Full Data For Intercept's Liver Disease Drug Show Rivals Where To Differentiate

Full Phase III data for Intercept Pharmaceuticals Inc.'s recently approved rare liver disease drug, Ocaliva, have highlighted potential treatment gaps for upcoming pipeline drugs, including candidates from Gilead Sciences Inc., Novartis AG, Shire Pharmaceuticals plc and GlaxoSmithKline plc.

Despite Intercept Pharmaceuticals Inc. winning US FDA approval in May for its chronic liver disease therapy Ocaliva (obeticholic acid) – which became the first new drug for the treatment of rare liver disease primary biliary cholangitis (PBC) to reach the market in more than 20 years – full Phase III data published in the New England Journal of Medicine have highlighted some flaws in the study exposing potential gaps that could be filled by upcoming pipeline drugs.

On May 27, 2016 the FDA granted accelerated conditional approval for Intercept's Ocaliva for the treatment of PBC, a chronic disease that causes the small bile ducts in the liver to become inflamed, damaged and ultimately destroyed, in combination with Impax Laboratories Inc.'s ursodiol (ursodeoxycholic acid; UDCA) or as a monotherapy in adults unable to tolerate UDCA. Aside from Ocaliva, UDCA is the only other available drug for treatment of the disease, having been approved in 1997. The FDA approval for Intercept's new therapy was based on Phase III data from 216 patients that showed Ocaliva reduced levels of alkaline phosphatase in patients – a surrogate endpoint regulators said could be relied upon to be "reasonably likely to predict clinical benefit, including an improvement in transplant free-survival". Still, the US approval for Ocalvia is conditional and continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

Meanwhile full data reported in NEJM, and in an accompanying discussion paper, show that while the study met its primary endpoint there were flaws in its design. Ocaliva is considered a valuable new treatment option for a disease where available therapeutic options are scarce, but there is still room for improvement.

This is good news for the healthy-looking pipeline of novel drug candidates targeting PBC – including Phase II therapies from Gilead Sciences Inc., Novartis AG, Shire PLC and GlaxoSmithKline PLC.

The NEJM article, A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis, highlighted that though the trial met its primary endpoint and response to Ocaliva was rapid with a significant difference observed between each dosage group and the placebo group by week two and at each time point thereafter in the double-blind phase (P<0.001 for all comparisons), the study had limitations.

Firstly, PBC is a chronic liver disease. The study reported results for only two years of treatment; the focus of the trial was therefore limited to surrogate biomarkers, imaging, and symptom end points, with no statistical power to assess clinical outcomes. A multiyear study to assess the effects of Ocaliva on clinical outcomes in patients with PBC who have more advanced liver disease is currently enrolling.

To show greater benefits, it would seem companies with pipeline PBC assets will need to carefully assess surrogate endpoints and possibly provide longer-term data to regulators, and eventual physicians and payers, to promote usage.

Also, the shorter study time meant no long-term side effects were able to be measured. Pruritus, severe itching of the skin, was the most common adverse event across all groups in the Phase III study, with a higher incidence reported in the 5-10mg Ocaliva group (56%) and the 10mg Ocaliva group (68%) than in the placebo group (38%). Although pruritus is the most common symptom in patients with primary biliary cholangitis, study authors noted that neither its incidence nor its severity correlated with disease stage. However, the mechanism for obeticholic acid-related pruritus is unclear. Discontinuation of treatment owing to pruritus occurred in seven patients (10%) in the 10mg group and in one patient (1%) in the 5-10mg group; no patients in the placebo group discontinued the trial regimen owing to pruritus.

Ocaliva, which is expecting a regulatory decision in Europe by the end of September, may well be the catalyst for a number of new treatments for PBC to start reaching regulatory filing stages; and companies following in Intercept's footsteps will be able to learn from its data reporting.

Coming up in the pipeline are nine Phase II programs, two Phase I and I/II candidates, and more than 10 preclinical assets.

Positive topline Phase II PBC data for CymaBay Therapeutics Inc. and Johnson & Johnson's offering, MBX-8025, were published earlier this year – gaining the product a 5% likelihood of approval boost from Biomedtracker. MBX-8025 is the only drug in clinical development for PBC targeting PPAR delta.

Approved And Pipeline Products For Treatment Of PBC

Biomedtracker

Drug Name	Lead Company	Lead Indication	Current Phase	Target	Drug Classification
Ocaliva	Intercept Pharmaceuticals, Inc.	Y	Approved	Farnesoid X receptor	NME
URSO Forte	Impax Laboratories, Inc.	N	Approved	Hydrophilic bile acid	NME
FFP104	Fast Forward Pharmaceuticals BV	N	Development Outside U.S.	CD40 Ligand	NME
Cenicriviroc	Tobira Therapeutics, Inc.	N	I	Chemokine Receptor 2	NME
ND-L02-s0201	Nitto Denko Corporation	Y	I/II	Heat Shock Protein 47	NME
A4250	Albireo Pharma	Y	II	Ileal Bile Acid Transporter	NME
GS-9674	Gilead Sciences, Inc.	N	II	Farnesoid X receptor	NME
GSK-2330672	GlaxoSmithKline plc	N	II	Ileal Bile Acid Transporter	NME
LJN452	Novartis AG	Y	II	Farnesoid X receptor	NME
MBX-8025	CymaBay Therapeutics, Inc.	N	II	PPAR delta	NME
NGM282	NGM Biopharmaceuticals, Inc.	N	II	Fibroblast Growth Factor	Biologic
RhuDex	Dr. Falk Pharma GmbH	Y	II	Cluster of Differentiation 80	NME
SHP625	Shire Pharmaceuticals Group PLC	N	II	Ileal Bile Acid Transporter	NME
Simtuzumab	Gilead Sciences, Inc.	N	II	Lysyl oxidase-like 2	Biologic
avß1 integrin inhibitor	Pliant Therapeutics	N	Preclinical	Integrin Alpha-V Family	NME
EDP-305	Enanta Pharmaceuticals, Inc.	N	Preclinical	Farnesoid X receptor	NME
Elafibranor	Genfit SA	N	Preclinical	PPAR delta	NME
EMT inhibitor	Pliant Therapeutics	N	Preclinical	Unknown	NME
GS-444217	Gilead Sciences, Inc.	N	Preclinical	Apoptosis Signal Regulating Kinase 1	NME
PXS-5033A	Pharmaxis Ltd	N	Preclinical	Lysyl oxidase-like 2	NME
SC-435	Shire Pharmaceuticals Group PLC	Y	Preclinical	Ileal Bile Acid Transporter	NME
TCM-808FB	TCM Biotech International Corp	N	Preclinical	Unknown	Unknown
VBY-825	Virobay, Inc.	Y	Program Hold	Cathepsin A	NME
BB3	Angion Biomedica Corp.	N	Suspended	Hepatocyte growth factor receptor	NME
LJPC-201	La Jolla Pharmaceutical Company	N	Suspended	Galectin-3	NME
NI-0801	NovImmune SA	Y	Suspended	Chemokine (C-X-C motif) ligand 10	Biologic
Oral Tetrathiomolybdate	Synthetic Biologics, Inc.	N	Suspended	Copper molecules	NME

Ocaliva, which has orphan drug status, is a potent and selective farnesoid X receptor (FXR) agonist derived from natural human bile acid CDCA (chenodeoxycholic acid). While it is similar in structure to its predecessor ursodeoxycholic acid, Ocaliva acts by means of the FXR-mediated transcriptional mechanisms (as shown by the FGF-19 and bile acid levels), whereas UDCA acts mainly through post-transcriptional mechanisms.

Additionally, FXR also modulates immune response and inflammation. Several immune and inflammatory mediators were examined in an exploratory manner in the Phase III study of Ocaliva. Gilead, Novartis and Enanta Pharmaceuticals, Inc. are all pursuing the FXR mechanism and might be able to shed more light on immune responses in their upcoming studies.

Geordie Shore Effect?

Liver disease does present an open market for pharma companies with drugs in development and a population in need of further treatment options. The increased number of products entering later stages of development is running in parallel with a rise in disease numbers.

PBC (formerly known as primary biliary cirrhosis) affects approximately 35 per 100,000 of the population overall, with an incidence of approximately five per 100,000 per year. It is significantly more common in women than men. The peak age for the diagnosis is between 55 and 65 years, although patients can present from their 30s onwards and younger patients may experience more aggressive, less treatment responsive disease.

Studies have leaned towards the theory that cases of PBC are on the increase, however it has not been determined if greater awareness of the disease is the cause for the rise in patient numbers.

However, Medscape notes that there is an abnormally high incidence of PBC in Newcastle, UK (estimated as 24 cases per 100,000 population) compared with other big cities worldwide (for example, it is estimated that there are 1.9 cases per 100,000 population in Victoria, Australia).