Drug prices quietly rise as politicians pounce

Drug prices quietly rise as politicians pounce

Source EP Vantage
Company Valeant Pharmaceuticals International, Alembic Pharmaceuticals, Almirall, Apotex, Aspen Pharmacare, Aytu BioScience, Boehringer Ingelheim, Kaléo, Mylan, Romark Laboratories, Salix Pharmaceuticals, Taro Pharmaceutical Industries, TOLMAR 
Tags Analysis, Company Strategy, Patent, Fines & Regulatory Issues, Free Content, Data Story
Date October 27, 2016

After a year of anti-pharma rhetoric from US politicians, it might be assumed that the sector would want to lie low on price increases at least until after the presidential election. The evidence shows that such an assumption would be misplaced.

An analysis of drug prices shows that while pharma companies have been more reluctant to use monopoly power to push through huge increases in 2016, in more competitive markets the rises have been every bit the equal of 2015’s (see tables below). And despite its drubbing last year and promises to change its ways, Valeant is still a notable presence on this year’s list (After Turing, the industry’s biggest price gougers, September 23, 2015).

This finding means that the reintroduction of Auvi-Q  announced yesterday may not yield any additional relief for the severely allergic patients who need an  emergency  epinephrine  injector. Indeed,  Kaléo  has little incentive to come in much below the $300 per pack list price pledged for the  authorised Epipen generic announced in August by  Mylan , the biggest drug-pricing villain of 2016 (EpiPen’s new lease of life a Mylan windfall, March 2, 2016). 

Modest brands

These lists are taken from EvaluatePharma’s US pricing analysis, based on the federal government’s National Average Drug Acquisition Cost weekly survey of pharmacy level prescription drug costs. They are ranked on the biggest percentage change between the second quarters of 2015 and 2016.

It does not incorporate additional rebates over the NADAC price, nor include drugs administered in hospitals. However, it provides a snapshot of drugmakers’ pricing strategy over a recent 12-month period.

No generic availability 
Product  Company  FDA approval   Price increase* 
Cuprimine   Valeant   1970  +330% 
Leukeran   Aspen Pharmacare   1957  +95% 
Alinia   Romark Laboratories   2002  +87% 
Primsol   Aytu BioScience   2000  +69% 
Altabax   Almirall   2007  +58% 
*Pharmacy acquisition cost, Q2 2016 vs Q2 2015.  

A big change from the last time EP Vantage did this analysis is the magnitude of the biggest increase among the products with no generic competitors – just a 330% jump for chelating agent  Cuprimine  compared to 2015’s huge 928% for beta blocker Dutuprol. And instead of six with triple-digit increases, as in 2015,  Cuprimine  was the only one in 2016.

This suggests that the bad publicity and political pressure has yielded some moderation, at least in this space of older or off-patent branded drugs that have yet to see competition.

Cuprimine  is sold by Valeant, the speciality pharma embattled over its pricing and distribution practices. As he sought to reassure investors and the public about its strategy earlier this year, former chief executive J. Michael  Pearson  said “any future price increases will be more modest and in line with industry practices and managed-care contracts.”

 Generics available 
Product  Company  FDA approval   Price increase* 
Locoid   Valeant   1987  +786% 
Benzamycin   Valeant   1984  +679% 
Zegerid   Salix   2006  +620% 
Librax   Valeant   1961**  +478% 
Metrogel-Vaginal   Valeant   1992  +351% 
*Pharmacy acquisition cost, Q2 2016 vs Q2 2015. 
**Year launched 

That statement is belied by this analysis, which finds that six Valeant products appear in these analyses of the biggest price increases.

Competing to raise prices

One of those six, the skin cream cream Locoid , saw the single biggest increase. A product with a generic equivalent, Locoid  saw its price rise a staggering 786%. That was matched by an exactly identical percentage increase for  Taro ’s hydrocortisone butyrate , ie generic Locoid . A similar pattern was seen with Valeant’s Benzamycin  and  Tolmar ’s generic equivalent, erythromycin  and  benzoyl peroxide .

Product  Company  FDA approval   Price increase 
Hydrocortisone Butyrate   Taro   2004  +786% 
Ofloxacin   Valeant 
Leflunomide   Emcure 
Erythromycin  and  Benzoyl Peroxide   Tolmar   2004  +679% 
Naproxen   Boehringer Ingelheim   1994  +565% 
*Pharmacy acquisition cost, Q2 2016 vs Q2 2015.  

Counterintuitively, it was this more competitive area of branded products with generic equivalents where Valeant and its comrades were most successful in pushing through price increases. Cuprimine ’s 330% jump was exceeded by the top five price increases in both the category of branded drugs with generic competition and the category of generic drugs.

With this many triple-digit increases, it is no wonder that pharma has become such a lightning rod for criticism and that both major US presidential candidates agree on some policies to bring drug prices under control. Among major industry leaders, Allergan ’s Brent Saunders appears to be responsive to this criticism and has vowed to keep price increases to less than 10% a year.

Yet despite Mr Pearson ’s pledge, Valeant can still be seen pushing the public’s tolerance for fast-rising drug costs. If his successor, Joseph Papa, is intent on following words with deeds, at this time next year Valeant’s name will not be listed in this analysis.

Therapy focus – Ovarian cancer field readies for phase III readouts

Therapy focus – Ovarian cancer field readies for phase III readouts

Source EP Vantage
Company AstraZenecaAbbVieArray BioPharmaBoehringer IngelheimClovis OncologyEisaiGradalisImmunoGenJohnson & JohnsonMerck KGaAOXiGENEPfizerPharmaMarRocheTESARO 
Tags Analysis, Company Strategy, Europe, USA, Phase II, Phase III, Oncology, Free Content, Therapeutic Focus
Date March 18, 2016

Ovarian cancer specialists are in for a lively few months, with a run of pivotal trial readouts, two or more filings and the outcome of an EU submission for a long-forgotten project – events that could collectively move the field forward.

Any such development will be welcome as ovarian cancer remains a difficult-to-treat disease that has seen little progress in recent years (see table below). Moreover, it has so far not been much of a target for immuno-oncology, which has taken great strides in other indications.

Some progress was made with the late 2014 conditional approval of a targeted agent, AstraZeneca ’s Lynparza , but the mainstay of treatment remains surgery followed by platinum and taxane chemotherapy. Nevertheless, a review of the field reveals a full phase III pipeline, with 11 different agents being examined in a total of 15 studies, and a further six agents in or entering registration-directed phase II or II/III trials.

Moving towards approval

Four of the phase III agents are PARP inhibitors, namely LynparzaTesaro ’s niraparib , Clovis’s rucaparib  and  AbbVie ’s veliparib . The first three are being studied as maintenance therapies in BRCA -mutant patients, an approach thought to take best advantage of PARP inhibition's role in DNA repair. AbbVie , though, is conducting a larger study of veliparib  in combination with first-line chemo, enrolling both wild-type and  BRCA -mutant patients.

AstraZeneca 's Solo-2 trial should read out this quarter, but some analysts believe that data are more likely later in the year. If this is the case, Tesaro ’s Nova  trial will probably be the first of the PARP studies to report. This evaluates three different subpopulations based on patients’ mutation status, and effectively has three opportunities to achieve a positive result (Therapy Focus – PARP inhibitor class set to come of age in 2016, March 1, 2016).

Tesaro  also expects data from its Quadra phase II trial in fourth-line ovarian cancer around the same time as  Nova  reports, and believes the combined data sets would support an NDA submission planned for the second half.

Lynparza  somewhat controversially gained early US approval – despite a negative advisory committee vote – for third/fourth-line use based on a subgroup analysis of gBRCA mutant patients. This highlighted the fact that regulators, perhaps mindful of the relative lack of new agents in ovarian cancer, were keen to give physicians new therapies.

Back from the dead

One surprise is that AstraZeneca ’s almost forgotten anti-VEGF tyrosine kinase inhibitor  cediranib  – which was pretty much consigned to history with a phase III failure in colorectal cancer in 2012 – is in fact under EMA review for ovarian cancer. The project was quietly filed in July 2015 based on phase II data and thus must now be approaching a decision.

AstraZeneca  is seeking approval as a monotherapy in Europe, although cediranim is being developed in combination with  Lynparza  in the third-line setting in an NCI-sponsored phase II/III study,  Cocos

In the shorter term, AstraZeneca  could face competition to  Lynparza  in 2017 from Clovis, which is expected to start a rolling NDA for its PARP inhibitor  rucaparib  in the second quarter. This will be for platinum-sensitive, relapsed,  BRCA -mutant disease, based on the phase II Ariel-2 study in the fourth-line setting.

Clovis is also conducting Ariel-3 in third-line treatment, which is expected to complete enrolment in the next few months and render results around a year later.

Project  Company   Setting/subtype   Trial ID  Data 
Phase III 
Lynparza   AstraZeneca   >2L maintenance, gBRCA mutant  NCT01874353   Feb 2016 
Niraparib   Tesaro   3L maintenance, pt-sensitive,  gBRCA mutant   NCT01847274   Q2 2016 
Perjeta   Roche   <3L recurrent pt-resistant, low HER3  mRNA expression  NCT01684878  Apr 2016 
Lynparza   AstraZeneca   1L maintenance, gBRCA mutant  NCT01844986   Jul 2016 
Rucaparib   Clovis  >3L maintenance, pt-sensitive  NCT01968213   Q2 2017 
binimetinib   Array  2-4L, low grade serous  NCT01849874  H2 2017 
Lynparza   AstraZeneca   3L relapsed gBRCA mut    NCT02282020   Dec 2017 
Vigil  Ovarian  Gradalis   1L maintennance  NCT02346747  Dec 2017 
Niraparib   Tesaro   1L maintenance,  pt-sensitive, HRD-positive  NCT02655016   Mar 2018 
Avelumab   Pfizer   <3L, pt-resistant /refractory  NCT02580058  Mar 2018 
Yondelis   J&J/Pharmamar  3L, BRCA  mutant  NCT01846611  Sep 2018 
Lurbinectedin   Pharmamar   <4L, pt resistant  NCT02421588  Oct 2018 
Veliparib   Abbvie   1L maintenance  NCT02470585   Jan 2019  
Lynparza   AstraZeneca   >3L maintennance  pt-sensitive, relapsed, sBRCA or HRR mutant  NCT02392676   Jun 2019  
Yondelis   Pharmamar /J&J  <3L, partial pt sensitive  NCT01379989  Dec 2019 
Phase II/III 
Cediranib /Lynparza   AstraZeneca   <3L, recurrent pt-resistant or refractory  NCT02502266  N/A 
Fosbretabulin   Oxigene   Pt-resistant  NCT02641639  N/A 
Phase II 
Farletuzumab   Eisai   Low CA125, pt sensitive  NCT02289950  Nov 2017 
AZD1775   AstraZeneca   Pt-resistant TP53 -mutated  NCT02272790  Jul 2017 
Mirvetuximab soravtansine   Immunogen   Folate receptor alpha positive  NCT02631876  Mar 2018 
Vargatef   Boehringer Ingelheim   >3L  NCT01610869  Oct 2017 

Regulators have been prepared to accept PFS as a primary endpoint in ovarian cancer, and indeed most of the pivotal phase III studies use this. An exception is Pfizer /Merck  KGaA ’s Javelin Ovarian 200 study of the PD-L1  inhibitor  avelumab . This is one of only two immuno-oncology approaches in the disease, the other being Gradalis ’s personalised cancer vaccine  Vigil

Ovarian is the fifth-most common cancer affecting women and has a 46% five-year survival rate. Other than achieving earlier diagnosis, there has been relatively little improvement in chemo in recent years, so it will be welcome indeed if some positive data emerge in 2016. 

Revisiting a predictor of failure in the post-Celator world

Revisiting a predictor of failure in the post-Celator world

Source EP Vantage
Company Celator PharmaceuticalsÆterna ZentarisArgos TherapeuticsArQuleCyclacel PharmaceuticalsCytRxImmunoCellular TherapeuticsImmunomedicsMolMedMologenNanobiotixNorthwest BiotherapeuticsOncogenerixOncoGenex PharmaceuticalsOnxeoOrient EuropharmaOSE PharmaOXiGENEProvectus BiopharmaceuticalsSoligenixSyndax PharmaceuticalsTokai PharmaceuticalsTransgeneVaccinogenVascular BiogenicsXBiotech 
Tags Analysis, Clinical Setback, Company Strategy, Trial Results, Phase III, Vaccine, Monoclonal Antibody, Oncology, Free Content
Date March 17, 2016

Celator’s success in beating the notorious Feuerstein-Ratain rule, as well as bettering one of the longest-established standards of care in oncology, raises the question of whether this shortcut for predicting the outcome of phase III cancer trials still holds after the recent collapse in biotech share prices.

Perhaps the fact that a company has a sub-$300m market cap ahead of a pivotal readout now no longer guarantees a failed study. Maybe investors are losing their ability predict oncology clinical outcomes and price shares accordingly (see table below). Alternatively, the $300m threshold might be too high given the extent of the recent biotech sell-off.

Celator’s stunning trial result is also not the only one that calls into question this otherwise trusty rule of thumb. Celldex had a market cap of over $2bn six months before its now-halted Act IV phase III trial of Rintega  in glioblastoma multiforme, showing that having a significantly higher market cap is no guarantee of success (No good reaction to Celldex's Act IV, March 7, 2016).

The rule

The rule, named after the TheStreet.com’s biotech commentator Adam  Feuerstein and University of Chicago oncologist Mark Ratain, forecasts the outcome of  cancer drug  phase III studies based on the sponsor companies’ market capitalisation six months before the data due date.

Based on an exhaustive examination of phase III cancer readouts over the past 20 years or more, it has until this week had a 100% success record in predicting failure for companies whose market cap is below $300m. If a company's market value was above this figure success was not guaranteed but was at least possible.

Of course a few factors have come into play over the recent biotech stock market cycle. With three or four years of good access to capital markets, many more companies have been able fund pivotal trials alone and build up significant cash piles on their balance sheets. On the other hand, the sharp correction in share price since the middle of last year might have brought otherwise promising companies’ valuations into the failure zone.

These changes notwithstanding, in recent weeks the Feuerstein-Ratain rule correctly predicted the interim futility stop for Peregrine Pharmaceuticals ’ phase III study of bavituximab  in second-line non-squamous non-small cell lung cancer (NSCLC). Similarly, it certainly forecast  Threshold Pharmaceuticals ’ simultaneous double phase III failure of evofosfamide  in pancreatic cancer and soft tissue sarcoma in December.

Last year, the rule accurately predicted futility stops for Synta with ganetespib  in NSCLC and for  Verastem ’s defactinib  in mesothelioma, among others.  EP Vantage has screened the public company universe for sub-$300m market cap groups with phase III cancer trials.

Companies likely to test the Feuerstein-Ratain rule 
Market cap* ($m)  Project  Company  Data 
150  Aldoxorubicin   CytRx   Q2 2016 
157  DCVax-L   Northwest Biotherapeutics   Sep 2016** 
25  Custirsen   OncoGenex   Q3 2016 
15  Sapacitabine   Cyclacel   Dec 2016 
23  SGX301   Soligenix   Dec 2016 
36  Zoptarelin doxorubicin   Æterna Zentaris   Dec 2016 
101  Tivantinib   ArQule   Dec 2016 
160  NGR-hTNF   MolMed   Dec 2016 
251  90Y-clivatuzumab tetraxetan   Immunomedics   Dec 2016 
284  Xilonix   XBiotech   Dec 2016 
259  NBTXR3   Nanobiotix   Mar 2017 
112  Rocapuldencel-T   Argos Therapeutics   Apr 2017 
138  Nanoplatin   Orient Europharma   Jun 2017 
139  Galeterone   Tokai  Jun 2017 
25  Custirsen   OncoGenex   Jul 2017 
142  Livatag  (doxorubicin  transdrug Onxeo   Jul 2017 
208  Entinostat   Syndax   Jul 2017 
83  PV-10   Provectus   Sep 2017 
105  Lefitolimod   Mologen   Oct 2017 
121  Pexastimogene devacirepvec   Transgene   Oct 2017 
83  VB-111   Vascular Biogenics   Dec 2017 
82  Tedopi   OSE Pharma  Mar 2018 
13  Rigosertib   Onconova  Jun 2018 
18  Fosbretabulin   Oxigene   Jun 2018 
33  ThermoDox   Celsion   Nov 2019 
251  Sacituzumab govitecan   Immunomedics   Dec 2019 
29  ICT-107   ImmunoCellular Therapeutics   Dec 2019 
65  OncoVAX   Vaccinogen   Jul 2020 
Notes: *as at March 15; **recruitment suspended, data likely to be later. 

First up to test the rule in this new environment is CytRx , whose 433-patient study of aldoxorubicin  in soft-tissue sarcoma reads out in the second quarter.  Aldoxorubicin  is an albumin-linked prodrug designed to release  doxorubicin  in the  acidic  conditions inside the tumour.

This study could succeed since doxorubicin  has long been used in the disease, but its dose is limited by cumulative toxicity.  CytRx ’s project might overcome this and a positive result here would add further strain on the Feuerstein-Ratain rule's validity.

Nine other companies are scheduled to report data in 2016, most towards the end of the year. If they report on time, the six-month pre-data timing of the Feuerstein-Ratain rule will be coming up soon.

Double showing

Interestingly, two companies appear twice in the table thanks to a second phase III readout in later years. Perhaps a positive result in the first study will project them out of the sub-$300m zone – as was the case with Celator – and improve the odds for a second positive result.

The first is OncoGenex, which has two phase III trials under way with custirsen , in prostate and lung cancers, both of which have had their designs changed to reduce recruitment or focus on poor-prognosis patients after custirsen 's earlier phase III failure in castrate-resistant prostate cancer.

And Immunomedics  has two phase III studies under way, this time with different antibody-drug conjugates. The first is 90Y-clivatuzumab  tetraxetan  in metastatic pancreatic cancer, and the other  sacituzumab govitecan  in triple negative breast cancer.

Companies with the smallest market valuations are either poorly financed or have already endured some major setback. Cyclacel’s phase III study has, for example, already failed its interim analysis, but in its case the data safety monitoring board requested that the study continue to completion. Other companies might effectively be repeating a previously failed study with some minor changes, as is the case with Celsion .

One thing is certain: these companies will enjoy huge stock market gains if they deliver unambiguously positive phase III results.