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Tuesday, August 9, 2016

HedgePath Reports Positive Interim Phase 2b Data With SUBA-Cap In Hereditary Skin Cancer

Last week, I published an article introducing investors to HedgePath Pharmaceuticals (HPPI) and the company's improved formulation of itraconazole for the treatment of Basal Cell Carcinoma Nevus Syndrome (BCCNS) / Gorlin Syndrome. Investors can view that article >> HERE

HedgePath shares are up 40% since that article came out, driven in part by the positive interim results released last week from the company's Phase 2b clinical trial with SUBA™-Itraconazole in patients with BCCNS, also known as Gorlin Syndrome. Below I provide a review of the positive Phase 2b data and compare it to Erivedge®, a leading product approved for metastatic and locally advanced basal cell carcinoma, but not for BCCNS, sold by Roche.

A Little Background

HedgePath is currently enrolling patients in a Phase 2b open-label trial (NCT02354261) of SUBA-Itraconazole in subjects with basal cell carcinoma nevus syndrome (BCCNS). Target enrollment for the Phase 2b trial is 40 patients with BCCNS. Entry criteria stipulate that each subject exhibit significant BCC target tumors at baseline consisting of a minimum of 10 surgically eligible lesions. Additionally, the subject must have a history of surgical removal of at least 10 BCC tumors. For each subject, 10 to 15 of the largest lesions are selected by the investigator at baseline to represent a valid sample of overall lesions (target tumors).The sum of the longest diameters of these tumors make up the “target tumor burden.”

HedgePath is collaborating with the BCCNS Life Support Network, a philanthropic organization dedicated to supporting the patients and families of patients with BCCNS / Gorlin Syndrome for this trial. The Phase 2b study is a single arm, multicenter, open-label study with a primary endpoint of the response rate of BCC target lesions. Enrollment began in September 2015. Interim results presented below are for the first 13 subjects who completed at least 16 weeks of SUBA-Itraconazole dosing (oral 150 mg BID).

Previously completed Phase 2a clinical study with a generic formulation of itraconazole in patients with BCC is published in the Journal of Clinical Oncology (March 2014) (2), with data presented at AACR in April 2011. Eight subjects with multiple BCC tumors were treated with itraconazole. A total of 57 tumors were biopsied. Results show itraconazole reduced cell proliferation by 45% (P = 0.04), Hh pathway activity by 65% (P = 0.03), and reduced tumor area by 24% (95% CI, 18.2-30.0%). A waterfall plot published by Kim DJ, et al., can be found >> HERE.

The Phase 2b Data

The interim data reported by HedgePath last week was derived from results of the first 13 subjects who have completed at least 16 weeks of SUBA-Itraconazole dosing. SUBA-itraconazole is a patented unique (non-substitutable) formulation of itraconazole which offers substantially improved bioavailability. Management conducted two separate interim analyses: (A) the change in target tumor burden for each subject (which is based on the change in the sum of the longest diameters of each subject’s target lesions) to measure the change in target tumor burden from baseline; and (B) the change in the longest diameter of all individual target lesions from baseline across all subjects in the study, which the company believes documents clinical impact.

On target tumor burden (A), among the 13 subjects who have dosed for at least 16 weeks, the company saw 92% of patients had a target tumor burden reduction (12 of 13). Importantly, target tumor burden did not increase in any subject and was reduced by greater than 30% in 8 of the 13 subjects (62%) with an average reduction of 60%. This is important because the FDA guides that a tumor response rate, defined as a greater than 30% reduction in size, must occur in 30% of subjects in order to be considered for approval. These results are graphed below:

On changes in the longest diameter of individual target lesions (B), the company conducted an interim analysis of 167 individual target lesions across all 13 subjects. All of these tumors were primary tumors, meaning none were metastatic lesions. The interim analyses showed that 25% of cancerous lesions have disappeared (CR or complete response), an additional 25% have exhibited greater than a 30% reduction but less than 100% (PR or partial response), and 42% have remained stable (< 20% increase and < 30% reduction). The overall median tumor reduction among responders was 75%. These results are graphed below:

The growth of a primary tumor increases the likelihood that an individual tumor will require surgical treatment. Although 8% of target lesions analyzed in the interim data have increased by more than 20% in longest diameter, to date no primary tumors have required surgical intervention. In addition, management reported that SUBA-Itraconazole continues to be well tolerated with Grade 1 or no toxicity reported in 90% of subjects assessed to date in the trial, including an additional six subjects (total of 19) with eight or more weeks of dosing.

Putting The Numbers In Perspective

Roche's Erivedge® (vismodegib) is an oral small molecule inhibitor of the Hedgehog pathway (Hh) signaling. Erivedge was approved in January 2012 for the treatment of adults with metastatic basal cell carcinoma (mBCC) or with locally advanced basal cell carcinoma (laBCC) that has recurred following surgery or who are not candidates for surgery or radiation (1). The U.S. FDA approval of Erivedge was based on results from a pivotal single-arm, multicenter, two-cohort, open-label, Phase 2 study that enrolled 104 patients with advanced BCC, including laBCC (n=71) and mBCC (n=33). Gorlin syndrome (BCCNS) was diagnosed in 22 of the 104 patients (21%).

Efficacy results published in the New England Journal of Medicine show an ORR of 30.3% for mBCC and 42.9% for laBCC (2). Complete response (CR) rates for mBCC and laBCC were 0% and 20.6%, respectively. Partial response (PR) rates were 30.3% and 22.2%, respectively. Median response duration was 7.6 months for both mBCC and laBCC. Only 7.7% (7/104) had disease progression.

Adverse events in the trial were significant and included muscle spasms (65%), alopecia (61%), dysgeusia (49%), weight loss (44%), fatigue (34%), nausea (28%), loss of appetite (22%), and diarrhea (21%). Several grade 3/4 events, including muscle spasms, weight loss, and fatigue were reported.

Novartis' Odomzo® (sonidegib) is an oral hedgehog pathway inhibitor indicated for the treatment of adult patients with locally advanced BCC that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. The U.S. FDA approved Odomzo in July 2015 based on a Phase 2, randomized, double-blind, multicenter clinical trial that enrolled 94 patients with locally advanced or metastatic BCC (3).

Efficacy results published in the Journal of the American Academy of Dermatology show an ORR of 57.6% for the 200 mg dose and 43.8% for the 800 mg dose in patients with locally advanced BCC. Patient with metastatic BCC has only a 7.7% and 17.4% ORR to the two doses, respectively. Among all patients, 19% progressed or died during the 12-month trial. Grade 3/4 adverse events and those leading to discontinuation were less frequent with sonidegib 200 versus 800 mg, but still were measured at 38.0% vs. 59.3% and 27.8% vs. 37.3%, for the locally advanced and metastatic patient populations, respectively (4).

The following table compares the Phase 2 data (full for BCC Erivedge and Odomzo vs. interim BCCNS for SUBA-Itraconazole) based on ORR (CR + PR) and disease progression. Although more of an Apples-to-Oranges comparison, investors can see the ORR and rate of progression when comparing tumors treated with SUBA-Itraconazole compares favorably with Erivedge and Odomzo.

Erivedge® Data In BCCNS

Roche conducted a separate Phase 2 with Erivedge (vismodegib) in patients with BCC Nevus Syndrome (also known as Gorlin Syndrome). The trial enrolled a total of 41 patients, 26 which received vismodegib and 15 on placebo. Data were published in the NEJM and although the reduction in the number of new tumor appearing in vismodegib treated subjects was impressive (primary endpoint of that study), the discontinuation rate in BCCNS patients was a staggering 54% due to adverse events (5). This contrasts starkly with the low toxicity profile observed thus far in subjects with BCCNS / Gorlin in the current Phase 2b SUBA-Itraconazole trial. Management reports that ~90% of the patients experienced either no or grade-1 toxicity after 16 weeks of treatment.

What's Next For HedgePath?

Data for SUBA-Itraconazole demonstrate impressive interim Phase 2 results for HedgePath Pharma. Certainly, the trial needs to continue. Target enrollment is 40 patients and as per the company's press release, 19 have completed eight or more weeks. I do not know the current number of patients that have been enrolled, and some investors have expressed concern over the fact that enrollment initiated in September 2015 and has yet to complete. Per the protocol, 33 subjects must complete 16 weeks of active dosing, so enrollment up to 40 may not be necessary. That being said, enrollment is likely over 50% at this point and with these sorts of positive interim results, I would not be surprised to see the pace accelerated in the next few months.

Perhaps the most important takeaway from the interim Phase 2b results is that SUBA-Itraconazole compares very favorably with Erivedge and Odomzo on efficacy and safety. These are two drugs that each cost over $10,000 per month. Roche posted global sales of Erivedge of CHF167 million ($162 million) in 2015, up 31% from 2014 levels. Approximately 70% of these sales were derived from the U.S. market. And importantly, approval of both Erivedge and Odomzo came after Phase 2b data in only around 100 patients.

HedgePath management intends to continue collecting data and will interact with the U.S. FDA regarding ongoing results demonstrating efficacy and tolerability for SUBA-Itraconazole treatment for BCCNS. Erivedge and Odomzo are not approved for BCCNS, which presents HedgePath the opportunity to petition the FDA for approval if the final results of this 40-patient trial are as encouraging as the interim data above.

In my opinion, the company stands a good chance. For statistical analysis, HedgePath modeled the number of subjects needed assuming a 30% target tumor burden reduction at 16 weeks with a null hypothesis (control) of a 10% reduction. Accordingly, it was anticipated that at least 11 of 33 subjects (33%) would need to have at least a 30% reduction in target tumor burden in order to meet a successful primary endpoint. At this date, the study has 8 of 13 subjects (62%) who have a target tumor burden reduction in excess of 30% (mean 60%). The company is encouraged by these interim results which are twice the company's expectations for the percentage of subjects achieving the required target tumor reduction and the effect size of the drug. Nevertheless, there can be no assurance that this trial will enable an NDA filing. As a reminder, in June 2016, the U.S. FDA granted HedgePath's SUBA-Itraconazole Orphan Drug designation for the treatment of BCCNS (6).


HedgePath remains an interesting story for small-cap biotech investors. The company is likely to report full enrollment over the next few months, with top-line Phase 2b results expected during the first half of 2017. If the full data look as strong as the interim data presented last week, I expect the company to seek approval for SUBA-Itraconazole via the 505(b)(2) pathway before the end of 2017. As outlined in my initiation article, I see the peak opportunity in BCCNS at $375 million, with obvious upside if management can expand the program to metastatic or locally advanced BCC, or other solid tumors where itraconazole has demonstrated utility such as lung cancer or pancreatic cancer.


This article was written by Jason Napodano, CFA of BioNap, Inc.
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