A PHASE III TRIAL OF ALD-101 ADUVANT THERAPY of UNRELATED UMBILICAL CORD BLOOD TRANSPLANTATION (UCBT) IN PATIENTS WITH INBORN ERRORS OF METABOLISM

Umbilical cord blood is a good source of haematopoietic stem cells for patients
who need a haematopoietic stem cell transplant but who are without a matched
sibling or unrelated bone marrow donor. However, significant disadvantages of
CBT compared to bone marrow transplantation are the relative delays in
post-transplant platelet and neutrophil recovery. The delay in platelet
engraftment is particularly pronounced and is managed by support with platelet
transfusions, restriction of physical activities, and local measures to control
bleeding when possible. Patients typically are neutropenic for a period of 3 to
4 weeks and are susceptible to potentially life-threatening bacterial and
fungal infections during that period. These neutropenia-associated infections
represent the major cause of death following cord blood transplant.

The hypothesis underlying this trial is that infusion of ALD-101 cells
manufactured from umbilical cord blood administered 4-8 hours after a
conventional UCBT will facilitate rapid, sustained hematopoietic engraftment in
patients undergoing UCBT. This will result in accelerated restoration of normal
levels of circulating platelets and neutrophils in patients receiving ALD-101
after a conventional UCB graft.

The current trial which started in the US is being expanded to Europe. Goal is
to demonstrate efficacy and safety of ALD-101 in patients with inborn errors of
metabolism who will undergo a umbilical cord blood transplant.

Primary objective of this study is: To assess the efficacy of adjuvant therapy
of ALD-101 in accelerating platelet engraftment in patients also receiving a
standard unrelated UCBT for treatment of inborn errors of metabolism
The secondary objective of this study is: To assess the safety of adjuvant
therapy of ALD-101 in infusional toxicity, adverse events, and primary graft
failure. To assess the efficacy of ALD-101 in accelerating neutrophil
engraftment
The exploratory objectives of this study are: To assess the improvement of
180-day survival To describe the clinical outcomes in these patients in terms
of incidence of infection, incidence of acute GvHD, and restoration of immune
function

Open label study

An adjuvant infusion of ALD-101 4 to 8 hours following a standard cord blood
transplant

The burden to the patient resulting from participation in this study is limited
to one additional infusion of umbilical blood via a venous catheter the patient
already as a result of the standard procedure.

No infusional toxicity or unexpected adverse reactions were noted in patients
receiving ALDHbr cells in UCBT-001. It may however always happen dat
unexpected, not previously reported adverse event occur. To date no serious,
ALD-101 related adverse events have been reported but only adverse events
related to the standard procedure.

First, ALD-101 adjuvant therapy potentially could delay engraftment because
patients do not receive the full UCB unit. Rather, they receive the
unmanipulated 80% fraction and then only the ALDHbr cell population derived
from the 20% fraction as an adjuvant. The ALDHbr population is a small
percentage of the 20% fraction. However, the 80% fraction alone must meet
criteria for standard of care for minimally acceptable total cell dose of 2.5 X
10*7 cells. The efficacy data from the UCBT-001 trial suggests that this is not
a significant risk. Patients receiving ALD-101 engrafted neutrophils and
platelets at an accelerated rate compared to the COBLT historical control
cohort. Indeed, this is the basis for the proposed UCBT-002 trial.
Consequently, we assess this outcome to be a low risk to patients.

Second, infusing patients with ALD-101 raises the risk of infection from
potential contamination during cell sorting or from impurities introduced
during manufacturing. No increase in infection in the frequency of infection or
other toxicological event was observed in the treated patients during the
UCBT-001 trial. All cell products prepared during that trial passed release
criteria that included sterility tests. The manufacturing process for ALD-101
has been simplified, and fewer in-process reagents and processing steps are
involved. Existing manufacturing and quality control procedures have been
effective in managing this risk to date.

Third, manufacturing reagents used to identify ALDHbr cells potentially could
be transferred with the cells into patients and cause pathologic reactions.
However, the sorting process involves efflux of all detectable reagents and
reaction products as described below. Exposure to these reagents is the only
difference between the cells in ALD-101 and the other cells in cryopreserved
cord blood that are administered to patients at doses that are average 10,000
fold higher than the ALD-101 in this protocol. Preclinical studies explored the
effects of very high doses of the reagents used to detect ALDH in tissue
culture and in animals in standard preclinical toxicology assays. In addition,
high doses of the ALDH substrate were directly injected into dog hearts, and
the animals were subsequently assayed by histological and electrophysiological
methods for acute and chronic pathological effects. No adverse effects of the
reagents were detected. It was demonstrated that ALDHbr cells manufactured from
UCB rapidly efflux all BAA, the ALDH reaction product, detectable by
cytofluorimetry within minutes of being incubated at room temperature. Because
of this, the amount of reagent transferred to patients is very low.
Calculations show that the maximum possible estimated dose of reagents
administered to patients with cells in ALD-101 is 104 to 109 times lower than
the doses used in the preclinical toxicology tests that showed no toxic effects
of the reagents. Thus, the risk to patients from administered reagents is
acceptably low.