Successful and timely completion of clinical
studies will require that we enroll a sufficient number of patient candidates. Studies may be subject to delays as a result of
patient enrollment taking longer than anticipated or patient withdrawal. Patient enrollment depends on many factors, including
the size and nature of the patient population, eligibility criteria for the study, the proximity of patients to clinical sites,
the design of the clinical protocol, the availability of competing clinical studies, the availability of new drugs approved for
the indication the clinical study is investigating, and clinicians’ and patients’ perceptions as to the potential advantages
of the drug being studied in relation to other available therapies.
Generally, the specific target population
of patients and therapeutic time windows may make it difficult for us to enroll enough patients to complete clinical studies for
our products in a timely and cost-effective manner. Delays in the completion of any clinical study of our product candidates will
increase our costs, slow down our product candidate development and approval process and delay or potentially jeopardize our or
our collaboration partners’ ability to commence product sales and generate revenue. In addition, many of the factors that
cause, or lead to, a delay in the commencement or completion of clinical studies may also ultimately lead to the denial of regulatory
approval of our product candidates.
If serious adverse, undesirable or unacceptable
side effects are identified during the development of our product candidates or following approval, if any, we may need to abandon
our development of such product candidates, the commercial profile of any approved label may be limited, or we may be subject to
other significant negative consequences following marketing approval, if any.
If our product candidates are associated
with serious adverse, undesirable or unacceptable side effects, we may need to abandon their development or limit development to
certain uses or sub-populations in which such side effects are less prevalent, less severe or more acceptable from a risk-benefit
perspective. Many compounds that initially showed promise in preclinical or early stage testing have later been found to cause
side effects that restricted their use and prevented further development of the compound for larger indications.
Genentech has not disclosed detailed information
about serious adverse events associated with crenezumab either publicly or to us. However, at the 2014 Alzheimer’s Association
International Conference, it was reported that in the combined Phase 2 study populations, serious adverse events occurred at similar
rates in patients treated with crenezumab (16.5%) and in patients given a placebo (11.9%). In addition, adverse events identified
in the clinical studies of crenezumab initiated to date have included inflammation of the throat and nasal passages, urinary tract
infections and upper respiratory infections. At the 2016 Clinical Trials on Alzheimer’s Disease (CTAD) AAIC meeting it was
reported that in a Phase 1 clinical trial no dose-limiting toxicities were observed at doses of crenezumab of up to 120mg/kg. At
the 2017 AAIC meeting it was reported that in a Phase 1b study to evaluate higher doses of crenezumab, no dose-limiting toxicities
occurred. Twelve non drug related serious adverse events were observed in nine AD patients during the randomized and active extension
phases including malignant melanoma; an accidental overdose; pneumonia; fall; subdural hematoma; contusion; nephrolithiasis; non-cardiac
chest pain; pulmonary emboli; urinary bladder hemorrhage; subdural hematoma and atypical chest pain.
In January 2019, Roche announced that no
safety signals for crenezumab were observed in an interim analysis but that it will only continue the trial of cognitively healthy
individuals and will discontinue the CREAD 1 and CREAD 2 studies.
As previously reported, five serious adverse
events were observed in three patients during clinical studies of ACI-35. Three of them occurred in two patients and were study
drug-related. Acute pyelonephritis and dizziness were observed in one patient and sick sinus syndrome was reported for a second
patient, and these were labeled as possibly related due to the close timing proximity with the last administration of ACI-35. In
the third patient, urosepsis and pyelonephritis were described and classified as unlikely related to the drug.
Fifteen non-drug related serious adverse
events have been observed during clinical studies of ACI-24 in AD patients so far. Fourteen were reported in the phase 1/2 study:
one malignant colon polyp, one wound infection associated with a planned hip replacement, one radius fracture, one intra-abdominal
cancer of unknown origin followed by the death of the patient, one fall complicated by vertebral compression fracture, one acute
chest pain, one death due to Alzheimer’s disease, one death considered to be due to complications from coronary artery disease,
one case of pneumonia, one case of breast cancer, three successive episodes of pancreatitis in addition to gallstones in one patient
and inguinal hernia in one patient. Another serious adverse event, urinary retention, also considered unrelated to study drug,
has been reported in the ongoing phase 2 study. There have been no serious adverse events to date in the ACI-24 Down syndrome study.
None of the adverse events to date have been classified as related to the study drug.