases. I know this is not much consolation but I don't see that we can do much more
except to offer our support and encouragement to those who are involved. Everyone wants to see
the best possible results in the shortest possible time without compromising our children's health any more than it is already.
[Regarding how long it takes for trials to begin]... I too have had steam coming out of my ears on occasion! Be assured that the trials have started! The start of the trial is in devising the protocol, a difficult job for NPC but this has been done and things are moving forward. Just think, six of our children will be given this drug in January! Many of us wish it was our child but at the same time it is quite something to be a pioneer and not an easy decision to make. The people who are responsible for conducting the trial are the drug company, OGS...which is why we will try to get OGS to provide us with more timely information and regular updates. Families and drug companies operate on different timescales. A year is not a long time as far as a drug company is concerned, as families we find too hard to look beyond tomorrow and a day is a long time! We will do our best to help OGS to see how important it is for us to be kept well informed.
I hope this message has been helpful and please be assured that we are all doing our very best to
ensure that this trial will progress as fast as it possibly can! The directors of all of the foundations are in regular touch with each other and we will try to ensure that you are kept up to date with information as soon as it is available.
Susan H Green
Family Support Co-ordinator
Niemann-Pick Disease Group (UK)
Update from Barb Vorpahl dated December 3, 2000:
I talked with Dr. Patterson this evening.
He will be meeting with Oxford Glyco Science (OGS), the company sponsoring the drug trial, the
week of December 11. Because we have not heard from the FDA as of yet as to their
approval, Phase I of the drug trial may probably take place in the UK, this is to move the trial
along a little faster. They are hoping this can get started in January, which is pretty close to the anticipated starting time.
The information learned from Phase I has to be compiled befored starting phase I/II which will
involve a larger number of patients. So we are probably looking at March or April for Phase I/II.
As you recall, Phase I will only take a short time and will only involve a small number of patients (see web site for specifics). It will be mainly to decide the dosage for Phase I/II of the trial. It should not make any difference where phase I takes place but may move things along faster.
Phase I/II of the drug trial will take place at Columbia [University in New York] as well as [at the Willink Clinic] in the UK. Dr. Patterson will
start in his new position at Columbia as head of Neurology, January 1st. The department at
Columbia which organizes clinical trials is already getting things in place for the drug trial.
I know the amount of time it is taking to get this drug trial in place is very frustrating. But I know being involved with the cholesterol blocking medication drug trial 9 years ago, it all takes time. Believe me, this is moving along a lot faster than the cholesterol medication trial.
The FDA approval and all of the other regulations are actually for our protection and safety and
Dr. Patterson is doing all he can at this point.
Barb Vorpahl
NNPDF Chair
Update from Marc Patterson dated October 6, 2000:
I understand that families are curious about progress on the proposed trial of OGT 918 in NPC, and wanted to provide an update.
I have met with the OGS team both here and in the UK on several occasions, as has Ed Wraith. We have most of the details of the pharmacokinetic study worked out, and should be able to commence enrollment in the US once the FDA has approved testing of the liquid formulation of OGT 918
(expected in November).
In order to ensure that accurate information is provided to families in the most timely fashion, I have proposed that the protocol be posted on the Foundation websites as soon as it is finalized. In addition, we will request the help of the Foundations to mail information to all
prospective participants as well.
The initial pharmacokinetic study will require a relatively small number of participants. Individuals with NPC do NOT need to participate in the first study to be eligible for the second (efficacy) trial that will follow.
I hope that this addresses and concerns that may have arisen. Please let me know if there are additional issues that I can help with.
Sincerely,
Marc Patterson, MD
Every family of an NPC patient who is listed in the database of the NNPDF or the NPDG-UK will receive mailings on OGT-918 trials. To be certain you are included, please be sure you are in our databases. To add your name and address to the NNPDF mailing list, contact Nadine Hill. For the UK mailing list, contact Jim and Susan Green.
Update from Barb Vorpahl dated August 30, 2000:
Treatment of NPC with OGT 918
At the 2000 NNPDF Family Conference Dr. Steven Walkley provided evidence that gangliosides, particularly GM2, play an important role in the neuronal dysfunction seen in NPC. He reported on the promising results with OGT-918, (chemical name N-butyldeoxynojirimycin or NBDNJ) an inhibitor of ganglioside synthesis, in the NPC mouse. These mice demonstrated a later onset of disease and a longer survival.
Dr. Marc Patterson presented information on a potential drug trial with 0GT-918 for patients with NP-C. Oxford GlycoSciences (OGS) has agreed to fund these clinical trials. Dr. Patterson is working closely with OGS as well as the NNPDF, the Ara Parshegian Medical Research Foundation and the NPD Group - UK in writing a protocol for use of OGT-918 in NPC patients. The protocol will describe who will participate in the trial, procedures, medications, and dosages; and the length of the study.
Dr. Patterson discussed the clinical trial process required to judge the efficacy and safety of potential treatments. He also discussed the phase I/II clinical trial and addressed specific questions about the clinical trials.
PHASE 1 - Dose Finding Studies. To determine a maximum tolerable dose. To determine any differences in a capsule or liquid preparation. .
This phase will take place over several days and include approximately 10 - 12 patients. A canula would be inserted and blood samples taken before, and after 24 hours. Researchers will measure the rate of change to determine how often the drug should be given. Participation in this study would not preclude participation in the next study. i.e. could do both.
Phase1/11 A randomized, double-blind, study of OGT918 in NPC. To assess the efficacy of OGT918. And further evaluate safety. To assess other neurologic or biochemical markers between OGT918 treated and controls
This phase will take 12 - 18 months and include a larger number of patients. Statisticians will determine how many patients will participate in the study. The study will include a control group where some patients would for a time receive a placebo instead of the drug, but ALL patients would get the drug at some point during the trial.
Researchers will measure changes in saccadic velocity/amplitude (fine eye movements) between treated patients and controls and also other neurological functioning tests. This would be recorded on video tape which would be reviewed and scored by a "blinded" reviewer.
Selection Criteria: Anyone is a candidate. If more people volunteer than they need, there would be a method of selection which is fair so that everyone has an equal chance of being included.
Inclusion Criteria: Patients would need to be older than two years and showing some symptoms of Supranuclear Gaze Palsy (abnormal eye movements) which could be measured.
Exclusion Criteria: If patient, or parents are not able to give informed consent. If of childbearing age and not able to use a contraceptive or if pregnant. If unable to tolerate procedures or travel. If undergoing therapy with other investigational agents.
This would be a two center study in USA and the United Kingdom. It would be possible for patients to be monitored locally through blood tests, etc. for some of the time. There would be no costs to families taking part in the trial and travel costs would be paid.
All Families who are on the NNPDF and the Niemann-Pick Group (UK) mailing lists will receive more details once the protocol is finalized and approved by the Institutional Review Board. To add your name and address to the NNPDF mailing list, contact Nadine Hill. For the UK mailing list, contact Jim and Susan Green.
