A phase 2, 12-week, randomized, double-blind, placebo-controlled study of DS-1211b in individuals with pseudoxanthoma elasticum

The molecular basis of PXE is the inactivating mutations in the gene encoding
ABCC6, an ATPdependent efflux transporter that is present mainly in the liver.3
Extracellularly, the excreted nucleoside triphosphate is hydrolyzed by
ectonucleotidases to nucleoside monophosphate and
inorganic pyrophosphate (PPi), the latter a potent endogenous inhibitor of
mineralization. In PXE, the absence of ABCC6-mediated adenosine triphosphate
release from the liver results in
reduced PPi levels, leading to ectopic calcification.
Pyrophosphate is rapidly degraded to inorganic phosphate by tissue-nonspecific
alkaline phosphatase (TNAP), encoded by the ALPL gene. It has been hypothesized
that inhibition of TNAP activities would increase endogenous substrate PPi
levels, leading to amelioration of the ectopic mineralization phenotype in PXE.
Indeed, a growing number of in vitro and in vivo pharmacology studies
(including animal models of PXE) have confirmed and supported this
approach.

Although not acutely life threatening, PXE is associated with significant risks
of visual impairments including blindness, comorbidity from peripheral and
cardiovascular diseases, and adverse impacts on the quality of life in
afflicted individuals. No specific treatment is currently available for PXE in
retarding or reversing the disease progression or its complications in multiple
organs, except for the off-label use of anti-VEGF therapy against ocular
complications of choroidal neovascularization.

DS-1211b is a potent small-molecule inhibitor of TNAP being developed by
Daiichi Sankyo for the treatment of ectopic calcification diseases such as PXE.
In vitro and in vivo animal studies have shown that it is effective in
inhibiting TNAP activities, increasing PPi levels, and reducing ectopic
calcification.

To date, Daiichi Sankyo has conducted 3 Phase 1 healthy volunteer studies to
evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics
(PD) of DS-1211b. Oral administration in the single- and repeat-dose Phase 1
clinical studies in healthy volunteers over a wide dose range has shown that
DS-1211b is safe and well tolerated, has a predicable PK profile, inhibits ALP
activities, and raises PPi levels. Therefore, Daiichi Sankyo is proceeding with
this study in individuals with an established diagnosis of PXE to continue the
development of DS-1211b for the treatment of PXE and potentially other
progressive ectopic calcification diseases.

Primary:
To assess the safety and tolerability of DS-1211b compared with placebo in
subjects with PXE.
To assess the dose response by assessing the treatment changes in PD endpoints.

Study DS1211-A-U201 is a 12-week, randomized, double-blind, placebo-controlled,
parallelgroup study that aims to assess the safety, tolerability, and
pharmacokinetic (PK) and pharmacodynamic (PD) dose response of DS-1211b in
individuals with Pseudoxanthoma Elasticum (PXE) by using biomarkers relating to
tissue-nonspecific alkaline phosphatase (TNAP) inhibition.

Eligible individuals with established diagnosis of PXE will be randomized to 1
of 4 arms in a 1:1:1:1 ratio, to receive 20 mg, 40 mg, or 60 mg of DS-1211b or
placebo in tablet form for once daily dosing (Figure 3.1 of the protocol), for
a total of 12-week dosing, followed by a postdose biomarker assessment and a
2-week follow-up safety check. Approximately 12 to 16 individuals with PXE will
be enrolled in each group for a total of approximately 48 to 64 enrolled study
participants.

The study drugs for this study are:
• DS-1211b film-coated tablet in 20-mg dose strength for study dose levels of
20 mg,40 mg, and 60 mg
• Matching placebo tablets

This safety, tolerability, and dose-ranging study will evaluate DS-1211b doses
that will inhibit TNAP sufficiently to give rise to peak inorganic
pyrophosphate (PPi) increases of approximately 2-fold from baseline while
allowing alkaline phosphatase (ALP) activity and pyridoxal 5*- phosphate (PLP)
levels to return towards normal after cessation of dosing.
Safety, tolerability, PK, and mechanism of action (MOA)-related PD biomarkers
(ALP, PPi, and PLP) will be assessed from the 3 active doses, 20 mg, 40 mg, and
60 mg, of DS-1211b versus placebo. TNAP inhibition increases PPi levels, the
MOA by which DS-1211b is proposed to reduce ectopic calcification. However,
excessive TNAP inhibition increases the risk of recapitulating clinical
manifestations of hypophosphatasia, a genetic mineralization disorder of TNAP
deficiency accompanied by abnormally and persistently elevated PPi and PLP
levels.
Therefore, a careful benefit-to-risk characterization of the extent of TNAP
inhibition that achieves a balance between increases in PPi versus increases in
PLP is critical for selecting a target DS-1211b dose for later studies.

Nonclinical studies demonstrated that the potassium salt of DS-1211a
significantly reduced the ectopic calcium deposition in the murine model of
PXE, KK/HIJ mice. Significant inhibition of ectopic calcification was observed
at a DS-1211a concentration of approximately 15.6 nmol/L.
The exposure at this pharmacological active dose could be estimated to be 0.374
µmol·h/L (0.137 µg·h/mL) in AUC24h, assuming a relatively stable drug exposure
throughout treatment under food admixture route of administration.
Data from nonclinical toxicology studies suggest a potential risk for a
reversible nephrotoxicity at high concentration of DS-1211b. The observed
nephrotoxicity correlated with DS-1211b dose and systemic exposure and was
accompanied by an increase in serum UN and serum CRE, suggesting that
occurrence of nephrotoxicity may be monitorable in clinical trials. The NOAEL
was established in nonclinical toxicology studies, and the drug exposure at the
NOAEL in most sensitive species, monkeys (36.4 µg·h/mL in AUC24h), was 266-fold
above the corresponding exposure that retarded calcium deposition in KK/HIJ
mice and 95-fold above with adjustment of species differences in IC50 (factor =
36.3 / 13.0 = 2.79). The margin of exposure between the NOAEL in monkeys and
the estimated high dose of 50 mg in humans is approximately 20-fold.

Besides the potential renal toxicity identified from animal toxicity studies,
hypophosphatasia is a potential safety risk for DS-1211b, based on the known
mechanism of action of TNAP inhibition. Hypophosphatasia is a rare, inherent,
metabolic disorder characterized by low activity of TNAP due to mutations on
ALPL gene encoding TNAP. The disease manifestation and severity are varied in a
broad range from very severe type in infant to milder form in adult.
The elevated levels of TNAP substrates, PLP, PPi and PEA, have been reported
and among those, PLP is used as a sensitive marker which correlate with
hypophosphatasia severity. In Ph2 study, PLP will be measured as one of safety
monitoring measures.

In the SAD and MAD studies, 96 healthy volunteers were given doses of 3 to 3000
mg. There were no deaths, SAEs, severe TEAEs, apparent renal toxicity detected
by serum UN or CRE increases, or urinary kidney impairment markers. There were
no safety signals that were severe or dose-related trends observed in TEAE
occurrences. In the rBA/FE study, multiple doses were evaluated in tablet and
equivalent PIB dose under fasting and fed conditions in 18 healthy subjects.
The subjects had an acceptable safety profile, and the study drug was well
tolerated.

In conclusion, a wide dose range of DS-1211b was evaluated in the SAD
(1000-fold), MAD (30-fold), and rBA/FE studies in healthy volunteers. DS-1211b
doses from 3 mg to 3000 mg (a single dose), 30 mg to 300 mg once daily, and 150
mg twice daily for 10 days were generally safe and well tolerated. The PD
effects were observed on PPi, PLP, PEA, and ALP activity, which corroborates
the proposed mechanism of action of DS-1211b as a TNAP inhibitor in human
subjects. Thus far, the human experience of DS-1211b in healthy volunteers (18
to 45 years old) did not reveal safety concerns with single and multiple oral
doses up to 3000 mg.
In addition, the nonclinical safety profile demonstrated monitorable and
reversible target organ toxicities with adequate safety margins. Given the
totality of clinical and nonclinical data, the benefit/risk assessment is
favorable for further clinical development.