DRugwatch Blog > February 2012

Contributor: Gideon Heap

After a second FDA Advisory Committee meeting, Qnexa received a landslide 20-2 vote in favor of approval. Opinion seems to have turned in Qnexa’s favor following reassurance that the proposed REMS will prevent the use of Qnexa in pregnant women and will serve to monitor the emergence of adverse effects. This vote does not guarantee approval; the final decision will come from the FDA in April 17, but the agency will be under pressure to approve Qnexa following such a positive result.

Vivus knows its way around an Ad Com meeting. Last time, in 2010 the Advisory Committee panel voted 10–6 against approval and a complete response letter followed from the FDA. Advisors and regulators concluded that Qnexa met weight loss efficacy standards but approval was declined due to two major uncertainties of Qnexa’s safety. Firstly, topiramate has a known, although poorly defined birth defect risk. Secondly the agency wanted reassurance that a mean heart rate increase of 1.6bpm does not increase the risk of cardiovascular events. Vivus was also asked to submit data from the OB-305 (or SEQUEL) trial that was incomplete at the first NDA submission.

Since the 2010 rejection, Vivus has conducted the Fetal Outcome Retrospective Topiramate Exposure Study (FORTRESS) and performed a review of studies linking topiramate to potential birth defects. Vivus also performed a retrospective analysis of MACE events that occurred in its clinical trial program. FORTRESS was statistically limited by low events, and SEQUEL data were positive but compromised by a selection bias. There was never any hope of providing reassurance of CV event risk without a randomized, outcomes-driven trial. Where Vivus has really managed to win the panel over is with its risk evaluation and mitigation strategy (REMS). Vivus’s plans are to limit the supply of Qnexa to a network of pharmacies for which specific training will be required. Additionally, prescriptions will be accompanied with obligatory patient education materials and the drug will be subject to periodic REMS assessments. With a category X pregnancy label, obese female patients of child bearing potential will be free to use Qnexa without the requirement of monthly pregnancy tests. The REMS is subject to change prior to approval, but if the final version grants access to Qnexa to all women of child bearing potential, it will be a huge win for Vivus. Vivus appears to have persuaded the Advisory Committee that Phase IV trials and careful monitoring in a post approval setting is the most appropriate way forward for Qnexa. Pressure to approve new therapies for a growing unmet need and the risk associated with preventing the approval of Qnexa also seem to have factored heavily into the voting decisions.

Another hot topic of debate was regarding the most appropriate point to conduct a cardiovascular outcomes trial (CVOT): pre- or post-approval? Vivus has had already outlined an 11,000 patient, event-driven trial that would take over 4 years to be conducted after approval. Panel members expressed considerable concern that this timeframe is too long given the degree of patient exposure likely to occur in the period immediately after approval. Although the Advisory Committee reluctantly agreed that a post-approval trial would be sufficient, Qnexa is not home and dry yet. Another important Advisory Committee meeting: the role of cardiovascular assessment in the preapproval and post approval settings for obesity drugs, is scheduled for March 28 and 29. This meeting could define what the FDA considers acceptable cardiovascular risk in obesity, and how one goes about proving it. This would have implications on the endpoint design, enrollment and potentially the initiation timeframe of the CVOT Vivus is planning for Qnexa. Without a marketing partnership, Vivus and potential partners will be watching the March meeting closely to see what kind of investment will be required to keep obesity drugs on the market going forward.

The huge voting swing from 10 - 6 against in 2010, to 22 - 2 in favor in 2012, may just indicate the regulatory environment for obesity drugs is softening, especially given that the additional data generated between the two meetings was unimpressive. When justifying their voting, most panel members expressed how difficult the decision was. Whilst safety uncertainties surround Qnexa, the growing feeling that failing to introduce new obesity therapies carries its own risk to the U.S public, seemed to factor quite highly into the panel’s decision. Our position on Qnexa remains unchanged; we forecast a U.S launch in 2012 and for it to approach blockbuster peak sales.
Posted on: 2/23/2012 3:16:55 PM | with 0 comments

Matt KileenContributor: Andrew Merron, Biosimilars Advisory Service Director at BioTrends Research Group

On 9th February 2012, the FDA finally published draft guidance addressing the over-arching requirements for biosimilar medicines to gain approval in the United States. The publication has been met with considerable relief throughout the biosimilar industry after much anticipation and speculation, although provides only general guidance and little detailed information.  Back in September 2011, the FDA hinted that their guidance for biosimilar medicines could be just a matter of days or weeks away. However, with no formal guidance published, the industry grew impatient. The only other publically available information from the FDA concerning biosimilar requirements were published in August in a New England Journal of Medicine article.

At the start of 2012, many biosimilar manufacturers were hoping for some clear guidance from the FDA on biosimilar product development, and the wait has been extensive compared with their European colleagues.  The European Medicines Agency (EMA) first published over-arching guidelines on biosimilar medicines in 2005, more than six years before the FDA, and there are currently 14 biosimilars approved for use in Europe by the EMA. Despite the frustration over the lack of any guidance from the FDA, Hospira is the first company to initiate a pivotal Phase III trial for a biosimilar in the US even prior to the availability of FDA guidelines. The first patient was enrolled onto the clinical trial in January this year.

It is now nearly two years since the necessary legislation was signed into law allowing for biosimilars to enter the US market. On the 23rd March 2010, President Obama passed the Patient Protection and Affordable Care Act (PPACA); this act amended the Public Health Service Act (PHS Act) through the creation of the abbreviated pathway (also known as the 351(k) route) -allowing biosimilar approval. The 351(k) pathway is provided as part of the Biologics Price Competition and Innovation Act (BPCI Act) within the PHS.

The guidance that the FDA has issued comprises three documents: scientific guidance, quality guidance, and commonly asked questions and answers for the industry. Currently, the guidance is still in a draft version, and the FDA will welcome any public input prior to finalizing these documents. In addition, there is no product-specific guidance for individual classes of biologics. Nevertheless, we expect that eventually the FDA will issue product-specific guidance for demonstrating biosimilarity.

New Guidelines

Overall, there are no major surprises in the draft guidelines compared to what we had expected. Essentially, the FDA is drawing on similar themes already presented by the EMA’s over-arching biosimilar guidance documents. The FDA clearly presents three over-arching themes:

  • A stepwise, risk-based approach to biosimilar product development including strong recommendation for early consultation with biosimilar sponsors
  • Justifications are required from biosimilar sponsors for their pre-clinical and clinical development strategies; also, explanations are sought for any differences seen between the biosimilar and the reference product
  • A ‘totality-of-the-evidence’ approach to approving biosimilars in the US on a case-by-case basis

The stepwise approach to demonstrating biosimilarity is critically important to streamline clinical trial design through later stages of evaluation. The scientific guidelines propose assessment of biosimilarity through three main steps:

1. Firstly, analytical studies are required. This rigorous structural and functional comparability exercise is important in order to smoothly proceed to the following steps. State-of-the-art techniques should be employed to assess the biosimilar and reference product. 
2. Secondly, because subtle changes in functionality between a biosimilar and the reference product may not be detected in analytical studies, the biosimilar sponsor is required to perform further studies. Therefore, animal studies (including the assessment of toxicity) may be required.
3. Thirdly, a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics and pharmacodynamics) are required to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed. Because product-specific guidance is not yet available, discussion of specific end points are not included in the current draft guidelines.  However, the clinical safety and effectiveness studies should select clinically relevant end points which can detect meaningful differences.
Indication Extrapolation Possible but Interchangeability is Challenging
Importantly, as we expected, the FDA is allowing for indication extrapolation for biosimilars as long as the extrapolation is founded on scientific justification. Indication extrapolation may be allowed assuming the biosimilar sponsor has considered potential differences in each indication with respect to the mechanism of action, pharmacokinetics, biodistribution, and toxicities. Despite the FDA allowing a biosimilar to undergo indication extrapolation, our research has suggested that physicians are unwilling to automatically accept and prescribe a biosimilar without specific clinical data in that indication. This suggests that clinical trials will be required in most indications in order to gain access to all indications for which the reference product is approved.

The draft FDA guidelines also consider interchangeable biosimilars. An interchangeable biosimilar must demonstrate a higher standard of interchangeability over a non-interchangeable biosimilar product. This greater standard includes demonstrating that the biosimilar produces the same clinical result as the reference product in any given patient and the risk of switching between the biosimilar and the reference product (in terms of safety or diminished efficacy) is not greater than using the reference product alone. The questions and answers document highlights that this will be a difficult barrier to overcome; although an interchangeable product may be considered eligible for automatic substitution at the pharmacy level.

Quality Guidelines

The quality guidelines also released on the 9th February for biosimilar products focused on physiochemical considerations for demonstrating biosimilarity, including the expression system, manufacturing process, immunochemical properties, impurities, stabilities, and reference standards.

New Era of US Biosimilars is Imminent

The guidance is welcomed by industry and we now anticipate the confirmation of the guidelines after any public comments and expect product-specific documents to then be considered. Based on the growing number of biosimilar players, and the impending patent expiries for major blockbuster biologics, the future of the biosimilar industry can really start to gain momentum despite a somewhat sluggish start over the past five years in Europe. Once biosimilar versions of the commercially compelling products are developed, and biosimilars finally enter the US, growth in sales of biosimilar products will be significant from 2015 through 2020.

Despite the high burden, development of biosimilars represents a significant cost-saving opportunity for State-sponsored healthcare systems.  In an age of increased austerity, lower cost biosimilars have the opportunity of saving in excess of $10 billion across the seven major pharmaceutical markets in 2020 - a highly attractive proposition.  The publication of the draft guidelines by the FDA last week (while there is still much more we are waiting for) represents a major milestone in bringing these lower-cost products to market in the US.

The Biosimilars Advisory Service Director, Dr. Andrew Merron, will be hosting an analyst call describing the implications of these recently published guidelines on the 27th February. Learn more.
Posted on: 2/14/2012 3:06:54 PM | with 0 comments

Matt KileenContributor: Christine Helliwell

Well, it has been a busy start to the year for the type 2 diabetes market, with both good and bad news from the FDA for some of the major players in this market. First came the news on the 19th of January that the FDA had issued a Complete Response Letter (CRL) for Bristol-Myers Squibb/AstraZeneca’s dapagliflozin, the first-in-class sodium glucose cotransporter-2 (SGLT-2) inhibitor. This news actually came earlier than anticipated, because the drug’s PDUFA date was scheduled for January 28th, 2012. But the news itself was not at all unexpected. As we discussed in our 'Dapagliflozin – What Now?' blog post on July 20th, 2011 on July 19th 2011 an FDA Advisory Committee voted 9-6 against recommending approval of dapagliflozin. The Committee’s concerns revolved around an excess number of cases of both breast and bladder cancer cases observed among patients taking dapagliflozin rather than a placebo or comparator drug, as well as a case of severe liver injury that was deemed to be likely to be caused by dapagliflozin. Although the overall number of cases of cancer was small, the FDA CDER’s Office of Surveillance and Epidemiology (OSE) noted that the imbalance was statistically unlikely to have occurred by chance. 

Following the Advisory Committee meeting, the FDA requested further data from recently completed and ongoing clinical trials of dapagliflozin, and pushed back the original scheduled PDUFA date from October 28th, 2011, to January 28th, 2012, in order to allow enough time for the data to be submitted and assessed. However, as we suspected, the data provided were insufficient to allay the FDA’s concerns over dapagliflozin’s safety, resulting in the issuance of the CRL. Although the precise details of the CRL have not been disclosed, AstraZeneca and BMS did report that the FDA has requested additional clinical data to allow a better assessment of the benefit-risk profile for dapagliflozin. These data will come from extensions of and follow-up to ongoing clinical trials (which we estimate will lead to a delay of up to two years before dapagliflozin is approved), but, crucially, new clinical trials may also be required. We assume that new clinical trials will only be required if the data from ongoing trials are insufficient to provide adequate reassurance of the safety of dapagliflozin. This seems unlikely, given that over 2,500 patients are still enrolled in five different trials or trial extensions, all due to finish by mid-2013. However, should one or more new clinical trials be required, then any such trial would most likely have to be large and lengthy, because the safety concerns noted so far are very rare. The expense of such a trial, and the inevitable delay to dapagliflozin’s approval, may cast a question mark over dapagliflozin’s further development. For now though, we assume that this will not be the case, and that dapagliflozin will be approved in the United States in 2014.

Another question that remains over the future of dapagliflozin is: what will happen in Europe? According to AstraZeneca’s latest pipeline update, the European regulatory submission for dapagliflozin is slated to occur during the second half of 2012. By the time the EMA comes to make a decision on the drug, at least some of the data requested by the FDA will be available, and so a straight-forward approval (most likely with warnings on the drug’s label) is more likely in Europe. And yet another question is the impact of this scrutiny of dapagliflozin’s safety on other SGLT2 inhibitors in development, in particular Johnson & Johnson’s canagliflozin and Boehringer Ingelheim/Eli Lilly’s empagliflozin, both of which are in Phase III development and expected to launch in 2014. Until a detailed analysis of late-stage clinical trial data becomes available, it is impossible to say whether these drugs are also associated with the same safety concerns as dapagliflozin. What is certain, however, is that the developers of canagliflozin and empagliflozin can expect a high level of scrutiny of their drugs’ safety profile. These companies will be watching the dapagliflozin story unfold with great interest.

Amylin and Alkermes were the recipient of better news from the FDA; their drug Bydureon (a once-weekly version of the GLP-1 analogue Byetta), was finally approved in the United States on January 27th, 2012. The NDA for this drug was originally submitted in May 2009, but approval was delayed first by issues with the product label and manufacturing procedures (leading to a CRL in March 2010), and then by a request (in the form of a second CRL in October 2010) for further clinical data including data from a thorough QT (tQT) study. These data were submitted to the FDA in July 2011, and were sufficient for the drug to be deemed approvable in January 2012. This delay dearly cost Amylin and Alkermes (and, until November 2011 when the company terminated its involvement in Bydureon and Byetta, Eli Lilly; see our November 17th, 2011 blog post 'The End of the Road for Amylin and Lilly’s Diabetes Pact' (for more on this), because it gave the once-daily GLP-1 analogue liraglutide (Novo Nordisk’s Victoza), a significant head-start after its launch in February 2010.

Victoza has seen strong growth since its launch, resulting in blockbuster sales in 2011, its first full year on the market. However, Victoza now faces a serious challenger in the form of the once-weekly Bydureon. Although in the head-to-head DURATION-6 study Bydureon failed to demonstrate non-inferiority to Victoza on the primary endpoint of HbA1c reduction, Bydureon is tolerated better and only requires once-weekly injections rather than the once-daily injections required for Victoza. In the near term, we expect that Victoza’s strong lead will allow it to stay well ahead of Bydureon in the race for leadership of the GLP-1 analogue space. Looking further ahead, at a ten-year horizon, the picture is somewhat different, with sales of Bydureon almost catching up with sales of Victoza. Who will be the ultimate winner is likely to be a close call that will depend heavily on the ability of the respective developers to market each drug. Given that both Victoza and Bydureon are expected to be blockbusters and big players within the type 2 diabetes space, it will be interesting to see how their relative fortunes fare.
Posted on: 2/7/2012 5:51:17 PM | with 2 comments

Matt KileenContributor: Rachel Webster

Medivation/Astellas Pharma’s MDV3100 took center-stage at the annual ASCO Genitourinary Cancers Symposium, and was heralded as practice-changing treatment for metastatic castration-resistant prostate cancer (mCRPC). MDV3100 becomes the fifth novel agent to significantly improve median overall survival (MOS) in mCRPC in less than three years.

Data from the Phase III AFFRIM trial showed that MDV3100 extended MOS by almost 5 months over placebo (18.4 months versus 13.6 months, respectively; P < 0.0001) in mCRPC patients who had received prior chemotherapy. Eagerly anticipated data of secondary efficacy end points were also met. Most notably, treatment with MDV3100 extended median radiographic progression-free survival (rPFS) compared with placebo (8.3 months versus 2.9 months, respectively; P < 0.0001) and improved PSA response rates (defined as at least a 50% decline in PSA levels from baseline) (54% versus 1.5%; respectively; P < 0.0001). MDV3100 also has an enviable safety and tolerability profile, as evidenced by data showing that MDV3100 displayed fewer adverse events than placebo. Concerns over the frequency of seizures observed in earlier studies were quashed; the grade 3 or higher frequency of seizure in the MDV3100-treatment group (0.6%) is likely too small to establish a causal relationship.

Over the last 2-3 years there has been a surge in new diverse treatments for prostate cancer – Dendreon’s Provenge (sipuleucel-T), Sanofi’s Jevtana (cabazitaxel), GlaxoSmithKline/Daiichi Sankyo/AstraZeneca’s Xgeva (denosumab), Johnson & Johnson/Janssen Biotech/Janssen-Cilag’s Zytiga (abiraterone) – ending decades of stagnation. To further add to this list of agents, Algeta/Bayer Healthcare’s radium-223 (Alpharadin), an alpha-emitting radiopharmaceutical, has also demonstrated a statistically significant improvement in MOS in progressive, symptomatic mCRPC patients who are ineligible to receive docetaxel. Filing for regulatory approval of Alpharadin is anticipated in mid-2012.  MDV3100 will increase treatment options for mCRPC patients in the post-docetaxel setting even further and will surely pose a serious threat to Zytiga, which was granted FDA approval in April 2011.

The growing number treatments for mCRPC underscore the dynamism of the prostate cancer market. The prostate cancer landscape is now entering a new era of intense competition where we will see varied treatment strategies vie for patient share and pole position. It will become increasingly important for developers to differentiate their agents over those currently available. With new agents such as MDV3100 and Alpharadin showing impressive MOS advantage – the gold standard end point for obtaining regulatory approval – and a rich pipeline of therapies waiting in the wings, we forecast that the prostate cancer market will soar to in excess of $10 billion by 2020.

However, the emergence of a plethora of treatments for mCRPC and resultant increased complexity of medical practice has unveiled an air of uncertainty over the optimal choice of treatment in any given mCRPC setting. Arguably, this is a nice problem to have after a long period of drought in effective treatments options. There is now unquestionably a pressing need to understand the most effective sequence of treatments. Many questions remain unanswered: Should novel agents be used in combination with one another? If so, which combinations? Or should treatments be prescribed sequentially?  Further clinical trials can only unequivocally answer these important questions. Identification of markers that predict which patients will most likely benefit from each treatment will also be pivotal for assisting effective and efficient decision-making in mCRPC.
Posted on: 2/7/2012 1:44:31 PM | with 0 comments

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