contd: "After review of the documents, we continue to believe there is a good likelihood of a favorable vote," noted J.P. Morgan's Geoff Meacham, according to Reuters. The review raised no new concerns about the safety and efficacy of the drug, he added. "Net-net, we would be buyers ahead of the panel."
The FDA review also raises questions about the difference in dose interruption/reduction and response rates for sorafenib, noting inconsistencies with other studies. And there are likely to be a number of questions regarding the small number of Americans who were included in the final data readout.
As for the OS data, Aveo has asserted that slightly more than half of the patients in the sorafenib arm went on to receive a subsequent treatment after their disease progressed, and in many cases the subsequent therapy was tivozanib. That could have skewed the survival data, according to Aveo.
The FDA review certainly didn't offer any definitive conclusions, but it cast a cloud over Aveo's shot this week. The biotech has circled its wagons around tivozanib, confidently setting the stage for a launch in the second half of this year. A negative vote this week, though, would raise serious doubts about a drug that had been getting mixed reviews from analysts.
Aveo reorganized last fall, laying off staffers as it concentrated on the regulatory process. The downsizing occurred just weeks after Leerink Swann analyst Howard Liang downgraded the stock, unconvinced that the company's argument that positive progression-free survival data could win the day at the FDA. And with other kidney cancer drugs on the market, troubling safety signals could scuttle its chances with regulators.
"In our regulatory reviews, we could not find another case where the FDA approved an agent on progression-free survival benefit that has a clear unfavorable survival trend as in tivozanib's TIVO-1 trial or a similar pivotal trial design," Liang noted at the time.
Other analysts, though, have not had the same doubts. And today's FDA review changed nothing for them.
"After review of the documents, we continue to believe there is a good likelihood of a favorable vote," noted J.P. Morgan's Geoff Meacham, according to Reuters. The review raised no new concerns about the safety and efficacy of the
Aveo shares plunge after FDA review raises fears of tivozanib rejection
April 30, 2013 | By John Carroll
Regulators at the FDA have weighed the data for Aveo's tivozanib, raising a simple question that could prove vexing for the biotech: Should another clinical trial be required before the agency delivers its verdict on the cancer drug, given that alternative treatments are available? Aveo ($AVEO) will make its case for immediate approval to an outside panel of FDA experts on Thursday, but the slim review document released this morning clearly spooked hopeful investors, pushing down the biotech's stock more than 25%.
Why the jitters? Tivozanib hit its primary endpoint, demonstrating a slim but statistically significant improvement in progression-free-survival of patients with advanced renal cell carcinoma when compared to Nexavar (sorafenib). But the sorafenib arm experienced a slightly better overall survival rate, and Aveo has been trying to explain it away ever since.
The developer had to start in the spring of 2012 at a pre-NDA meeting. According to the review document, "the FDA expressed concern about the adverse trend in overall survival in the single Phase III trial and recommended that the sponsor conduct a second adequately powered randomized trial in a population comparable to that in the US."
Earlier in the development game, though, the FDA told Aveo that the right PFS data could be used for an approval. In their words "a substantial, robust improvement in PFS that is clinically meaningful and statistically persuasive may be considered for regulatory decision." FDA also stated that "... a statistically significant improvement in OS is not required for regulatory approval, but a pre-specified OS analysis plan is still helpful in the regulatory decision making process."
rates for sorafenib, noting inconsistencies with other studies. And there are likel
deja vu (continued)
Tuan Ha-Ngoc, Aveo's president and chief executive, stressed that meeting the goal of a statistically significant improvement was key while calling the result "fantastic." He said the Onyx drug used for comparison performed at the high end of expectations based on prior evidence, but noted the Aveo drug met its study goal nonetheless.
"That's what matters," he said in an interview.
Specifically, the drug showed median progression-free survival of 11.9 months in the overall study population, while the Onyx drug had a 9.1-month result. Among the 70% of studied patients who didn't have prior anti-cancer therapy--a key group because these are likely real-world candidates, according to Aveo--the result was 12.7 months for the Aveo product compared with 9.1 months for the Onyx drug.
Aveo also said tivozanib had a "well-tolerated safety profile" in the company-sponsored, late-stage study, which included 517 patients. Safety results were similar to what the company saw in its prior mid-stage study, with hypertension ranking as the most commonly reported side effect. As the company's shares dropped Tuesday, Ha-Ngoc suggested the safety result was being overlooked.
But the company declined during a conference call to offer more details on that safety profile or on some other aspects of the study. Instead, the company--along with commercialization partner Astellas Pharma Inc. (ALPMY, 4503.TO) -- aims to submit detailed findings for presentation at the American Society of Clinical Oncology's conference in early June.
Aveo wants to make a big splash at the event, known as ASCO, which will draw thousands of oncologists. But to get its study accepted, the company can't release too much information ahead of time, Ha-Ngoc said. Still, Aveo did disclose the most material information, and more than some other companies in the same position, he said. He referenced a more sparse Pfizer Inc. (PFE) announcement from November on a kidney-cancer drug that company h
Interesting story from jan 2012, deja vu
Jan. 3, 2012, 2:43 p.m. EST
Aveo cancer treatment meets goal, but shares drop
By Jon Kamp
--Aveo says kidney-cancer treatment meets goal in late-stage study
--Company stock plunges as analysts seek more details, suggest expectations ran high
--Aveo and commercialization partner aim to show more at big cancer conference
(Updates throughout with details on study, comments from analysts and CEO.)
Drug developer Aveo Pharmaceuticals Inc. (NASDAQ:AVEO) announced positive results Tuesday in a key study for its investigational treatment for advanced kidney cancer, but its stock traded off sharply as the company butted up against lofty expectations.
Shares of the Cambridge, Mass., firm were recently down 17.1% to $14.26 despite a sharp surge in the broader market.
Aveo's drug, called tivozanib, met its main goal in a late-stage study that matched it up against Nexavar, a treatment already on the market from Onyx Pharmaceuticals Inc. (NASDAQ:ONXX) . Specifically, tivozanib showed statistically significant improvement on a measure known as progression-free survival compared with the Onyx drug.
Analysts said results were positive, although they raised questions on a conference call about whether the Onyx drug might have done better than expected, narrowing the performance gap. RBC Capital Markets suggested tivozanib "may have slightly missed the high efficacy hurdle set by the Street."
Analysts wanted more study details and forecasts on regulatory timelines than Aveo was willing to give, in part because the company doesn't want to spoil its chances to have a big role at a significant cancer conference later this year.
Tuan Ha-Ngoc, Aveo's president and chief executive, stressed that meeting the goal of a statistically significant improvement was key while calling the result "fantastic." He said the Onyx drug used for comparison performed at the high end of expectations based on prior evidence, but noted the Aveo drug met it
With a short interest of about 15% of the float and considering it was around $8 just a few days ago, even a split panel vote could send AVEO to well over $10 ($14 ?!)
From fly on the wall:
May 1, 2013
Raptor Pharmaceuticals price target raised to $12 from $9 at Leerink
Leerink raised its fair value estimate to $12 for Raptor Pharmaceuticals shares after the company received FDA approval for its treatment of nephropathic cystinosis. The firm reiterates an Outperform rating on the stock.
Dr.Lee (continued..) : The company is also developing Convivia for the treatment of acetaldehyde toxicity resulting from ALDH2 deficiency and is seeking potential partners in other Asian countries. RPTP also has a tezampanel program that targets thrombosis and intends to initiate a Phase I study in healthy volunteers by the end of calendar 2012.
Here's an excerpt from an interview with Think Equity analyst Dr.Lee:
Can you tell us about some other significant products in Raptor's clinical-stage pipeline?
Lee: Raptor is developing RP103 in two other indications, Huntington's disease and NASH. With potential opportunities, we believe this de-risks the development program slightly. The most advanced indication following cystinosis is Huntington's disease, a hereditary neurodegenerative disorder that negatively affects cognition and muscle coordination. The company initiated a randomized, placebo-controlled, multi-center, 18-month, 96-patient Phase II study in collaboration with CHU d'Angers in France in October 2010. This will be followed by an open-label study with all placebo patients rolling onto RP103 and all other patients continuing on drug for up to an additional 18 months. The primary endpoint is the Unified Huntington's Disease Rating Scale. We anticipate interim data release in Q2:14 (company guidance is H1:14). Given the graveyard of drug candidates that have been developed to treat Huntington's, we believe there is a low regulatory bar.
Development of RP103 in NASH, a progressive liver disease caused by inflammation and accumulation of fat and fibrous tissue in the liver, helps further diversify the development risk of the RP103 program, in our opinion. The company initiated a Phase IIb study in juvenile patients in Q2 with completion of the trial by YE:13 followed by data in Q2:14. In an open-label, uncontrolled 11-patient Phase IIa study, 7 of 11 patients demonstrated a greater than 50% reduction in ALT levels (p=0.004) while 6 of 11 reduced levels to within normal limits. The reduction in transaminase levels was largely sustained during a 6-month post-treatment monitoring phase. The company holds WW rights in this indication but intends to partner this program given the large developmental undertaking.
Raptor is investigating the possibility of using RP-103 as an eyedrop in order to reduce the cystine levels in the eyes of NC patients. It is also currently in Phase II/III trial for RP-103 to treat Huntington's Disease, which affects up to 30,000 people in the U.S.
Also in Raptor's pipeline is the use of RP-103/104 for the treatment of Non-alcoholic Steatopheatits (NASH), a progressive liver disease that currently is untreatable. Conviva is another Raptor drug, and its use is being investigated in the treatment of ALDH2 deficiency, a disorder that inhibits patients from metabolizing alcohol efficiently.
This should boost Procysbi's prospects in treating Huntington's disease, again with an orphan designation
Next up is Huntington's disease (Phase 2/3), again with orphan indication!!!!
Sentiment: Strong Buy
Analysts see annual sales for Procysbi of around $150 million. Considering that Raptor's current market cap is around $350 million, the stock may double!
FDA approves Procysbi for rare genetic condition
The U.S. Food and Drug Administration today approved Procysbi (cysteamine bitartrate) for the management of nephropathic cystinosis in children and adults. Procysbi was granted orphan product designation because it is intended to treat a rare disease or condition.
Cystinosis is a rare genetic condition that affects an estimated 500 patients in the United States and about 3,000 patients worldwide. Fatal if not treated in early childhood, cystinosis causes a protein building block called cystine to build up in every cell of the body. The buildup of cystine causes kidney problems, which can cause the body to lose too much sugar, proteins and salts through the urine. Cystinosis may lead to slow body growth and small stature, weak bones and developing and worsening kidney failure. There are three types of cystinosis, the most severe being nephropathic cystinosis, which severely damages the kidneys.
Currently the FDA approved drugs used to treat cystinosis include Cystagon (cysteamine bitartrate), an immediate-release tablet that was approved in 1994, and Cystaran (cysteamine ophthalmic solution) eye drops, approved last year to treat corneal cystine crystal accumulation.
Procysbi is a delayed-release capsule intended for patients ages 6 years and older. While Cystagon is taken every six hours around the clock to control cystine levels, Procysbi is a long-acting formulation that is taken every 12 hours.
“Procysbi is the only delayed-release product approved by FDA to treat nephropathic cystinosis, offering patients with this rare disease an important new treatment option,” said Andrew E. Mulberg, M.D., deputy director, Division of Gastroenterology and Inborn Errors Products, Center for Drug Evaluation and Research, FDA.
The major study supporting Procysbi’s safety and effectiveness involved 43 adult and pediatric patients with nephropathic cystinosis. Patients were randomly assigned to receive Cystagon or Procys
Sentiment: Strong Buy
This from Aveo's briefing doc:
A favorable risk-benefit prof
ile for tivozanib was demonstrated by a clinically
meaningful and statistically
significant prolongation of
PFS and improvement in ORR
over an approved VEGFR TKI, sorafenib. Tivozanib has also demonstrated antitumor
activity when used in patients follow
ing radiographic progression on sorafenib.
Tivozanib has a well-characterized and manageab
le safety profile that is distinct from
other approved TKIs. Overall, tivozanib repr
esents a valuable addition to the treatment
armamentarium for advanced RCC.
End-of-phase 2 meetings in December 2008 and May 2009 reached agreement concerning the
basic design of the Phase 3 trial. During the December 2008 meeting, the Agency and Aveo
discussed several study designs a
nd FDA stated that “a substantia
l, robust improvement in PFS
that is clinically meaningful
and statistically persuasive may be considered for regulatory
decision.” FDA also stated that “...a statis
tically significant improvement in OS is not
required for regulatory approval, but a pre-specifi
ed OS analysis plan is still helpful in the
regulatory decision making process.” In a May
2009 meeting, the Agency and Aveo discussed
the final Phase 3 protocol. Crossover was not di
scussed and was not included in the Phase 3
study itself (a later protocol provided cross
over). A pre-NDA meeting was held in May 2012.
Here, the FDA expressed concern about the adve
#$%$ trend in overall su
rvival in the single
Phase 3 trial and recommended that the s
ponsor conduct a second adequately powered
randomized trial in a population comp
arable to that in the US.
5. Issues for ODAC
In considering the results from a single random
ized trial submitted in support of marketing
approval of a new molecular entit
y, FDA expects that the trial wi
ll be adequately designed and
well conducted and that the result
s will be internally consistent. We are asking the ODAC’s
advice on whether this single trial is suffici
ent to support approval of tivozanib for the
indication of treatment of patients with advanced renal cell cancer or whether an additional
trial is necessary before considering marketing approval.
FDA ODAC Briefing Document
Page 2 of 13
On September 28, 2012, Aveo Pharmaceuticals subm
itted an application for tivozanib for the
treatment of advanced renal ce
ll carcinoma. This applicati
on was supported by a single Phase
3 trial, a randomized Phase 2 trial,
and an extension/crossover study.
Tivozanib is being brought to th
e ODAC to discuss the findings of the Phase 3 trial. In this
open label trial, 517 patients with
metastatic renal cell carcinoma were randomly allocated 1:1
to either tivozanib or sorafenib. The primary
endpoint was progression-
free survival (PFS) as
determined by an independent review committee
(IRC). Overall survival (OS) was a secondary
PFS: The analysis of PFS showed a stat
istically significant improvement in PFS
with tivozanib; HR = 0.80, p = 0.04. Median
PFS was 11.9 mos. in the tivozanib
arm and 9.1 mos. in the sorafenib arm.