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A Revised Look at Strongbridge's Recorlev...and Korlym & Relacorilant

14:38 EDT 18 Aug 2018 | Biotech Watcher


On August 8, 2018, Strongbridge Pharmaceutical (SBBP) announced positive results from its SONICS pivotal trial – using Recorlev (levoketoconazole) to treat Cushing’s syndrome. It is a potential competitor to Corcept’s drugs and especially to NovartisSignifor.

Recorlev is a specific isomer, an allegedly kinder and gentler form of ketoconazole. Ketoconazole earned a black box warning for liver toxicity, on rare occasion necessitating a liver transplant or causing death.

We wrote tentative(mildly) positive commentary, even though information was missing from the announcement and subsequent conference call.

Why the Revised Opinion?


Since then, we came across a recently published paper on liver toxicity with ketoconazole in Cushing’s patients. In a recent study published out of France[1], ketoconazole (KTZ) was used to treat Cushing’s syndrome patients. Recorlev is now cast in a different light with potential red flags.

As our previous benchmark, we used a published aggregation of prior ketoconazole studies. It was a heterogenous group of patients, some were (likely) compromised enough to be vulnerable to liver toxicity. This inflates the markers for liver toxicity, thus making Recorlev look comparatively good.

In Strongbridge’s defense, we have not spoken to them. Their management should be able to directly address this matter. For this reason, we are outlining the red flags, and refrain from hitting hard.

However, on the conference call, the Strongbridge team didn’t offer general color about the strength of the efficacy or relate additional information about liver toxicity. This mildly concerns us. You don’t have to spill the numbers but please describe and reassure.

French Study & Recorlev


108 patients were analyzed for markers of liver functioning. 47 patients were naïve to KTZ (KTZ-naïve), while 61 were previously treated with another KTZ formulation (KTZ-switch).

As stated: “Most abnormalities observed were asymptomatic mild increases of liver enzymes. This is no different than what we observed in the Strongbridge study. It’s not a surprising result. As we stated before:

Severe toxicity episodes were a relatively rare event (1:2,000 to 1:15,000), but it was enough to warrant the FDA’s attention. That’s because these rare events sometimes forced a transplant or even death!

The French investigators concluded: These findings highlight the need for close monitoring of liver enzymes

Comparative Results


Although we await further numbers from Strongbridge’s investigators, the percentages exceeding the upper limit of normal (ULN) were similar for KTZ vs. Recorlev. Strongbridge stated that there was “no severe drug-induced liver injury” and no incidents of Hy’s law, a solid indicator of injury.

That’s a good thing, except that a severe liver injury is a rare event. The French investigators used a definition that includes non-severe liver injury. This creates a different picture.

Liver Injury Definition


The French Study included other markers than reported in the Strongbridge study. We present their entire definition. Because the Strongbridge study largely presented only partial data, you should focus on the levels of alanine aminotransferase (ALT).

The markers evaluated were ALT, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), alkaline phosphatase (ALP) and total bilirubin (TB). Levels of each serum marker were expressed as multiples of the upper limit of the normal range (ULN).

A patient was defined as having liver injury if any of the following four conditions occurred:
1. ALT > 3x ULN;
2. AST > 3x ULN;
3. TB > 2x ULN;
4. ALP > 2x ULN & ALT > ULN.

Toxicity Comparison


Results from Strongbridge & French Studies

Recorlev

(N=94)
KTZ-naïve

(N=47)
KTZ-switch
(1-6 mos)
(N=10)
KTZ-switch
(> 6 mos)
(N=51)
ALT
n=61?
n=31
n=4
N=35
Abnormal value at baseline
?
6
0
5
> ULN at least once
?
10
(32.3%)
0
(0%)
8
(22.9%)
ALT > 3x ULN
TBA
(10.6%)
4
(8.5%)
0
(0%)
1
(2.0%)
ALT > 5x ULN
TBA
(3.2%)
4
(8.5%)
0
(0%)
0
(0%)
Total Bilirubin




> 1.5x ULN
0
(0%)
Maybe 1*
(2.1%)
0
(0%)
0
(0%)
*Reports 1 patient exceeded ULN at least once but does not specify if > 1.5x ULN

The following procedure from the French Study stands out: “If the level of any liver function marker was ≥ 3x ULN, KTZ had to be discontinued immediately and irrevocably.”

And “If the levels were ≥ ULN but < 3x ULN, the dose of KTZ had to be decreased by ≥200 mg per day and the marker monitored tightly until the liver function test normalized and treatment continued thereafter at the lower dose."We can reasonably expect that some of the Strongbridge patients fall into this category.

The French Study’s procedure was echoed by the Endocrine Society and its standard practice guideline for treating Cushing’s syndrome: “It is recommended that liver function be closely monitored during treatment with ketoconazole and dose reduction or discontinuation is advised when liver enzymes are 3-fold elevated.[2]

Let’s apply the French Study protocol to the Strongbridge patients.

Based on ALT levels alone, over 10% of the Strongbridge patients would have to cease taking Recorlev. This is in addition to the 12.8% who discontinued treatment with Recorlev due to adverse events.

Based on the available data, it’s difficult to claim a superior toxicity profile for Recorlev. We can see why the prior company that owned Recorlev reportedly halted further work due to liver toxicity. There’s enough here to raise a red flag.

Will the FDA have the same concerns? Does the French Study change the context? We await the release of additional ALT data as well as other biomarkers in the Recorlev SONICS study. Unless there’s something reassuring, Strongbridge is in a difficult situation.

Supplement: Efficacy Comparisons


Pivotal Phase 3 & (Latest) Phase 2 Results

Recorlev
(N=94)
Signifor
(N=80)
High-Dose[3]
Korlym
(N=50)
Recorilant
(N=18)
High Dose[4]
Mechanism of Action
1o Endpoints at 6 Months




UFC Normalization at Month 6
30%
26.3%
(21/80)
UFC ↑
Mild UFC ↑
≥ 50% Reduction in UFC
48%[5]
41.3%
(33/80)
N/A
N/A
≥ 25% Reduction in AUCglucose
TBA
Mixed[6]
60.0%
(15/25)
(p) < 0.0001
TBA
Improved Glucose Control:
≥ 0.5% HbA1c ↓
OR ≥ 50 mg/dl ↓ in Glucose Test
OR ≥ 25% ↓ in antidiabetic meds
Likely Better
Worse[7]
48%
(12/25)
58%
(7/12)
≥ 5 mmHg reduction in Diastolic BP
Likely Better

Better[8]
38.1%
(8/21)
< 0.05
TBA[9]
≥ 5 mmHg reduction in Diastolic
or Systolic BP
Likely Better[10]
Better
44.4%
(8/18)
< 0.05
54.5%
(6/11)
2o Endpoints (avg change)




Fasting Blood Glucose
< 0.0001
(n=61?)
31.0mg/dl ↑
Worse[11]

-44.3mg/dl
(n=25)
< 0.03
Better,
Dose Response
Maintained
HbA1c
< 0.0001
(n=61?)
1.58%↑[12]

-1.14%
(n=22)
< 0.001
Better,
Dose Response
Maintained
Total Cholesterol
< 0.0001
-0.4mmol/L
p=n.s.[13]
Likely Better[14]
TBA
LDL-Cholesterol
< 0.0001
-15mg/dl
Likely Better
TBA
Body Weight Loss
< 0.0001
-8.7kg
-5.7kg[15]
< 0.001
TBA
Body Mass Index
< 0.0001
-2.1 kg/m2
p=n.s.
Likely Better
TBA
Reduction in Hypertensive Meds
Among Hypertensive Pts
Likely Better
Likely Better
(11/40)
27.5%
Likely Better
Overall Clinical Response
Better
Likely Better
87%
(40/46)
< 0.0001
TBA
Quality of Life
TBA
Improved
Improved
=0.01, 0.02
TBA

Signifor’s problems with worsening glucose tolerance makes it the clear loser. Like Recorlev, it also inhibits the manufacture cortisol. It also has a high discontinuation rate, partly because patients simply feel worse. Furthermore, Signifor seems to lose some efficacy with repeat administration.

To compare with Korlym, additional SONICS data needs to be released. This should include Recorlev’s actual magnitude of improvement and longer-term efficacy.Korlym patients continued to improve over an extended treatment period. On the surface, Recorlev looks pretty good.

When you examine the preceding table, it’s no surprise that Korlym eventually trumped Signifor in the U.S. market. Signifor worsens glucose tolerance in most patients and kicks several patients into type 2 diabetes. These symptoms do not immediately abate after Signifor is withdrawn.

The introduction of Recorlev especially hurts Signifor. They both inhibit the body’s manufacture of cortisol and reduce the cortisol levels. Recorlev and Signifor will thus compete for endocrinologists that focus on (free) cortisol reduction.

We will remove Signifor from the next table. There’s much more insight to gain with inserting relacorilant into the discussion. And by the way, we recently discovered that Novartis is pitching its Cushing’s franchise to potential buyers. The Signifor revenues are too small for Novartis and without a large pharma’s marketing muscle, Signifor may no longer be counted as a worthy competitor.

Competitive Ecosystem


Drug Comparison
Korlym vs Relacorilant vs Recorlev

Korlym
Relacorilant
Recorlev
Disease Indication
Endogenous Cushing’s Syndrome
Endogenous Cushing’s Syndrome
Endogenous Cushing’s Syndrome
Physical Origin
Tumor on Pituitary, Adrenal, and/or Ectopic
Tumor on Pituitary, Adrenal, and/or Ectopic
Tumor on Pituitary, Adrenal, and/or Ectopic
Active Ingredient
Mifepristone
Relacorilant
Ketoconazole Isomer
Mechanism of Action
GR-II Antagonist
Selective GR-II Antagonist
Steroidogenesis Inhibition
Strength
Faster acting

Reduces metabolic symptoms

Feel Better[16]
Restores Cortisol Rhythm

Dampens associated psychiatric disturbances

Differentiated Mechanism of Action
Faster acting

Reduces metabolic symptoms

Feel Better[17]
Restores Cortisol Rhythm

Dampens associated psychiatric disturbances

Differentiated Mechanism of Action

Reduce hypertension?
Fast acting

Cortisol level ↓

Reduces metabolic symptoms

May be gentler on liver than Ketoconazole

Uses Incumbent Biomarker
Major Side Effects, Weaknesses
“Requires White Glove Distribution”, thus higher cost of goods


Endrometrial Hypertrophy[18]
Vaginal Bleeding

Abortion & other progesterone blocking effects

Adrenal insufficiency

Cortisol levels ↑↑

ACTH levels ↑↑

Peripheral edema, episodic hypertension

Nausea, fatigue, headache

New Biomarker[19]
Less than White Glove distribution, thus lowercost of goods.











Adrenal insufficiency

Cortisol levels ↑

ACTH levels ↑

Far less edema & hypertensive episodes?

Nausea, fatigue, headache

New Biomarker
Liver toxicity
Still need to validate improved safety

Most don’t achieve normal UFC levels

Many Feel Worse
Flattens Cortisol Rhythm





Adrenal insufficiency


Red items are missing or much milder in relacorilant versus Korlym
The new biomarkershould eventually supplant the incumbent biomarker tests, but it will take time.

It’s clear that relacorilant is being positioned into the market as superior to Korlym. When (if) relacorilant enters the market, then Korlym is maintained for patients who are already successful on it. It may also be used as a backup, when patients don’t respond to relacorilant. But frankly, relacorilant will mostly vaporize the Cushing’s market for generic and branded Korlym. The Teva court case is a moot point…just one quick look at the table is enough!

If Recolev isn’t saddled with toxicity concerns, its entrance into the market may signify the final doom for Signifor. It should then be a stronger competitor to Korlym than Signifor.

Only if Recorlev isn’t saddled with toxicity concerns…

Toxic Thoughts


Strongbridge’s Chief Medical Officer expressed excitement over Recorlev. The management aspires to “position Recorlev as first-line, first-choice therapy” and a “Targeted pricing corridor of ~200K-$400K per patient per year”.

Will the future Phase 3 data show Recorlev’s advantage over KTZ? We didn’t see a defining advantage in efficacy and especially toxicity. The current practice guidelines for treating Cushing’s with KTZ:

It is recommended that liver function be closely monitored during treatment with ketoconazole and dose reduction or discontinuation is advised when liver enzymes are 3-fold elevated.[20]

Because KTZ-induced severe liver injury is such a rare event, Strongbridge will be fighting a ghost. Its Phase 3 sample size is so small that it likely can’t not escape a requirement for monitoring the first several thousand patients.

The only alternative?Can Strongbridge convince the FDA to soften its attitude towards KTZ. We don’t know the answer, but we’re afraid of the chances.

…and if there’s ever a hint of a severe or even a moderate injury to a Recorlev patient, then the black-box warning becomes an ugly spector. It’s over.

What do we think?

We are very nervous. We like things about Strongbridge, but the existing data doesn’t show that Recorlev ≠ ketoconazole.[21]There better be some unforeseen magic in the additional data or else it’s a hard road.

Feeling Better, Sleeping Better


The other issue for Recorlev is that patients simply feel better on Korlym. Many Cushing’s patients report sleeping better, soon after starting Korlym.

Cortisol levels normally follow a daily cycle. It resembles a daily sine wave that rises in the morning to waken and enable alert focus, and descends towards the evening to enable rest and feelings of well-being. Cushing’s patients have a flat, chronically high levels of cortisol. Recorlev and Signifor serve to further flatten the cycle while Korlym accentuates a daily rhythm. The cortisol levels are “released” so that it enables sleep and well-being in the evening. This is a significant issue and motivates switching.

The Relacorilant Potential


Relacorilant looks clearly superior to Korlym. We said that it will clean Korlym’s clock…and be the real first choice for treating Cushing’s. Why?
1. A greatly reduced risk of hypokalemia;
2. Much milder increase in cortisol and ACTH;
3. And perhaps (modestly) greater efficacy.

Mifepristone treatment has 2 main drawbacks: (1) the blockade of glucocorticoid receptors leads to increased ACTH and cortisol levels, making it difficult to adapt the treatment and diagnose adrenal deficiency, and (2) increased cortisol levels can also lead to severe hypokalemia.[22]

First, a surprising result: no hypokalemia.[23] This is a major benefit! In Korlym’s pivotal trial, 44% of the patients experienced hypokalemia. We have seen none in the ongoing relacorilant trial…yet. Higher doses may yet elicit hypokalemia, but it should be less frequent and milder relative to Korlym.

Second, even though relacorilant is very good at blocking the GR receptor, the consequent rise in cortisol and ACTH is unexpectedly mild. It’s not even in the same playing field as Korlym. This was unexpected: antagonize the GR receptor and the cortisol level rises…strong. Relacorilant is obviously not the same as Korlym.

Third, will relacorilant be also known for blood pressure reduction?

Even though Korlym reduced blood pressure in some of the hypertensive patients, 12 Korlym patients had adverse blood pressure and peripheral edema events in the pivotal trial. This is related to evoking higher ACTH and cortisol levels…which are muchmilder with relacorilant. These adverse events are not being seen with relacorilant.

These adverse events were a major reason for discontinuation with Korlym.

Our Thoughts


Can Recorlev compete with Korlym and relacorilant?It must address three conditions:
1. Free of toxicity concerns;
2. Matches Korlym’s metabolic performance; and
3. Patients don’t feel worse.

Korlym will be faster acting, that’s a given and will thus capture many Cushing’s patients in crises.

The First Three Issues


First, the liver toxicity is a key issue. For Strongbridge, this will define the difference between capturing a major market share versus “game over”. If the FDA comes down on Recorlev, it’s over, fated to be a minor player at best.

If the toxicity issue doesn’t overwhelm Recorlev, it should enjoy some ready-made niches. The endocrinologists who liked using ketoconazole will have their drug “returned”.Also, some patients cannot be adequately treated by Korlym alone. Lastly, there are still many endocrinologists who are focused on reducing cortisol levels.

Second, Recorlev will first be battling the other drugs as they share a common mechanism: inhibiting cortisol synthesis. It will capture many docs who focus on cortisol reduction. Besides Signifor, Recorlev will be battling off-label drugs that more closely “resemble” KTZ. If the rest of the Phase 3 results are good, then Recorlev may do very well.

On the other hand, the diabetics are currently triaged to Korlym. The practice guidelines recommend it…and this is not a small group.

Consequently, glucose intolerance or type-2 diabetes secondary to insulin resistance occurs in approximately 80% of patients with Cushing's syndrome (CS).[24]

This is a central reason that explains Korlym’s dominance. Recorlev must approach or exceed Korlym’s ability to reduce diabetes or glucose intolerance.

Third, what is the value of better sleep? What is the value of feeling better? Signifor had dreadful discontinuation rates. Patients switched and simply felt better on Korlym.

The Future


Fourth, relacorilant is the potential first choice. If the current results are confirmed, it’s a clear choice over Korlym…and even “a mildly toxic” Recorlev. It might even win over a few docs that previously favored off-label KTZ. It looks that good.

Fifth, the FKBP5 test should push the endocrinologists to Corcept.

There are three incumbent tests for measuring cortisol activity: plasma, urine, and saliva tests. Why would Corcept develop yet another test?

1. The incumbent tests lack enough reliability; and
2. The incumbent tests are incapable of assessing Corcept’s drugs.

This last issue is important: Moreover, the lack of available biological parameters of follow-up on treatment obviously represents a limitation for the use of mifepristone.[25]

The incumbent tests lack reliability and validity. Even when elevated, they do not correlate well with disease severity, nor does it measure actual cortisol receptor activity - where the true action resides. Most of the cortisol resides in the tissues – less than 1% of total cortisol may be freely circulating. The urinary and other tests are crude instruments.

In the presence of cortisol or prednisone, the FK506-binding protein 5 (FKBP5) mRNA expression is increased. It’s an accurate indicator of cortisol receptor activity. Corcept continues to expand the data for using its assay test. The published and presented results look good, and sensitively measures the effect of Corcept’s drugs on reducing cortisol-induced receptor activity.

This validation and dissemination take time, but we expect the endocrinologists to begin significant adoption in 2019. With the FKBP5 test, the endocrinologists will quickly and confidently titrate Korlym and relacorilant to its optimal dose. This removes a major impediment to adoption.[26]

Small Segment


Sixth, Corcept’s drugs are good for combination therapy. The unique mechanism of action is a positive. Korlym and relacorilant don’t add to the toxic side effects in other drugs, and thus can be a part of combination therapy for refractory patients. Corcept owns the patent for such a combination. We don’t expect this to be anything other than a minor segment, but it’s real.

(At the time this post was written, one or more BioWatch authors held a position in CORT)

This commentary is from BioWatch News:


[1]Young J, Bertherat J, Vantyghem MC, et al. (2018). Hepatic safety of ketoconazole in Cushing’s syndrome: results of a Compassionate Use Programme in France, European Journal of Endocrinology, 178, 447-458.
[2]Nieman LK, Biller BM, Findling JW, et al.(2015). Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. Journal of Clin Endocrinol Metab. 2015;100(8):2807–31.
[3]Reporting high-dose (900mg) Signifor dose cohort only
[4]High-dose cohort results for first levels (250mg & 300mg) – these pts will later receive 350mg & 400mg
[5]About 75% of KTZ-treated Cushing’s patients achieve ≥ 50% reduction.
[6]One study found that AUCglucose improved even as fasting blood glucose and HbA1c got worse.
[7]41% not on antidiabetic drug at baseline required new meds; 64% already on meds required more!
[8]Mean reduction with 6-month diastolic BP was 5.0mm Hg ↓
[9]As more high-dose data is added, we’d like to see the data separated into Systolic vs. Diastolic.
[10]KTZ is documentedto normalize hypertension in Cushing’s syndrome. We await further Recorlev results.
[11]73% of Signifor pts had hyperglycemia-related AEs. FBC increased from 97.0mg/dL to 128.0mg/dL at 6 months of treatment. A recent Italian studyconfirmed increased 12-month prevalence of diabetes (p=0.015) and HbA1c levels ↑ (p=0.001).
[12]Mean HbA1c increased from 5.76% at baseline to 7.34% & 7.21% at 12 & 24 months of treatment.
[13]A recent Italian study had much more optimistic 6-month results: total cholesterol ↓ (p=0.003), LDL-cholesterol ↓ (p=0.014), weight loss (p=0.001), BMI ↓ (p < 0.001). As seen in other studies, there is some decline in efficacy at 12-months: total cholesterol ↓ (p=0.032), LDL-cholesterol ↓ (p=0.033)
[14]Non-Cushing’s studies have documented that mifepristone significantly improves the total and LDL-cholesterol.
[15]The weight loss improves with extended long-term data with median treatment duration of 29.2 months. There is a mean 10.3kg ↓. This is a robust 9.3% reduction (N=29, p=0.0008)!
[16]Your body normally regulates cortisol levels so that it has a daily cycle that spikes to enable alert focus in the morning. The cortisol levels are “released” so that it enables sleep and well-being in the evening. For some, a flat curve is very uncomfortable and fuels severe symptoms. This flatness occurs in Cushing’s. Recorlev and Signifor serve to further flatten the daily rhythm. It’s akin to how some patients feel with strong doses of oral prednisone. Korlym accentuates the daily flux, and thus many patients report the restoration of good sleep as well as “feeling better”.
[17]See previous footnote.
[18]Endometrial hypertrophy is detected as thickening of the endometrium on sonography which represents excessive proliferation of the endometrium cells. About 38% of female Korlym patients have this adverse event.
[19]Corcept is marketing the FBPK5 expression test as a clinical marker of GR receptor activity. It is an endocrinologist’s tool for faster and “more confident” dose optimization.
[20]Nieman LK, Biller BM, Findling JW, et al.(2015). Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. Journal of Clin Endocrinol Metab. 2015;100(8):2807–31.
[21]We find it odd that Strongbridge management did not respond to conference call queries about the strength of efficacy and sample size…even on a non-quantitative, general description. They could have done that, it doesn’t hurt the chances for an academic publication or presentation. If they can’t provide a firm answer, then perhaps some caution is warranted.
[22]Castinetti F, Conte-Devolx B, Brue T. (2010).Medical treatment of Cushing's syndrome: glucocorticoid receptor antagonists and mifepristone. Neuroendocrinology, 92 (Suppl 1), 125-30.
[23]The GR receptor impacts can be logically divided between transactivation vs. transrepression. Korlym antagonizes both processes, while relacorilant is a milder antagonist of GR transrepression. Hitting transrepression translates into higher cortisol levels and associated side effects. This has been an (unattainable) holy grail for drug development: hit transactivation but not transrepression. With relacorilant, Corcept is achieving a bit of this…and we see the benefit!
[24]Catargi B, Rigalleu V, et al. (2003).Occult Cushing’s Syndrome in Type-2 Diabetes. The Journal of Clinical Endocrinology & Metabolism, 88(12):5808–5813
[25]Castinetti F, Conte-Devolx B, Brue T. (2010).
[26]With the FKBP5 test, endocrinologists will understand that Cushing’s syndrome is better reflected in cortisol (receptor) activity rather than the general levels of freely circulating cortisol. This rethinking meshes with the MOA for Corcept’s drugs.

Original Article: A Revised Look at Strongbridge's Recorlev...and Korlym & Relacorilant

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