Corbus's OLE Data Is Fool's Gold For Biotech Treasure Hunters

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About: Corbus Pharmaceuticals Holdings, Inc. (CRBP)
by: Alpha Exposure
Summary

We believe Corbus bulls mistakenly point to lenabasum’s OLE study for diffuse SSc (dSSc) as evidence of efficacy.

We believe Corbus recruited patients who were much further along in their disease resolution phase, and that these patients should experience naturally decreasing mRSS scores over time.

Additionally, ~90% of OLE patients were on concomitant immunomodulating therapy, which is associated with statistically significant reductions in mRSS.

We believe the mRSS improvement in OLE patients is primarily due to natural disease resolution and from use of concomitant immunomodulating therapies, and is not a treatment effect of lenabasum.

We are short Corbus with a price target of $0.22 which is 97% downside to its current valuation.

We have previously written an article on Corbus Pharmaceuticals (CRBP) that details our beliefs that the company has ties to investors convicted of or alleged to have committed securities fraud and outlines our view of the failed clinical trial history of lenabasum. Many Corbus bulls have tried to ignore the evidence presented in our article and have instead focused on lenabasum’s open label expansion (OLE) study data in diffuse systemic scleroderma (dSSc) as a strong indicator of efficacy.

Bulls, such as the one show in the screenshot below, choose to ignore the failed placebo-controlled portion of the Phase 2 trial. Instead, they focus on the non-randomized, single-arm, open label expansion portion of the Phase 2 study and take the OLE data at face value. Bulls believe the benefits seen in the OLE study are evidence of the drug’s efficacy in dSSc based off what we believe is an incorrect assumption that patients could not have improved as much as they did in the OLE study if lenabasum wasn’t efficacious.

We believe the Corbus bulls are wrong and that the OLE data does not show that lenabasum meaningfully improves mRSS scores in dSSc patients. We will provide:

  1. A factual overview of the course of the disease as we see it, including the three main stages of disease (sclerotic, plateau, resolution/atrophy) as documented by our analysis of the scientific literature and supported by our conversations with systemic scleroderma (SSc) Key Opinion Leaders (KOL’s).
  2. An explanation of why Corbus’s recruitment of patients unusually far along in the disease resolution phase is important when interpreting the OLE data.
  3. How the use of immunomodulatory therapies has been shown to improve (decrease) mRSS scores in SSc patients.
  4. Why we believe patient mRSS improvement in the OLE data series can be almost entirely explained by the natural disease course and concurrent immunomodulator therapy.

We remain convinced that Corbus’s Phase 3 trial is almost certain to fail and we remain short Corbus.

We believe mRSS is the most important component of CRISS and that lenabasum must still show improvement in mRSS

Corbus recently announced its decision to change the Phase 3 primary endpoint measure from mRSS to CRISS. We believe this is a risky move on the part of Corbus for three reasons. First, lenabasum failed on the CRISS endpoint in its Phase 2 trial. More specifically, we don’t believe the drug was even close to hitting statistical significance in its Phase 2 trial. In that trial, Corbus utilized a 1-sided statistical test, which requires p <0.025 to reach significance as generally accepted by the scientific community. The Phase 2 trial’s reported p-value was 0.044 using a 1-sided statistical test, which is nearly double the value that is needed to demonstrate superiority to placebo. This makes the failed Phase 2 result similar to a reported p-value of ~0.09 for the more common 2-sided test at the standard significance level of p<0.05.

Second, Corbus used an unvalidated time period of 16-weeks for the CRISS endpoint in its Phase 2 study. CRISS has only been internally validated using data from 12-months of treatment. Furthermore, the authors of the CRISS publication that characterized CRISS specifically mention that any CRISS findings using data from time periods shorter than 12 months (such as Corbus’ 16-week placebo-controlled portion of its Phase 2 trial) should only be viewed as exploratory given “there is a lack of data to support its performance at earlier time points.” We believe this means even if lenabasum had demonstrated a statistically significant CRISS benefit at the 16-week time point in the Phase 2 trial, there is risk to the translatability of such a result to 52-weeks on the basis of the scale alone.

Lastly, we believe that Corbus will still have to show, at minimum, a convincing trend for the mRSS endpoint in its Phase 3 trial for lenabasum and that FDA would likely prefer seeing the drug statistically separate from placebo for mRSS as well.

Based upon our review of the scientific literature on CRISS, we believe that mRSS: 1) is a critical component of CRISS since it explains the most variability in the CRISS data; 2) is the most objective measure of skin involvement for dSSc in our view, and 3) has long been considered the gold standard of measuring skin thickness that is highly useful in characterizing SSc. We believe it is a large contributor to most other CRISS components as well, including patient (PTGA) and physician (MDGA) global assessments and the Health Assessment Questionnaire Disability Index (HAQ-DI). Furthermore, because mRSS has historically been considered the clinically-validated, gold standard metric for characterizing SSc involvement compared to the recently-developed CRISS, there is a much greater body of relevant academic literature measuring mRSS that can be compared to Corbus’ OLE data.

Importantly, in its May 8, 2019 press release, Corbus did not state that the FDA wanted the company to change the endpoint to CRISS. In fact it appears to us that the FDA is hesitant to rely solely on CRISS since Corbus noted, “The FDA deferred selection of the primary efficacy endpoint to Corbus. The FDA stated that the components of ACR CRISS reflect relevant aspects of SSc, and they will consider the totality of the data during review of any marketing application in SSc.”

We interpret this to mean that the FDA will continue to rely on clinically validated metrics such as mRSS when reviewing SSC, and we believe any statistically significant improvements that lenabasum shows over placebo with CRISS will need to be consistent with convincing numerical mRSS improvements in order to gain approval. In essence, we now believe that Corbus will have to show meaningful improvement across two endpoints, mRSS and CRISS, in order for the Phase 3 trial to be successful and for lenabasum to be approved by the FDA.

Ultimately, we believe that an understanding of lenabasum’s impact on mRSS provides real insight into the efficacy of the drug and its potential for obtaining marketing approval for treatment of dSSc. Based on our analysis of Corbus’ OLE data for mRSS, we believe that lenabasum is highly unlikely to provide any meaningful efficacy for dSSc patients and that lenabasum will fail its Phase 3 study.

We believe the vast majority of patients entering Corbus’s Phase 2 trial in SSc were experiencing natural disease resolution which results in decreasing mRSS scores

We conducted a thorough literature review of the natural progression of dSSc (sample articles such as this and this) and consulted with multiple KOLs who see a high volume of dSSc patients and/or lead large, academic tertiary SSc referral centers. While dSSc is a highly heterogeneous disease for individual patients, the general disease course can be summarized in three phases:

  1. Phase 1: Progressive disease (6 months to 3 years). This is characterized by an initial period of progressive thickening of skin (mRSS increases) by fluid and collagen until peak mRSS;
  2. Phase 2: Plateau (6 months to a 1 year). A period of minimal change or plateau;
  3. Phase 3: Disease regression (indefinite). Also referred to as the atrophic phase, the skin naturally softens and thins over time. During this period, mRSS scores decreases (skin thins).

Image1

Corbus has published (see slide 6) that the average disease duration at patient entry to Part A (the randomized, placebo-controlled portion) of the Phase 2 trial was ~37 months and ~41 months for the lenabasum arms and placebo arms, respectively:

Given the disease typically regresses after the patient has dSSc for about 12-48 months (midpoint ~30 months), we believe that the vast majority of patients involved in the company’s Phase 2 trial during Part A were either well into their plateau phase or had already begun their disease resolution phase.

In other words, we think most patients were experiencing improving mRSS scores without any therapy due to the natural history of the disease, with a few straggler patients who were in the last portions of the plateau stage and were about to experience improving mRSS.

Not only did our KOL discussions confirm that this was an accurate assessment of where patients were in their disease course on trial entry, a study that Corbus itself cites on a footnote in slide 22 of the company’s May investor presentation, Merkel et al., corroborates this as well:

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We’ve already provided a detailed analysis of why we believe the drug failed the placebo-controlled portion of the study and why we do not believe sudden numerical (and not even statistical) separation of the drug at 16 weeks (4 weeks after cessation of therapy) is a robust efficacy signal. In our opinion, the above analysis reinforces that a decrease in mRSS scores relative to baseline for both drug and placebo arms should be expected.

Additionally, patients who enrolled in the OLE portion of the trial after Part A of the Phase 2 trial was completed were an additional 7-8 months further along in their disease course by the time they enrolled (Part A treatment phase duration [12 weeks on drug or placebo] + average time off drug before enrolling in the OLE [20 weeks], according to the trial protocol and a company presentation [slide 22]), meaning that by the time patients began their OLE dosing, we estimate patients were somewhere in the 44-48 month timeframe of their disease.

This time frame is approaching the end of the plateau phase for patients who have an extremely slow disease course (~48 months) according to literature and the KOLs to which we spoke. Therefore, we believe essentially all of the patients in Corbus’s Phase 2 dSSc study were experiencing naturally declining mRSS scores by the time they reached the start of the OLE treatment. This is very important when interpreting the OLE data and explains why we believe the mRSS improvements should not be taken at face value as a treatment effect of lenabasum.

Approximately 90% of patients in Corbus’s Phase 2 were on concomitant immunotherapy, which we believe further contributes to the improvement in mRSS scores in Corbus’s Phase 2 OLE data

Through our research, we’ve learned that nearly all patients in the Phase 2 SSc trial were on immunosuppressant therapy, with CellCept (mycophenolate mofetil) being the most commonly used immunosuppressant.

CellCept is a powerful immunosuppressant which has been shown to reduce mRSS scores in SSc patients over time in two major randomized, blinded, well-controlled scleroderma studies ( SLS I and SLS II), and further analyzed by Volkmann et al. While the majority of the Volkmann paper performs analysis on both local and diffuse SSc patients together from the SLS I and SLS II studies, the Supplementary Materials reports on CellCept-induced mRSS reduction over time in dSSc patients. Within the dSSc subgroup, the authors found that from months 3-12 the mRSS score improved (declined) at a faster rate in the CellCept arm compared to the placebo arm (p=0.0017).

In our view, this study offers substantial validation that builds on prior, less well-controlled studies ( here, here, and here) documenting CellCept’s efficacy in reducing mRSS scores in patients with dSSc.

We believe the OLE data from Corbus mirrors dSSc patients who are in late stage disease and are on immunosuppressant therapy

In the above, we show that late stage dSSc patients typically see improving mRSS scores and that use of immunosuppressants also reduce mRSS scores in dSSc patients. So what would patients who are ~36-48 months along in their disease progression and who are using CellCept look like?

Fortunately, the CellCept investigators running SLS I and SLS II recruited patients into their studies that appear to us to be very similar to patients in Corbus’s OLE portion of its Phase 2 lenabasum study. When we compare the OLE data to the performance of the CellCept arm in our above studies, we find that the mRSS curves essentially overlap. This indicates to us that lenabasum was likely not the primary driver of the improving mRSS scores seen in the OLE study.

We perform a patient-weighted average calculation to estimate patient baseline characteristics for the OLE arm, with the exception of the mean mRSS score that is provided on slide 22 of the May presentation. In our opinion, the baseline characteristic values of Volkmann et al. patients closely resembles those of patients in the Phase 2 trial that Corbus ran (see below), which we believe is very important when performing cross-trial comparisons. The notable exception to similarity is disease duration, which is lower in the Volkmann arm compared to the lenabasum/PBO weighted average. Based on our above analysis, we believe this would benefit the lenabasum/PBO weighted average arm relative to the Volkmann arm since we would expect the later disease progression patients in the lenabasum/PBO weighted average arm to have a greater tendency toward spontaneous disease improvement compared to the Volkmann arm.

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We would note the following points when comparing the baseline values:

  • The baseline mRSS values appear to match nearly identically (~20.5 for Volkmann to 20.4 for Corbus’s OLE).
  • The disease duration appears lower for Volkmann than for lenabasum/PBO. However, based on our above analysis, we believe this imbalance may benefit the lenabasum/PBO arm relative to the Volkmann arm in terms of rates of spontaneous mRSS improvement (25.2 month median disease duration for Volkmann compared to 38.4 month weighted mean for lena/PBO).
  • The immunosuppressant use is very similar (100% for Volkmann compared to 88% weighted average for lena/PBO).
  • The mean age of patients is very similar (52.6 years for Volkmann compared to 47.9 years weighted average mean for lena/PBO).
  • The % of patients who are female is very similar (69.6% for Volkmann vs. 76.2% weighted average for lena/PBO).
  • HAQ-DI and % predicted FVC are both less severe for Volkmann et al.; however, we believe this is likely due to Volkmann baseline values being a ~1.5:1 mix of more functionally deleterious dSSc mixed with less functionally deleterious lSSc that we are comparing to only more functionally deleterious dSSc patients in Corbus’s Phase 2.

Furthermore, when looking at Corbus’s OLE data, we believe it is important to point out a detail that we think is being lost in some investors’ analyses. Corbus shows that at time point 0 for the OLE stage of the trial, patients had a -3.5 drop from baseline compared to when they started the trial (see slide 22). However, because patients had a mean 20 weeks off drug from Part A to the OLE phase of the trial (also slide 22), this acted as a thorough drug wash-out period. In analyzing the OLE data in isolation, we reset the drug’s efficacy to “0” at the start of the OLE period and analyze the data from that time point onwards because the difference in experimental conditions, particularly with the drug interruption period and change in trial protocol between Part A and the OLE section, makes it very difficult to directly compare to any other clinical data point that is published.

Following normalization of these data to the 20.4 OLE baseline, we can then apply the CellCept mRSS curve from Volkmann et al. to determine to what degree immunotherapy may have contributed to the mRSS improvement over time in Corbus’s Phase 2 OLE.

Doing so yields essentially identical mRSS improvement curves over time:

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While some might point to a small difference between arms as indicative of a small drug effect, we believe this is more likely explained by other factors, such as: 1) The OLE was unblinded while the Volkmann trials were blinded. One KOL we talked to indicated that there is a substantial subjective component to the mRSS measurement by an evaluator that can lead to positive bias in an unblinded setting; 2) The Cellcept arm recruited patients whom we think were earlier in their disease progression than our estimates of those enrolled in the OLE study (25.2 month median for Volkmann, 38.4 months for lenabasum/PBO weighted mean); 3) The OLE trial could have been subject to selection bias in which the patients enrolled in the OLE portion were those who experienced the greatest magnitude of improvement from baseline due to natural improvement of disease, the severity of disease, or were most prone to experience a large placebo effect and may thus be more likely to experience continued mRSS improvements in the OLE portion of the trial compared to the Volkmann patients.

We think these data, in addition to what we believe to be negative Part A data, provide strong evidence that lenabasum is not offering any benefits in improving patient mRSS, which is a key consideration for approval and the largest-weighted component of the CRISS primary endpoint for lenabasum’s phase 3 trial. Consequently, we continue to believe that the failure of lenabasum in their ongoing Phase 3 trial is a near certainty.

Our price target for Corbus is $0.22

We believe lenabasum is almost certain to fail its upcoming Phase 3 trial in dSSc and Phase 2 trial in CF, and we place no value for lenabasum in other indications or Corbus’ other assets. The only value we assign to Corbus is its cash balance, the majority of which we believe the company is likely to burn through to fund operations.

Disclosure: I am/we are short CRBP. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.