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Impact of the Supreme Court case on adverse events including cancer

By MaverickNY on January 11, 2011

My colleague who writes the Biotech Strategy Blog, posted an interesting analysis this morning on the Matrixx Zicam case currently being reviewed by the United States Supreme Court (SCOTUS). At the heart of the issue is whether or not adverse events should be disclosed to investors, even if not statistically significant. The way the questioning appears to be going from the Justices so far, it looks like they believe they should be.

The reason I bring this topic up is because it has important implications for Pharma and Biotech companies.

Recently, several obesity drugs were reviewed by the FDA Advisory Committees. It’s not an area I usually follow, except that one of them, Arena Pharmaceuticals ($ARNA), caused a stir when many analysts and investors were surprised by the FDA briefing documents. In it, was a hidden gem – the drug in question appeared to have an increased risk of developing cancer in rats – but the company hadn’t publicly revealed this fact. Why? Because the CEO, Jack Lief, and the Board didn’t think it was material.

Inevitably, a lot of investors were rather dismayed not to have known that information before deciding whether or not to invest in the company. Most of the industry watchers on Twitter, including myself, were certainly a little flabbergasted to hear it for the first time from the FDA.

Of course, the drug did not get recommended for approval, partly because of the marginal efficacy data, but also there was genuine concern over heart valve problems, and it is hard to imagine that the undeclared rat cancer didn’t factor in either. In the end, a complete response letter (CRL) was issued.

I love Adam Feuerstein of The Street’s tweet around that time:

Now, if we fast forward to the SCOTUS discussion on this very issue, it is not hard to see that this kind of information ought to be revealed to allow investors to make a rational decision on whether to invest or not.

The final SCOTUS decision is expected by the summer, so it will be interesting to see what happens if they decide that adverse events, whether significant or not, should be declared. personally, I think they should and people can then do their own due diligence and research on whether they think it increased their risk tolerance or not.

This decision may well have a far reaching impact on the Pharma and Biotech industry and force company Boards to be far more rigorous and diligent in providing relevant information to potential investors.

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DNMT3A Mutations in Acute Myeloid Leukemia – an update

By MaverickNY on December 21, 2010

The current New England Journal of Medicine has an in-depth article on DNMT3A Mutations in Acute Myeloid Leukemia (AML). Many of you will remember the discussion on this topic last month based on the two case studies that the same authors covered in the journal, where the DNMT3A mutation was shown to be associated with a poorer prognosis. They now offer an update to the story:

“We did not find new recurring mutations in the first study but did observe a recurrent mutation in IDH1, encoding isocitrate dehydrogenase 1, in the second study. Subsequent work has confirmed and extended this finding, showing that mutations in IDH1 and related gene IDH2 are highly recurrent in patients with an intermediate-risk cytogenetic profile (20 to 30% frequency) and are associated with a poor prognosis in some subgroups of patients.

Improvements in sequencing techniques prompted us to reevaluate the first case with deeper sequence coverage, during which we discovered a frameshift mutation in the DNA methyltransferase gene DNMT3A.”

DNMT1, DNMT3A, and DNMT3B are genes that encode DNA methyltransferases. These are enzymes that catalyse the addition of a methyl group to the cytosine residue of CpG dinucleotides. Clusters of CpG dinucleotides are concentrated in regions upstream of genes. It is known that increased methylation of these CpG islands is often associated with reduced expression of the downstream gene.

Aberrant DNA methylation has long been hypothesized to contribute to the pathogenesis of cancer. However, cancer genomes tend to be hypomethylated, but hypermethylation of CpG islands in the promoters of tumor-suppressor genes (TSG) is also common in many tumours. DNA methyltransferase inhibitors are currently one available option for the treatment AML, and includes drugs such as decitabine and azacitidine. The response rates are generally fairly low and unpredictable, however, because there is no biomarker available to determine which patients will most likely respond to therapy.

Given the differences in the two case studies, the next step was clear:

“After discovering a frameshift mutation in DNMT3A with whole-genome sequencing, we conducted a study to determine whether DNMT3A is recurrently mutated in AML samples and whether DNMT3A mutations are associated with poor survival.”

To give an idea of the sheer scale of the datasets that these kind of GWAS studies generate in one patient, I was fascinated to read the following:

“We previously sequenced the AML genome of a sample obtained from Patient 933124 and obtained short single-end reads, yielding 98 billion base pairs of sequence and 91.2% diploid coverage of the genome. In this study, we obtained 116.4 billion base pairs with paired-end reads from the genome of the relapsed tumor, yielding 99.6% diploid coverage of the genome.”

What did they find?

The survival results based on the Kaplan-Meier curves clearly showed that those AML patients with no DNMT3A mutation clearly had better survival than those who did have the mutation, regardless of age and FLT3 mutation status. You can check out the curves in the reference below.

The authors concluded that:

“DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome.”

What these results mean in practice (for now), is that the DNMT3A mutation offers a way to classify intermediate risk AML and thus an indication for earlier, more intensive treatment such as allogeneic stem cell transplant. Whether the mutation is druggable or not for future therapeutic intervention isn’t clear yet.

References:

Ley, T., Ding, L., Walter, M., McLellan, M., Lamprecht, T., Larson, D., Kandoth, C., Payton, J., Baty, J., Welch, J., Harris, C., Lichti, C., Townsend, R., Fulton, R., Dooling, D., Koboldt, D., Schmidt, H., Zhang, Q., Osborne, J., Lin, L., O’Laughlin, M., McMichael, J., Delehaunty, K., McGrath, S., Fulton, L., Magrini, V., Vickery, T., Hundal, J., Cook, L., Conyers, J., Swift, G., Reed, J., Alldredge, P., Wylie, T., Walker, J., Kalicki, J., Watson, M., Heath, S., Shannon, W., Varghese, N., Nagarajan, R., Westervelt, P., Tomasson, M., Link, D., Graubert, T., DiPersio, J., Mardis, E., & Wilson, R. (2010). Mutations in Acute Myeloid Leukemia. New England Journal of Medicine, 363 (25), 2424-2433 DOI: 10.1056/NEJMoa1005143

Ley, T., Ding, L., Walter, M., McLellan, M., Lamprecht, T., Larson, D., Kandoth, C., Payton, J., Baty, J., Welch, J., Harris, C., Lichti, C., Townsend, R., Fulton, R., Dooling, D., Koboldt, D., Schmidt, H., Zhang, Q., Osborne, J., Lin, L., O’Laughlin, M., McMichael, J., Delehaunty, K., McGrath, S., Fulton, L., Magrini, V., Vickery, T., Hundal, J., Cook, L., Conyers, J., Swift, G., Reed, J., Alldredge, P., Wylie, T., Walker, J., Kalicki, J., Watson, M., Heath, S., Shannon, W., Varghese, N., Nagarajan, R., Westervelt, P., Tomasson, M., Link, D., Graubert, T., DiPersio, J., Mardis, E., & Wilson, R. (2010).
Mutations in Acute Myeloid Leukemia New England Journal of Medicine DOI: 10.1056/NEJMoa1005143

FDA moves to withdraw Avastin in breast cancer

By MaverickNY on December 16, 2010

Well, the long awaited decision by the FDA on bevacizumab (Avastin) in breast cancer has finally been published and is probably the least surprising decision by the agency in 2010:

“The Office of New Drugs (OND) recommends withdrawing approval of the breast cancer indication for bevacizumab (Avastin). This indication was approved on February 22, 2008, under accelerated approval provisions for use in combination with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer.

As a condition of the accelerated approval, Genentech was required to submit data from two ongoing trials (AVADO and RIBBON1) to provide verification of the treatment effect on progression free survival (PFS) and to provide additional information on the effects on overall survival (OS). These two trials failed to confirm the magnitude of benefit originally observed in the E2100 study on which accelerated approval was based. In addition, there was an overall increase in serious adverse events related to bevacizumab.

The modest benefit observed with Avastin together with the substantial adverse reactions observed in breast cancer trials to date fail to provide a favorable risk-benefit profile to support continued marketing of Avastin for a first-line metastatic breast cancer indication. It is the conclusion of OND that the breast cancer indication for Avastin be withdrawn.”

Source: FDA

This is not a surprising decision following the recent ODAC vote of 12-1 to withdraw the drug for the treatment of breast cancer based on the AVADO and RIBBON1 trial results, which was discussed in detail previously on this blog. The overall survival data actually showed a slight benefit in favour of the chemotherapy (docetaxel) only arm in AVADO, for example, (31.9 vs. 30.2 months).

Also of interest to many is the more results from the neoadjuvant trial with bevacizumab prior to surgery. Negative trial results were announced at the San Antonio Breast Cancer Symposium last week, essentially adding another nail in the coffin for a solid rationale for earlier use in breast cancer.

For now, the drug will remain on the market and available in this indication, but the clear intent by the FDA is that they plan on withdrawal following the lack of confirmation for full approval. The company, Roche/Genentech, have 15 days to request a hearing and judging by the press releases so far, this will be sought. No doubt significant patient advocacy will also be mobilised in support.

There is no question that some women with breast cancer have benefitted from treatment with bevacizumab, but without a biomarker to determine who is most likely to respond to the therapy, it is difficult to see how it can remain on the market given three overwhelming negative trials demonstrating little overall benefit and some not insignificant risk of systemic side effects.

For me, though, what this body of data consistently shows is that, combined with the negative bevacizumab in adjuvant colorectal cancer, VEGF plays a much clearer role in metastatic disease such as colorectal cancer where the tumours are more vascular and often larger. In breast cancer, the tumours are typically much smaller by comparison. It may well be that we learn more about the process of angiogenesis from negative data and how tumours grow. Angiogenesis is a highly complex process and we still need to learn how other growth factors such as PDGF, angiopoeitins, Tie-2 etc, may play a role in tumour growth. This has yet to be elucidated but research is ongoing. The recent post discussing cancer cell seeding teaches us that we have much to learn about the whole process of angiogenesis from early growth to metastasis. VEGF is clearly not the only target involved.

Meanwhile, this developing story will clearly continue to unfold in 2011. The New York Times has a different angle on this story, so check it out for yourselves.

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Disclosures

By MaverickNY on December 13, 2010

IMGP2338 After the recent cancer conference and travel schedule, I’m a bit pushed for time today as the consulting work we’re doing at Icarus is frantically busy at the moment.

This is a great thing of course, but not so good for blogging 🙂

Still, I get a lot of questions about what we do job-wise, during the day, so you can head over to our new business website and check that out, if interested.

Meanwhile, some housekeeping updates here on Pharma Strategy Blog:

A disclosures tab has also been added to the top of this blog and going forward, all information relating to this will be curated there rather than on individual posts. It will save me forgetting 🙂
Our first cancer conference newsletter is almost ready to go out, so if you haven’t already subscribed and would like to, just add your name and email to the sign-up form at the top of the right hand column —>. Be warned – regular blog subscribers will not automatically receive the reports unless you choose to sign up.

Have a great day, everyone – the Holidays will soon be upon us.

AACR San Antonio Breast Cancer Symposium #SABCS

By MaverickNY on December 8, 2010

Sadly, a nasty ear infection has grounded me and I’m unable to attend the San Antonio Breast Cancer Symposium after all :(.

However, I’m aggregating the Tweet commentary from the various attendees and will be following remotely in the back channel. Various breast cancer specialists such as enthusiastic and enigmatic Dr Naoto Ueno will be tweeting live, so it should be a good meeting! Today is mostly the education symposia.

You can see all the tweets, posts and comments from the meeting in the widget below:

<a href="http://www.coveritlive.com/mobile.php/option=com_mobile/task=viewaltcast/altcast_code=5fff5fd716" >SABCS</a>

What’s Hot at ASH in 2010?

By MaverickNY on December 2, 2010

Here’s my 2010 list of a few pipeline and approved products that I’ll be watching out for at the upcoming American Society of Hematology (ASH) meeting , which begins tomorrow and runs over the weekend. Some of them will not the expected hot ‘news’ items so beloved of the medical media who often seem to delight in over-hyping things.

Saturday and Sunday typically embrace the posters, education and plenary sessions, while Monday and Tuesday heralds the oral sessions.

In no particular order, and by no means extensive, these are agents I personally find interesting and worth checking out at the meeting:

1. ARRY-520 (Array Biopharma)

There is still no cure for multiple myeloma, although a wealth of new therapies and combinations has definitely improved survival and outcomes for this disease. It is always good to look out for new agents in development in the relapsed/refractory setting.

ARRY-520 is interesting because it’s a kinesin spindle protein (KSP) inhibitor. KSP is required for cell cycle progression through mitosis and inhibition of KSP has been shown to induce mitotic arrest and cell death, in a similar fashion to taxanes and vinca alkaloids. The company has a number of small molecule compounds in development for cancer:

Source: Array Biopharma

ARRY-520 has been researched specifically in hematologic models such as myeloma, so this will a poster I’ll be looking out for.

What I love about this compound:
While ARRY-520 may target the spindle like taxanes, it appears to do so without the associated peripheral neuropathy and hair loss.

2. SGN-35/brentuximab vedotin (Seattle Genetics/Millennium):

I wrote about the recent promising data from the NEJM by Dr Anas Younes and colleagues. At ASH the same group are presenting on SGN-35 in relapsed/refractory Hodgkin Lymphoma including adverse events and ORR (Mon 6th, 7am) and another group is looking at the agent in Anaplastic Large Cell Lymphomas (Tues 7th, 7.30am) where they will be presenting data on complete remissions.

What I love about this compound:
The concept of a monoclonal antibody combined with chemotherapy as a drug conjugate is an exciting new disruptive biotechnology with a lot of promise.

3. CAL-101 (Calistoga)

Most (but not all) of the other PI3-kinase inhibitors in development seem to have been focusing primarily on solid tumours with mixed results to date. There is also a potential role for the delta form of PI3 kinase inhibitors in B-cell signalling, which encompasses Non Hodgkins Lymphoma (NHL), Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL). Calistoga have been looking at CAL-101 specifically in hematologic malignancies and 7 abstracts are being presented this year either alone or in combination.

What I love about this compound:
When everybody zigs, zag.

4. Crizotinib (Pfizer)

This year, we’ve all heard a lot about ALK rearrangements in non-small cell lung cancer (NSCLC), but such translocations also occur in anaplastic large cell lymphoma (ALCL). It would be most logical to see if crizotinib has any effect in these people with this uncommon form of lymphoma, so I’m looking forward to seeing what the data looks like in the poster session on Sunday evening. I’m expecting/hoping it will show some positive signs in this particular subset who are chemorefractory.

What I love about this agent:
It’s highly and specifically targeted to ALK, a constitutively active translocation (and occasional mutation) that appears to be driving some lung cancer, lymphoma and other rarer cancer subsets.

5. Imatinib/nilotinib (Novartis)

How low should you go? It is now clear from the evidence that people living with CML who attain a major molecular response (MMR) are less likely to relapse than those with a complete cytogenetic response (CCyR).

Ten years ago, the expected life span was only 3-4 years. Imatinib has dramatically shifted the paradigm for the treatment of CML, with people having a realistic goal of living for at least a decade after diagnosis with early chronic phase disease. It is likely that the baton will soon pass to the new second generation TKIs such as nilotinib and dasatinib, which can help achieve an earlier response into the ‘safe haven’ zone. They typically all achieve 90% response rates, but differ in their side effect profiles owing to the additional targets they inhibit.

It will be interesting to see what new data will be presented at this meeting in the annual IRIS trial update and other presentations in several sessions on Monday 6th.

What I love about this drug:
You can’t keep an old warhorse down!

6. Ponatinib (Ariad):

None of the TKIs currently approved for CML target the rare T315I mutation, which ponatinib does target, based on preclinical data. Initial phase I data in the relapsed/refractory setting including T315I mutations is due to be presented in Orlando in the oral session (Monday 6th, 8:15am).

What I love about this compound:
Resistance to all of the TKIs is not that common in CML, but I do think it would be good to have an option for those who find themselves in that unfortunate situation.

7. Rituximab (Roche/Genentech):

Most of the plenary presentations on Sunday afternoon are scientifically focused this year, but there is some preliminary clinical data on rituximab in follicular lymphoma (FL).

The randomised trial from the UK looks at rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky FL. The reason for this is that patients with asymptomatic, advanced stage, follicular lymphoma have shown no benefit of immediate chemotherapy when compared with a watchful-waiting approach, so chemotherapy is typically deferred until disease progression. Rituximab (when used with the CHOP chemotherapy regimen) has become the standard of care for NHL, so looking at it’s activity in another lymphoma subset makes sense.

What I love about this compound:
Anything that significantly delays disease progression without the side effects of chemotherapy would be a welcome addition to treatment options in FL.

8. Concomitant VEGF and MEK inhibition

There are a couple of novel approaches looking at new combinations at the ASH meeting. Thoughtful research studies can often inform us about a potential new approach that might be worthwhile considering in the clinic. One such example I came across was dual VEGF and MEK inhibition in pediatric 11q23 AML. In AML, it has been found that simultaneous activation of these pathways results in a poor prognosis, so this would be a logical therapeutic combination to consider in appropriate children. Chromosomal translocations involving the Mixed Lineage Leukemia (MLL) gene at locus 11q23 are also associated with a poor outcome. These translocations represent approx. 15-20% of pediatric AML.

What I love about this concept:
As a result of the preclinical research, future studies looking at a VEGF-MEK combination are now being planned in pediatric AML and will be worth watching out for.

9. Panobinostat and everolimus (Novartis)

Believe it or not, I was actually trying very hard to avoid selecting another Novartis drug or combination, but they have a very broad portfolio in oncology and lots of interesting early data coming out. The reasoning behind this combination is that mTOR and deacetylase (DAC) inhibitors have demonstrated single agent activity in patients with relapsed and refractory lymphoma. Synergy between DAC inhibitors and mTOR inhibitors has also been observed in lymphoma cell lines in vitro. This is a phase I dose finding trial, so the results will be preliminary, but we should see whether the promise is possible from the early signals.

What I love about this concept:
HDAC and mTOR is a highly logical combination to explore in lymphomas based on the preclinical research to date.

10. TET2 mutations in myeloid malignancies

In case you’re thinking this might be a bit obscure, this presentation actually kicks off the Plenary session on Sunday and I have to say that it’s cool to see a Masters student present some really cool research.

“TET2 mutations are frequently found across broad spectrum of myeloid malignancies but how these mutations contribute to diseases is still unknown.”

I’m not going to spoil the presentation, but what I suspect they may have is a new therapeutic target in myeloid malignancies based on a mutation that occurs through epigenetic changes.

To check out some other top lists, take a look at Dr Anas Younes Facebook page, where he has posted his top 10 lymphoma clinical abstracts. I haven’t seen any other 10 ten abstracts for ASH yet, so we may well be the first two to stick our necks over the parapet 🙂

Disclosures:

– I own no stock in any of these companies (perhaps I should!)
– I’m a former employee of Novartis who worked on imatinib and my company has done consulting work for them.

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What's new in Biosimilars?

By MaverickNY on November 29, 2010

Biosimilars are very much a hot topic of late. They are approved new versions of innovator biopharmaceutical products, following patent expiry. Essentially, this is like a generic version of the biologic product, hence their alternative name, follow-on biologics.

Recently, the FDA approved the Momenta/Sandoz’s follow-on versions of sanofi-aventis’s Lovenox, a low molecular weight heparin (LMWH), used to prevent and treat deep vein thrombosis or pulmonary embolism. The patent expired in July 2010 and approval was given on July 23rd. Reports in the press suggest that erosion of the brand was both fast and steep, with a 60% shift in market share to the cheaper versions almost overnight.

At present, the FDA doesn’t have a recognised approval system for follow-on biologics, so the process is somewhat fuzzy. I’m not sure why the FDA approved Momenta’s versionof enoxaparin, but not Teva or Amphastar’s, although inevitably, there was a lot of noise surrounding the issue in the press over the last year. I’m not going to go into the details of the shenanigans over this, but a quick Google search will offer more information than many will have time to read!

What was interesting to me was that Momenta scientists published an interesting paper in Nature Biotechnology (reference below) on Chinese hamster ovary (CHO) cells. CHO cells are the most common cells used to synthesise recombinant proteins used in many drugs and are extremely well studied. Previously, however, CHO cells were thought to lack the biosynthetic ability necessary to synthesize a particular glycoprotein, but the Momenta scientists found otherwise, underlining their expertise and research in this field.

These players – Momenta, Sandoz, Teva and Amphastar – probably have the lead in follow-on biologics for now, so they will be interesting companies to watch out for as the patent cliffs in biologics begins to hit big Pharma between now and 2015.

Now, while the FDA still doesn’t have any official regulations for follow-on biologics, the European Medicines Agency (EMA) has begun to tackle the issue head on, posting draft guidelines last week. You can check them out online. According to the EMA:

“The Agency has released the draft guideline on similar biological medicinal products containing monoclonal antibodies for a six-month consultation period.

The guideline lays down the requirements for medicines containing monoclonal antibodies that claim to be similar to another such medicine already marketed.

Comments on the draft guideline can be submitted to the Agency up to 31 May 2011.”

Unfortunately, I haven’t had time to digest the EMA proposals yet, but we will post a full synopsis in a future blog post soon.

If you have any thoughts, comments or questions, please feel to add them in the comments below.

References:

Bosques, C., Collins, B., Meador, J., Sarvaiya, H., Murphy, J., DelloRusso, G., Bulik, D., Hsu, I., Washburn, N., Sipsey, S., Myette, J., Raman, R., Shriver, Z., Sasisekharan, R., & Venkataraman, G. (2010). Chinese hamster ovary cells can produce galactose-α-1,3-galactose antigens on proteins Nature Biotechnology, 28 (11), 1153-1156 DOI: 10.1038/nbt1110-1153

11 Comments

Pharma Strategy Blog conference newsletter is finally here!

By MaverickNY on November 1, 2010

By popular request, we are now rolling out the PSB conference newsletter.

This will be an occasional event that will be sent out after some scientific meetings we’ve attended. They will contain snippets and summaries of data or new drug classes that we found interesting and worth highlighting and will be an adjunct to the blog, so you won’t get the same things twice 🙂

The first one will roll out by the end of this week and cover last week’s meeting from AACR on colorectal cancer biology.

You can sign up in the side bar on the top right —->

If you are a subscriber for this blog, you still need to opt-in to receive the newsletter. Sorry for the inconvenience, but personally, I hate it when people use my email address to send me things I didn’t request, so the same courtesy is extended to every one here too.

If you wish to stop receiving the newsletter, you can easily unsubscribe with 1-click.

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AACR Colorectal Cancer Meeting: Biology to Therapy

By MaverickNY on October 27, 2010

Later today I’m heading off to Philadelphia to attend a special conference at the American Society of Cancer Research (AACR) meeting on colorectal cancer entitled Biology to Therapy. There’s still time to pack a back and head on down as the main meeting doesn’t start until tomorrow.

Tonight, I’m very much looking forward to the Keynote from Prof Bert Vogelstein (Johns Hopkins) who is doing a talk entitled:

“Colorectal cancer genomes and their implications for basic and applied research.”

You can check out the full program here.

Over the next couple of days I’ll post some blogs on a few topics of interest from the sessions – watch this space for more.