I have three estimates for peak sales:
1. Seeking Alpha, May 2015 - $30M.
2. H.C Wainright & Co analyst Reni Benjamin opinion from Apr 2014 - $25-50M.
3. Griffin Report from Aug 2013 - $17,857M royalty for Ligand. Assuming 20% rate, it means $88M revenue for Spectrum.
Patent description contains a lot of interesting info about the mechanisms of Apaziquone action and how Apaziquone and Mitomycin C are similar and different in killing cancer cells. It explains why most patients should have benefits from Apaziquone treatment but some should have not, regardless of blood inactivation.
INTRODUCTION AND OBJECTIVES
APZ was investigated as an immediate post-TURBT instillation in patients with low grade Ta (Grade 1 or 2) NMIBC in two randomized trials, SPI-611 and SPI-612, which evaluated the 2 Year Recurrence Rate (2YRR) and Time to Recurrence (TTR).
Both studies enrolled patients with presumed low grade Ta NMIBC eligible for TURBT. Patients were randomized (1:1) to receive a single 4 mg dose of APZ or placebo (PBO) instilled intravesically in 40 mL within 6 hours. Key eligibility criteria included: central pathology confirmed low grade Ta tumor, no individual tumor 3.5 cm, and no more than 4 tumors (Target Pop). Patients were evaluated by cystoscopy every 3 months for 2 years.
In the US, Canada and Poland, 1,614 patients (SPI-611- 802; SPI-612- 812) were randomized (APZ- 808; PBO- 806) in the two studies, with 1,146 patients (APZ- 577; PBO- 569) evaluable in the Target Pop. Demographics of the 2 treatment groups were similar. APZ resulted in a clinically and statistically significant decrease in tumor recurrence rates in the Target Pop, demonstrating a 6.7% absolute decrease in 2YRR (APZ-38.8%; PBO- 45.5%; p=0.0218), and 14.7% relative reduction in the 2YRR compared to PBO. Similarly, a longer mean TTR of 18.2 vs 16.8 months (p=0.0096; HR=0.79) was seen with APZ vs. PBO, respectively. The incidence of adverse events (AEs) was similar between treatment groups (APZ- 80.0%; PBO- 78.5%), with dysuria and UTI being the most common AEs. Dysuria was the also most common treatment-related AE (APZ- 4.6%; PBO 4.1%).
Immediate intravesical instillation of APZ following TURBT in patients with low grade Ta NMIBC, significantly decreased the 2YRR, delayed the TTR, and was well-tolerated.
Phase 2 trial "Evaluation of Lucanthone to Whole Brain Radiation Therapy in Patients With Brain Metastases From Non-Small Cell Lung Cancer", NCT02014545, could be restarted.
On 08-10-2015 trial was suspended with explanation "PI left the University of Alabama at Birmingham and study will not be resumed by another institutional PI".
Yesterday trial was updated with a new sponsor, Comprehensive Cancer Center of Wake Forest University. Seems like Lucanthone is still alive.
$3M and $2.7M, highest quarterly numbers for each.
INTRODUCTION AND OBJECTIVES
Apaziquone (APZ), a synthetic alkylating prodrug activated in bladder cancer, was evaluated for immediate instillation post-TURBT in patients with low grade Ta (Grade 1 or 2) NMIBC in two studies (SPI-611; SPI-612). Because APZ can be inactivated by blood, an analysis was performed by time window of APZ dosing post-TURBT to determine the optimal timing; data on the 2 Year Recurrence Rate (2YRR) and Time to Recurrence (TTR) are reported here.
Both studies enrolled patients eligible for TURBT with presumed low grade Ta NMIBC, who were randomized (1:1) to APZ 4mg or placebo (PBO). An immediate (within 6 hours), single 40 mL intravesical instillation was given and retained for 1 hour. Eligibility included: central pathology confirmed low grade Ta tumors, no individual tumor larger than 3.5 cm, and no larger than 4 tumors (Target Pop). Patients were evaluated with cystoscopy every 3 months for 2 years.
In total, 1614 patients (SPI-611- 802; SPI-612- 812) in the US, Canada and Poland were randomized (APZ- 808; PBO- 806) with 1146 patients (APZ- 577; PBO- 569) evaluable in the Target Pop. There were 456 patients treated in less than 30 min, 217 in 31-90 min, and 473 in longer than 90 min post-TURBT with similar demographics across time window subgroups. Patients in the APZ 31-90 min subgroup demonstrated a significant absolute decrease of 21.8% in 2YRR (APZ- 28.2%; PBO- 50.0%; p=0.0010), resulting in a relative reduction of 43.6%. Improvements in other subgroups were not significant. Similarly, a longer TTR (HR=0.48, p=0.0096) was observed in the APZ 31-90 min subgroup.
Adjuvant intravesical APZ administered 31 to 90 min post-TURBT significantly improved the 2YRR and TTR in these large phase 3, blinded, randomized placebo controlled studies.
From a recent article “Systematic Review and Individual Patient Data Meta-analysis of Randomized Trials Comparing a Single Immediate Instillation of Chemotherapy After Transurethral Resection with Transurethral Resection Alone in Patients with Stage pTa–pT1 Urothelial Carcinoma of the Bladder: Which Patients Benefit from the Instillation?” Eur. Urol.69 (2016) 231-244
The authors analyzed 13 studies where 2278 patients after TURB were treated by single postoperative instillation (SPI) of epirubicin, mitomycin C, pirarubicin, or thiotepa. They made a few interesting observations:
1. SPI reduced the risk of recurrence by 35% and the 5-yr recurrence rate from 58.8% to 44.8%, a 14% reduction.
2. All chemotherapeutic drugs, except thiotepa, showed similar efficacy.
3. Better efficacy was seen when the instillation was given within 2 h after surgery.
4. SPI did not prolong either the time to progression or the time to death from bladder cancer.
5. Unexpectedly, SPI increased overall risk of death for patients with EORTC recurrence score higher than 5 (patients with multiple tumors, at least one of which is larger than 3 cm)
In conclusion, the authors recommend SPI only for patients with these characteristics: (1) single or multiple (up to seven lesions) primary papillary tumor(s) smaller than 3 cm; (2) single primary papillary tumors larger than 3 cm; (3) single small recurrent papillary tumors with an interval longer than 1 yr since the previous recurrence.
Reading a description for a new Apaziquone phase 3 trial, I was puzzled with restrictions on tumor size, number and recurrence status. It seems like Spectrum almost exactly followed the authors recommendations.
My point was that you compare two failed phase 3 studies which need to be combined for submission, approach that brings high level of uncertainty, to one successful phase 3 study which worked as predicted. I don't see any positive impact from Nuplazid Adcom meeting on future Apaziquone developments.
I already told you two times that my point was not to compare issues that both drugs have. I know that they are different. No need to bring it here over and over again. Perhaps, it was my fault that I was not able to make my point more clear.
I did not say they were concerned with pooled data. They pooled two non-failed studies which did not use statistics with analysis of p values. My post was not about data, good or bad, but about bureaucracy of approval process. Raj spent three years asking FDA to accept the filing. He succeeded and said "we won". I am questioning the value of his victory. Many investors think that FDA desperately wants this drug on the market. No drug approved in 40 years etc. However, Clovis case illustrates that ODAC is not concerned about what FDA wants. And I don't believe that accepting NDA, FDA did not know about unconfirmed responses. This info must be present in filing documents.
If you want to compare placebo effect on patients from different time subgroups in Apaziquone study, you need to see KM curves in the abstract.
They had accelerated clinical development program for Rociletinib. FDA granted Breakthrough Therapy designation. But ODAC voted 12-1 not to approve Rociletinib. They want to see more data from an ongoing Phase 3 trial expected to finish in 2019. Hope, it won't happen with Eoquin.
Read the comment from Barry H Kaplan to this article. It is an oncologist view on Cobi, Cabo and Opdivo. He said that "Opdivo's benefits have been outrageously overstated".
He said Hanmi might be able to file NDA in Korea based on data from a small phase 2 study with Poziotinib. They are negotiating it now with Korean FDA. It shows how strong their data is.
ASH is American Society of Hematology. Why should they accept any abstract on breast cancer? And I don't understand why everybody is so excited about Raj's excitement. He is a specialist in hematologic oncology and does not have any experience in breast cancer and HER inhibitors. We need to hear about how exciting is a new Korean data from more knowledgeable person.
Aside from showing less than desirable efficacy, other major problems exist: 25% of people taking BCG cease treatment due to toxicity. BCG causes painful and bloody urination, incontinence, groin pain and high fever when infection sets in, which is often.
To make matters worse, manufacturing problems at Sanofi (NYSE:SNY), makers of BCG created a worldwide shortage when FDA found mold within the plant. Merck (NYSE:MRK), the only other producer of BCG had its own production problems. In an interview with Forbes, Dr. Joe Eid, Merck Oncology's Head of Global Medical Affairs, stated batch production of BCG was challenging. Reportedly, it takes three months for a BCG batch to mature and there is no way to tell if the yield is good or bad during that time.
It is not CLEARLY works if you take timing into account. How do you explain that placebo patients in 30-90 group performed worse than in the other groups? Why do you need a third arm with additional instillation? What was the rationale for designing multiple instillation Phase 3 trials? Do you have CLEAR answers?