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2019-06-25 23:26:48

Introduction

CymaBay (NASDAQ:CBAY) has been in the news lately for reasons other than the Phase 3 PBC clinical trial. Specifically, the 12-week interim topline data on the effect of seladelpar on relative liver fat reduction was not clinically successful. Unfortunately, these 5 keywords ongoing 52-week Phase 2b dose-ranging, paired liver biopsy study of seladelpar for NASH did not register. For this reason, CBAY stock depreciated ~40%.

As noted by the company, biopsy data is expected at 52 weeks. Besides, the ultimate clinical goal of all biopharmas involved in NASH trials is to demonstrate therapeutic efficacy for their respective investigative drug candidates in one or both of the histological clinical endpoints mandated by the FDA for NASH fibrosis.

Since my last comprehensive review of the PBC program, I believe we have seen significant additional clinical information on the clinical efficacy of seladelpar in PBC. The focus of this article is to elaborate how the Phase 3 PBC study has been suitably designed to reveal the clinical effects of seladelpar that could be of benefit in all PBC patient population.

The Phase 3 Clinical Trial

Drug development is an ongoing innovation. In the last 2 decades since the first PBC therapeutics, ursodeoxycholic acid (UDCA) was approved, and 3 years into the approval of obeticholic acid by Intercept (ICPT) for PBC, it has become very evident that therapeutics with improved safety and tolerability profiles are required. Moreover, the progressive pathophysiology of PBC is further justification on the clinical need for more innovative therapeutics for PBC as depicted in Fig. 1.

PBC is a rare/orphan, chronic liver disease, triggered by the dysregulation of bile acids homeostasis that causes the bile ducts in the liver to become inflamed, damaged and, destroyed. Bile is a fluid produced in the liver and plays an important role in digesting food, but induces toxicity when it accumulates in the bile ducts leading to an imbalance that causes cholestasis and associated symptoms of pruritus (i.e. intense itch) see Fig. 1.

As reported in clinical trials govt. on the pivotal global Phase 3:

A 52-week, placebo-controlled, randomized, Phase 3 study to evaluate the safety and efficacy of seladelpar in subjects with primary biliary cholangitis (PBC) and an inadequate response to or intolerance to UDCA. To evaluate the safety and effect on cholestasis of two seladelpar regimens (5 mg/day titrated to 10 mg/day and 10 mg/day) over 52 weeks of treatment compared to placebo.

Patient Population: There are no differences in the PBC patient population utilized in the Phase 2b study versus ongoing Phase 3. Meaning that, both studies involve patient population with non-cirrhotic PBC (mild PBC) and mild cirrhotic PBC (i.e. Child Pugh A; moderate PBC) see Fig. 1. The Child-Pugh score is used to assess the prognosis of chronic liver disease, mainly cirrhosis, with an A score denoting mild cirrhosis and B/C describing severe/advanced cirrhotic disease states.

As with most diseases, patients with moderate and advanced PBC remain underserved patient group. This is because of the low clinical response rates of these patients to FDA approved PBC therapeutics, UDCA and OCA. Specifically, the scientific evidence attributes the low response rates in these patients to possibly increased mechanical pressure in the remaining intact bile ducts, leading to bile infarcts and liver damage (Fig. 1). For this reason, my first question to CEO Sujal Shah was on the patient population.

CEO Shah noted that:

the documented anti-cholestatic and anti-inflammatory benefits coupled with decreased pruritogenic responses in cirrhotic and non-cirrhotic PBC patients in the 52-week Phase 2b study is a demonstration of the potential therapeutic appeal of seladelpar.

Data presented at EASL in Q2/2019 demonstrated the clinically meaningful benefits of seladelpar on cholestasis (AP.), inflammation (ALT.), total bilirubin and pruritus (i.e. VAS) were similar in non-cirrhotic and cirrhotic (Child-Pugh A) PBC patients. Overall, seladelpar maintained a potent anti-cholestatic effect over 52 weeks, appeared to be safe and well tolerated; not associated with pruritus and demonstrated no apparent difference in efficacy or safety between cirrhotic and non-cirrhotic patients.

Pruritus: Is an intense itch that is characteristic of cholestatic liver diseases. Pruritus remains the most problematic symptom of PBC that impairs the quality of life. The Phase 2b PBC study provided preliminary evidence demonstrating an improvement trend in pruritogenic responses in PBC patients in response to seladelpar. treatment.

Once again to CEO Shah on assessing pruritus in Phase 3 ENHANCE study:

Although we observed decreased trend in pruritogenic effects by seladelpar in the Phase 2b, that trial was not specifically designed to evaluate the effects of seladelpar on pruritus. In Phase 3, patients will be given a hand-held device as an electronic diary to record their itch intensity. This will assess the change from baseline to six months in pruritus. We are using a numerical scale (1-10) which is FDA's preference.

I have often described pruritus as a nasty itch with an inward scratch . No one can describe the impact and the feeling of pruritus like a PBC patient living with the disease. Therefore, this study with CymaBay drives home the urgent need for effective therapeutics beyond current approved therapies which have been reported to enhance pruritus.

In previous articles on cholestatic liver diseases, my working hypothesis on pruritus has always been that-drug candidates for cholestatic liver diseases that effectively decreases serum bile acid levels could induce anti-pruritogenic relief. Conversely, those drug candidates that do not suppress serum bile acid levels may not suppress pruritus.

In PBC, seladelpar has been shown to decrease serum levels of the metabolite, 7α-hydroxy-4-cholestene-3-one (C4.) routinely measured in the serum as a marker of new bile acid synthesis. Furthermore, seladelpar was associated with decreased synthesis of cholesterol in healthy subjects, an effect that would lead to reduction of bile acids conversion from cholesterol.

Clinical Endpoints: As a breakthrough designate drug candidate by the FDA and EMA, CymaBay similar to Intercept for OCA is expected to file for accelerated conditional approval for seladelpar if primary clinical composite endpoint is met:

Composite endpoint of AP and total bilirubin [ Time Frame: 12 months ]

AP < 1.67 × ULN,

≥ 15% decrease in AP, and

Total bilirubin ≤ ULN

Interim data from the Phase 2b PBC study achieved a composite responder rate (AP <1.67xULN, ≥15% decrease in AP, total bilirubin ≤ULN) of 59 and 71% in the 5/10mg titration and 10mg seladelpar dose groups, respectively. Of note, the same doses of seladelpar are being used in the Phase 3 global trial.

CEO Sujal Shah commenting on AP levels and then the primary composite clinical endpoints for the Phase 3 study:

If the Phase 3 data replicates the AP composite responder rates and AP normalization rates observed in Phase 2 to date, we believe seladelpar has the potential to be the preferred second-line treatment alternative for patients with PBC.

Worth pointing out that a global epidemiological clinical study by Lammers and colleagues reported overall liver transplant free survival in patients who achieved lower AP levels (i.e. <1.67 ULN).

Actionable Event, Financials and Risks

Patient recruitment is expected to conclude by Q4/2019. Several catalytic events are expected in the next 12 months starting with: (i.) completion of the ongoing PBC Phase 2 extension in late 2019 or early 2020; (ii.) end of patient enrollment for PBC Phase 3 by Q4/2019; (iii.) 52 week Phase 2 full data NASH readout most likely early Q2/2020.

At the end of Q1/2019, cash, cash equivalents, and marketable securities totaled ~$264.8M. Existing cash is expected to fund the current operating plan into 2021. At the end of Q1/2019, CymaBay had a cash burn of $18.6M versus Q4/2018.

Epilogue

Patients diagnosed with orphan liver diseases such as PBC have limited FDA approved therapeutic options. PBC is not an emerging epidemic. Notwithstanding, the pathophysiological consequences of PBC progression in patients that are unresponsive to current therapies are very dire. Make no mistake, significant clinical progress was made with the approval of OCA.

As we all know, drug development is an ongoing innovation. There is a recognized therapeutic void in PBC therapeutics. Seladelpar represents an advanced second line of therapy for PBC that should provide therapeutic relief to patients due to efficacy coupled with tolerability and safety profiles. Seladelpar could make a lot of PBC patients smile! Citing Mother Teresa:

We shall never know all the good a smile good could do.

Disclosure: I am grateful to CEO & President of CymaBay, Sujal Shah, for granting me this interview.

The full length article was discussed in more depth with members of my private investing community, Liver Therapy Forum

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Disclosure: I am/we are long CBAY. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Additional disclosure: As always, my articles are meant to facilitate your understanding. Readers are expected to form their own trading plan, do their own research and take responsibility for their own actions. Investing in common stock can result in partial or total loss of capital. Please implement due diligence and invest wisely.


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