NR in Chemo-induced Peripheral Neuropathy

Peripheral neuropathies are a dose-limiting, disabling, and debilitating side effect of
virtually every known class of chemotherapeutic agent, and are referred to as
chemotherapy-induced peripheral neuropathies (CIPN) (Seretny et al., 2014). The incidence and
severity of CIPN increase as the cumulative dose, frequency of administration, and the number
of therapeutic cycles increase. As many as 68% of patients have CIPN when assessed within 30
days of completing treatment. Patients experience paresthesias, dysesthesias (an unpleasant
abnormal sensation, whether spontaneous or evoked), hyperalgesia (increased pain from a
stimulus that normally provokes pain), allodynia (pain due to a stimulus that does not
normally provoke pain), numbness or loss of sensation, or ongoing pain that is burning,
lancinating or electric shock-like in nature. CIPN can seriously diminish a patient's quality
of life, and can interfere with self-care and activities of daily living. The severity of
CIPN may also necessitate reducing the dose of chemotherapeutic agent, delaying the next
cycle of chemotherapy, or terminating treatment entirely (Argyriou et al., 2012; Argyriou et
al., 2014; Miltenburg et al., 2014; Park et al., 2013).

Nicotinamide adenine dinucleotide (NAD+) is an essential redox coenzyme required for cell
viability, basic bioenergetics, and fast axonal transport (Yang and Sauve, 2016). It plays an
important role in protection against axonal injury from either mechanical or neurotoxic
injury (Araki et al., 2004; Sasaki et al., 2006; Sasaki et al., 2009; Gerdts et al., 2015;
Khan et al., 2014; Conforti et al., 2014; Di Stefano et al., 2015). Nicotinamide riboside
(NIAGEN®) is a form of vitamin B3 and a precursor in the pathway for synthesis of NAD+
(Bieganowski et al., 2004; Trammell et al., 2016; Chi and Sauve, 2013). Oral administration
of NIAGEN® increases levels of NAD+ in the blood, liver, skeletal muscle, and other tissues
(Canto et al., 2012; Hamity et al, 2017; Airhart et al., 2017; Martens et al., 2018).

NIAGEN®) has been reported to prevent tactile hypersensitivity and blunt the affective
dimension of nociception in a rat model of CIPN (Hamity et al., 2017) It also prevents signs
of peripheral neuropathy in a mouse model of diabetes (Trammell et al., 2016) The proposed
single-arm pilot phase II study will examine whether daily dosing with NIAGEN®) can prevent
the progression of CIPN in persons with stage IV breast cancer receiving once weekly
infusions of paclitaxel for 12 weeks.

In this study, persons with metastatic breast cancer who are receiving weekly infusions of
paclitaxel and anticipated to survive for at least 3 months will be offered the opportunity
to enroll in this study when they develop a peripheral neuropathy of at least grade 1.
Persons with peripheral neuropathy of no greater than a grade 2 from prior therapy may also
enroll in this study if they are receiving weekly infusions of paclitaxel. Upon enrollment,
health care providers will review the overall severity of the participant's neuropathy and
assign a baseline grade. Participants will also complete two short questionnaires that will
more specifically score how the peripheral neuropathy interferes with daily functions of
living. A small sample of blood will be taken at the completion of the paclitaxel infusion to
measure levels of paclitaxel. The participant will then be sent home with capsules of NIAGEN®
to take twice daily. Each week upon return to the clinic a small sample of blood will be
taken before the infusion of paclitaxel to measure biomarkers for NIAGEN®, and other samples
of blood will be taken to evaluate clinical chemistries, kidney, and liver function. Another
sample of blood will be obtained after the paclitaxel infusion to measure levels of
paclitaxel. The health care provider will meet with the patient each week to score the
overall severity of the peripheral neuropathy, and the participant will answer another
questionnaire with more specific questions. Once a month, the participant will be asked to
fill out a second questionnaire. Participants will take 300 mg/day NIAGEN® in the first week
and 1000 mg/day in the subsequent 11 weeks. The study will conclude one week after the 12th
infusion of paclitaxel. Health care providers will contact the participant at various times
up to 6 months to monitor their status.

Beginning with completion of the trial by the 10th participant and continuing with each
subsequent participant up to 39, we will use a Bayesian statistical approach (Lee and Liu,
2008; i.e. predictive probability) to determine whether NIAGEN® has prevented a worsening of
the peripheral neuropathy. This approach we let us make an early determination of futility.
We will also determine whether NIAGEN® has decreased the need to delay or diminish the doses
of paclitaxel due to severity of the peripheral neuropathy. The results of this trial will
inform the design of a subsequent randomized, placebo-controlled, blinded clinical trial.

Inclusion Criteria:

- Be able to give written informed consent and HIPAA authorization

- Be 18 to 80 years old

- Have been diagnosed with stage IV breast cancer of any type, and are anticipated to
survive for at least three months

- Have an ECOG Performance Status of 0-2

- Able to take medication orally - up to four capsules in the morning (am) and four
capsules in the evening (pm).

- Be undergoing weekly infusions of paclitaxel for treatment of breast cancer and be
determined to have at least a grade 1 neuropathy based on the CTCAE version 4.03
guidelines for peripheral sensory neuropathy.

- Females must be either postmenopausal for at least 1 year or surgically sterile for at
least 6 weeks. Females of childbearing potential must have a negative pregnancy test
at screening to be eligible for study participation, and agree to take appropriate
precautions to avoid pregnancy from screening through follow-up.

- Males must agree to take appropriate precautions to avoid fathering a child from
screening through follow-up. The following methods have been determined to be more
than 99% effective (<1% failure rate per year when used consistently and correctly)
and are permitted under this protocol for use by the patient and his/her partner:

- Complete abstinence from sexual intercourse when this is in line with the
preferred and usual lifestyle of the patient

- Double barrier methods including condom with spermicide in conjunction with use
of an intrauterine device or condom with spermicide in conjunction with use of a
diaphragm

- Surgical sterilization (bilateral oopherectomy with or without hysterectomy, tubal
ligation or vasectomy) at least 6 weeks prior to taking study treatment. In the case
of oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow-up levels of luteinizing hormone (LH), follicle-stimulating
hormone (FSH), and/or estradiol Non-hormonal intrauterine device used as directed by
provider placing this is also acceptable.

Exclusion Criteria:

- Pre-existent peripheral neuropathy that is unrelated to chemotherapy

- Pre-existent chemotherapy-induced peripheral neuropathy greater than grade 2

- Known metastases to the brain, spinal cord or peripheral nerves, or leptomeningeal
disease

- Diabetes requiring management by medication

- Renal or hepatic dysfunction

- Heavy alcohol use defined at > 8 drinks/week by women or 12 drinks/week by men

- Chronic pain greater than 3 months duration within the past year.

- Severe psychiatric illness

- Pregnancy

- Current imprisonment

- Limitations of self-expression, defined as an inability to answer questions posed by
physicians, nurses, care-givers, or other members of the investigative team or an
inability to describe somatosensations.

- Known HIV, not on therapy

- Regular use of nutritional supplements that contain nicotinamide or NIAGEN® within the
previous 30 days

- Use of duloxetine (Cymbalta®) within the previous 30 days

- Pancreatic insufficiency requiring exocrine enzyme replacement therapy

- GI conditions where malabsorption of B complex vitamins is known to occur.

- Known allergy to paclitaxel

- Breastfeeding