A DOUBLE-BLIND, PLACEBO-CONTROLLED, STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 24 WEEKS TREATMENT WITH REN001 IN PATIENTS 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. Two further
rhabdomyolysis SAEs also occurred in this FAOD study, which were considered
related to the underlying condition.

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, with no treatment-related SAEs reported in the completed
clinical studies. Three possibly treatment-related SAEs (in 2 subjects) have
been reported in an ongoing FAOD study. 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.

The planned maximum duration for each patient in this study will be 36 weeks (8
weeks screening, 24 weeks treatment and 4 weeks follow up). Each patient will
be given either REN001 treatment or placebo (dummy medication) treatment for 24
weeks. Neither the doctor nor the patient will know who is given which study
drug treatment (double-blind). This is important to ensure that any effects are
due to the medication and not to any other potential factors (e.g. more
interaction with medical staff or hospital visits).

This study will determine how well REN001 works and whether it is safe and well
tolerated in patients with PMM.

Main Objective:To evaluate the efficacy of REN001 in subjects with PMM treated
for 24 weeks, assessed by the effect on exercise endurance.

Secondary Objective:To evaluate the efficacy of REN001 in subjects with PMM
treated for 24 weeks, assessed by the effect on fatigue.

Other Objectives:
Safety:
To evaluate the safety and tolerability of REN001 in subjects with PMM during
24 weeks of treatment.

Pharmacokinetic (PK):
To investigate the pharmacokinetics of REN001 in subjects with PMM.

Exploratory:
To evaluate the efficacy of REN001 in subjects with PMM treated for 24 weeks,
assessed by the effect on functional capacity.
To evaluate the effect of REN001 on quality of life (QoL) of subjects with PMM
after treatment for 24 weeks.

This is a randomised, double-blind, placebo-controlled, parallel group,
multicentre study in patients with PMM.

Approximately 200 subjects will be recruited into the study.

There will be a total of 8 visits for each subject.

Each subject who provides informed consent will complete screening activities
to confirm eligibility to enter the study.

The Screening Visit (Visit 1) must be completed no more than 8 weeks prior to
the start of dosing and will take place at the Study Center. There must be a
minimum of 4 weeks between the Screening 12MWT and the Baseline 12MWT. If
laboratory tests are outside of the normal range at initial screening, tests
may be repeated once (this can be done as a home nurse visit). Where possible
subjects should be pre-screened to assess the requirement for genotyping. The
Screening Visit may be accomplished over more than 1 day. Subjects who are
receiving prohibited medications must suspend the medications, if this can
safely and appropriately be done and have sufficient washout during the
screening period prior to randomization. Re-screening of subjects is allowed
only once and requires prior approval by the Sponsor, for instance, if the
wash-out of prior medications or genotyping is longer than 6-8 weeks. Where a
Study Center requires it, subjects may be asked to have a negative COVID-19
test prior to undertaking scheduled visits at the Study Center.

At selected sites, subjects may choose to participate in study exit interviews
upon their completion in the study.

Each patient will be given either REN001 treatment or placebo (dummy
medication) treatment for 24 weeks. Neither the doctor nor the patient will
know who is given which study drug treatment (double-blind).

There will be 8 site visits, as follows:

The Screening Visit (Visit 1) must be completed no more than 8 weeks prior to
the start of dosing and will take place at the Study Center. There must be a
minimum of 4 weeks between the Screening 12MWT and the Baseline 12MWT. If
laboratory tests are outside of the normal range at initial screening, tests
may be repeated once (this can be done as a home nurse visit). Where possible
subjects should be pre-screened to assess the requirement for genotyping. The
Screening Visit may be accomplished over more than 1 day. Subjects who are
receiving prohibited medications must suspend the medications, if this can
safely and appropriately be done and have sufficient washout during the
screening period prior to randomization. Re-screening of subjects is allowed
only once and requires prior approval by the Sponsor, for instance, if the
wash-out of prior medications or genotyping is longer than 6-8 weeks. Where a
Study Center requires it, subjects may be asked to have a negative COVID-19
test prior to undertaking scheduled visits at the Study Center.

The following procedures will be performed:

SCREENING: VISIT 1
• Subject demography
• Complete medical history (including prescription and non-prescription
drugs/treatments, non-drug treatments,
topical products, vitamins and dietary supplements taken in the last 4 weeks,
alcohol, drugs of abuse and tobacco use)
• Full physical examination (including height and weight)
• 12-lead ECG
• Vital signs (including temperature)
• Obtain blood samples for:
o Hematology and HbA1c
o Biochemistry, HIV/Hepatitis B/C serology, serum FSH test (post-menopausal
females only) and serum pregnancy
test (WOCBP only)
o Genotyping (only with prior approval of Sponsor)
• Obtain urine samples for:
o Urinalysis
o Drugs of abuse
• MFIS
• PGIS - muscle symptoms
• PGIS - fatigue symptoms
• PROMIS Short Form - FACIT Fatigue 13a
• 12MWT
• Eye examination (maybe completed at any time between the initial Screening
and Baseline visits)
• For subjects <25 years old (only) a wrist radiograph will be required to
confirm bone growth plate closure.
• Input of the Pro-forma Screening data into eCRF for Patient Screening
Oversight Committee (PSOC) approval
• Subjects will be provided with a pedometer and instructions on how to use the
device and complete the eDiary prior to leaving the Study Center (including the
requirement for collecting the Screening, pre-treatment, pedometer data for 14
days from the Screening visit)
• Subjects will be provided with a urine collection cup and instructions for
collecting a second morning void at the Baseline visit if they are unable to do
this at the Study Center for any reason.
Provided the subject fulfils all the inclusion and exclusion criteria, and the
PSOC has confirmed their agreement, the subject may enter the study and proceed
with the Baseline Visit.

BASELINE (DAY 1): VISIT 2
Subjects will attend the Study Center for the Baseline Visit when the following
assessments will be carried out prior to dosing:
• Obtain second morning void urine sample for:
o Bone marker - N-terminal telopeptide (NTX)
o Urinalysis
o Drugs of abuse
o Urine for pregnancy testing (WOCBP only)
• Obtain blood samples for:
o Hematology
o Biochemistry
o Additional bone and calcium metabolism markers
o Additional serum for possible use as baseline reference, to be stored frozen
at the central laboratory through to completion of the study
o Pre-dose plasma sample for pharmacokinetic analysis of REN001
• Review of concomitant medications including contraception and non-drug
treatments
• Review of pre-treatment events (see Section 7.1.1.1 of protocol)
• Physician completion of subjects PMM phenotypic description
• Review of Screening pedometer eDiary data
• Full physical examination (including weight)
• 12-lead ECG
• Vital signs (including temperature)
• MFIS
• BPI
• SF-36
• PGIS - muscle symptoms
• PGIS - fatigue symptoms
• PROMIS Short Form - FACIT Fatigue 13a
• WPAI:SHP
• 12MWT
• 30STS
Assessments should be conducted to ensure that the PRO questionnaires are
completed prior to exercise testing and the 12MWT must be done at least 1 hour
before the 30STS. Provided the subject meets all the study entry criteria they
will be randomized to study treatment. The IWRS will allocate study drug to be
dispensed to the subject. The first dose should be taken with food under the
supervision of site staff and the time of dosing recorded. Subjects will remain
in the Study Center after study drug administration for the following
assessments to be carried out:
• Obtain plasma samples for pharmacokinetic analysis of REN001 (1, 2, 3 and 4*
hours post dose)
• Review of adverse events
• Subjects will be provided with a urine collection cup and instructions for
collecting a second morning void at the Week 12 visit if they are unable to do
this at the Study Center for any reason
* To ease subject burden, the 4-hour post dose blood may be omitted if the
visit is extending beyond what is reasonable, at the Investigator*s discretion.
Subjects may then leave the Study Center at the discretion of the supervising
clinical staff after being provided with sufficient study medication to last
until their next scheduled Study Center visit. Subjects will be reminded of the
study restrictions and instructed on study medication dosing requirements. If
feasible, and at the Investigator*s discretion, the Baseline Visit may be
conducted over two days.

WEEK 2 (DAY 14): VISIT 3
Subjects will either attend the Study Center or receive a home nursing visit
(in countries where the regulatory authority allows) on Day 14. On this day,
the subject will take their daily dose at home as usual and record the time of
dose on the subject dosing card. The following assessments will be carried out:
• Review concomitant medications, non-drug treatments and study medication
compliance
• Review of adverse events
• Vital signs (including temperature)
• Obtain blood samples for:
o Haematology
o Biochemistry
o Plasma sample for pharmacokinetic analysis of REN001
• Obtain urine samples for:
o Urinalysis
• Capsule counts of remaining capsules including any opened IMP bottles
Subjects will be reminded of the study restrictions and instructed on study
medication dosing requirements.

WEEKS 4 and 18 (DAYS 28 and 126): VISITS 4 and 6
Subjects will either attend the Study Center or receive a home nursing visit
(in countries where the regulatory authority allows) on Days 28 and 126. On
these days, the subject will take their daily dose at home as usual and record
the time of dose in the subject dosing card. The following assessments will be
carried out:
• Review concomitant medications, non-drug treatments and study medication
compliance
• Review of adverse events
• Vital signs (including temperature)
• Obtain blood samples for:
o Haematology
o Biochemistry
o Plasma sample for pharmacokinetic analysis of REN001
• Obtain urine samples for:
o Urinalysis
o Urine for pregnancy testing (WOCBP Week 4 only)
• Review of last 7 days pedometer data
• MFIS
• BPI
• SF-36
• PGIS - muscle symptoms
• PGIS - fatigue symptoms
• PROMIS Short Form - FACIT Fatigue 13a
• WPAI:SHP
• Capsule counts of remaining capsules including any opened IMP bottles

Subjects will be reminded of the study restrictions and instructed on study
medication dosing requirements.

WEEKS 8, 16 and 20 (DAYS 56, 112 and 140)
Subjects who are WOCBP at risk of pregnancy will be supplied with urine
pregnancy tests to use at home at Weeks 8,16 and 20. Study Center staff will
need to contact the subjects by telephone to obtain the result of the pregnancy
test and enter the result into the eCRF. Subjects may be given a reminder
telephone call to conduct the test if necessary.

WEEKS 12 and 24 (DAYS 84 and 168): VISITS 5 and 7
Site staff will need to provide subjects with meals and snacks at appropriate
times during the visit to ensure subjects have enough energy prior to
completing the exercise tests.
Subjects will attend the Study Center on Days 84 and 168. On these days, the
subject will take their daily dose in the Study Center. The following
assessments will be carried out:
• Obtain second morning void urine sample for:
o Bone marker - NTX
o Urinalysis
o Drugs of abuse
o Urine for pregnancy testing (WOCBP only)
• Obtain blood samples for:
o Haematology (including HbA1c at Week 24 only)
o Biochemistry
o Additional bone and calcium metabolism markers
o Pre-dose plasma sample for pharmacokinetic analysis of REN001
• Administer the study drug with food under supervision of clinical staff and
the time of dosing recorded.
• Review concomitant medications, non-drug treatments and study medication
compliance
• Review of adverse events
• Physician completion of subjects PMM phenotypic description (Week 24 only)
• Review of pedometer eDiary data
• Brief physical examination (including weight)
• 12-lead ECG
• Vital signs (including temperature)
• Obtain plasma samples for pharmacokinetic analysis of REN001 (1, 2, 3 and 4*
hours post dose)
• Review of last 7 days pedometer data
• MFIS
• BPI
• SF-36
• PGIS - muscle symptoms
• PGIS - fatigue symptoms
• PGIC - muscle symptoms (Week 24 only)
• PGIC - fatigue symptoms (Week 24 only)
• PROMIS Short Form - FACIT Fatigue 13a
• WPAI:SHP
• 12MWT
• 30STS
• Capsule counts of remaining capsules including any opened IMP bottles
• Subjects will be provided with a urine collection cup and instructions for
collecting a second morning void at the Week 24 visit if they are unable to do
this at the Study Center for any reason (Week 12 only)
• Eye examinations (may be completed ± 14 days of the visit if required)

Assessments should be conducted to ensure that the PRO questionnaires are
completed prior to exercise testing and
the 12MWT must be done at least 1 hour before the 30STS.

*To ease subject burden, the 4-hour post dose blood may be omitted if the visit
is extending beyond what is reasonable, at the Investigator*s discretion.
At the end of Visit 7 (Week 24) subjects must return all their unused study
medication and may then leave the Study Center at the discretion of the
supervising clinical staff after being provided with details of their Follow Up
visit.

FOLLOW UP VISIT
Subjects will either attend the Study Center or receive a home nursing visit
(in countries where the regulatory authority allows), 21-28 days following the
last dose of study medication for a Follow Up Visit. This visit will not be
required if a REN001 open label extension study is recruiting and subjects
choose to enter the extension study at their Week 24 visit.
At this visit, the following activities will be completed:
• Review concomitant medications and non-drug treatments
• Review of adverse events
• Vital signs (including temperature)
• Obtain a urine sample for pregnancy testing (WOCBP only)
If clinically significant safety laboratory findings were apparent at the
subjects last visit these should be followed up until resolved with blood
samples for haematology and biochemistry and a urine sample for urinalysis as
appropriate.

EARLY TERMINATION VISIT
Subjects who discontinue taking study drug early should, if possible, have an
Early Termination visit as soon as possible after the subject stops taking
study drug. Where possible the Early Termination visit assessments should be
completed in the study center as listed below. Site staff will need to provide
subjects with meals and snacks at appropriate times during the visit to ensure
subjects have enough energy prior to completing the exercise tests.
• Review concomitant medications and non-drug treatments*
• Review of adverse events*
• Brief physical examination (including weight)
• Physician completion of subjects PMM phenotypic description
• 12-lead ECG
• Vital signs (including temperature) *
• Obtain blood samples for:
o Haematology (inc HbA1c)*
o Biochemistry*
o Additional bone and calcium metabolism markers
o Plasma sample for pharmacokinetic analysis of REN001*
• Obtain second morning void urine sample for:
o Bone marker - NTX*
o Urinalysis*
o Drugs of abuse*
o Urine for pregnancy testing (WOCBP only) *
• MFIS*
• BPI*
• SF-36*
• PGIS - muscle symptoms*
• PGIS - fatigue symptoms*
• PROMIS Short Form - FACIT Fatigue 13a*
• PGIC muscle symptoms (with respect to how they were on their last dosing day)
*
• PGIC fatigue symptoms (with respect to how they were on their last dosing
day) *
• WPAI:SHP*
• 12MWT
• 30STS
• Capsule counts of remaining capsules including any opened IMP bottles*
• Eye examination (may be completed ± 14 days of the visit if required)

If the subject is unable to attend the Study Center for the full visit, then
every effort should be made to complete the assessments marked with an asterisk
(*).

If the subject is withdrawing from the study: after their Early Termination
Visit they should be instructed to return for the Follow Up Visit 21-28 days
after their last dose of study medication. If the Early Termination Visit is 21
or more days after the last dose, then the Follow Up Visit is not needed.

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.

FORESEEABLE RISKS AND MEASURES TO PREVENT/TREAT UNFORESEEABLE/UNDESIRABLE
EVENTS:

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 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
Cataracts were observed in a 6-month rat chronic toxicology study, but not in
any other animal studies. As a precaution, ophthalmology examinations were
therefore included in all REN001 trials. Although no safety findings have been
identified during the detailed ophthalmological examinations conducted to date,
slit lamp eye examinations will be conducted during this study, at screening
and at the end of REN001 treatment (week 24) and a visual acuity test will be
conducted at week 12 as part of the safety evaluations. Any clinically
significant finding will require a further slit lamp eye examination.

Potential Drug-Drug interactions
There may be a potential for drug interactions between REN001 and drugs that
are metabolized through the CYP3A4 pathway. Therefore, drugs metabolized by
CYP3A4 should be administered with caution.

REN001 has also been identified as a P-glycoprotein (P-gp) substrate in vitro.
Substrates of P-gp are susceptible to changes in pharmacokinetics due to drug
interactions with P-gp inhibitors or inducers. However previous clinical
studies have demonstrated relatively high absorption of REN001 following
multiple oral doses likely saturating REN001 P-gp efflux and hence a drug-drug
interaction with P-gp inhibitors is unlikely to be a clinical issue.

The Sponsor anticipates that exposure to REN001 concomitant to short-term
exposure to a P-gp inducer is not a major concern. However, a subset of
subjects with PMM present with seizures and it is possible that some of these
subjects may need to receive long-term antiepileptic drugs known to induce P-gp
function (i.e., Carbamazepine, Phenobarbital, Phenytoin, Fosphenytoin). At low
free concentrations in plasma REN001 could be expected to be subject to P-gp
mediated efflux. Thus, strong P-gp inhibitors and inducers should be used with
caution.

Fertility and contraception
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 with partners who are WOCBP must agree to use a condom from
Baseline until 14 weeks after the last dose of study medication. A condom must
also be used by vasectomized men.

Since REN001 is a weak inducer of CYP3A4 in vitro, it could potentially
decrease concentrations of CYP3A4 substrates such as hormonal contraceptives.
Therefore, caution with co-administration of REN001 and hormonal contraceptives
is advised. Women receiving highly effective hormonal contraception therapy
will be required to also use an 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 contraceptive will not be required to use
additional methods of contraception.

Carcinogenicity
Preclinical findings suggest that some PPAR agonists may have carcinogenicity
potential.

Subjects with a history of cancer, except in situ basal cell carcinoma in the
skin, will not be allowed to participate in the study. Close safety monitoring
will occur during the study.

Bone
Non-Clinical Finding of Premature Bone Plate Closure in Rats: This finding has
not been replicated in non-human primates. As a precaution, subjects under 25
years of age in studies over 12 weeks duration will have a wrist radiograph
(x-ray) prior to enrolment to confirm skeletal maturity.

Bone Turnover:
Given the study requirements for walk tests, and taking a highly conservative
approach, Reneo has excluded subjects with osteoporosis, defined as a previous
fragility/stress fracture or a documented history of osteoporosis (for example,
a previous T-score of -2.5 or lower). Currently, it is not known if REN001 will
have any impact on bone density. Nonetheless, Reneo has excluded subjects with
a history of fragility/stress fractures or an osteoporosis concomitant
condition and will monitor markers of bone turnover and capture any reports of
fracture as adverse events 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 the 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.