AN OPEN-LABEL, MULTI-CENTRE STUDY TO EVALUATE THE LONG-TERM SAFETY AND TOLERABILITY OF REN001 IN SUBJECTS WITH PRIMARY MITOCHONDRIAL MYOPATHY (PMM)

Primary mitochondrial myopathy (PMM) is an illness that results in muscle
symptoms including muscle weakness, fatigue and pain. These symptoms are
extremely common and often debilitating in patients with PMM. To date, there
are no effective treatments and no cures. Hence, there is an urgent need to
find an effective drug treatment.

To date, five clinical studies (HPP593-101, HPP593-102, HPP593-103, REN001-101
and REN001-103), involving a total number of 181 PMM subjects, of which 124
received the study drug REN001, have been conducted in accordance with GCP
principles. Study results indicate that REN001 was overall considered safe and
well tolerated. No treatment-related SAEs were reported, and in the randomised
trials the incidence of AEs was similar between REN001 treated and placebo
arms. In another clinical study REN001-102, which involved PMM subjects with
FAOD, REN001 was similarly considered to overall be safe and well tolerated.

Elevations in serum CPK have been reported in all studies conducted with
REN001. It should be noted that CPK levels were raised in some subjects at the
time of screening and/or baseline, and most were considered clinically mild by
the treating investigator, and typically related to the underlying condition.
As a conservative measure, the Sponsor does not rule out a potential
association between treatment with REN001 and elevations on CPK. The Sponsor
concludes that, if elevations in CPK are associated with treatment with REN001,
such elevations are typically modest and reversible.

In the Phase 1b FAOD study, SAEs of rhabdomyolysis and acute renal failure were
reported following unspecified COVID-19 vaccination which were considered
possibly related to vaccination, underlying FAOD, and REN001. Three further
rhabdomyolysis SAEs also occurred in this FAOD study, which were considered not
related to the underlying condition but likely due to underlying factors
including exercise and infection. An episode of pancolitis in an individual
with underlying bowel disorder was considered possibly related to study drug
although the computed tomography scan was consistent with infection

No clinically important abnormalities were observed in vital signs, ECGs,
urinalysis or ophthalmic examinations, and clinically significant physical
examination findings were rare. The majority of AEs were considered mild to
moderate in severity. Three possibly treatment-related SAEs (in 2 subjects)
have been reported in an ongoing FAOD study as noted above. There were no
deaths in any study conducted to date. Weight gain or oedema, complications
known to be associated with other PPAR agonists, were not observed in any
studies.

A Phase 2b study, involving this study drug is currently in progress (study
REN001-201, aka "STRIDE"). The aim of STRIDE is to determine how well REN001
works and whether it is safe and well tolerated in patients with PMM. The
planned maximum duration for each patient in this study is 36 weeks (8 weeks
screening, 24 weeks treatment and 4 weeks follow up). Each patient is given
either REN001 treatment or placebo (dummy medication) treatment for 24 weeks.
Neither the doctor nor the patient know who is given which study drug treatment
(double-blind).

The aim of this study is to evaluate the long-term safety and tolerability of
REN001 administered once daily to subjects with PMM who have previously
completed STRIDE or participated in Study REN001-101 and withdrew from that
study due to the COVID-19 pandemic.

Primary Objective:
To evaluate long-term safety and tolerability of REN001 in subjects with PMM.

Secondary Objective:
To evaluate subjects with mtDNA-PMM who are receiving long-term treatment with
REN001 in terms of PMM associated symptoms, exercise endurance, quality of life
(QoL) and work productivity

This is a long-term safety study for subjects who have completed treatment in
the STRIDE study or who were participating in the REN001-101 study when it was
ended due to the COVID-19 pandemic. (REB001-101 study was open in the UK only).
At sites with the IEC and regulatory approvals, eligible subjects will be
treated for 24 months. A Safety Review Committee will review safety data during
the study.

Subjects enrolling from the STRIDE study will be switching from taking blinded
REN001 or placebo in the STRIDE study to open label REN001 in this study. At
the time of enrolment into this long-term study, prior treatment allocation in
the STRIDE study will be unknown. Subjects who are nearing completion of the
STRIDE study will be invited to discuss continuing into this long-term safety
study and provide informed consent prior to any study activities. It is
expected that most subjects transferring from the STRIDE study will do so at
the STRIDE Week 24 visit to prevent an interruption in dosing and reduce the
number of study visits and assessments. Subjects who are enrolled at the STRIDE
Week 24 visit will not need to complete the STRIDE follow up (FU) visit.

Enrolment at the STRIDE FU visit will require additional baseline assessments.
Subjects who wish to take part in this study after leaving the STRIDE study
(i.e., after their STRIDE FU visit) and subjects who participated in Study
REN001-101, will require additional screening and baseline visits; for details
of enrolment options please refer to the protocol Section 6.1 and Table 2.

After the baseline visit, subjects will have study visits at Months 1, 3, 6,
12, 18 and 24 months. As a final follow up there will be a telephone call from
the study centre to the subject approximately 30 days after the last dose of
study drug.

If the site permits, a concierge service will be available to subjects to
arrange hotel accommodation and transport to and from study centre visits and
to reimburse any subject study expenses, if applicable. If a study centre
requires it, subjects may be asked to have a negative COVID-19 test prior to
undertaking scheduled visits at the study centre.

N/A
This is an open-label study and all participants will receive the study drug
REN001

The Risk:Benefit profile of REN001 is overall considered positive for subjects
with PMM participating in this study, subject to appropriate subject selection
and safety monitoring.

Elevated CPK
Serum CPK data from subjects with PMM in the Phase 1b study (REN001-101)
demonstrated a pattern of transient, elevated CPKs following exercise and the
collection of muscle biopsies; none of these elevations were associated with
myoglobinuria. The elevations seen were self-limiting and resolved with no
intervention despite continued treatment with REN001 and continuation of the
subject*s normal activities of daily living including exercise. In all the
clinical trials that have included REN001 to date, elevations in CPK tended to
be modest and reversible and were usually determined by investigators as
unlikely to be associated with REN001 treatment. In the current study CPK
levels will be assessed throughout the study with particular emphasis at
Baseline and Week 2, based on the expected (asymptomatic) increases in CPK
previously observed in subjects with PMM.

Cataract formation
A single-species finding of cataract was observed in a high dose 6-month rat
chronic toxicology study, but not in any other animal studies (including the 12
month non-human primate study). Taking a conservative approach, ophthalmology
examinations were therefore included in all REN001 trials. Slit lamp eye
examinations will be conducted, together with assessments of best corrected
visual acuity at Screening and months 3, 6, 12, 18 and 24 in this study.

Potential Drug-Drug interactions
REN001 is not a direct or time-dependent inhibitor of CYP3A4. However, REN001
has been shown to be a weak inducer of CYP3A4 in vitro. A potential for drug
interactions between REN001 and drugs that are metabolized through the CYP3A4
is considered low but cannot be ruled out. Therefore, drugs that are
metabolized primarily by CYP3A4 and have a narrow therapeutic index should be
administered with caution in subjects participating in REN001 studies.

REN001 was identified as a P-glycoprotein (P-gp) substrate in vitro. Strong
P-gp inhibitors may have an impact on the absorption and metabolism of a P-gp
substrate, however preliminary human metabolism for REN001 indicates numerous
metabolic pathways are involved in the clearance of REN001. Therefore, it is
unlikely that co-administration of a strong P-gp inhibitor with REN001 will
result in higher systemic exposures of REN001. Co-administration of REN001 with
a strong P-gp inducer may reduce REN001 plasma concentrations.

Fertility and contraception
In accordance with the latest European regulatory discussions and guidelines
(Clinical Trials Facilitation Group, 2014 and 2020), women of child-bearing
potential (WOCBP) are eligible for the study provided they are using a highly
effective form of contraception from Screening, whilst taking the drug and for
30 days after stopping investigational medication. Serum pregnancy testing will
be completed at Screening. In addition, urine pregnancy tests will be carried
out monthly and at Follow Up.

Fertile males (unless permanently sterile by bilateral orchidectomy) with
partners who are WOCBP must agree to use a condom from Baseline until at least
14 weeks after the last dose of study medication. A condom must also be used by
vasectomized men to prevent delivery of the drug via seminal fluid.

As REN001 is a weak inducer of CYP3A4 in vitro, caution is advised when
co-administering REN001 and oral contraceptive agents. Therefore, as a
precautionary measure, women receiving highly effective hormonal contraception
therapy will be advised to use an additional highly effective non-hormonal
method of contraception during treatment with REN001 and for 30 days after the
final dose. Women using a highly effective non-hormonal contraception method
(i.e., intrauterine device) will not be required to use additional methods of
contraception.

Carcinogenicity
Carcinogenicity studies have been initiated but are not yet completed. Animal
carcinogenicity data in rodents suggest that some, but not all, PPAR agonists
have carcinogenicity potential. The mechanism by which implicated compounds
produce tumors in rodents is not well understood and the relevance of these
findings for other classes, if any, to humans is unknown. Subjects with a
history of cancer, except in situ basal cell carcinoma in the skin, are
excluded from participation in the study.

Bone
Non-Clinical Finding of Premature Bone Plate Closure in Rats: This finding has
not been replicated in non-human primates.

Bone Turnover: Currently, it is not known if REN001 (a selective PPARδ agonist)
will have any impact on bone mineral density. Nonetheless, given the study
requirements for walk tests and taking a highly conservative approach, the
Sponsor has excluded subjects with a history of fragility/stress fractures or
an osteoporosis concomitant condition which has not been addressed, and will
monitor markers of bone turnover during the study. Any reports of bone fracture
will be captured as an adverse event of special interest.

Blood draws
There may be some slight discomfort involved in taking blood by venepuncture.
There may be slight discomfort or pain in the area around the vein when the
blood is taken. There may be bruising, swelling and discomfort over the vein
after the procedure. There is a small risk of infection. The risks involved in
donating blood samples by needle are the same as for the routine blood tests
subjects have in routine clinic visits.

Risks Associated with Study Procedures.
Measurements of blood pressure and pulse rate are well established methods.
Subjects may experience some discomfort during blood pressure measurements when
using the blood pressure cuff. Subjects may experience skin irritation from the
electrodes or gel used during the ECG. Eye drops are used to dilate the pupils
for the slit-lamp eye test, the effects are temporary but subjects should not
drive until the effects have fully worn off. All of the study and exercise
tests are safe and regularly used in clinics. Subjects may feel tired after the
exercise tests.

Possible Side Effects And Risks of Taking The Study Medication
REN001 has been given to healthy volunteers, to obese subjects and to subjects
with PMM in previous clinical studies. REN001 was considered to be safe and
well tolerated in all these trials with no drug-related side effects (adverse
drug reactions) identified.

In a PMM subject study, involving 23 subjects, the most common side effects
reported were
• constipation in 4 out of 23 subjects and
• headache in 4 out of 23 subjects
which may have been due to the subject*s underlying PMM.