FDA | Pharma Strategy Blog

Thoughts on the pixantrone FDA ODAC meeting

By MaverickNY on March 23, 2010

Yesterday was quite day, with one thing and another. For starters, the FDA ODAC committee finally held a session for Cell Therapeutics pixantrone in 3rd line NHL and ChemGenenex's omacetaxine, for people with the T315i mutation in CML. The previously scheduled meeting was cancelled due to the Snowpocalyse that hit DC last month.

I had to dash off to a doctor's appointment myself so missed most of the action on Twitter and rushed back to catch up at lunchtime by checking Twitter buddies such as Kerri Wachter who was live tweeting from the meeting and Adam Feuerstein of The Street's excellent live blog.

Image via Wikipedia

You can see my original review of the February FDA documents here. Sadly, the analysis turned out to be accurate and Adam had noted:

"That was brutal."

Approximately 20 minutes into Richard Pazdur's opening introduction.

In particular, the FDA felt that:

"Pixantrone has demonstrated evidence of biologic activity, but the mere demonstration of biologic activity is not sufficient for approval."

Ouch! At that point it becomes incumbent upon the company presenters to argue persuasively to the nine panel members to convince them otherwise. However, that was going to be a tall order given the FDA concerns regarding:

Neutropenia and infections were higher in pixantrone than the control
Cardiac toxicity was higher in pixantrone than control, including heart failure and ejection fraction

As highlighted in the original analysis of the pixantrone filing, the FDA were also unhappy about the shortened study given only 140 people were enrolled out of the planned 320, leading them to conclude:

Study was not well executed or complete.
Study was inconsistent (only 8 people enrolled in the US and none had a complete response).
Trial did not demonstrate statistical significance or robust findings.

What was weird about the proceedings though, was a clear disconnect between the two parties, as Adam Feuerstein reported live via the webcast:

"Pazdur: FDA not consulted about halting enrollment in trial, not pre-specified in study's statistical plan."

"Bianco: In March 2008 after 140th patient was enrolled, study was closed to enrollment. We consulted with FDA about this."

Checking my Twitter stream, Kerri reported:

Personally, I was surprised that CTI thought that the statistical parameters would not change if they only recruited 140 of the 320 people expected and could proceed on that basis. This is basic college level statistics – if you majorly change one input, the outliers must also be adjusted. For this reason, the FDA's decision to treat the data as if an interim analysis had been done is fair and reasonable.

Going forward, it is likely that either all 320 patients would need to be enrolled in a study to meet the minimum FDA requirements or new studies in combination with other agents would be needed. This latter approach is probably more likely, because the US sites (28 of them) only enrolled 8 people because the preferred treatment in the 3rd line refractory setting is combination chemotherapy, not single agent therapy.

Perhaps the snowpocalypse last month was a portend of what was to happen. Either way, yesterday was a bad day in DC for CTIC.

FDA and ODAC to review $CTIC's pixantrone and $CXSPY's omacetaxine

By MaverickNY on February 8, 2010

This week, (10th February) the FDA's Oncologic Drugs Advisory Committee will be meeting to review the filings from Cell Therapeutics ($CTIC) and ChemGenix ($CXSPY) for pixantrone and omacetaxine, in relapsed refractory NHL and CML, respectively.

I've just taken a few minutes to read the briefing documents and here are my initial thoughts.

Cell Therapeutics, a Seattle based biotech company, are going to have a very tough morning on Wednesday in DC for the following reasons:

The pivotal study had a very poor accrual with only 140 out of 320 patients enrolled.
Substantial cardiac and hematologic toxicities.

Risk:benefit trade-offs are always going to be a question for debate in the third-line setting, but CTI may well have shot themselves in the foot by closing enrollment early. This led the FDA to raise an important question about the study and whether there was sufficient information:

"the level of evidence necessary to draw conclusions from this Phase 3 study and the reliability of these conclusions."

Ouch.

After recent trials and tribulations over studies in elderly patients with AML had problems with a placebo comparator, it was good to see that in PIX301, patients were randomized 1:1 to single agent pixantrone or the following choice of comparators:

Oxaliplatin
Ifosfamide
Vinorelbine
Etoposide (PO/IV)
Mitoxantrone
Gemcitabine (only at U.S. sites)
Rituximab (only at U.S. sites)

Patients were treated for up to 6 cycles.

However, perhaps the most damning part of the FDA briefing document is the impact of halting enrollment early:

"The pivotal trial, PIX301, was discussed at an End of Phase 2 meeting on October 8, 2003. At this meeting, FDA stated, “Accelerated approval could be based on an interim analysis of a surrogate endpoint with completion of the trial demonstrating an improvement on a clinical benefit endpoint (survival or symptom benefit).”

FDA recommended that the trial assess complete response and the duration of complete response. Subsequently, agreement was reached concerning a Special Protocol Assessment for PIX301.

On March 28, 2008, CTI notified the FDA of an early halt to enrollment for PIX301. The study was not stopped at a planned interim analysis and early study stopping invalidated the applicant’s Special Protocol Assessment."

Based on this history, I think CTI will have a tough time arguing for approval on the basis of a shortened 140 patient study. It is clear in the FDA's analysis that they do not believe statistical significance was reached for the key efficacy measures.

Meanwhile, ChemGenex, a biotech company based in Australia with an office in San Francisco, are applying for approval of omacetaxine (Omapro) as treatment of adults with chronic myeloid leukemia (CML) who have failed prior therapy with imatinib and have the Bcr-Abl T315I mutation.

Interestingly, the FDA had completely different concerns with this filing.

The main issue with omacetaxine was that a commercially available assay does not exist for the T315i mutation and the company apparently didn't submit any information on how they were going to address this going forward. It's one thing to have central labs and academic labs do testing for trials, but given the majority of CML patients are seen by community oncologists in the US, a commercial assay is crucial for enabling decisions to be made on when to start therapy if the T315i mutation appears.

I would be surprised if a such a test hasn't been considered, but we will see what happens at ODAC on Wednesday. Approval may possibly be delayed until one is made available.

InterMune gets priority review for pirfenidone

By MaverickNY on January 5, 2010

Priority Review designation may be granted by the FDA to an NDA for drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. This designation has the potential to expedite the NDA approval process by reducing the target review period for the application from approximately 10 months to six months. Based on the Prescription Drug User Fee Act (PDUFA), the FDA has set an action date for the NDA of May 4, 2010.

via phx.corporate-ir.net

Idiopathic pulmonary fibrosis (IPF) is a disease characterized by progressive scarring, or fibrosis, of the lungs, which leads to their deterioration and destruction. It occurs in older patients (aged 50-70 years) and has a median survival of approximately 2-5 years from diagnosis.

Pirfenidone is an orally active small molecule drug that may inhibit collagen synthesis, down regulate production of multiple cytokines and block fibroblast proliferation and stimulation in response to cytokines.

Phase II and III trials have been completed and it will be interesting to see what the FDA and it's advisory committee make of the data when they review it in a few months.

Posted via web from sally church's posterous

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What's hot in oncology? A review of 2009 and predictions for 2010

By MaverickNY on December 18, 2009

Back in February, I took a big picture look at some of the cancer drugs in development that might be reviewed by the FDA for approval in 2009.

You can see the review here.

Of the eight drugs that were highlighted in the post, all were discussed by ODAC, so that was a positive sign. Five (Afinitor in RCC, Folotyn and Istodax in t-cell lymphomas, pazopanib in RCC and Arzerra in CLL) all passed the final hurdle, receiving a positive FDA opinion, while others (clofarabine, trabectedin and denosumab) were less lucky and issues associated with the filings are still being discussed. The EU CHMP has issued a positive opinion for Prolia (denosumab) but the FDA seem less convinced so far and issued a complete response letter requesting further information before giving approval. Amgen seem confident of addressing these issues, so we may well seen a green light soon.

While Genzyme and Amgen should be able to resolve the concerns successfully and will likely obtain FDA approval in 2010, J&J may well be left at the altar again with Yondelis. The drug was approved in Europe for soft tissue sarcomas, but approval in ovarian cancer is being sought in the US and ODAC had major issues with the trials and the risk-benefit trade-off. Time will tell what will happen in 2010.

AstraZeneca have not had a lot of luck with their pipeline since the infamous Iressa troubles. This year, they withdrew their filing for Zactima, a combination VEGF/EGFR inhibitor with limited efficacy over existing therapies. It will be interesting to see if they rebound in 2010.

The most promising robust oncology pipelines at the moment are probably those of Roche/Genentech, Novartis and Pfizer. Merck, BMS and GSK also have some interesting solid bets in their pipelines, but are not renowned for their speed of R&D and marketing in oncology compared to the other three, who are much more aggressive and focused in their resources and efforts.

W2W4 (what to watch for) in 2010?

That's the big question I'm getting in my email bag this month.

2010 is going to be an interesting year for CML patients, who will see a lot of new activity. ChemGenex filed omacetaxine for T315i mutations and treatment in patients who had failed existing TKI therapy. They have an ODAC in February and based on the data presented at ASH this month, I think they have a good chance of approval.

Novartis and BMS are both expected to submit an NDA to both the FDA and EMEA for approval of nilotinib and dasatinib respectively, in newly diagnosed CML. The nilotinib data was presented at ASH and clearly showed a 12 month efficacy benefit over imatinib, the current standard of care. We are still awaiting the dasatinib vs. imatinib data, hopefully it will be presented at either ASCO or EHA. My guess is that we may well see approvals for both drugs in the front-line setting in 2010.

The biggest challenge both companies may well have though, is not getting approval per se from the EMEA, but rather getting past NICE in the UK given the disparity in price with imatinib, when 60-70% of patients do well on the drug and attain a complete cytogenetic response at 18 months. Currently, NICE has declined to approve the second generation TKI's even in the relapse/refractory/resistance setting, so that does not augur well for the frontline setting.

Genzyme will likely have data from randomised trials with clofarabine in elderly AML in 2010, which means that approval may well be possible if the data is positive.

Cell Therapeutics presented data at ASH on pixantrone in 3rd line NHL, with evidence of activity. This drug will be another candidate for approval and the ODAC is currently scheduled for April, according to the company.

Ariad, a biotech based in Boston, have two promising agents in development. Ridaforolimus is an mTOR being developed in soft tissue sarcomas with Merck in the second line setting. I think this agent is promising, but the placebo controlled trial design in a heterogeneous disease where some subsets respond well to therapy and some are insensitive makes me nervous what the final phase III results will bring. In such an allcomers trial, you run the risk that the responders will be drowned out by the non-responders. Of course, screening out subsets in a fairly uncommon disease makes for slower accrual and time to market so the risk is a high one. What I do know is that KOL's I spoke to who participated in the trial noted that those patients who did respond tended to do very well in a heavily pretreated setting. We should know by ASCO whether Ariad's big play paid off or not.

Ariad also have a interesting agent in development for CMl, which targets the T315i mutation, currently a gap not met by the current TKI's approved on the market. Given my interest in CML, this is a new agent worth following. The early phase I data presented by Dr Cortes from MD Anderson at ASH this month looked very encouraging indeed.

Dendreon's Provenge is always a controversial topic on this blog. I'm not going to make any predictions about the vaccine this time other than to say it will be fascinating to see what happens next year! It's been somewhat of a roller coaster ride so far and I suspect that trend will continue in 2010.

J&J and Cougar's abiraterone may have enough data in prostate cancer by ASCO mid year to determine if they have enough evidence for a filing too. If so, it could be an interesting year in prostate cancer given very little new therapies have made any headway in the middle to advanced settings in extending hormone sensitivity and delaying time to progression to metastases. If either of these drugs can achieve that lofty goal, it will be very good news indeed.

Medivation also have a novel compound (MDV-3100) in much earlier development, so while the others test the regulatory waters, we can see how the new partnership evolves with Astellas.

Two other compounds I'm watching are Novartis' Antisoma compound, ASA404, in lung cancer and ipilimumab in melanoma and prostate cancer from BMS. Both of these agents have shown early signs of efficacy, so data at ASCO may well tell us whether they look like showing real promise or turning into duds.

This year saw the evolution into the limelight from the PARP inhibitors, most noticeably sanofi-aventis and BiPar's BSI-201 in triple negative breast cancer and AstraZeneca and KuDos's AZD2281 in BRCA1 and 2 mutated cancers such as breast and ovarian. I'm really looking forward to seeing the latest data at ASCO in June 2010 after following their progress at ASCO and AACR this year.

So of all the new pipeline drugs mentioned in this post, what is particularly compelling? I'm probably most excited by the PARP inhibitors and ASA-404, all of which have a real chance to stand out from the crowd. We'll see this time next year whether that turns out to be a good prediction or not!

Further updates of interesting compounds in development will continue o
n this blog next year.

Of course, if anyone has any other favourites they're following in oncology, please add them in the comments or drop me an email. We'd love to hear what others think.

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Tarceva maintenance therapy in non-small cell lung cancer

By MaverickNY on December 16, 2009

Chomping at the bit, like many others today, to hear how the FDA ODAC meeting goes on regarding Tarceva maintenance therapy in lung cancer.

The initial OSI company presentation appeared to go well, but Q&A session did not; the committee clearly had concerns about the statistics. The SATURN data in adenocarcinoma was not as impressive as hoped, with the overall survival benefit being one extra month as opposed to taking the drug second line after initial chemotherapy failing and then getting 3 months of extra benefit with either Tarceva or docetaxel. Sometimes waiting and recovering will get you better results.

We posted about the original trial designs earlier this year in February and the initial results from the May ASCO meeting.

More at around 3pm ET today.

{UPDATE: ODAC VOTING 1 YES, 12 NO}

Clinical trial results show Denosumab is superior to Zometa in breast cancer patients with bone metastases

By MaverickNY on July 13, 2009

Amgen’s recent announcement of phase III trial data showing that it’s monoclonal antibody, denosumab was superior to Novartis’ Zometa (zoledronic acid) for the treatment of breast cancer patients with bone mestastases is further news that scientifically driven drug development can yield exciting results.

Denosumab is in essence a targeted therapy like Gleevec, Avastin or Herceptin. It’s development came about from basic research that discovered the cellular control of bone remodelling and regulation of bone density is reglated by the RANK Ligand pathway.

RANK Ligand is a TNF famly member, a protein that is expressed on the sufrace of marrow, stromal cells and osteoblasts (the cells responsible for bone formation). When RANK-L binds with its receptor RANK it stimulates the activity of osteoclasts (cells responsible for bone resorption). In the body, RANK-L production is naturally regulated by the protein Osteoprotegerin (OPG), which binds with RANK-L thereby preventing it from binding to its receptor, RANK. When there is insufficient OPG, or too much RANK-L produced, excess bone loss occurs. This occurs in post-menopausal women or in cancer related bone loss.

Denosumab acts by attaching itself to RANK-L, thereby inhibiting its action. Deprived of RANK-L, osteoclasts cannot form, function or survive. The result is less bone destruction and bone loss. Understanding the RANK Ligand pathway has been a breakthrough step in understanding bone biology.

Many cancer patients end up with bone metastases that not only causes pain, but also bone destruction. Roodman, in a 2004 New England Journal article, proposed the “vicious cycle” hypothesis to explain this: Tumor cells produce parathyroid hormone-related peptide (PTHrP), which stimulates osteoblasts to produce RANK ligand leading to less production (downregulation) of osteoprotegerin (OPG), thereby stimulating osteoclasts to resorb more bone. At the same time, production of PTHrP promotes tumor growth directly. Therefore, it should come as no surprise that denosumab would be effective in cancer patients with bone mets and skeletal related events.

What does the future hold for denosumab? In the postmenopausal osteoporosis market, a once or twice yearly injection is extremely attractive given its ease of use. Compliance is a real issue with bisphosphates such as alendronate or risedronate where a daily pill must be taken. Many primary care physicians are not set-up to administer an infusion, which is what Novartis’ once a year osteoporosis treatment, Reclast requires.

However, despite impressive clinical data, Amgen does not yet have a home run. It lacks a large sales force and infrastructure to sell to primary care physicians. Also with generic fosamax (alendronate) available, the cost/benefit trade off is going to be a key factor in uptake. The cost of denosumab will need to be carefully considered for Amgen to enter this competitive market. The FDA advisory board meets on August 13 to discuss Amgen’s BLA application and consider whether to recommend approval for the treatment and prevention of osteoporosis, and treatment of bone loss in patients undergoing hormone ablation for prostrate and breast cancer. Given the positive data from the phase III pivotal studies, a positive recommendation is expected with approval by the FDA expected in October.

For cancer patients, denosumab could become the gold-standard for treatment of bone metastases given its superiority over Novartis’ Zometa. For oncologists, the fact that denosumab only requires an injection while Zometa requires an infusion is less of an issue. The key to success for oncology drugs is based solely on the data. If the positive results continue, Amgen are likely to take market share from Zometa once approval for the treatment of bone metastases is obtained in 2010 or 2011.

So, my take on this is that denosumab is a real winner for Amgen. Whether it will capture the market for postmenopausal osteoporosis remains to be seen, but it is an exciting new drug that will benefit cancer patients. Further data on denosumab can be expected from the September meeting of the American Society of Bone and Mineral Research (ASBMR) in Denver.

Alimta gets a new approval in first-line non-small cell lung cancer with specific histologies

By MaverickNY on October 5, 2008

This week, Lilly received approval from the U.S. Food and Drug Administration (FDA) for the use of Alimta (pemetrexed), in combination with cisplatin, in the first-line treatment of locally-advanced and metastatic non-small cell lung cancer (NSCLC), for patients with non squamous histology. Alimta is not indicated for treatment of patients with squamous cell non-small cell lung cancer.

According to the American Cancer Society, lung cancer (small cell and non-small cell) is the second most common cancer in both men (after prostate cancer) and women (after breast cancer). It accounts for about 15% of all new cancers. During 2008, there will be about 215,020 new cases of lung cancer (114,690 among men and 100,330 among women).

Lung cancer is by far the leading cause of cancer death among both men and women. There will be an estimated 161,840 deaths from lung cancer (90,810 among men and 71,030 among women) in 2008, accounting for around 29% of all cancer deaths. More people die of lung cancer than of colon, breast, and prostate cancers combined.

Image courtesy of Upstate.edu

Approximately 80% to 85% of lung cancers are NSCLC rather than SCLC; there are 3 subtypes of NSCLC. The cells in these subtypes differ in size, shape, and chemical makeup when looked at under a microscope.

Squamous cell carcinoma:

About 25% to 30% of all lung cancers are squamous cell carcinomas. They are often linked to a history of smoking and tend to be found in the middle of the lungs, near a bronchus.

Adenocarcinoma:

This subtype accounts for about 40% of lung cancers. It is usually found in the outer region of lung. People with one type of adenocarcinoma, also known as bronchioloalveolar carcinoma, tend to have a better outlook (prognosis) than
those with other types of lung cancer and tend to be non-smokers.

Large-cell (undifferentiated) carcinoma:

This subtype accounts for about 10% to 15% of lung cancers. It may appear in any part of the lung. It tends to grow and spread quickly, which can make it harder to treat effectively.

Since Alimta is approved for non-squamous cell histology this means that approx. 70% of NSCLC are eligible for treatment with the drug.

Approval in first-line advanced NSCLC for non-squamous cell histology was based on a Phase III, open-label randomized study (n=1725 patients) that evaluated Alimta plus cisplatin (AC arm) versus Gemzar (gemcitabine) plus cisplatin (GC arm). Median survival was 10.3 months in the AC arm and 10.3 months in the GC arm. Median progression-free survival (PFS) was 4.8 and 5.1 months for the AC and GC arms, respectively. Overall response rates were 27.1% and 24.7% for the AC and GC arms, respectively.

The impact of NSCLC histology on overall survival was also determined. Clinically relevant differences in survival according to histology were observed. In the non-squamous cell NSCLC subgroup, the median survival was 11.0 and 10.1 months in the AC and GC groups, respectively. However, in the squamous cell histology subgroup, the median survival was 9.4 versus 10.8 months in the AC and GC groups, respectively.

This unfavorable effect on overall survival associated with squamous cell histology observed with Alimta was also noted in a retrospective analysis of the single-agent trial of Alimta versus Taxotere (docetaxel) in patients with stage III/IV NSCLC after prior
chemotherapy.

Patients treated with the Alimta regimen had less hematologic toxicity, fewer blood transfusions and decreased use of growth factors compared to those treated with the GEMZAR regimen. The most common adverse reactions (incidence greater than or equal to 20%) for Alimta in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia and constipation.

The main benefit from this trial is potentially a change in the treatment paradigm, because Alimta offers the first sign of activity of a drug in the maintenance setting in lung cancer. Although there is not yet full survival data from this trial, there is a significant benefit in PFS. Alimta can be administered over a prolonged period without cumulative toxicity, so it may allow the disease to be treated as a ‘chronic’ condition. If that is found to be the case, then it represents a major step forward in the treatment of patients who have non-squamous NSCLC.

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FTC warns about bogus cancer cures

By MaverickNY on September 19, 2008

The absolute last thing you need when you or a family member is seriously ill with cancer is an illegal scam from snake oil salesmen.

The Federal Trade Commission (FTC)
has charged five companies with making false and misleading claims for
cancer cures and said yesterday that it has reached settlements with several others. In their press release, the five companies being sued for false and deceptive advertising will go before administrative law judges and included the following:

Omega Supply

Native Essence Herb Company

Daniel Chapter One

Gemtronics

Herbs For Cancer

Settlements were reached with other companies who paid restitution ranging from $9,000 to $250,000. In all, over a 100 warning letters were sent out asking companies to address the bogus claims.

The FTC, the Food and Drug Administration FDA) and Canadian authorities, are launching a consumer education campaign warning about bogus claims for cures. It includes videos and a wealth of information in a cartoon format, including excellent snippets such as this:

"Natural doesn't always mean effective. Scammers take
advantage of the feelings that can accompany a diagnosis of cancer.
They promote unproven – and potentially dangerous – remedies like black
salve, essiac tea, or laetrile with claims that the products are both
“natural” and effective. But “natural” doesn’t mean either safe or
effective when it comes to using these treatments for cancer. In fact,
a product labeled “natural,” can be ineffective and even downright
harmful."

Interestingly, one of the lawyers for the five companies was maintaining that the FTC's actions represent censorship. The reality is that there are no credible scientific evidence that any of the products
marketed by these companies can prevent, cure, or treat cancer, since few if any, have undergone controlled clinical trials.

Given the high standards maintained by the FDA and other regulatory authorities, the burden of proof lies with the companies to prove their claims or risk being labelled snake oil salesmen at best.

Ensuring quality and safety in drug development

By MaverickNY on September 17, 2008

Yesterday, the FDA blocked the entry of over 30 generic drugs made by India's Ranbaxy due to manufacturing failures.

"Today's actions are clearly warranted based on the extent
and the seriousness of the violations uncovered during our
inspections of these two sites. The firm is
sufficiently out of control that we think an import alert should
be put into place until these deficiencies are corrected."

Deborah Autor, Director of the Food and Drug Administration's Drug Compliance Office

Earlier this year, the Justice Department asked a U.S. District
Court judge in Maryland to force Ranbaxy to turn over audits
completed by a contractor, which the company later agreed to
provide. The Government is
investigating allegations including conspiracy, false statements
and health-care fraud.

In the July court motion, the Justice Department claimed that "allegations from reliable sources and supporting
documents indicate a pattern of systemic fraudulent conduct,
including submissions by Ranbaxy to the FDA that contain false
and fabricated information.''

Ranbaxy has denied the
allegations, and no charges have been filed.

The FDA issued a warning to Ranbaxy after a February 2006
inspection of the plant in Paonta Sahib that found 'significant
violations'. The FDA inspected that plant again, along with the
plant in Dewas, earlier this year, resulting in the warning letters
issued yesterday, according to the agency's statement after the FDA
concluded that Ranbaxy's response to its inspections was
inadequate. Products will be blocked until Ranbaxy resolves
deficiencies at the plants, according to the FDA.

It's an interesting situation overall. Public awareness of quality and safety issues are at a high after the Heparin storm with Chinese suppliers using synthetic replacements in the raw ingredients and pets dying from contaminated pet food.

After all, it is not unreasonable that products entering the US market should be proven to meet the required standards for safety and efficacy. The public have a right to be reassured that the products are indeed what they are expected to be. The heparin incident taught everyone that vigilance is vital to quality and safety of drugs.

Sources:

FDA
Bloomberg

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