Progenics's Azedra: What's Wrong With This Picture?

Summary

Progenics has made a further presentation on AZEDRA’s trial results.

Several SA articles have been published with conflicting opinions.

This article is an update on my earlier analysis.

I previously wrote an article raising critical issues concerning Progenics AZEDRA, a radioactive therapy for the treatment of patients with malignant and/or recurrent pheochromocytoma and paraganglioma, who cannot be helped by surgery or current chemotherapy. On August 31, Progenics presented data from AZEDRA’s pivotal phase 2b study at the international symposium on Pheochromocytoma and Paraganglioma. This article is an update.

The trial results

From Progenics’ press release on August 31:

‘Study results show that treatment with AZEDRA produced clinically meaningful and durable responses across multiple study endpoints, including radiographic tumor response, tumor biomarker response and overall survival.’

While the above statement is not untrue, Dr. Pryma and Progenics are not indicating to the medical community and the public that these are composite results, combining two parts of one trial conducted by two different companies. The trial was started in 2009, and finished in 2016, but with a gap between 2010 and 2015.

What they are also not indicating is the discrepancy between the two sets of data, which were supposed to be studying the same drug in the treatment of patients with the same illness, under the same protocol.

The summery is this: the composite trial results met the primary end point and secondary end points, with 2/3 data generated by Molecular Insight (41 patients), and 1/3 data (27 patients) generated by Progenics.

I will comment on the overall survival data first, and on the primary and secondary end points in the next section.

Overall Survival

For the overall survival data, it should be noted that any data covering more than 24 months follow-up must come from Molecular Insight portion of the trial, since Progenics' part was completed less than 24 months ago.

It is positive to note that, in the subset of the trial patients with liver or lung metastasis, the data 'suggest the potential for AZEDRA to extend survival', although patient numbers are not disclosed.

However, in Molecular Insight's results, AZEDRA-treated patients in this study had no better overall survival at 48 months (<40%, as given in Dr. Pyrma's 2014 poster) than the published 5-year overall survival rate of 40% to 72% among pheo and para patients with unresectable metastases.

The discrepancies

The MI portion of the data was presented in 2014 by Dr. Pryma. Progenics presented the composite results. From these two, one can work out the Progenics' portion of the data.

In the following two tables, the numbers in italics with a (calculation) are those which one needs to calculate from the disclosed data of 2014 (MI alone) and 2017 (composite).

Primary Endpoint: Reduction in Antihypertensive Medications

Table 1

Composite Result

Molecular Insight

Progenics

Evaluable Patients

68

41

27 (68 – 41)

Patients who met the
primary end point

17

13

4 (17 – 13)

Percentage

25%

32%

15% (4/27)

The efficacy: MI 32% vs. Progenics 15% for their respective portions of the trial. (25% is required by the SPA to meet the primary end point)

Secondary Endpoints: Tumor Response Data (compare Partial Response, PR)

Table 2

Composite Result

Molecular Insight

Progenics

Evaluable Patients

64

41

23 (64 – 41)

Patients who had a
Partial Response (PR)

15 (23.4% of 64)

14 (34% of 41)

1 (15 – 14)

Percentage

23.4%

34%

4% (1/23)

The tumor response: MI 34% vs. Progenics 4% for their respective portions of the trial.

There are two significant discrepancies here, firstly Progenics' inferior efficacy comparing to MI's; and secondly Progenics' inconsistent efficacy data between their own primary (15%) and secondary (tumor response: 4%) end points.

It is these discrepancies in AZEDRA’s efficacy (both comparing to MI, and within Progenics' own data) that needs to be explained and clarified, something that has not been done to date.

For those who have difficulties following a scientific discussion, here is a simple example from daily life.

You are in the market for a new car. While the salesman does what salesmen do: sings the praises of a great model with outstanding performance, one of the kind design, etc., you dig out more info on your own.

Apparently, 2/3 of the parts in this new car came from a factory which is now closed-down, which did indeed have out-standing performance. However, the remaining 1/3 of the parts come from a new factory, which is under the new management of the car company. The 1/3 which comes from the new factory work less than half as well as the old factory’s parts, and do not even pass the required standard. However, when the two sets of parts are combined into one vehicle, the overall performance of the car just meets the required standards.

So, will this new car be sitting in your garage anytime soon?

Similarly, will the FDA overlook the discrepancies?

The CEO, SA authors and the investors

It was commented on the SA site by Progenics’ investors that the CEO, Mr. Mark Baker, during the conference call for the topline results on March 30, 2017, implied that Molecular Insight’s better data was the result of embellishment under their financial difficulties. I am unable to verify the transcript of this conference call because somehow it is not on SA, the company web site, or anywhere else online.

If Mr. Baker did make the remarks, it indicated that he and the Progenics’ team did not believe the MI data, which then begs the question as to why Progenics is still proceeding with their submission of the NDA in which 2/3 of the trial data cannot be trusted.

On the other hand, if Mr. Baker’s remark is unfounded, and that MI data is reliable, then the issue of the discrepancies remains.

Why did Progenics’ AZEDRA only work on less than half of the patients when compared to MI’s AZEDRA (Progenics 15% vs. MI 32%)?

Why in Progenics’ data did only 4% of evaluable patients show a reduction in tumor size, compared to 34% of patients for MI?

Why did Progenics' efficacy data show such an inconsistency between the primary and secondary end point results (15% vs. 4%)?

Other SA contributors have also weighed in on Progenics with a total of six articles, three blogs and numerous comments.

Bret Jensen published 3 articles (here, here, here) and three blogs (here, here, here) and John Engle 3 articles (here, here, here).

It should be noted that both Bret Jensen and John Engle offer in their articles no consideration of a possible downside on AZEDRA’s NDA application, and thus imply that the chance of FDA approval is 100%.

In John Engle’s second article on Progenics, he incorrectly summarized my article, and then called on the company to clarify the issues that I raised, but without his own analysis of the trial results. However, when the company did not produce further clarification in the latest press release, Mr. Engle made no comment on this fact. Instead, he merely repeated what he has previously stated in his first two articles, which is to accept whatever the company presented without critical analysis. His logic is this: as every investor knows, companies always know what they are doing!

Bret Jensen is no different, in his second blog and second article, he stated that John Engle’s second article had accurately rebutted my first article, when in fact it did not contain any analysis. Bret Jensen is of the opinion that the composite result is ‘good enough,’ and that there is no need to consider the impact of a negative NDA outcome. Again, he simply accepts whatever is presented by the company without any independent analysis.

In response to my first article on AZEDRA, John Balison, another SA contributor, expressed a view through numerous comments that only data from the two dose cohort (the trial's per protocol group) and not that of the overall evaluable patients (i.e. one and two dose cohorts) would be considered by the FDA as agreed in the SPA (special protocol assessment).

It should be noted that such a view is not supported by any official filings from either company, i.e. Molecular Insight and Progenics, nor is such a view consistent with how Progenics had presented the trial results to date, be it the MI part of the data in 2014, or the composite results in 2017.

Furthermore, if John Balison's assertion is indeed a correct understanding of the SPA requirement, agreed by the FDA in 2009, it is beyond reason that Progenics would not simply say so in their press releases and conference, instead of continuing to report the composite trial results of the overall evaluable patients, as well as the detailed data for one and two cohorts.

Another comment was made with regards to the fact that some patients 'felt better' after receiving AZEDRA. While this good news is to be celebrated on a human level, one should not confuse subjective, anecdotal testimony with objective, empirical evidence, which forms the base for any scientific study. In other words, just because some patients in the trial felt better, it does not replace the trial data which was generated, and analysed under a strict, FDA approved protocol. Any underlying problems with AZEDRA's trial data are not going to be solved by anecdotal stories.

Some investors also commented that for the intended patients, there was no other option and thus the FDA must approve this treatment. There are and have always been many medical conditions and rare diseases for which there is no approved treatment. However, this does not negate or circumvent the FDA's long-established standards of safety and efficacy, for granting approval.

Finally, in another press release, Progenics announced that their NDA submission, which was previously scheduled to take place in August 2017, has now been postponed, citing a delay in the preparation of the manufacturing facility for FDA inspection. This is an odd reason. The manufacturing facility can be made ready after the company submits their NDA, as the FDA will take 6 to 10 months for their decision on any NDA, if indeed Progenics submits their application.

Investment thesis

Based on my analysis of the trial results, I continue to be of the same view as presented in my first article, that the FDA approval of AZEDRA is highly doubtful due to the discrepancy between two parts of the trial and the inconsistency within Progenics' own efficacy data, notwithstanding what the company and some SA authors claim.

Any investment decision based on or influenced by a favorable FDA outcome concerning AZEDRA should be taken with caution. Since there are other assets of Progenics, readers should not think that AZEDRA is the only factor, though it is admittedly an important one.

Note: I like to acknowledge Mr. Andrea Polini, an SA contributor. It was his article on Progenics and some readers' reactions to it first caught my attention about AZEDRA's trial results.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

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.

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